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Women’s Health Sponsored by

MEDChronicle


HELP MANAGE HER

PCOS

SYMPTOMS

16,4 % Reduction in hirsutism 1**

45,5 %

Reduction in insulin resistance2

8,4 %

Reduction in

obesity3**

44 %

Increase in pregnancy success in patients undergoing IVF4#

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POLYCYSTIC OVARIAN SYNDROME & ASSOCIATED INFERTILITY##1-7 *Polycystic ovarian syndrome # IVF - In-vitro fertilisation **Studies were conducted on supplemental Alpha Lipoic Acid only ## Due to PCOS

References: 1. De Cicco S, Immediata V, Romualdi D, et al. Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin-independent action. Gynecol Endocrinol 2017;33(9):698–701. 2. Genazzani AD, Shefer K, Della Casa D, et al. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J Endocrinol Invest 2018;41:583–590. 3. Carbonelli MG, Di Renzo L, Bigioni M, et al. α-Lipoic Acid Supplementation: A Tool for Obesity Therapy? Curr Pharmaceut Design 2010;16: 840-846. 4. Rago R, Marcucci I, Leto G, et al. Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. J Biol Regulators Homeostatic Agents 2015;29(4):1-11. 5. Sinopol® package insert, February 2019. 6. Cappelli V, Musacchio MC, Bulfoni A, et al. Natural molecules for the therapy of hyperandrogenism and metabolic disorders in PCOS. Eur Rev Med Pharmacol Sci 2017; 21(2 Suppl):15-29. 7. Bellver J, Rodríguez-Tabernero L, Robles A, et al. Polycystic ovary syndrome throughout a woman’s life. J Assist Reprod Genet 2018;35:25 -39. Proprietary name (and dosage form): SINOPOL® granules. Composition: Each sachet contains: Myo-inositol 1 000 mg, Alpha Lipoic Acid 400 mg and Folic Acid 200 µg. Complementary Medicine: Health Supplement. D34.12 Multiple Substance formulation. This unregistered medicine has not been evaluated by SAHPRA for its quality, safety or intended use. Studies as part of the references were not conducted on Sinopol®. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert. Further information is available on request from iNova Pharmaceuticals. IN3396/19.


Dear healthcare professional, Welcome to Medical Chronicle’s Women’s Health digibook, sponsored by iNova Women’s Health has been in the spotlight recently and we bring you a selection of diverse articles featured in Medical Chronicle.

Happy reading!

Contents

Insulin resistance in PCOS patients........... 4 Pumping iron ..................................................... 6 Nutrition for children .......................................... 9 Ending endometriosis ........................................10 Diminishing dysmenorrhoea............................ 11 Taking the misery out of menopause ....... 12 The burden of vaginitis ................................... 15 The effect of diabetes on vitamin B ...... 16 Review of once-monthly oral ibandronate ....................................................... 21 Vitamin B12 deficiency indicators .............. 24 The role of Vit D and Zinc in BP control ............................................................ 29 Release me........................................................ 32 How to combat vitamin deficiencies in oral contraceptive use ........................................... 35 Family health crucial for children................38 The obese patient health risks and medical options......................................................... 41

Don’t leave actinic keratosis alone............... 45 Why bacterial vaginosis is all about balance .................................................48 Using bisphosphonates in managing osteoporosis..................................... 52 Battling the bulge ............................................. 53 Importance of natural balance..................... 55 Identification and care of external genital warts................................56 Fast-forward to pause............................58 COCS: Impact of oestrogen type on CV safety.................................................59 Folate - Benefits beyond NTD prevention.... 62 Optimising treatment for bacterial vaginosis.............................................64 Get the folic acid facts What you need to know about this wonder vitamin1....................................................... 66

Easing those dreaded

PMS symptoms....................................................... 67

MEDICAL CHRONICLE 3


CLINICAL | WOMEN'S WOMEN’S HEALTH Focus

HEALTH

Insulin resistance in PCOS patients

PCOS is a very common reproductive disorder that effects as many as 15 % of the female population.

P

OLYCYSTIC OVARY SYNDROME (PCOS) is defined as a hormonal disorder common among women of reproductive age. Studies have shown that up to 85% of women diagnosed with PCOS were unaware of their condition9. It is associated with many health conditions and has an impact on various metabolic processes in the body. A diagnosis of PCOS is made when a woman experiences at least two of the following signs: irregular periods, excessive androgen (elevated levels of this male hormone) and polycystic ovaries,8 (when ovaries may be enlarged and contain follicles that surround the eggs, which may result in the ovaries not functioning correctly). About 60%-80% of women with PCOS suffer from insulin resistance and excess body fat, 95% have irregular periods and may not ovulate, 60% suffer from hair loss, acne and unwanted hair growth and 20% have fertility problems. Alarmingly, more than 50% of women with PCOS will develop diabetes or prediabetes before the age of 40. Polycystic ovary syndrome is the most common cause of irregular menstruation that leads to infertility. According to Dr Johan van Schouwenburg of Medfem Clinic, Johannesburg said, “Insulin resistance occurs in the majority of PCOS patients. Correction of insulin resistance improves fertility dramatically, resulting in better conception rates. This may be through natural conception, by ovulation induction or through assisted reproduction techniques such as in vitro fertilisation (IVF).” He explained that PCOS-related hyperandrogenism results in low IVF pregnancy rates due to poor quality oocytes and endometrial changes reducing embryo attachment. Reduction of androgen levels can be achieved by:

• Metformin treatment. This drug is effective, even if insulin levels are normal • Laparoscopically performed ovarian drilling. According to him, ovarian hyper stimulation syndrome (OHSS) can be a life-threatening complication of ART stimulation. PCOS increases this risk. Preventative measures include: • Correcting insulin resistance before ovarian stimulation commences • Conservative ovarian stimulation • Using a GnRH antagonist for triggering ovulation before oocyte aspiration • Aregoline tablets for +-6 days from day of triggering • Freezing embryos for embryo transfer in a subsequent cycle. PCOS patients with amenorrhoea, not wishing to conceive, need to have their menstruation cyclically induced by progestogen withdrawal. This will reduce the important danger of developing endometrial carcinoma. Obesity, which is defined as having a body mass index of over 30, can affect fertility by causing hormonal imbalances and problems with ovulation. Insulin resistance, which usually presents with stubborn belly fat, is associated with polycystic ovary syndrome (PCOS), a common hormonal condition especially in infertile women, affecting up to one in five women

of reproductive age.PCOS is a complex hormonal disorder, affecting young women at a reproductive age. While obesity, hypertension and insulin resistance are a few of the symptoms of PCOS, it is also the leading cause of infertility and has now become an epidemic.”

A hormonal imbalance is the main difficulty with PCOS. In women with PCOS, the body manufactures more androgens than normal. Androgens are male hormones which females also produce. High levels of these hormones affect the development and the release of eggs during ovulation. Increased levels of androgens in a woman’s body are responsible for the majority of symptoms, however many symptoms are coming from an underlying insulin resistance.

PCOS has a variety of signs and symptoms, which do not necessarily include having identified cysts in the ovaries in order to diagnose this disease. In fact, they are often absent during an ultrasound diagnosis. PCOS symptoms and signs: • Irregular or absent menstrual cycles • Infertility or recurrent miscarriage • Hirsutism (excessive facial hair and body hair) • Oily skin/acne • Obesity /abdominal fat • Male pattern baldness • Insulin resistance • Dyslipidaemia (unhealthy levels of one or more kinds of lipid (fat) in the blood) • Hypertension • Depression and / or anxiety • Sleep apnoea. All of the above affect young women who are at a reproductive age. Statistics show that 50% of these women, if left untreated, can develop diabetes type 2 by the age of 40. Meanwhile, their chances of suffering from a cardio metabolic syndrome, heart attack or cerebrovascular insult is five and seven times higher, while the risk of contracting endometrial cancer is also increased by three fold. Rising obesity rates are posing a global public health challenge. While it is increasingly being recognised that this current obesity epidemic has also contributed to fertility problems, obesity is also associated with cardiovascular disease, diabetes, osteoarthritis and malignancies such as colon and endometrial cancer. Studies have shown that overweight and obese women with PCOS may have a greater chance of becoming pregnant if they lose weight before beginning fertility treatment. References available on request.

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Look out for Medical Chronicle’s Women’s Health focus, sponsored by iNova. Coming to your inbox soon

Helps to correct imbalances linked to POLYCYSTIC OVARIAN SYNDROME & REPRODUCTIVE HEALTH1,3-5

References: 1. Sinopol® package insert, February 2019. 2. Rago R, Marcucci I, Leto G, et al. Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. J Biol Regulators Homeostatic Agents 2015;29(4):1-11. 3. Cappelli V, Musacchio MC, Bulfoni A, et al. Natural molecules for the therapy of hyperandrogenism and metabolic disorders in PCOS. Eur Rev Med Pharmacol Sci 2017; 21(2 Suppl):15-29. 4. Bellver J, Rodríguez-Tabernero L, Robles A, et al. Polycystic ovary syndrome thro¸ughout a woman’s life. J Assist Reprod Genet 2018;35:25 -39. 5. Gambera A, Visenzi C, Fratus C, et al. Alternative insulin-sensitizers (Lipoic acid and Inositol) in polycystic ovary syndrome (PCO¸S). Giorn It Ost Gin (Giornale Italiano di Ostetriciae Ginecologia) 2012; XXXIV(1):182-183. Proprietary name (and dosage form): SINOPOL® granules. Composition: Each sachet contains: Myo-inositol 1 000 mg, Alpha Lipoic Acid 400 mg and Folic Acid 200 µg. Complementary Medicine: Health Supplement. D34.12 Multiple Substance formulation. This unregistered medicine has not been evaluated by SAHPRA for its quality, safety or intended use. Studies as part of the references were not conducted on Sinopol®. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley¸ Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For more information, speak to your healthcare professional. Further information is available on request from iNova Pharmaceuticals. IN3386/19.

22 AUGUST 2019 | MEDICAL CHRONICLE 4 MEDICAL CHRONICLE


HELP REBALANCE THE EFFECTS OF PCOS*

New supplement available which may assist with insulin resistance and hormonal imbalances associated with reproductive health.1,2 A new supplement containing a unique combination of ingredients which may help with hormonal and metabolic imbalances linked to insulin resistance and reproductive health in women with polycystic ovarian syndrome (PCOS) is now available in South Africa.1-4 Sinopol®, from iNova Pharmaceuticals, is a new three in one formulation to help address oxidative stress, insulin resistance and reproductive health.5 PCOS is a very common reproductive disorder6 that effects as many as 15 % of the female population.7 It is defined as a hormonal disorder common among women of reproductive age.8 Studies have shown that up to 85 % of women diagnosed with PCOS were unaware of their condition9. It is associated with many health conditions and has an impact on various metabolic processes in the body.6 A diagnosis of PCOS is made when a woman experiences at least two of the following signs: irregular periods, excessive androgen (elevated levels of this male hormone) and polycystic ovaries,8 (when ovaries may be enlarged and contain follicles that surround the eggs, which may result in the ovaries not functioning correctly).10

Myo-Inositol may help to reduce insulin resistance in patients with PCOS, Alpha-Lipoic Acid is an antioxidant which reduces oxidative stress and may help to promote healthy glucose metabolism and Folic Acid helps the body to metabolise proteins, helps to form red blood cells and helps to reduce the risk of neural tube defects when taken daily prior to becoming pregnant and during early pregnancy.5 While there is no cure for PCOS,6 medical treatments are available which may address individual symptoms of the condition.7 If you have concerns about your menstrual periods, if you are experiencing infertility or if you have signs such as excess unwanted hair, acne and male-pattern baldness, you need to consult your doctor.8 Sinopol® is the only 3-in-1 formulation that can help address metabolic, hormonal and reproductive aspects of PCOS.1-5 Sinopol® is available over the counter at pharmacies without a prescription. The recommended dose is one sachet twice a day, dissolved in water, or as recommended by your healthcare professional. Speak to your doctor or pharmacist or go to www.sinopol.co.za for more information.

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60-80 % of women with PCOS suffer from insulin resistance and excess body fat, 95 % have irregular periods and may not ovulate, 60 % suffer from hair loss, acne and unwanted hair growth and 20 % have fertility problems.6 Alarmingly, more than 50 percent of women with PCOS will develop diabetes or pre-diabetes before the age of 40.11 Polycystic ovary syndrome is the most common cause of irregular menstruation that leads to infertility.6

Sinopol®’s unique three ingredient combination includes Alpha-Lipoic Acid (400 mg), Myo-Inositol (1000 mg) and Folic Acid (200 µg).5

BRING BACK BALANCE

This editorial has been commissioned and brought to you by iNova Pharmaceuticals. Content in this editorial is for general information only and is not intended to provide medical or other professional advice. For more information on your medical condition and treatment options, speak to your healthcare professional. *Polycystic ovarian syndrome References: 1. Rago R, Marcucci I, Leto G, et al. Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. J Biol Regulators Homeostatic Agents 2015;29(4):1-11. 2. Genazzani AD, Shefer K, Della Casa D, et al. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J Endocrinol Invest 2018;41:583–590. 3. Carbonelli MG, Di Renzo L, Bigioni M, et al. α-Lipoic Acid Supplementation: A Tool for Obesity Therapy? Curr Pharmaceut Design 2010;16:840-846. 4. De Cicco S, Immediata V, Romualdi D, et al. Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin-independent action. Gynecol Endocrinol 2017;33(9):698–701. 5. Sinopol® package insert, February 2019. 6. Barthelmess EK, Naz RK. Polycystic ovary syndrome: current status and future perspective. Front Biosci (Elite Ed). 2014 Jan 1;6:104-19. 7. Web MD. Why is PCOS hard to diagnose (2016) at https://www.webmd.com/women/features/pcos-polycistic-ovary-syndrome-women#1 (Website accessed on 3 July 2019). 8. Mayo Clinic. Polycystic ovary syndrome (2017) at https://www.mayoclinic.org/diseases-conditions/pcos/diagnosis-treatment/drc-20353443 (Website accessed on3 July 2019). 9. Sharif, E. et al. The frequency of polycystic ovary syndrome in young reproductive females in Qatar. International Journal of Women’s Health 2017:9 1–10. 10. Healthline. Anovulatory Cycle: When You Don’t Release an Oocyte (2018) at https://www.healthline.com/health/pregnancy/anovulatory-cycle (Website accessed on 3 July 2019). Proprietary name (and dosage form): SINOPOL® granules. Composition: Each sachet contains: Myo-inositol 1 000 mg, Alpha Lipoic Acid 400 mg and Folic Acid 200 µg. Complementary Medicine: Health Supplement. D34.12 Multiple Substance formulation. This unregistered medicine has not been evaluated by SAHPRA for its quality, safety or intended use. Studies as part of the references were not conducted on Sinopol®. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For more information, speak to your healthcare professional. Further information is available on request from iNova Pharmaceuticals. IN3430/19.

MEDICAL CHRONICLE 5


CLINICAL WOMEN’S HEALTH Focus HAEMATOLOGY

PUMPING IRON Dr Jarrad van Zuydam, a GP with a special interest in endurance sports medicine, recently discussed iron deficiency at an event held in Cape Town.

Iron deficiency (ID) is the most common single nutrient deficiency disease in the world – 15% of the world’s population have some sort of iron deficiency. Iron is toxic in its free form but essential for life in the complex forms found in the human body. The body requires iron for the synthesis of its oxygen transport proteins, in particular haemoglobin and myoglobin. It is essential for the formation of heme enzymes and other iron-containing enzymes involved in electron transfer and oxidation-reductions. He explained that 70% iron is circulating in bloodstream; some is in the bones, and some in muscle tissue. “If we eat 10-20mg iron per day, only 1-2mg is absorbed. There is a balance between what we take in and what we lose. If there is an imbalance, this is when problems occur. If the body detects that it is low in iron, it can increase in iron intake from the duodenum.” Without haemoglobin, blood cannot distribute oxygen effectively. There is no means for the body to excrete iron. However, around 50% of SA women may have some degree of iron deficiency.

ANAEMIA

Anaemia is defined as abnormally low levels of haemoglobin in the blood. Reduced oxygen-carrying capacity of blood. Not everyone who is anaemic is iron deficient and not everyone who is iron deficient is anaemic. Symptoms of anaemia include: • Fatigue – a cardinal symptom • Shortness of breath • Headache • Dizziness (feeling faint) • Pale skin • Leg cramps • Insomnia. Symptoms specific to iron deficiency anaemia are pica (strange food cravings), koilonychia and angular cheilitis.

IRON DEFICIENCY WITHOUT ANAEMIA

Symptoms such as weakness, fatigue, difficulty in concentrating, and poor work productivity are nonspecific symptoms ascribed to low delivery of oxygen to body tissues and decreased activity of iron-containing enzymes. These symptoms might be noticed earlier in athletes, who are monitoring their training. RPE is perceived exertion. This is a sign of iron deficiency. These are non30 MARCH 2019 | MEDICAL CHRONICLE 6 MEDICAL CHRONICLE

haematologic effects of iron deficiency. A full blood count test will be completely normal.

WHO IS AT RISK?

Menstruating women, children, teenagers, strict vegetarians and blood donors are high-risk groups for the condition. What is termed the ‘tea and toast diet’, seen in the elderly or mentally ill is also a predisposing factor.

Dr Jarrad van Zuydam

ARE ATHLETES AT GREATER RISK?

• GI bleeding – occult loss from the gut is observed in runners (1-7ml/day) • Haematuria – 17-90% of runners after a marathon • Sweat losses (up to 2mg/ day) • Menstruation may be heavy in athletes using an IUCD. A female, distance runner, who is a vegetarian, is at very high risk. To diagnose, ferum ferritin is tested and iron studies will confirm the diagnosis. It is often misdiagnosed as ‘overtraining’.

TREATMENT

Dietary assessment and changes: Oral supplementation will almost always suffice – 100-200mg per day for at least three months. IV iron is only used in severe cases. “We need to remove the cause of iron deficiency. During pregnancy iron demand is at it's peak. “Haem iron is superior to non-haeme iron because of better absorption. Inhibitors of absorption are phytic acid (seeds, grains, legumes), polyphenols (found in coffee, tea and fresh produce), as well as calcium, tannins and peptides from partially digested protein. Promotors of absorption include vitamin C, certain organic acids, meat, fish and shellfish.

PRACTICAL CONSIDERATIONS OF IRON

Not everyone should be supplemented with iron. There is no way for the body to excrete it. It’s not ergogenic – if there is no deficiency, it won’t enhance performance.


Treat iron deficiency holistically

Amino Acid Chelated Ferrous Iron supplement with Folic Acid, Vitamin B12 and Vitamin C*

• High bioavailability1 • Fewer gastrointestinal side-effects2

The link in treating iron deficiency References: 1. Nagpal J, Choudhury P., Iron Formulations in Pediatric Practice. Indian Pediatrics 2004; 41: 807-815. 2. Dietary Supplement Fact Sheet: Iron [Internet] 2013 October 14 [Updated 2014 April 08]. Available from http://ods.od.nih.gov/factsheets/Iron-healthprofessional/. Proprietary name (and dosage form): Ferrous Forte® Tablets. Composition: Each tablet contains: 20 mg elemental iron, 350 µg folic acid, 15 µg vitamin B12 and 60 mg vitamin C. Proprietary name (and dosage form): Ferrous Forte® Syrup. Composition: Each 5 ml contains: 20 mg elemental iron , 350 µg folic acid, 15 µg vitamin B12. Name and business address: iNova Pharmaceuticals (Pty) Ltd Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information available on request from iNova Pharmaceuticals. *Only in tablets. IN100/15 A Valeant Company


BRAND FEATURE

ONG R T S A S I D L I H C THY L A E H A O T Y E K THE . IMMUNE SYSTEM

Can you believe that 64 % of South African children between the ages of 1-9 years have a vitamin A deficiency? 1 Every day is a germ day! When functioning properly, the immune system fights disease producing organisms such as bacteria, viruses, fungi, and parasites. Your child is continuously exposed to these germs. A strong immune system provides your child with powerful natural defenses against disease and makes them less vulnerable and susceptible to colds, flu or other more serious infections. 2

Proper nutrition is not negotiable Given the reality of time crunched parents, those well rounded, homecooked meals aren’t always possible. The problem is that a poor diet leads to an inadequate intake of vitamins and minerals that may compromise your child’s immune system, making them more susceptible to infectious diseases that could have a significant short-term and longterm impact on their health. 3 Vitamins and minerals are important for healthy growth and development in children. Children who eat a well-balanced diet usually does not need a vitamin or mineral supplement. However, some children are at risk for deficiencies and may need a supplement.4 This is one of the reasons paediatricians may recommend a supplement that contains vitamins and minerals. 5

This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health Supplements do not replace a healthy diet and lifestyle. For more information, speak to your healthcare professional. References: 1. National Vitamin A Supplementation Policy Guidelines For South Africa 2012. Department of Health. Republic of South Africa. [online] 2012. [cited 31 July 2018]; Available from URL: http://www.adsa.org.za/Portals/14/Documents/ DOH/Vit%20A%20policy%20guidelines%20OF%20S%20A%20-%20recent_1.pdf 2. Sheppard J. Strengthening Your Child’s Immune System. [online] April 2014. [cited: 31 July 218]; Available from URL: http://pathwaystofamilywellness. org/Children-s-Health-Wellness/strengthening-your-childs-immune-system.html 3. Impact of Malnutrition on Health and Development. [online] [cited 2018 March]; Available from URL: http://www.orphannutrition.org/understandingmalnutrition/impact-of-malnutrition-on-health-and-development/ 4. Does My Child Need A Supplement? [online] 2018 June. [cited 2018 July]; Available from URL: https://www.eatright.org/food/vitamins-and-supplements/dietarysupplements/does-my-child-need-a-supplement 5. Vitamins for Kids: Do Healthy Kids Need Supplements? [online] 2008 May. [cited 2018 July]; Available from URL: https://www.webmd.com/parenting/guide/vitamins-for-kids-do-healthykids-need-vitamins?print=true 6. 7 Nutrient Deficiencies That Are Incredibly Common. [online] 2015 October. [cited 2018 August]; Available from URL: https://www.healthline.com/nutrition/7-common-nutrient-deficiencies#section1 7. Data available on request. IMS TPM. 8. Vitamin supplements overview. [Internet]. 2018. [last revised: NO DATE] Available from: http://www.vitamins-supplements.org/ 9. Vitamin A (Beta Carotene) [Internet]. 2018. [last revised: 5/3/2018]. Available from: http://www.vitamins-nutrition.org/vitamins-guide/vitamin-a-beta-carotene-retinol.html 10. Natural Medicines Therapeutic Research Centre. Thiamine Monograph. [Internet]. 2018. [last revised: 10/1/2018]. Available from: https:// naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=965 11. Natural Medicines Therapeutic Research Centre. Vitamin E Monograph. [Internet]. 2018. [last revised: 15/8/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=954 Proprietary name (and dosage form): Creché Guard Immune Multivit Syrup. Composition: Each 5 ml contains: 2012 IU Vitamin A, 0.6 mg Vitamin B1, 0.7 mg Vitamin B2, 7.2 mg Vitamin B3, 2.2 mg Vitamin B5, 1.1 mg Vitamin B6, 0.4 mcg Vitamin B12, 108.0 mcg Biotin, 32.4 mg Vitamin C, 400 IU Vitamin D, 5.4 mg Vitamin E, 145.0 mcg Folic Acid, 5.0 mg Zinc. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For more information, speak to your healthcare professional. IN562/18

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CLINICAL

WOMEN’S HEALTH Focus

PAEDIATRIC NUTRITION

NUTRITION FOR CHILDREN

Nutrition is the relationship of foods to the health of the human body. It is present in all processes of life, right from the very moment the sperm fertilises an egg, through foetal development in the uterus to the birth, human growth, maturity, old age and eventual death.

Proper nutrition is when all essential nutrients are supplied and used in adequate balance to maintain optimal health and wellbeing. Good nutrition is essential for: • Growth • Maintenance • Normal organ development and function • Resistance to infection and disease • Ability to repair bodily damage or injury • Normal organ development and function. Food is the fuel of the body. It gives energy, vitamins, minerals and special compounds or nutrients that keep the body running smoothly. There are three principles of nutrition: • Right quantities • Wide variety of food • Balance intake with the rate the body uses it. The actual nutrient requirement will vary from individual to individual due to metabolism, increased nutrient demand due to illness or growth. Nutrients contain chemical substances that provide the body with heat and energy, administer material for growth and repair of body tissues and assist in the regulation of body processes. Nutrients operate synergistically. Any deficiencies result in imbalances where the body becomes vulnerable to numerous ailments and dysfunctions. The effects on health may be subtle and only harmful after a prolonged period of time.

VITAMINS AND MINERALS

Daily requirements of minerals and vitamins are usually expressed as:

• RDA Recommended Daily / Dietary Allowance • NRV Nutrient Reference Value. These quantities represent the levels of essential nutrients considered to be adequate to meet the known needs of healthy people. In an ideal world, everyone would get all the nutrients they need to stay healthy from their daily diet but due to a changed lifestyle this has become quite difficult. Parents often have little time to prepare and cook balanced meals and a large variety of fast foods and prepackaged foods are available. Children miss meals from time to time or do not eat a wide variety of different types of food. They are also bombarded with advertisements for sweets, soft drinks and snack foods.

IS HEALTHY FOOD NOT ENOUGH?

Healthy food is always the first choice but sometimes the quality and quantity of the vitamin and mineral content in fruit and vegetables are not good due to soil conditions, transport and subsequent food storage e.g. refrigeration, processing such as freezing and cooking methods, such as boiling vegetables, which can remove or destroy some of the valuable water soluble vitamins e.g. vitamins B and C.

HOW DOES THIS AFFECT CHILDREN?

Early childhood is a period of rapid growth and development and therefore imbalanced nutrient supply will alter body structure and function and will increase the risk of chronic disease in adulthood. In the long-term micronutrient deficiencies will lead to tiredness, irritation, moodiness, cuts and injuries

Nutrition should balance intake with the rate the body uses it

might take longer to heal and longer recovery times from illness such as colds. Even more serious is the fact that not choosing a healthy diet over a prolonged period of time can result in heart disease, diabetes or obesity.

DO CHILDREN NEED A MULTIVITAMIN?

Having a healthy varied and balanced diet is important. Vitamins and minerals do not provide energy but healthy food does. Supplements assist in food absorption and conversion of food to energy. There are components in food which cannot be replaced by supplements - such as carbohydrates, fat, protein and fibre. Multivitamins supplement a balanced diet but do not replace it. Taking this into consideration, should

47% OF HEALTHCARE APPOINTMENTS START YOUNGER ARE SCHEDULED AFTER HOURS. South Africa’s MED-E-MASS CLIENTS ARE RECEIVING THOUSANDS OF STAY STRONGER . 1 THE CONFIRMED ONLINE BOOKINGS PER MONTH NoWITH nge 1

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children take a supplement? Children rarely eat the four to five portions of fruit and vegetables recommended every day. It is also well-known that most children are very picky eaters and can be very selective about the vegetables that they eat e.g. broccoli. A lot of children mostly eat snack food that tends to contain more fat, sugar and salt and less fibre. Therefore a daily, good-quality multivitamin and mineral supplement can help to fill nutritional gaps. Multivitamins and minerals ensure an adequate wide spectrum of nutrients to fill the nutrient gaps that will protect a child’s health and help to prevent diseases. A multivitamin will ensure that the child is getting the full range of micronutrients. References available on request.

Reference: 1. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT May 2019. Proprietary name (and dosage form): B-CAL®-DM Tablets. Composition: Each tablet contains: 500 mg Calcium, 400 IU Vitamin D3 and 125 mg Magnesium. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Disclaimer: This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health Supplements do not replace a healthy diet and lifestyle. For more information, speak to your healthcare professional. IN788/19

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MEDICAL CHRONICLE 9


CLINICAL WOMEN’S HEALTH Focus WOMEN'S HEALTH

ENDING ENDOMETRIOSIS The following article is based on a presentation by Prof Charles Chapron, President of the Society of Endometriosis and Uterine Disorders (France).

Endometriosis, the presence of endometrial-like tissue outside of the uterine cavity, is a public health issue that bears a substantial economic burden. There are three endometriosis phenotypes - superficial peritoneal, ovarian endometrioma and deep

infiltrating endometriosis - that can infiltrate the uterosacral ligaments, the vagina, the bladder, the intestine, and the ureter. Inflammation is key to the pathophysiology of endometriosis, and it explains both the associated infertility and the pelvic pain.

PREFERRED BY SOUTH AFRICAN GYNAECOLOGISTS1

Diagnosing endometriosis is particularly difficult, as there are no pathognomonic signs for endometriosis. The overriding symptom is pain. This pain can manifest itself in several ways (e.g. dysmenorrhoea, chronic non-cyclical pelvic pain, or dyspareunia) that can

There’s a new way out of the pain

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Symptoms of endometriosis: Painful periods1 Heavy menstrual bleeding1 Pelvic pain1

MANAGEMENT

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First line management EMPOWERING for painfulWOMEN endometriosis1 vaginal gel

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Why treat orally when you can treat topically2

Comparable efficacy to oral metronidazole, with lower systemic absorption and improved systemic tolerability6,7

Comparable efficacy to intravaginal clindamycin, with little to no development of resistance8

References: 1. Impact Rx – September 2018, Data on file. Results of a survey of 64 South African gynaecologists, commissioned by iNova and undertaken by a third party in February 2017. 2. Metrogel V approved package insert, 2000/10/23. 3. Thrush and Bacterial vaginosis. Looking after your sexual health [online] [cited 22 March 2018]; Available from URL: http://www.sexualhealthsheffield.nhs.uk/wp-content/uploads/2015/03/thrush-bacterial-vaginosis-information-and-advice.pdf. 4. Ries AJ. Treatment of Vaginal Infections: Candidiasis, Bacterial Vaginosis, and Trichomoniasis. J Am Pharm Assoc. 1997;NS37:563-9. 5. Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR 2015;64(3):1-137. 6. Hanson JM, McGregor JA, Hillier S, et al. Metronidazole for bacterial vaginosis. A comparison of vaginal gel vs. oral therapy. J Reprod Med. 2000;45(11):889-96. 7. Wain A. Metronidazole Vaginal Gel 0.75% (MetroGeI-Vaginal®) A Brief Review. Infectious Diseases in Obstetrics and Gynecology 1998;6:3-7. 8. Beigi R, Austin M, Meyn L, et al. Antimicrobial resistance associated with the treatment of bacterial vaginosis. American Journal of Obstetrics and Gynecology 2004;191:1124-9. Scheduling status: S2 name (and dosageL,form): MetroGel Gel. Composition: mg/5 g. Preservatives: Methyl hydroxybenzoate 0.08%, Propyl hydroxybenzoate 0.02%. Pharmacological 20.2.6 Antimicrobial: References: 1. Proprietary Johnson NP, Hummelshoj for the WorldV Vaginal Endometriosis SocietyMetronidazole Montpellier37.5 Consortium. Consensus on current management of endometriosis. Human Reproductionclassification: 2013; 28(6):A1552-1568. 2. Petraglia F, Horning D, andObstet business address applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, medicines Indications: MetroGel V is indicated the treatment of bacterial Registration number: 33/20.2.6/0243. Seitzagainst C, etprotozoa. al. reduced pelvic pain in women withforendometriosis: efficacyvaginosis. of long-term dienogest treatment. ArchName Gynecol 2012; 285:of167-173. 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available ® ® Visanne Each tablet contains 2 mg dienogest. Reg No: 44/21.8.2/0159. NS2 Visanne Each tablet contains 2 mg dienogest. Namibia Reg No: 13/21.8.2/0230. Bayer (Pty) Ltd, Reg. No.:1968/011192/07. 27 Wrench Road, Isando, on request from iNova Pharmaceuticals. IN2900/18. South Africa, 1609. Tel: (+27) 11 921-5000. For full information, please refer to the package insert approved by the Medicines Regulatory Authority.

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10AUGUST MEDICAL CHRONICLE 22 2017 | MEDICAL CHRONICLE

be associated with one another. There are numerous non-gynaecological clinical signs that need to be probed for, particularly gastrointestinal and urinary tract signs that, in the context of endometriosis, are more intense during menstruation. Two out of three cases starts in adolescence. Associated pathologies should also be probed for, particularly auto-immune and/or endocrine diseases, chronic pain conditions and cancers. Transvaginal ultrasonography and magnetic resonance imaging allow a precise map of the lesion to be obtained before deciding on therapy. A suitable level of questioning with regard to symptoms and medical history, in addition to a thorough radiological assessment allow the phenotype and the precise location of the endometriosis to be determined prior to deciding on the eventual surgical intervention. Performing a laparoscopy for diagnosis should no longer be a consideration.

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Surgery is generally an effective way to treat pelvic pain. However, limitations include the risk of complications, impact on the ovarian reserve in case of surgery of ovarian endometriomas; and the risk of recurrences. The most commonly used medications are oral contraceptive pills. These pills are effective at treating the pelvic pain but do not block the development and the continued progression of lesions. They generally fail to prevent the eventual occurrence of deep endometrial lesions. Dienogest has recently been approved for the treatment of endometriosis. Other than its systemic activity, it also exerts specifi c local effects responsible for an inhibitory effect on the proliferation of endometrial-like tissue. It has an impact on endometriosis-related inflammatory mediators and suppresses angiogenesis in animal models of endometriosis. There is also modulation of prostaglandin E2 expression. Initial results show that with a dose of 2mg dienogest, oestrogen levels are maintained in the range of 30-50pg/ml. This prevents bone demineralisation and it prevents endometrial lesions from proliferating. Before starting, patients need to be warned of the risk of bleeding, a secondary effect that improves with continued treatment. Post-operative prescription of dienogest following surgery for endometriomas (OMA) decreases the risk of relapse.. References available on request.


CLINICAL

WOMEN’S WOMEN'S HEALTH Focus HEALTH

DIMINISHING DYSMENORRHOEA

Dysmenorrhoea interferes with the daily life of an estimated one in five women. And yet, there’s remarkably little research into the condition.

The prevalence of dysmenorrhoea is difficult to determine because of different definitions of the condition - prevalence estimates vary from 45%-95%. Absenteeism from work and school as a result of dysmenorrhoea is common (13%-51% of women have been absent at least once and 5%-14% are often absent owing to the severity of symptoms). There are two main causes of period pain: Primary and secondary dysmenorrhoea. The former is simply painful periods, with no certain medical explanation, that tends to affect women as soon as they start menstruation. But the distinction between the two conditions is not clear-cut, as many women suffering from dysmenorrhoea may have undiagnosed endometriosis. Common causes of secondary dysmenorrhoea include endometriosis, fibroids (myomas), adenomyosis, endometrial polyps, pelvic inflammatory disease, and the use of an intrauterine contraceptive device. Meanwhile, the medical reasons for primary dysmenorrhoea are largely unknown. Some believe the pain is partly caused by uterus cramps, while others say a combination of sensory processing, local uterine inflammation, and uterine blood flow issues are also factors. Why some people suffer more than others is not well understood.

should be performed. A pelvic examination is crucial for excluding uterine irregularities, cul-de-sac tenderness, or suggestive nodularities.

MANAGEMENT

Pharmacotherapy is used to relieve symptoms. Treatment of secondary

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References available on request.

First generic SYMPTOMS ® to market 1

Reg. No.: 47/18.8/0525

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The following may indicate secondary dysmenorrhoea: • Dysmenorrhoea beginning in the 20s or 30s, after previous relatively painless cycles • Heavy menstrual flow or irregular bleeding • Dysmenorrhoea occurring during the first or second cycles after menarche • Pelvic abnormality with physical examination • Poor response to NSAIDs or oral contraceptives (OCs) • Infertility • Dyspareunia • Vaginal discharge. A complete physical examination

ovulation, which could result in a reduction in dysmenorrhoea. The oral contraceptive reduces the amount of prostaglandin produced by glands in the lining of the uterus; which then reduces both uterine blood flow and cramps.

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SIGNS AND SYMPTOMS

Clinical features of primary dysmenorrhoea include the following: • Onset shortly after menarche (≤6 months) • Usual duration of 48-72 hours (often starting several hours before or just after the menstrual flow) • Cramping or laborlike pain • Background of constant lower abdominal pain, radiating to the back or thigh • Often unremarkable pelvic examination findings (including rectal).

dysmenorrhoea involves correction of the underlying cause. NSAIDs used to treat dysmenorrhoea include diclofenac, ibuprofen, aspirin, COX-2 inhibitors an montelukast. The synthetic hormones in combined oral contraceptive pills suppress

BRING BACK BALANCE

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• Control of dysfunctional uterine bleeding

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• Symptomatic treatment of primary dysmenorrhoea *Polycystic ovarian syndrome # IVF - In-vitro fertilisation **Studies were conducted on supplemental Alpha Lipoic Acid only ## Due to PCOS

• First to market generic1 • Cost-effective - offers savings2 • Manufactured in Europe3 References: 1. De Cicco S, Immediata V, Romualdi D, et al. Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an

insulin-independent action. Gynecol Endocrinol 2017;33(9):698–701. 2. Genazzani AD, Shefer K, Della Casa D, et al. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J Endocrinol Invest 2018;41:583–590. 3. Carbonelli MG, Di Renzo L, Bigioni M, et al. α-Lipoic Acid Supplementation: A Tool for Obesity Therapy? Curr Pharmaceut Design 2010;16: 840-846. 4. Rago R, Marcucci I, Leto G, et al. Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. J Biol Regulators Homeostatic Agents 2015;29(4):1-11. 5. Sinopol® package insert, February 2019. 6. Cappelli V, Musacchio MC, Bulfoni A, et al. Natural molecules for the therapy of hyperandrogenism and metabolic disorders in PCOS. Eur S3 Levette® Each yellow active film-coated tablet contains 0,15 mg levonorgestrel and 0,03 mg ethinylestradiol. Rev Med Pharmacol Sci 2017; 21(2 Suppl):15-29. 7. Bellver J, Rodríguez-Tabernero L, Robles A, et al. Polycystic ovary syndrome throughout a woman’s life. J Assist Reprod Genet 2018;35:25 -39.

Reg. No. 47/18.8/0525 For full prescribing information, please refer to the package insert approved by the Medicines Regulatory Authority.

and Folic Acid 200 µg. Proprietary name (and dosage form): SINOPOL® granules. Composition: Each sachet contains: Myo-inositol 1 000 mg, Alpha Lipoic Acid 400 mgApplicant: Actor Pharma (Pty) Ltd, Reg. No. 2008/008787/07 References: Complementary Medicine: Health Supplement. D34.12 Multiple Substance formulation. This unregistered medicine has not been evaluated by SAHPRAUnit for 7, itsRoyal quality,Palm safetyBusiness or Estate, 1. The Generics Dictionary. (http://www.generic.co.za/, last accessed ®February 2017) . Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. intended use. Studies as part of the references were not conducted on Sinopol 646 Washington Street, Halfway House, Midrand 1685 2. Database of Medicine Prices 18th February 2017. (http://www.mpr.gov.za/, last accessed February 2017) +27 11 312 3812, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to theTel: package insert. FurtherFax: +27 11 312 7814 3. DataNo. on1952/001640/07, File, Actor Pharma www.actorpharma.co.za information is available on request from iNova Pharmaceuticals. IN3396/19. AD/LEVE/1.1 02/2017

MEDICAL CHRONICLE | AUGUST 2017 31 MEDICAL CHRONICLE 11


CLINICAL

WOMEN’S HEALTH Focus WOMEN'S HEALTH

TAKING THE MISERY OUT OF MENOPAUSE

Menopause is the time that marks the end of the menstrual cycles. It's diagnosed after a patient has gone 12 months without a menstrual period. Menopause can happen in a woman’s 40s or 50s.

It is a natural biological process, but the physical symptoms, such as hot flashes, and emotional symptoms of menopause may disrupt sleep, lower energy or affect emotional health. There are many effective treatments available, from lifestyle adjustments to hormone therapy.

SYMPTOMS

In the months or years leading up to menopause (perimenopause), patients might experience these signs and symptoms: • Irregular periods • Vaginal dryness • Hot flashes • Chills • Night sweats • Sleep problems • Mood changes • Weight gain and slowed metabolism • Thinning hair and dry skin • Loss of breast fullness. Symptoms, including changes in menstruation, are different for every woman. Most likely, patients will experience some irregularity in your periods before they end. Skipping periods during perimenopause is common and

expected. Often, menstrual periods will skip a month and return, or skip several months and then start monthly cycles again for a few months. Periods also tend to happen on shorter cycles, so they are closer together. Hormone replacement therapy (HRT) uses female hormones to treat common symptoms of menopause and ageing. After a woman’s menstrual period ends, hormone levels fall, causing uncomfortable symptoms like hot flashes and vaginal dryness, and sometimes conditions like osteoporosis. HRT replaces hormones the body no longer produces. It’s the most effective treatment for menopause symptoms.

DIFFERENT FORMS OF HT

Administration of hormone therapy (HT) via the transdermal route avoids hepatic first-pass metabolism and therefore the high plasma levels of oestrogen metabolites that are associated with oral administration. Patch formulations have traditionally been the most common form of transdermal HT. Patch and gel formulations are effective in treating climacteric symptoms and improving bone mineral density, and the effects are comparable to those achieved by oral HT.

Systemic hormone therapy: Systemic oestrogen - which comes in pill, skin patch, gel, cream or spray form - remains the most effective treatment for relief of troublesome menopausal hot flashes and night sweats. Oestrogen can also ease vaginal symptoms of menopause, such as dryness, itching, burning and discomfort with intercourse. Low-dose vaginal products: Low-dose vaginal preparations of oestrogen - which come in cream, tablet or ring form - can effectively treat vaginal symptoms and some urinary symptoms, while minimising absorption into the body. Low-dose vaginal preparations do not help with hot flashes, night sweats or protection against osteoporosis. Long-term systemic hormone therapy for the prevention of postmenopausal conditions is no longer routinely recommended. But some data suggest that oestrogen can decrease the risk of heart disease when taken early in postmenopausal years. Menopause hormone therapy (MHT) can improve quality of life, sexual function and other menopauserelated complaints, such as joint and muscle pains, mood changes and sleep disturbances.

HT AND HEART DISEASE A randomised, controlled clinical trial - the Kronos Early Estrogen Prevention Study (KEEPS) - explored oestrogen use and heart disease in younger postmenopausal women. The study found no significant association between hormone therapy and heart disease. For women who haven't had their uterus removed, oestrogen is typically prescribed along with progesterone or progestin (progesterone-like medication). This is because oestrogen alone, when not balanced by progesterone, can stimulate growth of the lining of the uterus, increasing the risk of uterine cancer. Women who have had a hysterectomy don't need to take progestin.

CONSIDER

Systemic oestrogen is still the most effective treatment for menopausal symptoms. The benefits of hormone therapy may outweigh the risks if the patient is healthy and: • Experiences moderate to severe hot flashes or other menopausal symptoms • Has lost bone mass and either can't tolerate or isn’t benefitting from other treatments • Has stopped having periods before age 40 (premature menopause) or lost normal function of her ovaries before age 40 (premature ovarian insufficiency).

12 MEDICAL2017 CHRONICLE 42 AUGUST | MEDICAL CHRONICLE

Women who experience an early menopause, particularly those who had their ovaries removed and don't take oestrogen therapy until at least age 45, have a higher risk of: • Osteoporosis • Coronary heart disease • Earlier death • Parkinsonism (Parkinson’s-like symptoms) • Anxiety or depression.

VTE

The risk of venous thromboembolism (VTE) and ischaemic stroke increases with oral MHT, although the absolute risk of stroke with initiation of MHT before age 60 years is rare. Observational studies and a meta-analysis point to a probable lower risk of VTE and possibly stroke with transdermal therapy (0.05mg twice weekly or lower) compared to oral therapy.

BREAST CANCER

The risk of breast cancer in women over 50 years of age associated with MHT is a complex issue with decreased risk reported from RCTs for oestrogen alone (CE in the Women’s Health Initiative (WHI) in women with hysterectomy and a possible increased risk when combined with a progestin (medroxyprogesterone acetate in the WHI) in women without hysterectomy. The increased risk of breast cancer thus seems to be primarily, but not exclusively, associated with the use of a progestin with oestrogen therapy in women without hysterectomy and may be related to the duration of use. The risk of breast cancer attributable to MHT is rare. It equates to an incidence of <1 per 1000 women per year of use. The option of MHT is an individual decision in terms of quality of life and health priorities as well as personal risk factors such as age, time since menopause and the risk of VTE, stroke, ischemic heart disease and breast cancer. MHT should not be recommended without a clear indication for its use.

OTHER BENEFITS

Women experiencing a spontaneous or iatrogenic menopause before the age of 45 years and particularly before 40 years are at a higher risk for cardiovascular disease and osteoporosis and may be at increased risk of affective disorders and dementia. In such women, MHT reduces symptoms and preserves bone density. Observational studies that suggest MHT is associated with reduced risk of heart disease, longer lifespan, and reduced risk of dementia. MHT is advised at least until the average age of menopause.

References available on request.


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References: 1. Rago R, Marcucci I, Leto G, et al. Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. J Biol Regulators Homeostatic Agents 2015;29(4):1-11. 2. Genazzani AD, Shefer K, Della Casa D, et al. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J Endocrinol Invest 2018;41:583–590. 3. Carbonelli MG, Di Renzo L, Bigioni M, et al. α-Lipoic Acid Supplementation: A Tool for Obesity Therapy? Curr Pharmaceut Design 2010;16:840846. 4. De Cicco S, Immediata V, Romualdi D, et al. Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin-independent action. Gynecol Endocrinol 2017;33(9):698–701. 5. Sinopol® package insert, February 2019. 6. Cappelli V, Musacchio MC, Bulfoni A, et al. Natural molecules for the therapy of hyperandrogenism and metabolic disorders in PCOS. Eur Rev Med Pharmacol Sci 2017; 21(2 Suppl):15-29. 7. Bellver J, Rodríguez-Tabernero L, Robles A, et al. Polycystic ovary syndrome throughout a woman’s life. J Assist Reprod Genet 2018;35:25 -39. Proprietary name (and dosage form): SINOPOL® granules. Composition: Each sachet contains: Myo-inositol 1 000 mg, Alpha Lipoic Acid 400 mg and Folic Acid 200 µg. Complementary Medicine: Health Supplement. D34.12 Multiple Substance formulation. This unregistered medicine has not been evaluated by SAHPRA for its quality, safety or intended use. Studies as part of the references were not conducted on Sinopol®. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert. Further information is available on request from iNova Pharmaceuticals. IN3397/19.


CLINICAL

WOMEN’S HEALTH Focus WOMEN'S HEALTH

THE BURDEN OF VAGINITIS

Most women will have a vaginal infection at some stage in their lifetime, with bacterial vaginosis (BV) being the most common vaginal infection among women during their reproductive years.

*Supplied content

Biofilms ‘protect’ bacteria by acting as a barrier to antibiotics and preventing them from acting on micro-organisms, leading to difficulty in managing infections with standard treatment options. Povidone-iodine (PVP-I) has been shown to effectively eliminate infections that are associated with biofilm formation. Studies have also shown that the use

of PVP-I dramatically reduces harmful pathogens such as bacteria, viruses and fungi within 10 minutes of exposure, after which healthy microflora in the vagina is re-established within 30 to 120 minutes. PVP-I helps to bring down the pH value within the vaginal environment to a more favourable pH and discourages growth of agents that cause

vaginitis, such as Candida albicans and Trichomonas vaginalis. Hence antiseptics like PVP-I with broad spectrum anti-infective activity and low resistance potential offer an attractive option in both infection control and prevention. References available on request.

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Determining the prevalence of bacterial vaginosis is difficult because one-third to threequarters of affected women are asymptomatic. In contrast to this, symptomatic BV can be accompanied by foul-smelling, profuse vaginal discharge in the absence of any appreciable signs of inflammation. The symptoms of vaginitis are generally nonspecific and require clinical diagnosis. Amsel’s criteria can be used in-office where a clinical diagnosis can be made if three of the four signs are present: • Adherent and homogenous grayishwhite vaginal discharge • Vaginal pH exceeding 4.5 • Presence of clue cells (vaginal epithelial cells with such a heavy coating of bacteria that the peripheral borders are obscured - on saline wet mount) • Fishy odour after addition of 10% potassium hydroxide solution. A microbiological-based diagnosis may also be used according to the Nugent scoring. This requires in-office Gram-stain-based diagnosis, which may not be readily available, and practitioners aren’t often familiar with performing this diagnosis. The treatments recommended by the Centers for Disease Control for BV are either metronidazole or clindamycin administered orally or intravaginally. Metronidazole is a nitroimidazole with activity against anaerobic organisms, while clindamycin, a macrolide, has a broad spectrum of activity against a variety of microbes, including aerobic and anaerobic organisms. Despite treatment with either metronidazole or clindamycin, many women (approximately 10%-15%) fail therapy after one month. The proportion of women who relapse also increases over time. The recurrence rate of BV is approximately 30% at three months and approximately 50%-80% at one year following therapy with either medicine. Current therapy for managing recurrent BV is repeated treatment with antibiotics. An obvious problem and important health issue associated with repeated exposure to the same antibiotic is resistance of those microbes targeted by the medicine, which can result in alteration of flora and possible persistence of BV-associated pathogens. Biofilms are also important to consider when delay in healing occurs. Biofilms can be described as microbial communities and consists of both bacteria and fungi. Two of the most common organisms causing vaginal infections, Gardneralla vaginalis and Candida species, are associated with Biofilms.

IS THE MOST COMMON VAGINAL INFECTION, AFFECTING 1 out of 3 WOMEN3,4

Metronidazole Gel 0.75 % is a recommended regimen for the treatment of B

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1. Approved package insert 2. Kanagalingam J., et al (2015). Int J Clin Pract, November 2015;69(11):1247-1256. S2 Betadine® Douche. Each 1 ml contains povidone-iodine 100 mg, equivalent to 10 mg available iodine. Registration No. C/18.6/143. S2 Betadine® Vaginal Gel. Each gram contains povidone-iodine 100 mg, equivalent to 10 mg available iodine. Registration No. C/18.6/144.

full prescribing refer to the package approved the medicines authority. References: 1. Impact Rx – September 2018, DataFor on file. Results of a survey of 64information South African gynaecologists, commissioned by iNova andinsert undertaken by a third partyby in February 2017. 2. Metrogelregulatory V approved package insert, 2000/10/23. 3. Thrush and Bacterial vaginosis. Looking after your sexual health [online] [cited 22 March 2018]; Available from URL: http://www.sexualhealthsheffield.nhs.uk/wp-content/uploads/2015/03/thrush-bacterial-vaginosis-information-and-advice.pdf. 4. Ries AJ. Treatment of Vaginal Infections: Candidiasis, Bacterial Vaginosis, and further product contact: (Pty) LtdJM, McGregor JA, Hillier S, et al. Metronidazole for bacterial vaginosis. A comparison of Trichomoniasis. J Am Pharm Assoc. 1997;NS37:563-9. 5. Centers for Disease Control andFor Prevention Sexually Transmitted information Diseases Treatment Guidelines, 2015.Mundipharma MMWR 2015;64(3):1-137. 6. Hanson vaginal gel vs. oral therapy. J Reprod Med. 2000;45(11):889-96. Wain A. Metronidazole VaginalNewlands Gel 0.75% (MetroGeI-Vaginal®) Brief Review. Infectious Diseases in Obstetrics and Gynecology 1998;6:3-7. 8.7735, Beigi R, Austin M, Meyn L, et al. Antimicrobial resistance associated with the 2nd Floor, 7. Mariendahl House, on Main,AClaremont, 7708. PO Box 23162, Claremont, South Africa. treatment of bacterial vaginosis. American Journal of Obstetrics and Gynecology 2004;191:1124-9. Tel: +27 21 671 5251 | Fax: +27 21 671 5216

Scheduling status: S2 Proprietary name (and dosage form): MetroGel V Vaginal Gel. Composition: Metronidazole 37.5 mg/5 g. Preservatives: Methyl hydroxybenzoate 0.08%, Propyl hydroxybenzoate 0.02%. Pharmacological classification: A 20.2.6 Antimicrobial: medicines against protozoa. Indications: MetroGel V is indicated for the treatment of bacterial vaginosis. Registration number: 33/20.2.6/0243. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer towww.betadine.co.za the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. IN2900/18.

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CPD

WOMEN’S HEALTH Focus SUPPLEMENTATION

The effect of diabetes on

Vitamin B

Vitamin B12, also called cobalamin, is a water-soluble vitamin that plays a key role in the normal functioning of the central and peripheral nervous systems, hematopoiesis, and the DNA synthesis of every cell.

Vitamin B12 deficiency causes megaloblastic anemia, peripheral neuropathy that could be indistinguishable from the diabetic neuropathy even by nerve conduction studies. Memory and cognitive impairments could also result from B12 deficiency. Malabsorption of vitamin B12 in diabetic patients treated with metformin was first noted in 1969. Subsequent studies revealed a prevalence of vitamin B12 deficiency in the range of 10%-30% of diabetic patients using metformin. The mechanisms are thought to be related to slowing of the bowel transit time resulting in bacterial overgrowth and interference of the Biguanide with the absorption of vitamin B12.

cheese. About 2/3 to 4/5 of body’s content of vitamin B12 is stored in liver. Vitamin B12 is absorbed mainly in terminal ileum with the help of intrinsic factor secreted from parietal cells of stomach. Vitamin B12 can also be absorbed by the process of passive diffusion in the small intestine which doesn’t require intrinsic factor. However, only about 1% of the vitamin B12 dose is absorbed by passive diffusion. In other words, when 100μg of vitamin B12 is administered, approximately 1μg is likely to be absorbed by passive diffusion. The various causes of vitamin B12 deficiency includes nutritional deficiency, gastric mucosal damage, pernicious anaemia, drugs like metformin and proton pump inhibitors.

DEFICIENCY OF VITAMIN B12

PHYSIOLOGICAL ROLE OF VITAMIN B12 Vitamin B12 is important in methylation

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The principal source of vitamin B12 includes liver, egg yolk, meat and

of homocysteine to methionine and the conversion of methylmalonyl coenzyme A (CoA) to succinyl-CoA. Methionine is then converted into S-adenosyl-methionine, which acts as donator of methyl group to myelin, membrane phospholipids and to various neurotransmitters. The relationship between vitamin B12 deficiency and peripheral neuropathy has been shown in a number of previous studies. Metformin is the indispensable first-line treatment for type 2 diabetes mellitus (DM) worldwide. One of the adverse effects of the use of metformin is vitamin B12 deficiency. Vitamin B12 deficiency may lead to neuropsychiatric and hematological abnormalities. The relationship between vitamin B12 deficiency and peripheral neuropathy has been shown in previous studies. Metformin is the first and most important treatment for type 2 DM

ed C alci

um

worldwide if there is no contraindication. Metformin leads the insulin sensitising effect on the liver. Although gastrointestinal side effects are most common because of the use of metformin, it can also lead to serious side effects, such as lactic acidosis and vitamin B12 deficiency.

METFORMIN USE AND VITAMIN B12 DEFICIENCY One of the important side effects of long-term metformin therapy is malabsorption of vitamin B12, which could lead to megaloblastic anemia and peripheral neuropathy. Annual screening of serum vitamin B12 level or serum methylmalonic acid (MMA)/ serum homocysteine level should be done in cases taking metformin for more than four to five years with average dose of >1g per day, even in the absence of haematological or

Reference: 1. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT May 2019. Proprietary name (and dosage form): B-CAL®-DM Tablets. Composition: Each tablet contains: 500 mg Calcium, 400 IU Vitamin D3 and 125 mg Magnesium. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Disclaimer: This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health Supplements do not replace a healthy diet and lifestyle. For more information, speak to your healthcare professional. IN788/19

2019/07/31 08:44

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CPD neurological abnormalities. However, as the incidence of type-2 DM is increasing, cost of annual measurement of vitamin B12 level also increases. Jeetendra et al (2016) found that considering cost factor for annual screening, vitamin B12 supplementation appears to be more cost effective approach rather than annual screening for routine prophylaxis. Routine vitamin preparations available in the market may contain less amount of B12 and hence are not of much therapeutic use in treatment of B12 deficiency due to metformin. According to the authors, there is a need to look for higher doses of approximately 500-2000μg per day of vitamin B12.

microalbuminuria) and 52 non-diabetic control subjects. Plasma concentrations of pyridoxamine 5’-phosphate (PLP) were significantly lower in patients with type 2 diabetes than in control subjects (median: 22nmol/L, diabetes with microalbuminuria; 26nmol/L, diabetes without microalbuminuria; 39nmol/L, non-diabetic control; p <0.0001). The prevalence of low PLP (<30nmol/L) was 63%, 58%, and 25% in the diabetes groups with and without microalbuminuria and the control

group, respectively. Plasma levels of pyridoxine and pyridoxal were also lower (p <0.0001), but levels of pyridoxamine, pyridoxamine 50-phosphate, and pyridoxic acid were higher in both groups with diabetes compared to the control group (p <0.001). Thiamine deficiency was highly prevalent in all groups, whereas low vitamin B12 and elevated methylmalonic acid were rare. Increased levels of C-reactive protein and soluble vascular cell adhesion molecule-1 were observed in the groups with diabetes (p<0.05, vs healthy

WOMEN’S HEALTH Focus SUPPLEMENTATION

control). The authors concluded that deficiency of vitamin B6 (PLP, pyridoxine, pyridoxal) and vitamin B1 (thiamine) was prevalent in type 2 diabetes. Incipient nephropathy was associated with more pronounced alterations in vitamin B6 metabolism and stronger indications of endothelial dysfunction and inflammation.

B12 DEFICIENCY WITH PERIPHERAL NEUROPATHY The relationship between vitamin B12 deficiency and peripheral neuropathy

VITAMIN STATUS: LINK TO RENAL STATUS, GLYCEMIC CONTROL AND VASCULAR INFLAMMATION Diabetes is associated with mishandling of thiamine in the kidney and development of diabetic nephropathy. Adaikalakoteswari et al (2011) aimed to assess the disturbance of thiamine and other B-vitamin status of patients with type 2 diabetes in Indonesia. One hundred and fifteen patients with type 2 diabetes with and without microalbuminuria or albuminuria and 39 healthy people were recruited. After a two-month washout period for B-vitamin supplementation, markers of vitamins B1, B6, B9 and B12, were determined. Fractional excretion of thiamine (22% vs 33%; P <0.05) and urinary excretion of the vitamin B6 degradation product 4-pyridoxic acid (0.081 vs 0.133mmol/g creatinine, P <0.001) was increased in patients with type 2 diabetes with respect to healthy controls. There was also increased total plasma cobalamin (398 vs 547pmol/l, P <0.001) and holotranscobalamin (74 vs 97pmol/l, P <0.001) in patients with type 2 diabetes. In multiple regression analysis these were linked to HbA1c, duration of diabetes and systolic blood pressure, and fasting plasma glucose, folate and C-reactive protein, respectively. They concluded that there was renal mishandling of thiamine, increased degradation of vitamin B6 and cytosolic metabolic resistance to vitamin B12 in patients with type 2 diabetes in Indonesia.

NEW PACKAGING

VITAMIN B STATUS WITH AND WITHOUT INCIPIENT NEPHROPATHY Nix et al (2014) investigated the vitamin B status, with particular focus on vitamin B6, in adults with and without incipient nephropathy secondary to type 2 diabetes mellitus. Plasma and/or urine concentrations of vitamins B6, B1, B12, related vitamers and biomarkers (including total homocysteine, methylmalonic acid) were measured in 120 adults with type 2 diabetes (including 46 patients with

S5

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MEDICAL CHRONICLE 17


WOMEN’S HEALTH Focus SUPPLEMENTATION

has been shown in a number of studies. Metformin is the indispensable first-line treatment for type 2 diabetes mellitus (DM) worldwide. One of the adverse effects of the use of metformin is vitamin B12 deficiency. Olt et al (2017) investigated the relationship between vitamin B12 deficiency and peripheral neuropathy due to the use of metformin. Patient’s laboratory and electromyography data were retrospectively reviewed. Patients with no EMG report and other necessary information were excluded from the study. Eighty-six patients with type 2 DM using metformin were included in the study. Of these patients, 26 were males and 60 were females. The mean age of the patients was 55±7 years. The mean body mass index of the patients was 29±9kg/m2. The mean HbA1c level of the patients was 8%±2%. The mean duration of diabetes was 8±5 years. The incidence of vitamin B12 deficiency was 38%. Peripheral neuropathy was detected in 33% patients. There was no statistically significant difference in vitamin B12 levels between patients with peripheral neuropathy and those without peripheral neuropathy (p=0.64). Therefore, it can be concluded that the lack of vitamin B12 secondary to the use of metformin did not significantly increase the frequency of peripheral neuropathy. Long-term therapy with metformin was shown to decrease the Vitamin B level and manifested as peripheral neuropathy. Roy et al (2016) aimed to define the prevalence of vitamin B deficiency in early type 2 diabetic patients (duration ≤5 years or drug treatment ≤3 years) and the relationship among metformin exposure and levels of cobalamin (Cbl), folic acid, and homocysteine (Hcy) with severity of peripheral neuropathy. This was a cross-sectional study involving randomly selected 90 patients (male 56, female 34) between age

INSTRUCTIONS:

18 MEDICAL CHRONICLE

CPD

groups of 35 and 70 years, comparing those who had received >6 months of metformin (Group A) (n = 35) with those without metformin (Group B) (n = 35) and patients taking metformin with other oral hypoglycemic agent (Group C) (n = 20). Comparisons were made clinically, biochemically (serum Cbl, fasting Hcy, and folic acid), and with electrophysiological measures (nerve conduction studies of all four limbs). Comorbidities contributing to neuropathy were excluded from the study. Results showed that Group A patients (54%) were prone to develop peripheral neuropathy comparing Group B (28%) and Group C (35%). There was significantly low plasma level of Cbl in Group A (mean 306.314pg/ml) than in Group B (mean 627.543pg/ml) and Group C (mean 419.920pg/ml). There was insignificant low-level plasma folic acid in Group A (16.47ng/ml) than in Group B (16.81ng/ml) and Group C (22.50ng/ml). There was significantly high level of Hcy in Group A (mean 17.35μmol/L) and Group C (mean 16.99μmol/L) than in Group B (mean 13.22μmol/L). Metformin users even for two years showed evidence of neuropathy on nerve conduction velocity though their body mass index and postprandial blood sugar were maintained. There was significant difference in between groups regarding plasma Cbl, folic acid, and Hcy level as significance level <0.05 in all three groups (F [2, 87] = 28.1, P = 0.000), (F [2, 87] = 7.43, P= 0.001), (F [2, 87] = 9.76, P = 0.000). Post hoc study shows significant (P < 0.05) lowering of Cbl and Hcy level in Group A (mean = 306.314, standard deviation [SD] = 176.7) than in Group C (mean = 419.92, SD = 208.23) and Group B (mean = 627.543, SD = 168.33). Even short-term treatment with metformin causes a decrease in serum Cbl, folic acid and increase in Hcy, which leads to peripheral neuropathy in Type 2 diabetes patients. The authors suggest

prophylactic vitamin B and folic acid supplementation or periodical assay in metformin user.

NOT ALL NEUROPATHY IN DIABETES IS OF DIABETIC AETIOLOGY The neuropathy associated with B12 deficiency usually precedes the megaloblastic anemia. Although the associated anemia is reversible, the neuropathy may not be completely reversible in certain patients. Recommendations for periodic testing of vitamin B12 in metformin-treated patients, have recently been made by the American Diabetes Association (ADA) especially in those with peripheral neuropathy. Diabetic peripheral neuropathy is the most common peripheral neuropathy in the developed world. However, not all patients with diabetes and peripheral nerve disease have a peripheral neuropathy caused by diabetes. Several studies have drawn attention to the presence of other potential causes of a neuropathy in individuals with diabetes. Approximately 10%-50% of patients with diabetes may have an additional potential cause of a peripheral neuropathy and some may have more than one cause. Neurotoxic medications, alcohol abuse, vitamin B12 deficiency, renal disease, chronic inflammatory demyelinating neuropathy, inherited neuropathy, and vasculitis are the most common additional potential causes of a peripheral neuropathy.

CONCLUSION According to Jeetendra et al (2016), it appears that vitamin B12 deficiency occurs commonly among patients with type-2 diabetes taking metformin therapy for longer duration and at higher dosage. This emphasises routine screening of vitamin B12 level among type-2 DM, especially those consuming metformin for more than

four to five years with average dose of more than 1g/day, even in the absence of haematological and neurological abnormalities. The amount of B12 available in general multivitamins preparations seen in the market may not be enough to correct metformin induced vitamin B12 deficiency among those with diabetes. Hence vitamin B12 supplementation might be done in doses of >100μg/ day in alimentary causes and doses of 500–2000μg/day in disorders resulting from malabsorption for the treatment and prophylaxis of vitamin B12 deficiency Routine supplementation of vitamin B12 given to patients on long-term high dose metformin therapy seems to be clinically more prudent and a cost-effective approach. References

Olt S et al. Investigation of the vitamin B12 deficiency with peripheral neuropathy in patients with type 2 diabetes mellitus treated using metformin. North Clin Istanb 2017;4(3):233-236. Doi: 10.14744/ nci.2017.98705. Jeetendra S et al. Metformin Use and Vitamin B12 Deficiency in Patients with Type-2 Diabetes Mellitus. MVP Journal of Medical Sciences 2016:3(1),67-70. Roy R P et al. Study of Vitamin B deficiency and peripheral neuropathy in metformintreated early Type 2 diabetes mellitus. Indian J Endocrinol Metab. 2016:20(5):631-637. Doi: 10.4103/2230-8210.190542. Zalaket J et al. Vitamin B12 deficiency in diabetic subjects taking metformin: A cross sectional study in a Lebanese cohort. Journal of Nutrition & Intermediary Metabolism 2018(11)9-13. Freeman R. Not All Neuropathy in Diabetes Is of Diabetic Etiology: Differential Diagnosis of Diabetic Neuropathy. Current Diabetes Reports 2009, 9:423–431. Adaikalakoteswari A et al. Disturbance of B-vitamin status in people with type 2 diabetes in Indonesia - Link to renal status, glycemic control and vascular inflammation. Diabetes research and clinical practice 95(2012)415–424. Nix et al. Vitamin B status in patients with type 2 diabetes mellitus with and without incipient nephropathy. Diabetes research and clinical practice 2015(107)157–165. Obeid R et al. Serum vitamin B12 not reflecting vitamin B12 status in patients with type 2 diabetes. Biochimie 2013(95) 1056-1061.

1. Go to www.medicalacademic.co.za 2. Click the tab labelled ‘CPD Portal’ on the far right tab near the top of the page. 3. Select the relevant questionnaire from the list and complete the form. Disclaimer: Please note that this article might only be a section of a larger CPD programme. Kindly visit www.medicalacademic.co.za to complete the full questionnaire.


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References: 1. IMS:TPM Data (A11A, A11B, A11E, V6D, V3X / Constructed Class). MAT Oct 2017. 2. Gross, M and Klein, S. [Internet]: Fish Oil Triglycerides vs. Ethyl Esters [updated 2016; cited 2017 Aug 25]. Available from: http://www.bewellassociates.com/wpcontent/uploads/2013/08/Triglyceride_Fish_Oils.pdf. 3. Puremax.com [Internet]: Health benefits-Omega 3 during pregnancy [cited 2017 Jun 27]. Available from: http://www.puremax.com/home.aspx?d=content&s=154&r=316. Proprietary name (and dosage form): PregOmega® Plus Tablets and Soft Gel Capsules. Composition: Each fish oil soft gel capsule contains: 822 mg Pharmaceutical Grade Fish Oil (derived from tuna and deep marine fish oil) providing: 260 mg DHA, 91 mg EPA. Each calcium tablet contains: 500 mg Calcium, 400 IU Vitamin D3 and 125 mg Magnesium. Each vitamin & mineral tablet contains: 2 666 IU Vitamin A, 3 mg Vitamin B1, 2 mg Vitamin B2, 10 mg Vitamin B3, 1 mg Vitamin B6, 2 μg Vitamin B12, 50 mg Vitamin C, 100 IU Vitamin D3, 230 mg Calcium, 0,15 mg Copper (AAC), 500 µg Folic Acid, 15 mg Iron (AAC), 0,5 mg Magnesium, 0,05 mg Manganese (AAC), 0,025 mg Molybdenum (AAC), 0,84 mg Potassium, 0,085 mg Zinc. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, MEDICAL CHRONICLE 19 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information available on request from iNova Pharmaceuticals. IN354/17


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Reduces the risk of developing osteoporosis, when calcium intake is combined with sufficient vitamin D, a healthy diet and regular exercise

Assists with the normal function of the immune system

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% NRV/ VVW

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References: 1. Mason P. Dietary Supplements (4th edition). London: The Pharmaceutical Press, 2012; p. 493-510. 2. National Institutes of Health [Internet]: Vitamin D: Fact Sheet for Health Professionals [updated 2016 11 Feb; cited 2016 Nov 14] Available from: http:// ods.od.nih.gov/factsheets/VitaminD-HealthProfessional. 3. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT JAN 2019. Proprietary name (and dosage form): D-Drops liquid. Composition: Each 0,5 mℓ contains: 500 IU Vitamin D3 in sunflower oil, 3,63 IU Vitamin E. Pharmacological Classification: Complementary Medicine: Health Supplement - D34.11 Vitamins. This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Proprietary name (and dosage form): D-Vit Tabs. Composition: Each tablet contains: 400 IU Vitamin D3. Pharmacological Classification: Complementary Medicine: Health Supplement - D34.11 Vitamins. This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information is available on request from iNova Pharmaceuticals. IN693/19


CLINICAL

WOMENâ&#x20AC;&#x2122;S HEALTH Focus OSTEOPOROSIS CPD

REVIEW OF ONCE-MONTHLY

ORAL IBANDRONATE

An advisory board meeting of key opinion leaders was held in 2015 to discuss the clinical data on oral ibandronate in the treatment of postmenopausal osteoporosis. *Sponsored content

Ibandronate - The primary fracture prevention trial (BONE) The BONE study is the primary fracture

Ibandronate - The non-inferiority studies for the longer dosing regimens The European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) suggest that to register a different dosing regimen (e.g. weekly or monthly) of a bisphosphonate that has previously demonstrated efficacy in primary fracture prevention trials, â&#x20AC;&#x2DC;bridging studiesâ&#x20AC;&#x2122; using surrogate endpoints for fracture such as changes in BMD should be used. In other words, it is not necessary to reevaluate fracture prevention in order to obtain registration for a longer dosing regimen. It is accepted that if BMD gains of the comparator are non-inferior to the originator (within a predetermined range), then fracture efficacy can be expected to be similar. The Monthly Oral iBandronate In LadiEs (MOBILE) trial was a noninferiority BMD study that compared

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Reference: 1. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT May 2019. Proprietary name (and dosage form): B-CALÂŽ-DM Tablets. ÂŽ Composition: Each tablet contains: 500 mg Calcium, 400 IU Vitamin D3 and 125 mg Magnesium. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Disclaimer: This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or Pr e intended use. Health Supplements do m u s c r i150b mg tabletsaapproved i not replace a healthy diet and lifestyle. c References: 1. BonivaÂŽ package insert, March 2009. 2. Department of Health. Database of Medicine Prices 14 Nov 2016. [Accessed 21 Nov 2016]. Available at: http://www.mpr.gov.za/PublishedDocumentsaspx#DocCatld=21. 3. Harris ST, Reginster J-Y, Harley C, et al. Risk of fracture in women l bisphosphonates: The eValuation of IBandronate Efficacy (VIBE) database fracture study. Bone 2009;44:758-765. 4. Rossiter D (Ed). South African Medicines e d Cor weekly treated with monthly oral ibandronate Formulary. 11th Ed. 2014. p278. 5. Miller PD, Recker RR, Harris S, et al. Long-term fracture rates seen with continued For more information, speaklong-term to your ibandronate treatment: pooled analysis of DIVA and MOBILE long-term extension studies. Osteoporos Int 2014;25:349-357. 6. Miller PD, Recker RR, Reginster J-Y, et al. Efficacy of monthly oral ibandronate is sustained over 5 years: the MOBILE extension study. Osteoporos Int 2012;23:1747-1756. healthcare professional. IN788/19

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Ibandronate - The VIBE database study No prospective head-to-head trials comparing the anti-fracture efficacy of the currently marketed weekly and monthly bisphosphonates have been done. Due to the large sample size these studies would require to reliably detect differences in fracture risk, and the associated high costs. For this reason, observational database studies are increasingly being used as such studies can provide sufficient sample sizes and permit the comparison of marketed doses. Furthermore, it is unlikely that future fracture efficacy trials of bisphosphonate versus placebo will be conducted as it would be unethical to randomise patients to placebo. The eValuation of IBandronate

IN SUMMARY, WITH RESPECT TO FRACTURE DATA:

nge 1

Registration of a new bisphosphonate for the treatment of osteoporosis requires fracture data from a randomised, placebo-controlled, clinical trial, which has fracture reduction as its primary outcome. The primary fracture prevention trials for the currently available bisphosphonates include: Alendronate (10mg daily) - The Fracture Intervention Trials (FIT 1 and 2), which provided vertebral and hip fracture efficacy data. Risedronate (5mg daily) The Vertebral Efficacy with Risedronate Therapy (VERT-NA and VERT-International) studies which demonstrated vertebral fracture efficacy. The Hip Intervention Programme (HIP) study demonstrated hip fracture reduction with risedronate. Ibandronate (2.5mg daily) - The iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE), which demonstrated vertebral fracture efficacy. Hip fracture efficacy was demonstrated in high-risk patients. Zoledronate (yearly IV) - The Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly (HORIZON) trial, which demonstrated both vertebral and hip fracture reduction.

Efficacy (VIBE) head-to-head database fracture study compared fracture rates (hip, nonvertebral, vertebral and any clinical fracture) adjusted for confounding factors, over one year, between patients treated with monthly ibandronate 150mg orally and weekly oral bisphosphonates (alendronate, risedronate or a combined alendronate/risedronate group). The results showed that fracture risk was not significantly different between patients receiving monthly ibandronate or weekly bisphosphonates for hip, non-vertebral or any clinical fracture.

Ra

BONE AND VIBE DATA SUMMARY

the efficacy and safety of three oncemonthly oral ibandronate regimens with the ibandronate 2.5mg daily regimen. Oral ibandronate 150mg once monthly provides twice the annual cumulative exposure to ibandronate compared to the 2.5mg daily formulation. The efficacy of this increased dose was examined in the pivotal registration study (MOBILE), in which BMD gains were significantly greater with monthly oral ibandronate than with daily ibandronate. (See section on MOBILE and MOBILE LTE). Similarly, the Monthly Oral Therapy with Ibandronate for Osteoporosis iNtervention (MOTION) study which compared the efficacy of oncemonthly oral ibandronate with weekly alendronate in women with postmenopausal osteoporosis showed that the two regimens were comparable at increasing BMD after 12 months at both the lumbar spine and total hip.

prevention trial for oral ibandronate 2.5mg daily in postmenopausal women with osteoporosis and showed a significant (62%) reduction in the risk of new vertebral fractures with ibandronate 2.5mg daily over the threeyear study duration. The BONE trial was, however, relatively small and did not show hip fracture reduction. However, a posthoc analysis in a higher-risk subgroup of patients (T-score <-3) did show a 69% relative risk reduction in nonvertebral fractures. It is important to note that hip fracture reduction in a higher risk subgroup of patients has been accepted both locally and internationally as adequate data for the purposes of registration.

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Ibandronate 150mg oral once monthly is indicated for the treatment of osteoporosis in postmenopausal women, in order to reduce the risk of vertebral fractures.



 

2019/07/31 08:44

MEDICAL CHRONICLE | AUGUST 2017 27 MEDICAL CHRONICLE 21


CLINICAL WOMENâ&#x20AC;&#x2122;S HEALTH Focus OSTEOPOROSIS CPD

been shown to reduce vertebral fracture risk versus placebo. The study was conducted in 1 609 women aged 55 to 80 years, who were at least five years postmenopausal and had T-scores between <-2.5 and >-5.0. The primary endpoint of the MOBILE study was the percentage change from baseline lumbar spine bone density at one year. Reginster J-Y et al (2006) discussed the two-year MOBILE data to confirm the one-year results and to provide more extensive safety data. Secondary endpoints included the percentage change from baseline

However, monthly ibandronate-treated patients had a significantly lower risk of vertebral fracture than weekly bisphosphonate patients.

BMD NON-INFERIORITY STUDIES

The MOBILE study was a prospective, randomised, phase lll, non-inferiority study that compared the efficacy and safety of three once-monthly oral ibandronate doses (50+50mg monthly, given on two consecutive days; 100mg monthly; 150mg monthly) with 2.5mg daily ibandronate, which has previously

in lumbar spine and proximal femur densities over two years and the percentage change in serum concentrations of the biochemical marker of bone resorption, C-telopeptide of the Îą-chain of type l collagen (sCTX) from baseline. Substantial increases in lumbar spine BMD were seen in all treatment arms. It was confirmed that all oncemonthly oral ibandronate regimens were at least as effective as daily treatment, and in addition, 150mg once monthly showed superiority at the lumbar spine in terms of BMD

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Calcium effervescent with Vitamin D3

Speak to your pharmacist to determine which calcium supplement is best suited for you Reference: 1. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT May 2019. References: 1. BonivaÂŽ 150 mg tablets approved package insert, March 2009. 2. Department of Health. Database of Medicine Prices 14 Nov 2016. [Accessed 21 Nov 2016]. Available at: http://www.mpr.gov.za/PublishedDocumentsaspx#DocCatld=21. 3. Harris ST, Reginster J-Y, Harley C, et al. Risk of fracture in women Proprietary name (and form): B-CALofÂŽ-DM Tablets. Composition: tablet contains:4.500 Calcium, IU Vitamin D3 Ed. and 125 Magnesium. Proprietary name dosage treated with monthly oral ibandronate or weeklydosage bisphosphonates: The eValuation IBandronate Efficacy (VIBE) database fractureEach study. Bone 2009;44:758-765. Rossitermg D (Ed). South African400 Medicines Formulary. 11th 2014. p278.mg 5. Miller PD, Recker RR, Harris S, et al. Long-term fracture(and rates seen with continued ÂŽ extension study. Osteoporos Int 2012;23:1747-1756. ibandronate treatment: pooledÂŽanalysis of DIVA andComposition: MOBILE long-term extension Int 2014;25:349-357. 6. Miller PD,and Recker400 RR, Reginster J-Y, et al.D3. Efficacy of monthly oral ibandronate is sustained over 5 years: the MOBILE long-term -D Tablets. Eachstudies. tabletOsteoporos contains: 500 mg Calcium IU Vitamin Proprietary name (and dosage form): B-CAL Ultra Tablets. Composition: Each tablet form): B-CAL



     









     

    

contains: 500 mg Elemental Calcium, 400 IU Vitamin D3, 85 mg Elemental Magnesium, 1 mg Copper (AAC), 490 Âľg Folic Acid, 2 mg Manganese (AAC), 25 Âľg Molybdenum (AAC), 37 Âľg Selenium (AAC), 24 mg Vitamin B6, 24 Âľg Vitamin B12, 60 mg Vitamin C, 15 mg Zinc (AAC). Proprietary name (and dosage form): B-CALÂŽ Tablets. Composition: Each tablet contains: 500 mg Calcium. Proprietary name (and dosage form): Calcium Citrate DÂŽ Granules. Composition: Each sachet contains: 500 mg Elemental Calcium (from calcium citrate), 400 IU Vitamin D3. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Disclaimer: This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health Supplements do not replace a healthy diet and lifestyle. For more information, speak to your healthcare professional. IN788/19 

calcium med chron A4 ad_19.indd 1

22AUGUST MEDICAL CHRONICLE 28 2017 | MEDICAL CHRONICLE

    

2019/07/31 08:43

gains (p<0.001). Substantial increases in proximal femur (total hip, femoral neck, trochanter) BMD were also seen, with 150mg once monthly producing the most pronounced effect (p<0.05 vs. daily treatment). Pronounced decreases in sCTX were maintained throughout the study. Although this study did not assess fracture efficacy, the incidence of clinical fractures was similar in all treatment groups. In terms of adverse events, the incidence of upper gastrointestinal (GI) adverse events was similar across the treatment arms (20 to 26%) and events were generally mild to moderate in severity. The incidence of flu-like illness was higher with the 150mg monthly dosing (3.3%) compared with the other dosing regimens (0.3%1.3%). However, none of the patients experiencing flu-like illness during year one had a recurrence during year two and the two-year results confirm a low incidence of flu-like illness with ibandronate, similar to that seen with other oral bisphosphonates. Overall, it was concluded that once-monthly oral ibandronate is at least as effective and well tolerated as daily oral treatment. In addition, once-monthly administration may be more convenient for patients and improve therapeutic adherence, thereby optimising outcomes. The long-term efficacy and safety of once-monthly ibandronate was studied in the extension to the two-year MOBILE study, the MOBILE-LTE. In the long-term extension (LTE), 344 patients from MOBILE monthly ibandronate arms and 698 patients from all arms were reallocated to ibandronate 100mg monthly or 150mg monthly for a further three years. The primary endpoint was the change in lumbar spine BMD from month 24 to month 60. A secondary efficacy endpoint was the change in proximal femur BMD from the end of the two-year MOBILE study (month 24) to completion of the MOBILE-LTE at month 60. The primary focus of the study, however, was the change in lumbar spine BMD from MOBILE baseline to end of five years. The 344 patients receiving monthly ibandronate showed increases over five years in lumbar spine BMD (8.4% with 150mg once-monthly) from MOBILE baseline. Total hip BMD increased at 12 and 24 months compared to MOBILE baseline in both the 150mg monthly and the 100mg monthly treatment groups, but a plateau was reached between 24 and 36 months with no further increases. Only small changes in BMD were seen at the femoral neck and trochanter. Decreases in sCTX and procollagen type 1 amino-terminal propeptide (P1NP) seen in the two-year MOBILE results were maintained over five years. In terms of adverse events, the incidence of gastrointestinal events


CLINICAL

WOMEN’S HEALTH Focus OSTEOPOROSIS CPD

The 344 patients receiving monthly ibandronate showed increases over five years in lumbar spine BMD (8.4% with 150mg once-monthly) from MOBILE baseline

in MOBILE LTE was lower than in the MOBILE study (about 7.4% in each treatment group). Joint pain was reported in 4% of patients receiving ibandronate 150mg. In terms of serious adverse events, there was no evidence of renal compromise and there were no symptoms suggestive of osteonecrosis of the jaw (ONJ). The conclusion of the MOBILE-LTE study was that 150mg once-monthly oral ibandronate is an effective and well-tolerated treatment for postmenopausal osteoporosis. The BMD at the proximal femur is maintained, with further small gains in lumbar spine BMD. The efficacy of ibandronate once monthly is sustained over five years and there were no new safety signals.

HARRIS META-ANALYSIS

In the Harris ST et al meta-analysis, individual patient data from four phase

lll (BONE, IV fracture prevention, MOBILE and Dosing IntraVenous Administration [DIVA]) studies were grouped into three dose levels based on annual cumulative exposure (ACE), defined as the annual dose (mg) x bioavailability (0.6% oral; 100% IV). Non-vertebral and all clinical fractures in postmenopausal women over at least two years were examined and compared in the high-dose ACE group (≥10.8mg), the mid-dose ACE group (5.5-7.2mg) and the low-dose ACE group (2-4mg). Both the 150mg oral once monthly and the 3mg IV quarterly fall within the high-dose ACE group. All four trials had identical procedures for ascertainment of nonvertebral fractures (NVFs), including collection of NVFs as adverse events and mandatory X-ray confirmation. • The BONE and the IV fracture prevention studies were placebocontrolled three-year fracture

endpoint trials that examined vertebral fractures as the primary endpoint. Inclusion criteria required 1-4 prevalent vertebral fractures, lumbar spine BMD and a T-score of -2 to -5. • The MOBILE and DIVA studies were active-controlled two-year BMD studies. Inclusion criteria did not require prevalent vertebral fractures, lumbar spine BMD but did require a T-score of -2.5 to -5.

incidence of non-vertebral fractures. There was also a dose-response effect seen with increasing ACE doses (7.2-12mg) compared with ACE of 5.5mg, with hazard ratios ranging from 0.746-0.573. • An ACE of 12mg resulted in a 43% reduction in NVF risk • An ACE ≥10.8mg resulted in a 38% reduction in NVF risk • An ACE ≥7.2mg resulted in a nonsignificant NVF reduction of 25%.

Since high ACE ibandronate has been shown to result in larger increases in BMD, this study assessed whether these doses would also reduce fracture risk relative to placebo. The primary endpoint was key NVFs (clavicle, humerus, wrist, hip, pelvis, leg). All NVFs and all clinical fractures (a category that includes all NVFs and symptomatic vertebral fractures) were also examined. All-year data showed statistically significant reductions in the risk of key non-vertebral fractures, all NVFs and all clinical fractures for the high-dose ACE group compared with placebo. Reductions in fracture risk for the low- and mid-ACE groups compared with placebo did not reach statistical significance for most of the fracture types examined. The high-dose group (ACE ≥10.8mg) also showed a significantly longer time to fracture vs. placebo for key NVFs, all NVFs and all clinical fractures at two years.

The Kaplan-Meier plot of time to non-vertebral fracture for higher versus lower ACE ibandronate doses shows that higher doses prolong the time to non-vertebral fractures compared with lower doses.

CRANNEY POOLED ANALYSIS

The Cranney pooled analysis of ibandronate assessed the efficacy of high vs. low doses of ibandronate on non-vertebral fractures (humerus, clavicle, wrist, pelvis, hip and leg). Eight randomised treatment trials were considered for inclusion. Treatment trials were defined as those trials in which baseline lumbar spine T-score was ≤-2.5, or the baseline prevalent vertebral fracture rate was >20%, or the mean age of participants was over 60 years. Only two trials were selected for inclusion as they provided data on prevalent vertebral fractures and data on both higher and lower doses of ibandronate. Several doses in addition to the ones used in clinical practice were included in the analysis. As in the Harris meta-analysis, the annual cumulative exposure (ACE) was used to categorise doses as high (≥10.8mg) and low (≤7.2mg). The results showed that combining higher ACE doses of ≥10.8mg vs. ACE doses of 5.5mg resulted in a hazard ratio of 0.62 or a 38% reduction in the

In summary, higher doses of ibandronate significantly reduced the risk of NVFs in this pooled analysis. However, data on prevalent vertebral fracture is not available for all studies, plus the pooled analysis does not provide enough data in order to comment on effect on hip fractures because the NVF rate does not correlate with hip fracture rate.

IBANDRONATE LONG-TERM DATA

Ibandronate is a nitrogen-containing bisphosphonate. It has an increased potency compared to alendronate and risedronate and a higher bone affinity compared to clodronate and risedronate. Ibandronate offers greater ease of use compared with several other bisphosphonates. It is suitable for both oral and IV administration. The long-term safety and efficacy data for the currently available bisphosphonates are as follows: • Alendronate - 10 years, based on the Fracture Intervention Trial Extension • Risedronate - seven years, based on the Vertebral Efficacy with Risedronate (VERT) trial extension • Zoledronate - nine years, based on the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly (HORIZON) trial extension • Ibandronate - five years, based on the MOBILE-LTE study. Efficacy and safety of ibandronate has been demonstrated over five years: • Observational data over 12 months suggest that ibandronate is superior to alendronate and risedronate in vertebral fracture prevention • Observational data over 12 months suggest that ibandronate is equal to alendronate and risedronate in nonvertebral fracture reduction. References available on request.

CPD questionnaire on pg 58. Complete online: www.medicalchronicle.co.za/review-of-once-monthly-oral-ibandronate/

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WOMEN’S HEALTH Focus CLINICAL SUPPLEMENTS CPD

VITAMIN B12

DEFICIENCY INDICATORS Vitamin B12 deficiency is common, affecting up to 10 % of adults.1 As the symptoms can be variable, subtle and non-specific, the deficiency often goes unrecognised and if left untreated can have serious consequences.2 *Sponsored content

B12 is essential for the metabolism of all human cells and is required for two key reactions: 2 1) MUT reaction: energy extraction from protein and fat (part of mitochondrial citric acid cycle)2 2) MTR reaction: converts homocysteine to methionine (required for myelin synthesis)1,2 regenerates tetrahydrofolate (needed for DNA synthesis)2 A lack of methionine will result in nerve demyelination and damage.1 Neurological symptoms including peripheral neuropathy (limb weakness, numbness, tingling) and neuropsychiatric symptoms (depression, memory loss, dementia psychosis) are therefore common in B12 deficiency and may be the only presenting feature.1 Impairments in DNA synthesis lead to haematological abnormalities such as anaemia (pallor, fatigue, shortness of breath), leukopaenia and thrombocytopaenia.1

VITAMIN B12 ABSORPTION

Naturally occurring Vitamin B12 is only found bound to animal protein and its absorption is a complex process requiring normal functioning of several areas of the gastrointestinal tract (GIT).3 Pepsin and hydrochloric acid in the stomach separate B12 from animal protein, which then combines with an R-protein (transcobalaminI) secreted from the salivary glands and gastric mucosa.2-4 This B12-Rprotein complex travels to the small intestine where pancreatic enzymes release the B12, which then binds to intrinsic factor (IF).2-4 In the terminal

[ [ [

Protein-B12 Pepsin HCℓ

Stomach

Proximal small intestine

Ileum

B12 + R-protein (transcobalamin )

Pancreatic enzymes alkaline enviroment

B12 + IF

E n t e r o B + transcobalamin c 12 y t e s

(holoTC)

Blood vessel

Figure 5: Absorption of Vitamin B12

ileum the B12-IF is absorbed into the enterocytes,2-4 where it is degraded and B12 then binds to transcolabamin II to form holotranscobalamin (holo TC).2,4 This is then released into the portal circulation.2,4 About 60 % of B12 from food is absorbed through this pathway while about 1% of Vitamin B12 is absorbed by passive diffusion, even in the absence of intrinsic factor.2,4 See Figure 5.

VITAMIN B12 DEFICIENCY RISK FACTORS As humans cannot synthesise B12 a daily dietary intake of 2,4 μg per day is

required to maintain optimal B12 levels.5 Vitamin B12 deficiency is a multifactorial condition caused by insufficient intake (nutritional deficiency) as well as acquired or inherited defects that disrupt B12 absorption, processing and trafficking pathways (functional deficiency).5 Nutritional deficiencies are common in vegetarians and vegans, breast feeding infants with B12 deficient mothers as well as alcoholics and the elderly on a poor diet.1,6,7 Any alterations in the function and anatomy of the GIT such as gastric or ileal resection, inflammatory bowel diseases, malabsorptive disorders (eg coeliac disease), hypochlorhydria, or a lack of intrinsic factor (pernicious anaemia) can lead to B12 malabsorption and deficiency.1,3 Other risk factors include chronic medications that interfere with the absorption of B12 eg metformin or proton pump inhibitors and people infected with HIV, Helicobacter pylori or fish tapeworm.1,3,7

DIAGNOSIS Patients presenting with neurological or haematological symptoms of B12 deficiency should be investigated and those whose lifestyles, chronic medications or underlying conditions put them at increased risk should be screened routinely.8 See Figure 1. Currently, there is no consensus or guidelines for the diagnosis of B12 deficiency.2 The symptoms may also be ill-defined, so a high index of suspicion is necessary.1 A definitive diagnosis is usually based on a combination of the clinical picture, laboratory assessment and a response to treatment.2 There

is however no ‘gold standard’ test to diagnose B12 deficiency.2 The initial laboratory assessment includes: serum B12 levels, a full blood count (FBC) and a blood film examination.2 A folate test is often ordered alongside a serum B12 as a deficiency of either of these nutrients can cause neurological or haematological symptoms.9 Differentiation is important as exposure to large doses of folate can mask a B12 deficiency and lead to irreversible neurological damage.8 The FBC may show macrocytosis (MCV > 100fl) with or without anaemia, leukopaenia and thrombocytopaenia.1,10 Because a FBC is so commonly ordered, a low red blood cell count is often the first sign of a B12 deficiency.8

BIOMARKERS Total serum B12, though sometimes misleading, is a mainstay of clinical diagnosis8 and is usually the first test performed.5,6 Confirmatory tests in untreated patients (homocysteine and MMA) are done when B12 is normal or low-normal but clinical suspicion exists.2,6,7 Both homocysteine and MMA levels are raised in B12 deficiency but only homocysteine is raised in folate deficiency.1,2,7,8 Decreased serum holotranscobalamin (holoTC) level is another early indicator of B12 deficiency, often occurring before the elevation of homocysteine and MMA.2,8 HoloTC measures the bioactive fraction of B12 - the amount directly available to cells.4,5,8 It confirms the diagnosis of B12 deficiency when the serum B12 is in the low to normal range,1 but it is costly and

Neurobion® is the market-leading One supplement Make More of it. Vitamin B complex product in 74Endless Possibilities countries worldwide1 ENERGY

WELL-BEING

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This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health Supplements do not replace a healthy diet and lifestyle. For more information, speak to your healthcare professional. Reference: 1. Mahan, L.K. et al. Krause’s Food and the Nutrition Care Process. 13th edition. United States of America. Saunders, an imprint of Elsevier Inc. 2012. ENERGY: p516. DEFENCE: p88, 516. MENTAL VITALITY: p961-962. Proprietary name (and dosage form): StaminoGro® Woman Tablets. Composition: Each tablet contains: 93.75 mg L-Arginine, 75 mg L-Glutamine, 37.5 mg Glycine, 25 mg L-Lysine, 22.5 mg L-Ornithine,450Reference: μg Beta-carotene,15 Selenium (AAC), 50onmgIMS Health MIDAS sales for MAT 09/2015 through MAT 09/2016. 1. Internalμgcalculations based Vitamin C, 30 IU Vitamin E, 10 mg Zinc, 250 μg Folic Acid, 0,75 mg Vitamin B1, 1,25 mg Vitamin B2, 6 mg Vitamin B3, 6 mg Vitamin B5, 10 mg Vitamin B6, 6 μg Vitamin B12, 100 mg Calcium, 400 IU Vitamin D3, 20 μg Biotin, 4,1 mg Choline, 500 μg S1 Neurobion Tablets. Each tablet contains Vitamin B 100 mg, Vitamin B 200 mg and Vitamin B 200 μg. Reg. No.: H2487 (Act 101/1965). S3 Neurobion Ampoules. Each 3 ml ampoule contains Vitamin B Copper (AAC), 70 mg Magnesium, 1 mg Manganese, 5mg Iron (AAC). Name and business address: iNova Pharmaceuticals (Pty) Ltd Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma. 100 mg, Vitamin B 100 mg and Vitamin B 1000 μg. Reg. No.: H2488 (Act 101/1965). Applicant: Merck (Pty) Ltd. Reg. No.: 1970/004059/07. 1 Friesland Drive, Longmeadow Business Estate South, Modderfontein, co.za. Further information available on request from iNova Pharmaceuticals. IN513/18 South Africa, 1645. Tel: +27 (0) 11 372 5000 / Fax: +27 (0) 11 372 5252. Report adverse events to drug.safety.southeastafrica@merckgroup.com or +27 (0)11 608 2588 (Fax Line). SNA-NEU-1709-0259 September 2017 ®

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CLINICAL WOMEN’S HEALTH Focus SUPPLEMENTS CPD

Table 1: Sensitivity and specificity of biomarkers

has limited availability.11

DIAGNOSTIC CUTOFFS Although there is no universally accepted serum B12 cut-off, the value of < 150 pmol/L is often used.2 Higher levels of 220 – 258 pmol/L have been suggested.2 Different laboratories use different methods and there is often poor agreement when samples are assayed.6 Normal values of serum B12 do not exclude a B12 deficiency, and analysis of MMA and homocysteine can reveal these patients with borderline B12 concentrations.7 A cut-off value of MMA > 271 nmol/L, homocysteine > 13 μmol/L and holoTC < 35 pmol/L indicate a vitamin B12 deficiency.4,5,9 A folate deficiency is accepted with cut-off values of serum folate < 10 nmol/L and red blood cell folate < 340 nmol/L.9

Treat iron

Neurotropic B Vitamins (B1, B6 and B12) are all necessary for healthy nerve function, and symptoms deficiency holistically of a Vitamin B deficiency may include: 1-4*

Forgetfulness, confusion

Mood disturbance

Pins-and-needles, numbness or weakness (hands & feet)

Difficulty walking, maintaining balance and ataxia

Patients at risk of Vitamin B deficiency include: 1, 5-7

BIOMARKER SENSITIVITY AND SPECIFICITY The sensitivity of serum B12 as a biomarker for the detection of B12 deficiency is good overall, but the specificity is poor.9 Both are improved in conjunction with a MMA or holoTC test.9 Elevated MMA and homocysteine levels are more sensitive biomarkers than serumB12 but also have low specificity.2 The holoTC biomarker is the most sensitive and earliest test of B12 deficiency.2,4 In a South African setting, it is important to consider cost, convenience, availability and reliability of the diagnostic test.8,9 Serum B12 tests are readily available and inexpensive,2 whereas MMA and holoTC tests are more expensive with limited availability.1,4,8,11

FACTORS AFFECTING BIOMARKERS Both false positive and false negative results occur in up to 50 % of serum B12 tests.6 Pregnancy, inherited haptocorrin deficiency, multiple myeloma and folate deficiency cause false positive results, while liver disease, renal disease, myeloproliferative disorders, intestinal bacterial overgrowth or old age cause false negative results.1,2,10 Although elevated levels of MMA and

The elderly

Vegetarians and vegans

Those who consume excessive amounts of alcohol

Amino Acid Chelated Ferrous Iron supplement with Folic Acid, Vitamin B12 and Vitamin C*

Neurobion® - the market-leading 1 in Vitamin B complex product • High bioavailability 74 countries worldwide. 8**

• Fewer gastrointestinal side-effects2

* Symptoms may be related to another medical condition. ** Neurobion® is the market-leading Vitamin B complex product/ Vitamin B combination product for the last two-year period, based on a combined market of 74 countries worldwide. References: 1. da Silva L, McCray S. Vitamin B12: No One Should Be Without It. Pract Gastroenterol 2009:34-46. 2. Disorders of Nutrition and Metabolism. Section 11. In: The Merck Manual of Medical Information. Second Edition. (eds) Beers SL, Bowman MA. Pocket Books, New York, London, Toronto, Sydney. Pp 918-926. 3. National Institute of Health. Vitamin B12. Dietary Supplement Fact Sheet. [online] [cited] 2017 Jan 17]. Available from: URL: http://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/. 4. Frye RE, Griffing GT. Pyridoxine Deficiency Clinical Presentation. Medscape Reference: Drugs, Diseases and Procedures. [online] [cited 2017 Jan 2017]. Available from: URL: http://emedicine.medscape.com/article/124947-clinical. 5. Briani C, Torre CD, Citton V, Manara R, Pompanin S, Binotto G, Adami F. Cobalamin Deficiency: Clinical Picture and Radiological Findings. Nutrients 2013;5:4521-4539. 6. Stabler SP. Vitamin B12 Deficiency. N Eng J Med 2013;368:149-160. 7. Becker DA, Balcer LJ, Galetta SL. The Neurological Complications of Nutritional Deficiency following Bariatric Surgery. J Obesity 2012;2012. 8. Internal calculations based on IMS Health MIDAS sales for MAT 09/2015 through MAT 09/2016. For full prescribing information refer to the package insert approved by the Medicine Regulatory Authority

The link in treating iron deficiency

S1 Neurobion® Tablets. Each tablet contains Vitamin B1 100 mg, Vitamin B6 200 mg and Vitamin B12 200 μg. Reg. No.: H2487 (Act) 101/1965). Merck (Pty) Ltd. Reg. No.: 1970/004059/07 (South Africa). 1 Friesland Drive, Longmeadow Business Estate South, Modderfontein, South Africa, 1645. Tel: +27 (0) 11 372 5000 / Fax: +27 (0) 11 372 5252. Report adverse events to drug.safety.southeastafrica@merckgroup.com or +27 (0) 11 608 2588 (Fax Line). SNA-NEU-1706-0160b October 2017.

References: 1. Nagpal J, Choudhury P., Iron Formulations in Pediatric Practice. Indian Pediatrics 2004; 41: 807-815. 2. Dietary Supplement Fact Sheet: Iron [Internet] 2013 October 14 [Updated 2014 April 08]. Available from http://ods.od.nih.gov/factsheets/Iron-healthprofessional/. Proprietary name (and dosage form): Ferrous Forte® Tablets. Composition: Each tablet contains: 20 mg elemental iron, 350 µg folic acid, 15 µg vitamin B12 and 60 mg vitamin C. Proprietary name (and dosage form): Ferrous Forte® Syrup. Composition: Each 5 ml contains: 20 mg elemental iron , 350 µg folic acid, 15 µg vitamin B12. Name and business address: iNova Pharmaceuticals (Pty) Ltd Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information available on request from iNova Pharmaceuticals. *Only in tablets. IN100/15 A Valeant Company

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MEDICAL CHRONICLE | NOVEMBER 2017 21 MEDICAL CHRONICLE 25


WOMENâ&#x20AC;&#x2122;S HEALTH Focus CLINICAL SUPPLEMENTS CPD

homocysteine are more sensitive than serum B12 in diagnosing a deficiency, they may be increased in the elderly and people with renal disease and inherited metabolic defects.2 MMA alone is elevated in patients with intestinal bacterial overgrowth, and homocysteine alone is elevated in patients with a Vitamin B6 deficiency, folate deficiency or hypothyroidism.9 As with homocysteine and MMA, holoTC cannot be tested in patients with renal disease.2,9,11 The HoloTC test also has poor specificity in patients with liver disease, transcobalamin polymorphisms, or those receiving chemotherapy.5,9,11

PERIPHERAL BLOOD SMEARS A normal FBC does not necessarily exclude a B12deficiency,2 and performing a peripheral blood smear can identify early macrocytic changes associated with a B12 deficiency.12 The presence

of oval macrocytes, hypersegmented neutrophils, anisocytosis, poikilocytosis suggests megaloblastic anaemia associated with a B12 or folate deficiency.6,12 Leukopaenia and thrombocytopaenia may also be present, while panyctopaenia (similar to bone marrow failure) may be seen in the late stages of a deficiency.6 In contrast, a round macrocyte morphology is commonly seen in patients with liver disease, chronic alcoholism, hypothyroidism or patients taking certain medication.12,13

SPECIAL POPULATION GROUPS INFANTS Infant B12 status is determined by maternal B12 stores during pregnancy, placental function, gestational age and birth weight.5 Maternal B12 deficiency, prematurity and low birth weight are all associated with lower infant B12 stores and an increased risk of deficiency,

Figure 1: Algorithm for the diagnosis of Vitamin B12 deficiency

particularly if they are exclusively breastfed for more than four months before animal food is introduced.5 The decrease in serum B12 is accompanied by elevated biomarkers MMA and homocysteine.5 Homocysteine (cut-off level of 6,5 Îźmol/L) is considered the best metabolic marker in this age group.5

PREGNANCY Pregnant women are at increased risk for B12 deficiency due to an increased demand for the micronutrient.8 However, the condition is frequently underdiagnosed.5 In South Africa, screening for Vitamin B12 deficiency in all pregnant women may not be feasible, and serum B12 may also not accurately reflect B12 status in these women.1 It is suggested that the holoTC test is more accurate in determining Vitamin B12 status during pregnancy,11 however this test is expensive and not

readily available.2,9,11

ELDERLY Vitamin B12 deficiency affects up to 40 % of this population.2 Elderly people are at increased risk due to a high prevalence of atrophic gastritisassociated food-B12 malabsorption and the increasing prevalence of pernicious anaemia with advancing age.2 The elderly also have multiple comorbidities, coupled with multiple drug intake and increasing dependency that can lead to inadequate intake and B12 malabsorption.2 Diagnosing a deficiency in the elderly is not straightforward as they often have mild, sub-clinical deficiency, which is usually asymptomatic.2 Test sensitivity is particularly important in the diagnosis of a subclinical deficiency, and markers which have a high sensitivity (MMA, homocysteine and holoTC) may be useful in these circumstances.2,8 However concerns around using these biomarkers include higher costs, lower availability, non-standardised reference intervals and the fact that MMA and homocysteine levels increase with age.2

RENAL IMPAIRMENT In patients with renal impairment, serum B12 levels as well as MMA, homocysteine and holoTC levels are inaccurate and cannot be used as markers of Vitamin B12 status.1,2,7 In patients with renal impairment, B12treatment should be instituted as a prophylactic measure without confirming diagnosis in the laboratory or regardless of blood serum concentration.15

DIABETICS Chronic use of metformin for diabetes can lower B12 levels sufficientlyto cause peripheral neuropathy, which can easily be confused with diabetic neuropathy.3,8 Diabetics receiving metformin treatment should be routinely screened and B12 treatment, if necessary, is recommended.5

HEPATIC IMPAIRMENT Since 90 % of B12 is stored in the liver, patients with liver disease are at an increased risk for a B12 deficiency due to diminished storage capacity.3 A serum B12 test is inaccurate in patients with liver disease, and this marker may not reflect actual B12 stores.3 Measuring MMA may help to identify a tissue level deficiency.3

HIV PATIENTS HIV infection impairs B12 absorption and can lead to a deficiency,3,16 so these patients should be screened.8 B12 deficiency is an adverse prognostic factor in HIV-infected patients and any resultant anaemia can impair quality of life, accelerate the progression of the disease and decrease survival.16-18

22 2017 | MEDICAL CHRONICLE 26 NOVEMBER MEDICAL CHRONICLE


CLINICAL WOMEN’S HEALTH Focus SUPPLEMENTS CPD

sensitive (50 %) but more specific (98 %), and its presence is almost diagnostic of PA.2 Chronic atrophic gastritis, leading to hypochlorhydria and B12 malabsorption, can be diagnosed by an elevated fasting serum gastrin and a low serum pepsinogen.6 The gastrin test alone is somewhat sensitive and high levels are seen in 80 % to 90 % of patients with PA.8 Gastrin should not be used as an initial test for B12 deficiency but rather as a confirmatory test.8 Low pepsinogen I or ratio pepsinogen I to II are sensitive markers for severe food-B12 malabsorption, gastritis and PA.8 Some experts also recommend a once-off endoscopy to confirm gastritis and rule out gastric carcinoid and other gastric cancers.2,6

TREATMENT

In HIV-infected patients a low B12 concentration may not reflect a real deficiency and therefore the confirmatory biomarkers, MMA and homocysteine may be necessary.17 If these tests are not available, treatment is recommended.17

PERNICIOUS ANAEMIA Pernicious anaemia (PA), whereby the loss of IF-producing gastric parietal cells leads to poor B12 absorption is the most common cause of severe B12 deficiency.2,6 The Schilling test, traditionally used to diagnose IF-related malabsorption, is now rarely performed due to numerous drawbacks.2,8 Newer tests, positive anti-parietal cell and anti-intrinsic factor antibodies, allow for higher sensitivity and/or specificity in diagnosing B12 deficiency.2,6,8 Anti-parietal cell antibody is more sensitive (90 %) but less specific (50 %) for the diagnosis of PA as it can also be found in other autoimmune diseases.2 Anti-intrinsic factor antibody is less

Besides early replacement therapy, which is crucial in avoiding irreversible nerve damage,3,7 correction of risk factors is also important in the management of B12 deficiency.2 In long standing B12 deficiency, dietary modifications are not sufficient and patients require long term treatment to normalise their metabolism.19 Haematological response to treatment is rapid, with correction of anaemia in 6-8 weeks.6 However, neurological symptoms may worsen transiently and then take weeks to months to subside.6 The duration and severity of the neurological abnormalities before treatment influence the eventual degree of recovery.6 In certain instances, B12 treatment should be instituted as a prophylactic measure regardless of blood serum concentration or without confirming diagnosis in the lab.15 These include patients with renal impairment, diabetes, > 65 years, following gastrointestinal surgery, active Crohn’s colitis, early onset dementia, and severe signs and symptoms of B12 deficiency.15

Figure 2: Peripheral blood smear showing macrocytic anaemia with increased anisopoikilocytosis, hypersegmented neutrophils, and marked thrombocytopaenia consistent with megaloblastic anaemia. 14

INSTRUCTIONS:

DOSAGE & DURATION OF THERAPY 1 mg Vitamin B12 daily in the first week of treatment (or 1 mg 3 times/week for 2 weeks) followed by 1 mg weekly in the following month and then 1 mg every month thereafter is an appropriate therapeutic regimen.2,7,19 Regardless of the cause, oral treatment is feasible in most cases.3 Compared with intramuscular application, high oral doses of B12 (1 mg and 2 mg) are of comparable efficacy in terms of improved haematological and neurological symptoms, even in patients with PA or ileal disease.2,3,6,19 Individuals with conditions that put them at continued risk for B12 deficiency should receive ongoing treatment to maintain levels and prevent further deficiency.3 For patients with pernicious anaemia, lifelong treatment is required.6

FOLLOW-UP Replacement therapy should be associated with careful, follow-up of the patients to ensure compliance and adequate response to treatment.3,7 Measuring homocysteine and MMA concentrations is helpful in monitoring B12 therapy.19 Patients with PA should be monitored for iron deficiency and have a once off endoscopy to exclude stomach cancer.2,7 Hypokalaemia, due to uptake of circulating potassium by new haemopoietic cells, can occur with initial B12 therapy so potassium levels should be monitored and corrected.2

CONCLUSION Vitamin B12 deficiency is common, but often goes unrecognised.1,2 If left untreated the deficiency can have serious consequences, so early recognition and treatment is crucial.2,3 Any patients presenting with the neurological or haematological symptoms of B12 deficiency should be investigated and those at increased risk should be screened routinely.8 A definitive diagnosis is based on a combination of the clinical picture, laboratory assessment and a response to treatment.2 Total serum B12, though sometimes misleading, is a mainstay of clinical diagnosis.8 Confirmatory tests (homocysteine and MMA) are done when B12 is normal or low-normal but clinical suspicion exists.2,6 Besides early B12 replacement therapy (either oral or IM), correction of risk factors is also important.2 Regardless of the cause, oral treatment is feasible in most cases.3 Individuals with conditions that put them at continued risk should receive ongoing treatment to maintain B12 levels and prevent further deficiency.3 MUT = methylmalonyl coenzyme

A mutase MTR = 5-methyltetrahydrofolatehomocysteine methyltransferase MMA = methylmalonic acid IM = intramuscular. References:

1. Sacks S. Vitamin B12 Deficiency: New Diagnositic Assay. Clinipath Pathol [Online] [cited Sept 29] . Available from: URL: www.clinipathpathology.com.au/ media/76367/vitamin%20b12%20 deficiency.pdf. 2. Wong CW. Vitamin B12 deficiency in the elderly: is it worth screening? Hong Kong Med J 2015;21(2):155-164. 3. da Silva L, McCray S. Vitamin B12: No One Should Be Without It. Pract Gastroenterol 2009:34-46. 4. Hermannn W, Obeid R, Schorr H, Geisel J. Functional Vitamin B12 Deficiency and Determination of Holotranscobalamin in Populations at Risk. Clin Chem Lab Med 2003;41(11):1478-1488. 5. Hannibal L, Lysne B, BjørkeMonsen A-L, Behringer S, Grünert SC, Spiekerkoetter U, et al. Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency. Frontiers Molecul Biol 2016;3:1-16. 6. Stabler SP. Vitamin B12 Deficiency. N Engl J Med 2013;368(2):149-160. 7. Briana C, Dalle Torre C, Citton V, Manara R, Pompanin S, Binotto G, et al. Cobalamin Deficiency: Clinical Picture and Radiological Findings. Nutrients 2013;5:45214539. 8. Moridani M, Ben-Poorat S. Laboratory Investigation of Vitamin B12 Deficiency. Labmed 2006;37(3):166-174. 9. Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr 2011;94(suppl):666S-672S. 10. Snow CF. Laboratory Diagnosis of Vitamin B12 and Folate Deficiency. Arch Intern Med 1999;159:1289-1298. 11. Nexo E, Hoffmann-Lucke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr 2011;94(1):359S-365S. 12. Aslinia F, Mazza JJ, Yale SH. Megaloblastic Anemia and Other Causes of Macrocytosis. Clin Med Res 2006;4(3): 236-241. 13. Kaferle J, Strzoda CE. Evaluation of Macrocytosis. Am Fam Physician 2009;79(3):203-208. 14. Routh JK, Koenig SC. Severe vitamin B12 deficiency mimicking thrombotic thrombocytopenic purpura. Blood 2014;124:1844. 15. Vitamin B12 deficiency Charity Support Group. Protocol for excluding B12 deficiency (Megaloblastic anemia/Pernicious Anaemia) from adult and child patient presentation. [Online] [cited 2017 Oct 2]. Available from: UR: www.b12d.org/b12d/submit/ document?id=13. 16. Volberding PA, Levine AM, Dieterich D, Mildvan D, Mitsuyasu R, Saag M, for the Anemia in HIV Working Group. Anemia in HIV Infection: Clinical Impact and EvidenceBased Management Strategies. Clin Infect Dis 2004;38:1454-1463. 17. Remacha AF, Cadafalch J, Sardà P, Barceló M, Fuster M. Vitamin B-12 metabolism in HIV-infected patients in the age of highly active antiretroviral therapy: role of homocysteine in assessing vitamin B-12 status. Am J Clin Nutr 2003;77:420-424. 18. Cunha De Santis G, Menezes Brunetta D, Crivelenti Vilar F, Amorim Brandão R, Amorin de Albernaz Muniz R, Momo Nogueira de Lima G, et al. Hematological abnormalities in HIV-infected patients. Int J Infect Dis 2011;15:e808-e811. 19. Hermann W, Obeid R. Causes and Early Diagnosis of Vitamin B12 Deficiency. Dtsch Arztebl Int 2008;105(40):680-685.

1. Go to www.medicalacademic.co.za 2. Click the tab labelled ‘CPD Portal’ on the far right tab near the top of the page. 3. Select the relevant questionnaire from the list and complete the form.

MEDICAL CHRONICLE | NOVEMBER 2017 23 MEDICAL CHRONICLE 27


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Reference: 1. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT Dec 2017.

Proprietary name (and dosage form): Pregnavit M Fizzy. Composition: Each capsule Vitamin A, 6 mg Vitamin B1, 3 mg Vitamin B2, 20 mg Vitamin B3, 7 mg Vitamin B5, 5 mg Vitam B12, 120 mg Vitamin C, 1000 IU Vitamin D3, 100 mg Calcium, 1 mg Copper (from AAC), 500 Iron (from AAC), 75 mg Magnesium, 2 mg Manganese (from AAC), 1 mg Potassium, 60 µg S 10 mg Zinc. Name and business address: iNova Pharmaceuticals (Pty), Co. Reg. No. 19 Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further infor request from iNova Pharmaceuticals. Name and business address: iNova Pharmaceuticals (P 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za is available on request from iNova Pharmaceuticals. IN496/18

Reference: Rx. Script data & Minerals class). MAT 2017. Proprietary (and dosage Pregnavit M Fizzy. Composition: Each capsule contains: 1000 IU Vitamin A, 6 mg Vitamin B1, 3 Vitamin A,1. 6Impact mg Vitamin B1, (Vitamins 3 mg Vitamin B2,/ Constructed 20 mg Vitamin B3, Dec 7 mg Vitamin B5, 5name mg Vitamin B6,form): 5 µg Vitamin mg Vitamin B2, 20 mg Vitamin B3, 7 mg Vitamin B5, 5 mg Vitamin B6, 5 μg VitaminB12, 120 mg Vitamin C, 1000 IU Vitamin D3, 100 mg Calcium, 1 mg Copper (from AAC), 500 μg Folic Acid, 24 mg Iron (from AAC), 75 mg Magnesium, 2 B12, 120 mg Vitamin C, 1000 IU Vitamin D3, 100 mg Calcium, 1 mg Copper (from AAC), 500 µg Folic Acid, 24(Pty), mg Co. Reg. No. 1952/001640/07,15E Riley Road, Bedfordview. Tel. No. 011 087 0000. mg Manganese (from AAC), 1 mg Potassium, 60 μg Selenium (from AAC), 10 mg Zinc. Name and business address: iNova Pharmaceuticals Iron (from AAC), 75Further mg Magnesium, 2 mgonManganese (from AAC), 1 mgName Potassium, 60 µgaddress: Selenium AAC), (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 www.inovapharma.co.za. information available request from iNova Pharmaceuticals. and business iNova(from Pharmaceuticals 087 www.inovapharma.co.za. Further information is available request from iNova Pharmaceuticals. IN496/18 100000. mg Zinc. Name and business address: iNovaonPharmaceuticals (Pty), Co. Reg. No. 1952/001640/07,15E

Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information available on request from iNova Pharmaceuticals. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information


CLINICAL WOMEN’S HEALTH Focus SUPPLEMENTS CPD

THE ROLE OF VIT D AND ZINC IN BP CONTROL There are increasing rates of hypertension in SA. In fact, four in 10 people have hypertension in sub-Saharan Africa. Antihypertensives are the first-line treatment, but do they deplete zinc and vitamin D? *Sponsored content

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ACE inhibitors are the fist-line treatment for uncomplicated primary hypertension. They provide 10% reduction in relative risk for allcause mortality and 12% reduction in cardiovascular mortality. ACE inhibitors are indicated for: • HF • LV dysfunction • Post-myocardial infarction • Non-diabetic nephropathy • Type 1 diabetic nephropathy • Prevention of diabetic microalbuminuria • Proteinuria.

ROLE OF ZINC IN RAS & BP CONTROL Heart failure (HF) is a prevalent syndrome resulting in a high mortality rate. HF may be associated with zinc deficiency through a reduction in dietary intake, decreased absorption due to gastrointestinal edema, impaired motility or intestinal zinc losses. Diseases concomitant with HF such as diabetes mellitus (DM) and hypertension may enhance zinc deficiency. Zinc is essential for the activity of many enzymes [ACE, carbonic anhydrases (CA), neutral endopeptidase (NEP)], some of which are implicated in the regulation of fluid homeostasis, acid-base balance and vascular tone. Moreover, zinc has a critical role in the structure of cell membranes and apoptosis. Many enzymes essential for adequate function of the cardiovascular system are zinc dependent. However, conservative estimates suggest that 25% of the world’s population is at risk of zinc

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Vitamin D of essential VI -D ACEI-GAP, assists in the maintenance 1 . o. 1 nutrients that may asthe a absorption result of Nobe depleted • Promotes and highNblood Pa i 1 e d ia t i a n s’ C G P ’s Cand ho utilisation of calcium and r ic pressure the treatment thereof. D

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The renin–angiotensin–aldosterone system is a key therapeutic target in hypertension. A meta-analysis of mortality reduction with angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in hypertension featured

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158 998 patients from 20 contemporary hypertension trials. ACE inhibitors produced a 10% reduction in relative risk for all-cause mortality (p = 0.004) and a trend toward a 12% reduction in cardiovascular mortality (p = 0.051). European hypertension guidelines state that mortality reduction should be the ultimate goal of antihypertensive treatment, a goal confirmed by the 2011 NICE guidelines.

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Hypertension was the number one risk for death in 2010, estimated to cause 500 000 deaths and 10 million years of life lost. There was a 67% increase in hypertension between 1990 and 2010. Approximately 13% of deaths overall are caused by high blood pressure, while 40% of deaths in people with diabetes are caused by high blood pressure. Half of all heart disease, stroke and heart failure is caused by high blood pressure. Almost eight in 10 South Africans ≥50 years of age have hypertension, considered the highest incidence ever reported by a nationally representative survey. It is the third cause of natural death in South Africans ≥65 years after diabetes and cerebrovascular disease. A study used data from the World Health Organization’s Study on Global Ageing and Adult Health (SAGE) to examine patterns of hypertension prevalence, awareness, treatment and control for people aged 50 years and over in China, Ghana, India, Mexico, the Russian Federation and SA. The SAGE sample comprises 35 125 people aged 50 years and older, selected randomly. Hypertension was defined as 5140mmHg (systolic blood pressure) or 590mmHg (diastolic blood pressure) or by currently taking antihypertensives. Prevalence rates in all countries are broadly comparable to those of developed countries (52%; range 32% in India to 77% in SA). SA’s prevalence was the highest ever reported by a nationally representative survey of people aged 50 and over for any country. It is substantially higher than recently published estimates for

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DOSIS EN GEBRUIKSAANWYSINGS: Neem 1 mℓ daagliks of 0,5 mℓ twee maal daagliks, of soos aanbeveel deur jou gesondheidsorgkundige. Neem die dosis geleidelik, soos beste verdra. Slegs vir orale gebruik. Skud bottel voor gebruik. Moenie die aanbevole dosis oorskry nie. BERGINGSAANWYSINGS: Bewaar teen of benede 25 °C. Beskerm teen lig en vogtigheid. HOU BUITE DIE BEREIK VAN KINDERS. Komplementêre Medisyne: Gesondheidsaanvulling D34.11 Vitamiene. Hierdie ongeregistreerde medisyne is nie deur die SAHPRA geëvalueer ten opsigte van kwaliteit, veiligheid of voorgenome gebruik nie.

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For full prescribing information refer to the package insert. References: 1. Impact Rx. ScriptReg. data (Vitamins & Minerals / Constructed class). Private MAT SEPTBag 2018.X69, 2. National Institutes of 2021, Health [Internet]: D: FactTel. Sheet+27 for Health [updated 2016 11 Feb; cited 2016 Nov 14] Available from: http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional. Adcock Ingram Limited. No. 1949/034385/06. Bryanston, SouthVitamin Africa. 11 Professionals 635 0000. 3. MCC Guideline 7.04 Complementary Medicines- Health Supplements Safety & Efficacy, 2016; v2 p. 31-32. Proprietary name (and dosage form): D-Vit Tabs. Composition: Each tablet contains: 400 IU Vitamin D3. Proprietary name (and dosage form): D-Drops liquid. Composition: Each

1049566 09/2017 0,5 mℓ contains: 400 IU Vitamin D3 in sunflower oil, 3,63 IU Vitamin E. Pharmacological Classification: Complementary Medicine: Health Supplement - D34.11 Vitamins. This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information is available on request from iNova Pharmaceuticals. IN575/18

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MEDICAL CHRONICLE | NOVEMBER 2017 41 MEDICAL CHRONICLE 29


WOMEN’S HEALTH Focus CLINICAL SUPPLEMENTS CPD

deficiency. Major zinc deposits lie in the bone and muscle and are not readily responsive to changes in dietary zinc or urinary zinc loss. Instead, the human body draws from a small functional zinc pool located within the liver and other tissues for a few days, which allows zinc to rapidly exchange with the plasma. Once the functional zinc pool is depleted, deficiency ensues. It has been proposed that the sulphydryl group acts as a chelating agent and binds to bivalent metals such as zinc, thereby inducing zincuria. This theory has been used to explain why

inflammatory cytokines, which can play an important causative role in disease. Major zinc deposits lie in the bone and muscle and are not readily responsive to changes in dietary zinc. While the available data did not allow for meta-analysis of effect, the qualitative assessment of the current evidence suggests a protective effect of zinc in the development of cardiometabolic diseases, specifically CVD. The effect of zinc appears to be more pronounced in vulnerable populations, such as those with

captopril has a more potent effect on zinc levels, as measured by changes in urine, rum and erythrocytes, when compared with enalapril, whose effects are relatively less impressive. Concurrent zinc deficiency can complicate the clinical features of several chronic diseases, such as atherosclerosis, some malignancies, neurological disorders and•age-related degenerative diseases. Zinc deficiency complicates clinical consequences by adversely affecting immunological status, increasing oxidative stress and increasing generation of

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DOSIS EN GEBRUIKSAANWYSINGS: Neem 1 mℓ daagliks of 0,5 mℓ twee maal daagliks, of soos aanbeveel deur jou gesondheidsorgkundige. Neem die dosis geleidelik, soos beste verdra. Slegs vir orale gebruik. Skud bottel voor gebruik. Moenie die aanbevole dosis oorskry nie. BERGINGSAANWYSINGS: Bewaar teen of benede 25 °C. Beskerm teen lig en vogtigheid. HOU BUITE DIE BEREIK VAN KINDERS. Komplementêre Medisyne: Gesondheidsaanvulling D34.11 Vitamiene. Hierdie ongeregistreerde medisyne is nie deur die SAHPRA geëvalueer ten opsigte van kwaliteit, veiligheid of voorgenome gebruik nie.

Reference: 1. ACEI-GAP package insert, 2017.

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References: 1. Mason P. Dietary Supplements (4th edition). London: The Pharmaceutical Press, 2012; p. 493-510. 2. National Institutes of Health [Internet]: Vitamin D: Fact Sheet for Health Professionals [updated 2016 11 Feb; cited 2016 Nov 14] Available from: http:// ods.od.nih.gov/factsheets/VitaminD-HealthProfessional. 3. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT JAN 2019. Proprietary name (and dosage form): D-Drops liquid. Composition: Each 0,5 mℓ contains: 500 IU Vitamin D3 in sunflower oil, 3,63 IU Vitamin E. Pharmacological Classification: Complementary Medicine: Health Supplement - D34.11 Vitamins. This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Proprietary name (and dosage form): D-Vit Tabs. Composition: Each tablet contains: 400 IU Vitamin D3. Pharmacological Classification: Complementary Medicine: Health Supplement - D34.11 Vitamins. This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information is available on request from iNova Pharmaceuticals. IN693/19

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d range med chron fp ad_2019.indd 1

NOVEMBER 2017 | MEDICAL CHRONICLE 3042MEDICAL CHRONICLE

ROLE OF VITAMIN D IN CARDIOVASCULAR HEALTH The renin–angiotensin system (RAS) plays a central role in the regulation of blood pressure, volume and electrolyte homeostasis. Inappropriate activation of the RAS may lead to hypertension. Clinical and epidemiological studies have suggested a correlation between vitamin D-deficiency and high blood pressure. Our recent studies demonstrate that Vitamin D is a potent endocrine suppressor of renin biosynthesis to regulate the RAS. Observational studies strongly associate vitamin D deficiency with a variety of cardiovascular diseases beyond defects in bone and calcium metabolism. Vitamin D has multiple mechanisms that potentially may affect cardiovascular health. Because vitamin D deficiency is common, therapies directed at the replacement of vitamin D may be beneficial. Cutaneous synthesis of vitamin D3 from sunlight exposure is the major source (80%-90%) of vitamin D in humans under natural conditions. The dietary supply of vitamin D is minor compared to cutaneous formation but can become an important source of vitamin D with supplementation. Oily fish such as salmon, mackerel, herring, and sardines are rich sources of vitamin D. Vitamin D and RAS The world pandemic of vitamin D deficiency could possibly be explained by cellular inflammatory response activity induced by the renin-angiotensin system. On the other hand, inappropriate stimulation of the RAS has also been associated with the pathogenesis of hypertension, heart attack, stroke, and hypertrophy of the left ventricle and vascular smooth muscle cells. Because vitamin D receptors (VDRs) and RAS receptors are almost distributed in the same tissues, a possible link between vitamin D and the RAS is even more plausible. Vitamin D deficiency is a pandemic. This deficiency is probably due to environmental factors such as diet, sun exposure, sedentary lifestyle, and stress. Recent studies suggest that, in addition to its importance in bone metabolism, vitamin D plays a central role in such basic cell functions as multiplication, differentiation, and metabolism. This may explain why low vitamin D levels represent a risk factor for several apparently different diseases, such as infective, autoimmune, neurodegenerative, and cardiovascular diseases, as well as diabetes, osteoporosis, and cancer. Accumulating evidence suggests that an adequate intake of vitamin D may significantly decrease the prevalence and improve

Reduces the risk of developing osteoporosis, when calcium intake is combined with sufficient vitamin D, a healthy ACEI-GAP, assists in thediet and regular maintenance of essentialexercise

FOR HIGH BLOOD PRESSURE

existing Type 2 DM or established risk factors of diseases.

2019/03/18 13:39


ACE inhibitors and vitamin D, zinc Vitamin D

Impact of ACEIs

Factors that compound deficiency

Impact of deficiency on CV health the clinical outcomes of these diseases. Moreover, vitamin D insufficiency seems to predispose to hypertension, diabetes, metabolic syndrome, left ventricular hypertrophy, heart failure, and chronic vascular inflammation. Two main sources of vitamin D are available: Sunlight (exposure to solar UV-B radiation) and food (including dietary supplements). Vitamin D exists in two forms: Vitamin D2 (ergocalciferol) and Vitamin D3 (cholecalciferol). Vitamin D2, found in plants, is the product of UV-B (290-315mm) irradiation of ergosterol and can be consumed as a supplement or in fortified foods. Vitamin D3, a product of UV-B irradiation of 7-dehydrocholesterol, is synthesised in the epidermis or is found in oily fish, fortified foods, and supplements. Epidemiological studies have also recently linked Vitamin D deficiency with an increased risk of major adverse cardiovascular events. Accordingly, data from NHANES III show an elevated risk of cardiovascular death (coronary heart disease, heart failure, and stroke) in adults with 25(OH)D serum levels in the lowest quartile (mean 13.9 ng/ml) compared with those in the three higher quartiles (mean 21.6,

28.4, and 41.6ng/ml). As can be noted, the mean calcium and vitamin D intakes of the men and women are far below the recommended amounts (based on DRIs) of 1000mg and 10µg, respectively. However, despite national food fortification, the intake of numerous micronutrients still remain low, particularly calcium, folate, B vitamins, and vitamin C, and D. Results of the study demonstrate that chronic use of ACE inhibitors by hypertensive patients results in zinc depletion, as reflected by intramonocytic zinc levels.

VITAMIN D STATUS IN THE ELDERLY Vitamin D deficiency and polypharmacy are common in the elderly. However, knowledge on the associations between the use of specific medicines and serum 25-hydroxyvitamin D (25(OH)D) is limited. A study defined the associations between the use of specific medicines and serum 25(OH)D. In the first cohort, after adjustment for confounding, users of any kind of medicine, loop diuretics and inhaled corticosteroids (only men) had respectively 4.4nmol/l (P<0.01), 4.7nmol/l (P = 0.04) and 7.3nmol/l

Use of AECIs reduced serum vitamin D levels by 7.6nmol/L compared with non-use

Zinc Captopril act as a chelating agent that bind to zinc, thereby inducing zincuria Chronic ACEI use (enalapril, captopril) by hypertensive patients results in zinc depletion

Vitamin D deficiency is a pandemic Vitamin D intake of South African men and women is far below the recommended levels

25% of the world’s population is at risk of zinc deficiency Body stores are limited and zinc pool is depleted in a few days Diseases such as diabetes, heart failure and hypertension might also enhance zinc deficiency

Inappropriate stimulation of RAS has been associated with the pathogenesis of hypertension, heart attack, stroke and hypertrophy of the left ventricle and vascular smooth muscle cells. May increase risk of death from stroke, coronary heart disease and heart failure

Complicates the clinical features of atherosclerosis by adversely affecting immunological status, increasing oxidative stress and generating inflammatory cytokines

(P = 0.02) lower serum 25(OH)D than non-users. In the second cohort, the use of oral antidiabetics, CCBs and ACE inhibitors was associated with respectively 7.4nmol/l (P = 0.04), 7.7nmol/l (P = 0.01) and 7.6nmol/l (P<0.01) lower serum 25(OH)D. These data show that users of several medicines have lower serum 25(OH)D than non-users. Vitamin D supplementation may be considered in patients with chronic use of medicines.

RECOMMENDED DIETARY ALLOWANCES A wide variety of foods contain zinc. Oysters contain more zinc per serving than any other food, but red meat and poultry provide the majority of zinc in the Western diet. Other good food

sources include beans, nuts, certain types of seafood (such as crab and lobster), whole grains, fortified breakfast cereals, and dairy products. In otherwise uncomplicated primary hypertension, the initial first choice of antihypertensive drug is a diuretic (thiazide-like or thiazide), ACE inhibitor or ARBs, and/or calcium channel blockers (CCB) used as mono- or combination therapy. Vitamin D: Men and women ≤ 70 years: 600 IU/day. Men and women >70 years: 800 IU/day. Other sources include: Sunlight, oily fish, fortified food. Zinc: Men: 11mg/day, women: 8mg/day. Other sources include: Oysters, crab, lobster, red meat, poultry, beans, nuts, seafood, whole grains, fortified breakfast cereals and dairy products. References available on request.


WOMEN’S HEALTH Focus

RELEASE ME

In this article, Dr Johan van Schouwenburg, specialist in Reproductive Medicine at Medfem Clinic, looks at common reasons for infertility in women.

Infertility is defined as the inability to conceive within one year of unprotected coitus. This definition should only be used as a guide circumstances should dictate when and how aggressively the issue should be addressed. Ovulatory disorders manifest in irregular cycles, low

progesterone levels approximately a week before menstruation, and negative serial urinary luteinising hormone tests. Blocked or immobile fallopian tubes are also a common cause of infertility. In terms of uterine pathology, myomas – large intramural–, intra uterine – or submucosal myomas must be removed.

Other causes of female intertility include: • Endometrial polyps • Hormonal disturbances, manifesting in weight extremes, galactorrhoea, hyperandrogenism, thyroid disorders, insulin resistance • Endometriosis: dysmenorrhoea for

NEW! Indicated in the treatment of ANOVULATORY INFERTILITY1

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in FRIENDLY2 • Oral administrationReduction is PATIENT

obesity3**

• Little ovarian response monitoring is required2

16,4 %

• Well established safety profile2 Reduction in hirsutism 4**

References: 1. Registered Package Insert, dated 9 June 2016. 2. The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Human Reproduction Vol. 23, No.3 pp. 462–477, 2008. 3. Crosignani PG, Bianchedi D, Riccaboni A et al. Management of anovulatory infertility. Human Reproduction Vol 14, (Suppl. 1), pp. 108-119, 1999. 4. DOH database of medicine prices 27 May 2017 www.mpr.gov.za

E

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S4 FERTAB (TABLETS). Each tablet contains 50 mg clomiphene citrate. S E S No: 44/18.8/1034 IN Reg. F TR

Blood tests are done on Day 2 or 3 of the cycle: FSH, LH, oestradiol, prolactin, thyroid-stimulating hormone, T4, male sex hormones if clinically indicated, fasting insulin and glucose. AMH (anti-Müllerian hormone) is an important test for assessing ovarian oocyte reserve - done at any time of the cycle. Also look at blood group and rubella immunity. A hysterosalpingogram is indicated if tubal pathology is suspected. Book this test for directly after menstruation. Oral analgesia and local anaesthetic spray on the cervix are great helps to prevent discomfort.

TREATMENT

2 Reduction in insulin resistance 2,4

S

more than a day, bloating and changes in bowel movement during menses, dyspareunia, tenderness on palpation of the utero-sacral ligaments. Personality traits associated with stress (e.g. A-type personality, perfectionism and time urgency) are often present, especially in professional women • Age

SPECIAL INVESTIGATIONS

SHE MAY HAVE

Dr Johan van Schouwenburg, specialist in Reproductive Medicine at Medfem Clinic

MARKETED IN4,5SOUTH AFRICA BY: FERRING (Pty) Ltd. Route 21 Corporate Park, 6FORMULATION Regency Drive, Irene Ext 30. Pretoria, South Africa. Tel: +27 12 345 6358 Fax: +27 12 345 1156. www.ferring.co.za. For full prescribing information refer to the package insert approved by the medicines regulatory authority. 2017/058a

*Polycystic ovarian syndrome # IVF - In-vitro fertilisation **Studies were conducted on supplemental Alpha Lipoic Acid only ## Due to PCOS References: 1. Rago R, Marcucci I, Leto G, et al. Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. J Biol Regulators Homeostatic Agents 2015;29(4):1-11. 2. Genazzani AD, Shefer K, Della Casa D, et al. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J Endocrinol Invest 2018;41:583–590. 3. Carbonelli MG, Di Renzo L, Bigioni M, et al. α-Lipoic Acid Supplementation: A Tool for Obesity Therapy? Curr Pharmaceut Design 2010;16:840846. 4. De Cicco S, Immediata V, Romualdi D, et al. Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin-independent action. Gynecol Endocrinol 2017;33(9):698–701. 5. Sinopol® package insert, February 2019. 6. Cappelli V, Musacchio MC, Bulfoni A, et al. Natural molecules for the therapy of hyperandrogenism and metabolic disorders in PCOS. Eur Rev Med Pharmacol Sci 2017; 21(2 Suppl):15-29. 7. Bellver J, Rodríguez-Tabernero L, Robles A, et al. Polycystic ovary syndrome throughout a woman’s life. J Assist Reprod Genet 2018;35:25 -39. Proprietary name (and dosage form): SINOPOL® granules. Composition: Each sachet contains: Myo-inositol 1 000 mg, Alpha Lipoic Acid 400 mg and Folic Acid 200 µg. Complementary Medicine: Health Supplement. D34.12 Multiple Substance formulation. This unregistered medicine has not been evaluated by SAHPRA for its quality, safety or intended use. Studies as part of the references were not conducted on Sinopol®. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert. Further information is available on request from iNova Pharmaceuticals. IN3397/19.

Your PARTNER OF CHOICE in Gynaecology and Infertility

A multidisciplinary approach should be taken including the GP, general gynaecologist, specialist in reproductive medicine, urologist, psychologist, dietitian and psychologist/ counsellor. Diagnosed abnormalities should be addressed by the GP. Reference to a specialist might be required. The extent to which GPs should get involved with specific surgical and medical treatment depends on their training and the availability of facilities. There are two practical points of importance: Ovulation-inducing drugs should be started in low dosages. For instance, clomiphene 25mg (half a tablet) per day from Day 5-9. Ideally, sonar monitoring should be done. Triplet pregnancies, even due to a small dose, is not uncommon in women with polycystic ovarian syndrome. Use these drugs for a maximum of three months before referring. Laparoscopic surgery is currently associated with the most expensive litigation and insurance claims in our profession. Make sure that your training can back you up if complications occur as a result of surgery. Whether to refer the couple to the woman’s familiar gynaecologist or to an infertility specialist depends on the nature of the suspected pathology and the patient’s wishes. References available on request.

32 MEDICAL CHRONICLE 28 FEBRUARY 2018 | MEDICAL CHRONICLE


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WOMEN’S HEALTH Focus

START YOUNGER

STAY STRONGER

Look after your bones, and they will look after you

Calcium with Vitamin D3 and Magnesium

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Calcium with vitamins & minerals

Calcium

Calcium effervescent with Vitamin D3

Speak to your pharmacist to determine which calcium supplement is best suited for you Reference: 1. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT May 2019. Proprietary name (and dosage form): B-CAL®-DM Tablets. Composition: Each tablet contains: 500 mg Calcium, 400 IU Vitamin D3 and 125 mg Magnesium. Proprietary name (and dosage form): B-CAL®-D Tablets. Composition: Each tablet contains: 500 mg Calcium and 400 IU Vitamin D3. Proprietary name (and dosage form): B-CAL® Ultra Tablets. Composition: Each tablet contains: 500 mg Elemental Calcium, 400 IU Vitamin D3, 85 mg Elemental Magnesium, 1 mg Copper (AAC), 490 µg Folic Acid, 2 mg Manganese (AAC), 25 µg Molybdenum (AAC), 37 µg Selenium (AAC), 24 mg Vitamin B6, 24 µg Vitamin B12, 60 mg Vitamin C, 15 mg Zinc (AAC). Proprietary name (and dosage form): B-CAL® Tablets. Composition: Each tablet contains: 500 mg Calcium. Proprietary name (and dosage form): Calcium Citrate D® Granules. Composition: Each sachet contains: 500 mg Elemental Calcium (from calcium citrate), 400 IU Vitamin D3. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Disclaimer: This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health Supplements do not replace a healthy diet and lifestyle. For more information, speak to your healthcare professional. IN788/19 34 MEDICAL CHRONICLE


ITAMIN DEFECIEN ORAL CONTRACEPTIVE USE WOMEN’S CLINICAL HEALTH Focus WOMEN’S HEALTH CPD

HOW TO COMBAT VITAMIN DEFECIENCIES IN ORAL CONTRACEPTIVE USE

ception is one of the most powerful public health tools for any country. However, there i and effective contraception is a critical element of women’s health, and enabling wome owering. It offers women better economic and social opportunities. Contraception is one of the most powerful public health tools for any country. However, there is an unmet treatment need. Access to safe and effective contraception is a critical element of women’s health, and enabling women to make choices about their fertility is empowering. It offers women better economic and social opportunities.

CLINICAL

WOMEN’S HEALTH CPD

HOW TO COMBAT VITAMIN DEFECIENCIES IN ORAL CONTRACEPTIVE USE

Contraception is one of the most powerful public health tools for any country. However, there is an unmet treatment need. Access to safe and effective contraception is a critical element of women’s health, and enabling women to make choices about their fertility is empowering. It offers women better economic and social opportunities.

In private healthcare alone, 5.9 million packs of oral contraceptives (OCs) were sold in SA in 2016. This accounts for 60% of total contraceptive prevalence rate in southern Africa. With normal usage, combination OCs are 97%-98% effective. Side effects include: • Nausea • Mild headaches • Tender breasts • Irregular bleeding or spotting • Mood changes. Common medical disorders that require special attention in terms of

In private healthcare alone, 5.9 million packs of oral contraceptives (OCs) were sold in SA in 2016. This accounts for 60% of total contraceptive prevalence rate in southern Africa. With normal usage, combination OCs are 97%-98% effective. Side effects include: • Nausea • Mild headaches • Tender breasts • Irregular bleeding or spotting • Mood changes.

e healthcare alone, on packs of oral eptives (OCs) were sold in 16. This accounts for 60% contraceptive prevalence outhern Africa. With normal mbination OCs are 97%-98% Side effects Common include: medical disorders that require special attention in terms of

adaches breasts

contraceptive method include: • Hypertension • Venous thromboembolism • Arterial disease • Diabetes • Epilepsy • Cancers. Oral contraceptives and nutritional requirements OCs are a major class of prescription drug, used by a large proportion of women starting from early adolescence. Development of hormonal contraception marked a revolutionary step in social change that has improved the lives of women and families

contraceptive method include: • Hypertension • Venous thromboembolism • Arterial disease • Diabetes • Epilepsy • Cancers.

worldwide. Oral contraceptives (OCs) are currently among the most common used drugs in developed countries. Since they became available in 1960, they have influenced the lives of millions of individuals and are now listed among the most effective drugs available. The most frequently used agents are a combination of drugs containing both an estrogen and a progestin. This combination is considered to be highly efficacious, with a theoretical effectiveness generally considered 99.9% and a use effectiveness of 97%-98%. Ethinyl estradiol (EE) and mestranol are the two estrogens used

(with ethinyl estradiol being much more frequently used) and several progestins are currently used. The progestins are 19-nor compounds in the estrange or gonane series with vary degrees of androgenic, estrogenic and anti-estrogenic activities that may be responsible for some of their side effects. Combined OCs act by preventing ovulation. LH and FSH levels arc suppressed, a midcycle surge of LH is absent, endogenous steroid levels are diminished, thus ovulation docs not occur. While either component alone can be shown to exert these

worldwide. Oral contraceptives (OCs) are

(with ethinyl estradiol being much

more frequently used) and several among the most common used worldwide. Oral contraceptives (O contraceptive method currently include: progestins are currently used. The drugs in developed countries. progestins are 19-nor compounds in Since they became available in 1960, currently among the most commo • Hypertension the estrange or gonane series with vary they have influenced the lives of millions inofdeveloped countries. • Venous thromboembolism degrees androgenic, estrogenic and of individuals and are now listed amongdrugs anti-estrogenic activities that may be the most effective drugs available. Since they became available in • Arterial disease responsible for some of their The most frequently used agents sidehave effects. influenced the lives of m are a combination of drugs containing they Oral contraceptives and nutritional • Diabetes Combined OCs act by preventing both an estrogen and a progestin. requirements OCs are a major class ovulation. LH and FSH levels arc now listed a This combination is considered to be of individuals of prescription drug, used by a large and are • Epilepsy suppressed, a midcycle surge of highly efficacious, with a theoretical proportion of women starting from early theLHmost effective drugs available • Cancers. is absent, endogenous steroid effectiveness generally considered adolescence. Development of hormonal levels are diminished, thus ovulation 99.9% and a use effectiveness of contraception marked a revolutionary Thenotmost frequently used agen docs occur. While either component 97%-98%. Ethinyl estradiol (EE) and step in social change that has improved can be shown to exert these are the two estrogens used the lives of women and families arealone a combination of drugs contai Oral contraceptivesmestranol and nutritional both an estrogen and a progestin. requirements OCs are a major class MEDICAL CHRONICLE 35 MEDICAL CHRONICLE | MARCH 2018 21 This combination is considered to of prescription drug, used by a large


WOMEN’S HEALTH Focus CLINICAL WOMEN’S HEALTH CPD

effects in certain conditions, the combination acts synergistically decreasing plasma gonadotropin levels and suppressing ovulation more consistently than either alone. However, progestin-only contraceptives are sufficient to block ovulation in 60% to 80% of cycles. The effectiveness of these preparations is, thus, thought to be due to a thickening of cervical mucus, which decreases sperm penetration, and to endometrial alterations that impair implantation. Much research has been conducted to investigate the physiological changes that occur in women who take OCs.

These include changes in general health as well as in nutritional needs. In terms of nutrition, several studies investigated whether women on OCs need different amounts of some vitamins and minerals. In particular, a report from the World Health Organization (WHO) points out that the influence of OCs on nutrient requirements is a topic of high clinical relevance and should, therefore, receive great attention. It has been shown that the key nutrient depletions concern folic acid, vitamins B2, B6, B12, vitamin C and E and the minerals magnesium, selenium and zinc. Most research has focused on the levels of

these vitamins and minerals in the blood of women who take OCs compared to women who do not. Since women who take OCs do not always have adequate diet, may have unhealthy lifestyle or may suffer from pathologies of malabsorption, the possibility to prevent vitamin and mineral deficiencies by taking appropriate dietary supplements should be considered a first-line approach by clinicians.

VITAMINS

Folic Acid Folate is a water-soluble B vitamin (also known as vitamin B9 or folacin) that

START YOUNGER

STAY STRONGER

Look after your bones, and they will look after you

Calcium with Vitamin D3 and Magnesium

B - C A L ® S o u t h A f r i c a ’s N o . 1 P r e s c r i b e d C a l c i u m R a n g e 1

Calcium with Vitamin D3

Calcium with vitamins & minerals

Calcium

Calcium effervescent with Vitamin D3

Speak to your pharmacist to determine which calcium supplement is best suited for you Reference: 1. Impact Rx. Script data (Vitamins & Minerals / Constructed class). MAT May 2019. Proprietary name (and dosage form): B-CAL®-DM Tablets. Composition: Each tablet contains: 500 mg Calcium, 400 IU Vitamin D3 and 125 mg Magnesium. Proprietary name (and dosage form): B-CAL®-D Tablets. Composition: Each tablet contains: 500 mg Calcium and 400 IU Vitamin D3. Proprietary name (and dosage form): B-CAL® Ultra Tablets. Composition: Each tablet contains: 500 mg Elemental Calcium, 400 IU Vitamin D3, 85 mg Elemental Magnesium, 1 mg Copper (AAC), 490 µg Folic Acid, 2 mg Manganese (AAC), 25 µg Molybdenum (AAC), 37 µg Selenium (AAC), 24 mg Vitamin B6, 24 µg Vitamin B12, 60 mg Vitamin C, 15 mg Zinc (AAC). Proprietary name (and dosage form): B-CAL® Tablets. Composition: Each tablet contains: 500 mg Calcium. Proprietary name (and dosage form): Calcium Citrate D® Granules. Composition: Each sachet contains: 500 mg Elemental Calcium (from calcium citrate), 400 IU Vitamin D3. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Disclaimer: This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health Supplements do not replace a healthy diet and lifestyle. For more information, speak to your healthcare professional. IN788/19

calcium med chron A4 ad_19.indd 1

36 MEDICAL CHRONICLE 22 MARCH 2018 | MEDICAL CHRONICLE

2019/07/31 08:43

occurs naturally in food. Folic acid is the synthetic form of folate that is found in supplements and added to fortified foods. Folate itself is not biologically active, but its biological importance is due to tetrahydrofolate and other coenzymes that play a crucial role as donors and acceptors of a myriad of onecarbon entities required for important enzymatic reactions, including those involved in amino acid metabolism, purine and pyrimidine synthesis and DNA methylation. A lack of dietary folic acid leads to folate deficiency, which results in reduced DNA synthesis and cell division. Although this will be seen in all dividing cells, the deficiency will be more obvious in cells that rapidly divide, including for example red blood cells, thereby producing anaemia, or in cells derived from bone marrow, leading to leukopenia and thrombocytopenia. Particularly serious are the consequences of folate deficiency during early embryogenesis: • For instance, the neural tube has a high need of folate for cell differentiation, growth, and closure to form the spinal cord and brain, and folate deficiency during the periconceptional period can induce neural tube defects (NTDs). NTDs arise from failure of embryonic neural tube closure by the fourth week of pregnancy, causing malformations of the brain and spine, being in certain conditions incompatible with life (eg anencephaly). NTDs are the most frequent human malformations occurring during pregnancy. Nowadays, it is generally known that folic acid supplementation in the periconceptional period can prevent the majority of NTDs. In addition to NTDs, adequate folic acid intake during pregnancy is associated with a significant reduction of risk for congenital heart defects and orofacial clefts. • Taken together, the most common effects caused by folate deficiency result in neural tube defects in developing embryos, macrocytic anemia, and peripheral neuropathy • A typical consequence of folate deficiency is an elevation in plasma homocysteine which, in turn, is implicated in the aetiology of cardiovascular disease. The amino acid homocysteine is of considerable medical importance because it is involved in the etiopathogeny of cardiovascular diseases. Hyperhomocysteinemia is a factor in the vascular damage that predisposes thrombogenesis and arteriosclerosis. It has also been related to a range of obstetric and gynecologic complications. Numerous studies have demonstrated the association between increased levels of homocysteine and NTD and other congenital defects, spontaneous miscarriages, intrauterine growth retardation (IGR), preeclampsia and intrauterine fetal death. Folic acid and other B-group


WOMEN’S HEALTH Focus CLINICAL WOMEN’S HEALTH CPD

vitamins (B6 and B12) take part in the metabolism of homocysteine and the preventive administration of these vitamins may reduce some of the complications.

VITAMIN B6 Vitamin B6 is a water-soluble vitamin that is present in many foods, added to others, and available as a dietary supplement. It is the generic name for six compounds with vitamin B6 activity: pyridoxine, an alcohol; pyridoxal, an aldehyde; pyridoxamine, which contains an amino group; and their respective 5’-phosphate esters. Pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate (PMP) are the active coenzyme forms of vitamin B6. Vitamin B6 coenzymes participate to a wide variety of physiological functions in the body, being involved in more than 100 enzymatic reactions, mostly concerned with protein metabolism. Both PLP and PMP are involved in amino acid metabolism, and PLP -is also involved in the metabolism of onecarbon units, carbohydrates, and lipids. Vitamin B6 also plays a role in the biosynthesis of neurotransmitters. For instance, it is necessary for the conversion of tryptophan to both niacin and serotonin. Consequently, a dietary deficiency of vitamin B6 may result in low serotonin levels and/or impaired conversion of tryptophan to niacin. Vitamin B6 is important in maintaining normal levels of homocysteine. Furthermore, it is involved in gluconeogenesis and glycogenolysis, immune function, and hemoglobin formation. A recent large-scale population-based study performed in the US found that plasma PLP concentration were significantly reduced in 75% of women taking OCs who did not use dietary supplements. Lussana et al also reported low levels of vitamin B6 in women taking OCs, and they speculate that, since low vitamin B6 levels are independently associated with heightened risks for arterial and venous thromboembolism (TE), they could partly account for the increased TE risk of OC users. Altogether, more recent findings from users of currently formulated lower-dose OCs corroborate previous reports and suggest that supplementation may be necessary to maintain adequate vitamin B6 status in women taking OCs.

VITAMIN B12 Vitamin B12 (also known as cobalamin) is an essential nutrient that plays a significant role in cell metabolism, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. The active coenzymes methylcobalamin and 5-dcoxyadenosylcobalamin are essential

INSTRUCTIONS:

for cell growth and replication. Vitamin B12 deficiency is recognised clinically by its impact on the haematopoietic and nervous systems. The sensitivity of the haematopoietic system relates to its high rate of cell turnover. As a result of an inadequate supply of vitamin B12, DNA replication becomes highly abnormal. In case of vitamin B12 deficiency, maturation of red cell precursors is highly abnormal (megaloblastic erythropoiesis). Other tissues with high rates of cell turnover (eg, mucosa and cervical epithelium) also have high requirements for the vitamin. As with inadequate maternal folate status, impaired maternal vitamin B12 status is an independent risk factor for NTDs. Several studies have found low mean serum vitamin B12 levels in women using OCs, as compared to nonusers. Although there is a close interrelation between folate and vitamin B12 metabolism, the mechanism that causes low serum levels of vitamin B12 in patients using OCs seems to he different from the one that causes low serum levels of folate as there is no correlation between the levels of those substances, and folate therapy does not correct the low serum levels of vitamin B12 in OC users. The mechanisms by which serum vitamin B12 is reduced in OC users are not fully understood. Shojania et al found that the total vitamin B12 binding capacity of the serum was significantly lower in women using OCs than in nonusers; the levels of transcobalamin I, a glycoprotein serves to protect vitamin B12 from acid degradation in the stomach, were also lower in OC users. Since these

authors found that the absorption and the urinary excretion of vitamin B 12 in OC users were normal and their lower serum levels of vitamin B12 were not associated with evidence of tissue depletion, the lower total vitamin B12 binding capacity and lower transcobalamin I levels in the serum of the users could explain their low serum levels of this vitamin.

Several studies done during the following decades confirmed these findings. It has been thought that the decrease in serum zinc could be reflected in a reduction of tissue zinc status due to changes in zinc absorption, excretion or tissue turnover. If these changes occur, the dietary zinc requirement would be greater in women using OCs.

ZINC

TAKE-HOME MESSAGES

Lack of zinc leads to anorexia, loss of appetite, smell and taste failure, and other symptoms in humans and may affect the immune system, triggering arteriosclerosis and anemia. Zinc plays three major biological roles in the organism, the catalytic, the structural, and the regulatory one. Zinc is an essential mineral that has important biological functions. It is found in several enzymes and has roles in the metabolism of RNA and DNA, signal transduction, and gene expression. It also regulates apoptosis. In the brain, zinc is stored in specific synaptic vesicles by glutamatergic neurons and plays a key role in synaptic plasticity and learning processes. It also plays a key pathophysiological role in major neurological disorders, such as in Alzheimer’s disease, cancer, aging, diabetes, depression, and Wilson’s disease. A high concentration of zinc is found in muscle, bones, kidney, liver, in the prostate and parts of the eye. Semen is particularly rich in zinc, which is a key factor in reproductive function. The zinc status of women using OCs has been of concern since 1968, when it was observed that women using OCs had lower plasma zinc levels than women who were not.

Role of vitamin B6, vitamin B12, folic acid and zinc in the use of oral contraceptives:

DEFICIENCY • Women taking oestrogen-progestin combination agents had evidence of vitamin B6 deficiency. • Mean serum vitamin B12 levels were significantly lower in women using OCs than in nonusers. • OC users had lower mean serum levels of folate and higher percentage of subnormal folate levels than a control group. • Women using OCs had lower plasma zinc levels than women who were not. • Cardiovascular diseases. • Vascular damage that predisposes to: Thrombogenesis and arteriosclerosis. Folic acid and vitamins B6 and B12 take part in the metabolism of homocysteine. Increased homocysteine is involved in: • Cardiovascular diseases. • Vascular damage that predisposes to thrombogenesis and arteriosclerosis. References available on request.

1. Go to www.medicalacademic.co.za 2. Click the tab labelled ‘CPD Portal’ on the far right tab near the top of the page. 3. Select the relevant questionnaire from the list and complete the form.

23 MEDICAL CHRONICLE | MARCH 2018 37 MEDICAL CHRONICLE


WOMEN’S HEALTH Focus

NEWS

FAMILY HEALTH CRUCIAL FOR CHILDREN

Families are the most central and enduring influence in children’s lives. The health and wellbeing of children is entwined to their parents’ physical, emotional and social health and are powerfully influenced by parenting practices.

The concept of family is held in high regard in all societies, and families are ascribed a central role in creating and maintaining the cohesion of society. In keeping with the old African adage, it takes a village to raise a child, society too has a collective responsibility to its children. Increasingly, however, families function in a societal context that is not always supportive of parents or children.

QUALITY VS. QUANTITY

So while children today can expect to live longer than their parents, it is uncertain whether their lives will be entirely healthier. As infectious diseases and malnutrition recede as major causes of disease and death, the rising tide of obesity and chronic diseases loom large in the futures of 38 MEDICAL CHRONICLE

our children.

OBESITY IN CHILDREN

The Discovery Vitality sponsored Healthy Active Kids South Africa Report Card (HAKSA) 2016 highlights how obesity continues to increase among children in SA. Our country has one of the highest prevalence rates of childhood overweight and obesity - 19% of boys and 26% of girls - matching that of many high-income countries. Data from the Birth to Twenty Study showed that boys and girls who were obese between the ages of 4 and 8 were 20 times and a staggering 42 times more likely to be obese when they were 16 to 18 years old, respectively.

OUR RESPONSIBILITY

To limit the burden of chronic diseases

on our health system, and on our economy, requires a determined response from many sectors of society. Government has a crucial role in formulating policy, implementing regulations and executing programmes, particularly at school and community level, that promote a healthy lifestyle. Doctors have a central role in family-centred care. Family medicine and family-centred care, requires an active, productive partnership between the doctor and the family. Doctors play a vital role in advocating a healthy lifestyle that positively impacts the health and emotional or social wellbeing of the child.

FOCUS ON FAMILY

Discovery Vitality too has made the family, particularly the young

family, a key focus of attention. The Vitality Baby programme is a personalised wellness journey through pregnancy and the first two years following childbirth - a period that lays the foundation for future health and wellbeing. Another example of a rapidly growing family-based Discovery Vitality offering is parkrun, which organises free, weekly, 5km timed runs and walks every Saturday morning. parkrun is a social event open to everyone, and takes place in local parks and recreation areas within communities. The South African parkrun has 88 locations and about 300 000 participants. Families make up a substantial number of participants. The future health of our countries lies in the current health of our children and is largely dependent on what happens in the family.


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This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health supplements do not replace a healthy diet and lifestyle. For more information, speak to your healthcare provider. Reference: 1. Data available on request. IMS TPM. Proprietary name (and dosage form): Crèche Guard Immune Multivit Syrup. Composition: Each 5 ml contains: 2012 IU Vitamin A, 0.6 mg Vitamin B1, 0.7 mg Vitamin B2, 7.2 mg Vitamin B3, 2.2 mg Vitamin B5, 1.1 mg Vitamin B6, 0.4 mcg Vitamin B12, 108.0 mcg Biotin, 32.4 mg Vitamin C, 400 IU Vitamin D, 5.4 mg Vitamin E, 144.0 mcg Folic Acid, 5.0 mg Zinc. Proprietary name (and dosage form): Crèche Guard Brain Fuel Omega-3 Chews. Composition: Each Omega 3 chew contains: 180mg Omega 3 composed of: 100 mg Eicosapentaenoic acid , 60 mg Docosahexaenoic acid, 20 mg Alpha-linolenic acid. Proprietary name (and dosage form): Crèche Guard Cough and Cold Syrup. Composition: Each 5 ml contains: 15 mg Ivy leaf extract. Proprietary name (and dosage form): Crèche Guard Probiotic Skin Spray. Composition: Each ml contains 1 billion CFU’s a of Lactobacillus acidophilus La-5, Lactobacillus rhamnosus GG, Lactobacillus salivarius Ls-33. Proprietary name (and dosage form): Crèche Guard Digest Eeze Drops. Composition: Each 10 drops contain: 750 IU Tolerase L. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For more information, speak to your healthcare professional. IN645/19


NEW PACKAGING

S5


WOMEN’S HEALTH Focus CLINICAL OBESITY CPD

THE OBESE PATIENT HEALTH RISKS AND MEDICAL OPTIONS

Dr Gary Hudson, Physician in private practice, Randburg

Obesity is a global health problem. The obesity epidemic has been growing in developed nations, and has spread to developing nations.

3 CPD POINTS

The worldwide burden is estimated at 1.5 billion overweight and 500 million obese people in the global population. The negative consequences of obesity have been quantified as exceeding those of either alcohol abuse or smoking. Obesityassociated comorbidities, including major diseases like cardiovascular disease, cancer, and diabetes, are legion. Overweight and obesity constitute the fifth leading risk for global deaths. There is a global health crisis in adults,

adolescents and children with more than two thirds diagnosed as overweight and 30% defined as medically obese. This means that the average GP over a month period will see more than 100 patients with weight-related disease! Obesity is a dysfunction of adipose tissue, which leads to endocrine imbalances and results in inflammatory cascades, culminating in systemic disease. The mounting evidence shows the profound impact of obesity on morbidity, mortality, healthcare costs,

and professional and personal quality of life. The awareness of this crisis has unfortunately done little to reverse global obesity trends. Neither has the awareness that healthier habits for eating and exercise can help. There are many factors to blame for rising obesity: • The lack of access to healthy, affordable foods • The lack of safe places for physical activity • The inferiority of freshly prepared foods vs fast

YOUR PATIENT HAS COMMITTED TO WEIGHT LOSS

foods or prepackaged foods • The marketing of mostly unhealthy products by the food and beverage industry • Modern cultural habits increasing sedentary behaviors • Degrading eating cadences and locations • Excess stress levels • Sleep debt.

DEFINING OBESITY Obesity is a form of calorie excess

South Africa’s leading prescription appetite suppressant1

Duromine, South Africa’s leading prescription appetite suppressant and the ilivelite weight management program1 Committed to results S5

www.ilivelite.co.za program COMMITTED TO RESULTS

Reference: 1. Impact Rx - January 2018. Scheduling status: S5 Proprietary name (and dosage form): Duromine 15 mg and 30 mg Capsules. Composition: Sustained action ion-exchange resinate granules, available as capsules containing phentermine 15 mg and 30 mg Pharmacological classification: A 11.3 Anorexigenics. Indications: Duromine is an anorectic agent used in the management of obesity. Reference number: 15 mg: B657 [Act 101/1965]; 30 mg: B658 [Act 101/1965]. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the MCC (Medicines Control Council). Further information is available on request from iNova Pharmaceuticals. IN2656/18

MEDICAL CHRONICLE APRIL 2018 41 23 MEDICAL| CHRONICLE


WOMEN’S HEALTH Focus CLINICAL OBESITY CPD

girth of >94cm and adult female girth >84cm, as 60% of these are associated with nonalcoholic steatohepatitis and nonalcoholic fatty liver disease. Presenting and progressive cardio metabolic and biomechanical related comorbidities and complications. This includes the big pandemics of type 2 diabetes mellitus, hypertension, dyslipidaemia, occlusive cardiovascular disease, obstructive sleep apnoea, complicated fatty liver and osteoarthritis. Higher morbidity in association with overweight and obesity has also

protein deficient malnutrition. Proteins and amino acids are the essential building blocks for DNA, RNA, cellular function, endocrinal hormones, exocrinal enzymes and musculoskeletal structure.

3

There are three elements defining obesity: BMI, which is a weight: height ratio measured as kg/m2. WHO states obesity is BMI >30 or >27 with an associated co morbidity. Abnormal centripetal distribution of body fat with an adult male

1

2

been observed for coronary heart disease, gallbladder disease, respiratory problems and some types of cancer (endometrial, breast, prostate, and colon). Obesity is also associated with complications of pregnancy, menstrual irregularities, hirsutism, stress incontinence, and psychological disorders (depression).

MANAGEMENT Over 45% of all people meet the criteria for obesity management. The primary response to weight-related disease is lifestyle changes and the

YOUR PATIENT

IS READY TO

COMMIT TO WEIGHT LOSS

Negative consequences of obesity exceed those of either alcohol abuse or smoking, and increases the risk for cardiovascular disease, type 2 diabetes, dyslipidaemia and death1-3

It is important to take control of the 7 S's. Stop: 1. Sodas 2. Spirits 3. Salt 4. Sugars 5. Sitting 6. Sleep deprivation 7. Sadness.

NEW PACKAGING

EVEN MODEST WEIGHT LOSS PRODUCES STRIKING HEALTH BENEFITS:4 Approx. 10 mm Hg reduction in blood pressure 40 % - 60 % reduction in the incidence of diabetes 10 % reduction in total cholesterol > 20 % reduction in all-cause mortality

Duromine, South Africa’s leading prescription appetite suppressant and the ilivelite weight management program5 - Committed to results

www.ilivelite.co.za program S5

COMMITTED TO RESULTS

South Africa’s leading prescription appetite suppressant5

References: 1. Kim GW, Lin JE, Blomain ES, Waldman SA. Anti-Obesity Pharmacotherapy: New Drugs and Emerging Targets. Clin Pharmacol Ther. 2014; 95(1): 53–66. 2. Centers for Disease Control and Prevention. The Health Effects of Overweight and Obesity [online] [cited] 2017 Nov 29; Available from URL: https://www.cdc.gov/healthyweight/effects/index.html. 3. National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults [online] 1998 [cited] 2017 Nov 29; Available from URL: https://www.nhlbi.nih.gov/files/docs/guidelines/ob_gdlns.pdf. 4. Haslam D, Sattar N, Lean M. ABC of obesity. Obesitytime to wake up. BMJ 2006; 333: 640-642. 5. Impact Rx - January 2018. Scheduling status: S5 Proprietary name (and dosage form): Duromine 15 mg and 30 mg Capsules. Composition: Sustained action ion-exchange resinate granules, available as capsules containing phentermine 15 mg and 30 mg Pharmacological classification: A 11.3 Anorexigenics. Indications: Duromine is an anorectic agent used in the management of obesity. Reference number: 15 mg: B657; 30 mg: B658 [Act 101/1965]. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the MCC (Medicines Control Council). Further information is available on request from iNova Pharmaceuticals. IN2652/18

24 APRIL 2018 | MEDICAL CHRONICLE 42 MEDICAL CHRONICLE

debate continuously revolves around macronutrients calorie restriction diets such as the DASH diet for hypertension, the Banting diet for type 2 diabetes mellitus, the Paleo and the Nordic diets and the list goes on. The most important factors in dietary modification is increasing water consumption in place of cold drinks and fruit juices. Obesity is a form of calorie excess protein deficient malnutrition. Proteins and amino acids are the essential building blocks for DNA, RNA, cellular function, endocrinal hormones exocrinal enzymes and musculoskeletal structure. Protein intake should be 1.5g per 2.2 x kg of body weight. So a 90 kg adult should consume about 290g protein per day. Alcohol is the consumption of hidden calories and men are restricted to 14 units per week maximum and women to 7. Increasing fiber to 100g per day and eating fermented foods is essential in balancing colonic dysbiosis. Rapidly restricting ones dietary habits often leads to slowing down of ones basal metabolic rate and patients often become overwhelmed and disillusioned. This is followed by the advice for skeletal muscle activity with a minimum of walking for a period of 30 minutes three times a week.

These primary steps often fail to achieve success. Successful weight loss is measured over a period of time. One must achieve 5% weight loss in 3 months followed by 10% in 9 months up to 15% weight loss over 12 months. Changes are slow and frustrating which often fails due to poor adherence and basic inertia. Quick fixes such as fad diets are never practical nor sustainable. With regards to treatment: • 85% patients will be given dietary modification • 75% will be placed onto an exercise regime • 45% will undergo behavior modification • 30 % will be prescribed weight loss medication • 15% will undergo bariatric surgery. Outcomes with regards to goals met show: • 20% will have no weight loss • 50% will lose 2.5%-5% weight loss • Only 25% will lose 5%-15% of their weight • 5% will exceed their goals. If these are the statistics why do only 30% of doctors prescribe weight loss medication? Since 2012, the WHO obesity guidelines state that if diet, exercise


WOMEN’S HEALTH Focus CLINICAL OBESITY CPD

and behaviour modification fail to achieve 5% of weight loss, then weightmodifying medication can be initiated. The medication is also used if there is a regaining of weight. When lifestyle modifications fail to effect meaningful change, and the limitations of bariatric surgery, discussed later, anti-obesity drugs have a role as adjuncts in obesity therapy. The goal is to employ a safe and effective drug regimen, in combination with improved diet and exercise, to achieve a meaningful and sustainable reduction in body weight and enjoy the consequent benefits. Weight loss medication is an adjuvant to lifestyle changes not a substitute. Many practitioners view the medication as a sign of failure. There is concern that patients may become dependent on medication and forfeit lifestyle changes. Neurotransmitters (catecholamines, noradrenaline and dopamine and serotonin) in the body regulate: • Hunger • Satiety (fullness) • Catecholamines • Noradrenaline • Dopamine • Serotonin. Sympathomimetics reduce appetite or increase satiety by increasing the levels of neurotransmitters in the junctions or synapse between nerve endings. Sympathomimetic amines mimic the effects of the body’s sympathetic nervous system, increasing mental alertness and blood flow to muscles, namely phentermine. Peripherally acting lipase inhibitor, such as orlistat, cause malabsorbtion of fat. For regulatory agencies such as the US Food and Drug Administration (FDA), caution is key. Efficacy must go hand-in-hand with safety. The FDA's efficacy benchmarks

1

2

require that the difference in mean weight loss between the drug and placebo groups is at least 5% over at least one year and statistically significant; and that the proportion of subjects who lose at least 5% of baseline body weight in the activeproduct group is at least 35% and is approximately double the proportion in the placebo-treated group. Also, the obese population is heterogeneous, with variations in degree and duration of overweight, age, and associated comorbidities. A weight-loss drug must be compatible with the profile of an individual obese patient to be truly meaningful in terms of efficacy, safety, and durability.

necessary ongoing professional medical support for better success, and expert advice, there are tips to keep patients motivated on their path to attaining and maintaining their goal weight. Patients can register online at no cost. You can also register at no cost and track your patients’ progress, and access the same tools, such as individual meal plans, important information on treatment, expert advice on nutrition and exercise, and motivational support, which can be used to track and print progress in a weight-loss journey. Phentermine is well tolerated and does not cause withdrawal and has a low abuse potential.

PHENTERMINE

This is a pancreatic lipase inhibitor that decreases the amount of dietary fat absorption. The weight loss is slow with 5% achieved in 12 months but it has shown to reduce progression of type 2 diabetes mellitus by 45%. It must be avoided in chronic renal failure GFR <30mls/min, as well as pancreatic disease and when using cyclosporine A. The main side effects are intestinal especially steatorrhoea with oily stools and flatulence. It increases oxalate levels and is used with caution with nephrolithiasis. Due to the lipase inhibition it can lead to oil-based avitaminosis to vitamin A, D and E.

This is a sympathomimetic amine and has been available since 1959. It suppresses appetite and is a central nervous system stimulant. It is prescribed for short-term weight loss of 5% over 12 weeks. It has no addictive potential and a low side-effect profile and is offered in two strengths of 15mg and 30mg daily. The main side effect is latency stage insomnia and urinary retention. It is contraindicated in glaucoma, hyperthyroidism, anxiety disorders, pregnancy and when using monoamine oxidase inhibitors. It is used with precaution in hypertension and cardiac arrhythmias and the dose is reduced in hepatic dysfunction. Fast initial weight loss, decreased appetite and decreased food cravings, as well as support will help to keep patients motivated to continue with a weight loss programme. A very well researched and easy to follow dietary plan is laid out in www. ilivelite.co.za. The iLiveLite programme has the tools to help with menu plans, tracking weight and measurements on a weekly basis. While getting the

ORLISTAT

BARIATRIC SURGERY No discussion on obesity management is complete without considering bariatric surgery. Bariatric surgery reduces the size of the stomach, increases the feeling of fullness, and reduces the amount of food intake. Different types of bariatric surgery include: Rouxen Y gastric bypass, biliopancreatic diversion with duodenal switch,vertical sleeve gastrectomy, and adjustable gastric banding. Bariatric surgery has been effective in inducing sustained weight loss and improvements in blood pressure, glycaemic control, and lipid profiles. Improvements and innovations in surgical techniques have reduced invasiveness, surgical risk, and recovery times. And evolving guidelines have lowered the BMI thresholds and expanded the patient population eligible for this treatment option, which has traditionally been indicated for only the extremely obese. It has been increasingly prominent in diabetes management, with a dramatic effect on glycaemic control independent of weight loss. However, bariatric surgery still has serious risks of surgical and metabolic complications, and remains very expensive, making it less than ideal for the majority of the obese population.

Indications still remain BMI >40 or BMI >35 with an associated comorbidity. These restrictive operations increase the intrinsic levels of GLP-1 and there is up to 60% cure rate of early type 2 diabetes mellitus and obstructive sleep apnoea.

CONCLUSION Obesity profoundly impacts morbidity, mortality, health care costs, and professional and personal quality of life. Awareness of the obesity problem has done little to reverse the obesity trends among the global population. Recent data suggest that growth of the overweight and obese population in both children and adults have slowed. However, these populations remain substantial and growing. Given that the promotion of lifestyle modifications has proven inadequate, the adjunctive role of medical therapy is vital. The goal is to employ drug regimens in combination with improved eating habits and physical activity to achieve a meaningful, sustainable reduction in body weight. Obesity is driven by more than one factor. Create awareness about the existence of food addiction and the link it has with binge eating and obesity. Obese patients may not be able to lose weight and gain control of their eating habits on their own. Cravings, obsessions about food and a failure to cut back despite knowing how harmful it is, are the reality that these patients live with. Food addiction is a recognized condition, and can be just as debilitating as drug addiction. Faster initial weight loss is associated with a 5 times greater likelihood of achieving 10% weight loss from baseline vs slow initial weight loss. Faster initial weight loss doesn’t result in an increased susceptibility for weight regain. On the contrary, patients who lose weight faster initially, are more motivated to continue with their lifestyle changes and treatment than patients who see slow initial results and are more likely to achieve longterm success. To prevent relapse, it is important for patients to stick to their lifestyle changes. Small changes in weight have profound benefits in health. The patient and the practitioner should establish an encouraging and collaborative therapeutic relationship where the patient takes the primary responsibility to achieve weight loss and the practitioner screens, guides, prescribes and monitors the patient every 12 weeks.

References available on request.

MEDICAL CHRONICLE APRIL 2018 43 25 MEDICAL| CHRONICLE


WOMEN’S HEALTH Focus

ALDARA

®

CHANGING THE

NATURE OF

WITH ALDARA YOUR PATIENTS HAVE THE FREEDOM OF TREATMENT IN THE PRIVACY OF THEIR OWN HOME1

TREATMENT

EXTERNAL GENITAL WARTS Effective treatment – 40 % total clearance at 4 weeks2 Sustained clearance – 87 % at 3 months follow-up3,4 Significantly reduce HPV viral load – > 98 % to 100 % reduction in wart tissue and clearance of > 75 % in wart tissue5 An ideal choice for first-line therapy6

References: 1. O’Mahony C. Am J Clin Dermatol 2005; 6(4):239-243. 2. Garland SM, et al. Int J STD AIDS 2006;17:448-452. 3. Edwards L. J Am Acad Dermatol 2000; 43 (1 Part 2):S12-S17. 4. Edwards L, et al. Arch Dermatol 1998; 134:25-30. 5. Tyring SK, et al. J Infect Dis 1998; 178:551-555. 6. Maw R. Int J STD AIDS 2004; 15:357-364. Scheduling status: S4 Proprietary name and dosage form: ALDARA Cream. Composition: Each 2,0 g cream pump contains 5 % Imiquimod (100 mg). ALDARA Cream Sachet. Composition: Each 250 mg cream sachet contains 5 % Imiquimod (12,5 mg). Preservatives: Methyl hydroxybenzoate 0.2 % m/m, Propyl hydroxybenzoate 0.02 % m/m, Benzyl alcohol 2 % m/m. Pharmacological classification: A 34 Other. Indications: ALDARA Cream is indicated for the topical treatment of superficial basal cell carcinoma (sBCC), and of external genital/perianal warts (condyloma acuminata) and clinically typical, non hyperkeratotic, nonhypertrophic actinic keratosis (AKs) on the face or scalp in adult patients. Registration number: 32/34/0541. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd,. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert approved by the MCC (Medicines Control Council). Further information is available on request from iNova Pharmaceuticals. IN2610/18 44 MEDICAL CHRONICLE


WOMEN’S HEALTH Focus CLINICAL

DERMATOLOGY CPD

DON'T LEAVE

ACTINIC KERATOSIS ALONE

Dr Rakesh Newaj Dermatologist in Private practice, Gauteng and Pretoria

Patients can reduce the risk of actinic keratoses by protecting their skin from the harmful effects of UV rays either from the sun or other sources such as tanning beds.

An actinic keratosis (AK) is a rough, scaling patch on the skin that develops from longterm exposure to the ultraviolet rays. It is most commonly found on photosensitive areas, like, the face, lips, ears, dorsum of hands and arms, scalp or neck. Also known as a solar keratosis, the lesion enlarges slowly and usually causes no signs or symptoms other than a patch or small spot on the skin. These patches take years to develop, usually first appearing in people over 40. Later, few can become pruritic, but rarely painful. Some actinic keratosis lesions will eventually develop into squamous cell carcinoma. Thus AKs are classified as precancerous lesions and need to be attended to.

SYMPTOMS The signs and symptoms of an actinic keratosis include: • Rough, dry and scaling irregular plaque on the skin, usually less than 2.5cm in diameter • In some cases, a hard, wartlike surface • Colour as varied as skin coloured, pink, red or brown • Itching or burning in the affected area, which can become painful in a few places. Histopathologically, AK is an epidermal lesion consisting of dysplastic keratinocytes and is

classified as in situ squamous cell carcinoma (SCC). The intraepidermal proliferation of atypical keratinocytes is characteristic for AK. The disease occurs on the chronically sun-exposed skin and may appear as a single lesion or affect the whole photo exposed areas, where skin cancers are more prevalent. Actinic keratoses are mainly caused by non-ionising radiation, especially by the ultraviolet (UV) spectrum of sunlight. UV-A (ranging from 320nm-400nm) induces photooxidative stress and causes characteristic DNA mutations, while UV-B radiation (ranging from 290nm320nm) results in the formation of cyclobutane (thymidine) dimers which also affects the DNA. The DNA mutations inhibit predominantly the tumour-suppressor genes, thus allowing abnormal gene sequences to multiply. Epidemiological data show a significant prevalence of AKs among the Caucasian population of skin types I-II. The risk for AK has increased significantly in the last few decades. Immunosuppressed patients such as solid organ transplant recipients have a higher risk of developing AKs. This is a result of low immunity due to the use of anti-rejection medications. In addition, AKs are more frequent in older people and populations residing in geographic regions with high UV exposure and closer to the equator.

ACTINIC KERATOSIS

In Europe, a prevalence of 15% in men and 6% in women has been documented, and 34% of men and 18% of women older than 70 years have AKs. Studies in the US show prevalence rates between 11% and 26%. In Australia (Queensland) extraordinarily high prevalence of AK (55% of men between 30 and 70 years and 37% of women) has been reported. Rates of malignant transformation of AKs are considerable. Approximately 10% of AKs in immunocompetent patients develop into invasive squamous cell carcinoma (SCC), while in organ transplanted patients 40% show this progression. From a medical perspective, AKs should be treated early, as it is impossible to predict which lesions may become invasive and therefore carry the potential to develop into metastatic SCC. The immune system is believed to play a critical role in the response to cutaneous neoplasms. As an immunological organ, the skin contains many cells and mediators to respond to malignant cells that express abnormal DNA. Skin cancers associated with UV radiation are highly antigenic and normally induce a local immune response. This reaction against dysplastic cells appears to involve the recognition and presentation of tumour-associated antigens by antigen-presenting cells (Langerhans cells) to lymphocytes, leading

SUPERFICIAL BASAL CELL CARCINOMA

to the induction of an adaptive immune response. Despite this built-in response against abnormal cells, the immune system can be overwhelmed by excessive UV exposure in susceptible individuals. This may be due, in part, to the immunosuppressive effects of UV radiation that include the reduction in density and function of Langerhans cells and the production of immunosuppressive cytokines that modulate the expression of CD1a and ATPase activity. Additionally, UV radiation has been shown to induce natural killer T-cells to mediate antigen-specific immune suppression. Although the exact mechanism of these suppressive signals is not known, it is evident that photo-immune suppression is a significant risk factor for the development of skin cancers. In AK, the visible clinical lesions are the initial manifestation of a multi-step carcinogenesis process or disease continuum that can progress from initial subclinical keratinocyte dysplasia into invasive SCC. Field cancerization develops since ultraviolet light causes neoplastic changes across the entire sun-exposed field of skin. Within the cancerous field, all stages of AK may coexist including individual UVdamaged keratinocytes, subclinical (invisible, non-palpable) lesions, early clinical lesions, late clinical lesions, and in some patients, invasive SCC.

EXTERNAL GENITAL WARTS

WITH ALDARA YOUR PATIENTS HAVE EFFECTIVE SUSTAINED CLEARANCE FOR AK, sBCC AND EGW1-4 References: 1. Krawtchenko N, et al. Br J Dermatol 2007; 157(Suppl.2):34-40. 2. Stockfleth E et al. Arch Dermatol/Vol 140, Dec 2004:1542. 3. Gollnick H, et al. Eur J Dermatol 2005; 15(5):374-381. 4. Edwards L, et al. Arch Dermatol 1998; 134:25-30. Scheduling status: S4 Proprietary name and dosage form: ALDARA Cream. Composition: Each 2,0 g cream pump contains 5 % Imiquimod (100 mg). ALDARA Cream Sachet. Composition: Each 250 mg cream sachet contains 5 % Imiquimod (12,5 mg). Preservatives: Methyl hydroxybenzoate 0.2 % m/m, Propyl hydroxybenzoate 0.02 % m/m, Benzyl alcohol 2 % m/m. Pharmacological classification: A 34 Other. Indications: ALDARA Cream is indicated for the topical treatment of superficial basal cell carcinoma (sBCC), and of external genital/perianal warts (condyloma acuminata) and clinically typical, non hyperkeratotic, nonhypertrophic actinic keratosis (AKs) on the face or scalp in adult patients. Registration number: 32/34/0541. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd,. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert approved by the MCC (Medicines Control Council). Further information is available on request from iNova Pharmaceuticals. IN2659/18

MEDICAL CHRONICLE APRIL 2018 45 15 MEDICAL| CHRONICLE 8547L ALD Medical Chronicle Strip ad R.indd 1

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WOMEN’S HEALTH Focus CLINICAL DERMATOLOGY CPD

TREATMENT Different therapies have been established for the treatment of AKs. These include surgical procedures (CO2-laser-resurfacing, cryosurgery, surgical ablation of large AKs), photodynamic therapy and various topical drugs (5-fluorouracil (5FU), imiquimod (IMIQ), diclofenac). Important criteria to consider before deciding on a specific therapy for AKs are 1) duration and course of lesions, 2) localisation and extent of disease, 3) solitary or multiple AK, 4) age, co morbidities, mental condition,

compliance of the patient, 5) preexisting other (skin) cancer as well as the presence of other risk factors (especially immunosuppression). When a single lesion is treated, it is necessary to consider additional subclinical AK.

CRYOSURGERY Cryosurgery is a nonspecific technique and destroys dysplastic, but also intact cells, by disruption and separation of the epidermis from the dermis. It is the most popular therapy for AKs, especially for the treatment

ALDARA

®

CHANGING THE

NATURE OF TREATMENT

of solitary AK lesions. Cryosurgery is performed using liquid nitrogen or a Peltier element either as a spray or contact-cryosurgery. So far this treatment modality is not standardised for frequency, duration, intensity, and temperature of the application. Complete response rates per lesion treated vary from 75% to 98% and recurrence rates of AKs have been estimated at up to 12% within a one year follow-up period. Although frequently used, cryosurgery lacks controlled studies

WITH ALDARA YOUR PATIENTS HAVE EFFECTIVE SUSTAINED CLEARANCE FOR AK1,2

ACTINIC KERATOSIS (AK) Simultaneous treatment of clinical and subclinical Actinic Keratosis in the field of cancerisation3 85 % initial*† clinical clearance rate (p=0.03) in the imiquimod group 1 73 % initial*† histological clearance rate (p=0.008) in the imiquimod group1

with histological confirmation and long-term follow-up. Topical 5-FU is another method for the treatment of AK. Current recommendations propose a twice-daily application of a 5% cream for up to four weeks. The active derivative of 5-FU, 5-fluorodeoxyuridine-monophosphate (5-FdUMP), is a topical chemotherapeutic antimetabolite that blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. It, therefore, interferes with DNA synthesis and to a lesser extent inhibits RNA transcription. The mechanism of 5-FU action is not specific, and the application may result in severe dermatitis with acute inflammation, itching, pain, ulceration and rarely scarring. These features are limiting the application of 5-FU in the therapy of extensive AKs. Furthermore, clearance rates of approximately 50% and recurrence rates up to 55% have been reported in some studies.

From a medical perspective, AKs should be treated early, as it is impossible to predict which lesions may become invasive and therefore carry the potential to develop into metastatic SCC

73 % of imiquimod patients studied, showed sustained clearance at 12 months after the end of treatment1 86 % of imiquimod patients studied (n=22) patients had no recurrence of initially cleared lesions at 12 month follow-up1 81 %** of imiquimod patients studied showed an excellent cosmetic outcome1

* At test of cure which is 8 weeks after last application of imiquimod1 ** Based on the investigator’s assessments 4 % of patients in the 5-FU group and the cryosurgery group, but 81 % of patients in the IMIQ group showed an excellent cosmetic outcome1 † NPV (Negative predictive value) = A high NPV confirms a high likelihood of complete clearance. NPV is the ratio between histological and clinical clearance. Initial clearance (test of cure) of the treated areas were performed after the end of therapy (i.e. 6 weeks after the last cryosurgery, 4 weeks after last application of 5-FU, 8 weeks after last application of Aldara)1 References: 1. Krawtchenko N, et al. Br J Dermatol 2007; 157(Suppl.2):34-40 2. Stockfleth E et al. Arch Dermatol/Vol 140, Dec 2004:1542. 3. Malvehy J. JEADV 2015; 29 (Suppl. 1), 3–8. Scheduling status: S4 Proprietary name and dosage form: ALDARA Cream. Composition: Each 2,0 g cream pump contains 5 % Imiquimod (100 mg). ALDARA Cream Sachet. Composition: Each 250 mg cream sachet contains 5 % Imiquimod (12,5 mg). Preservatives: Methyl hydroxybenzoate 0.2 % m/m, Propyl hydroxybenzoate 0.02 % m/m, Benzyl alcohol 2 % m/m. Pharmacological classification: A 34 Other. Indications: ALDARA Cream is indicated for the topical treatment of superficial basal cell carcinoma (sBCC), and of external genital/perianal warts (condyloma acuminata) and clinically typical, non hyperkeratotic, nonhypertrophic actinic keratosis (AKs) on the face or scalp in adult patients. Registration number: 32/34/0541. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd,. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert approved by the MCC (Medicines Control Council). Further information is available on request from iNova Pharmaceuticals. IN2664/18

16 APRIL 2018 | MEDICAL CHRONICLE 46 MEDICAL CHRONICLE 8205L ALD AK 160x225 advert R.indd 1

2018/03/29 13:08

Imiquimod is representative of a novel class of immune response modifiers and is an agonist to toll-like receptor 7. It stimulates the immune response by induction, synthesis, and release of cytokines that increases immunity at the cellular level inducing indirect antiviral and anticancerous activity. Topical IMIQ causes a local skin reaction, including erythema, itching, and burning that are generally mild to moderate. Studies have shown that IMIQ is safe and effective in treating clinical and subclinical AKs. Several studies show complete clearance rates from 45% to 84% and recurrence rates of 10% within a 1-year follow-up period and 20% within a subsequent 2-year follow-up study. Due to the increasing prevalence of AKs worldwide and the variety of treatment options for the disease together with the lack of controlled clinical trials, Krawtchenko et al (2007), investigated three commonly


WOMEN’S HEALTH Focus CLINICAL

DERMATOLOGY CPD

RESULTS Sixty-eight percent (17⁄ 25) of patients treated with cryosurgery, 96% of patients treated with 5-FU, and 85% of patients treated with IMIQ achieved initial clinical clearance, p = 0.03. The histological clearance rate for cryosurgery was 32%, 67% for 5-FU, and 73% in the IMIQ group, p = <0.01. The 12-month follow-up showed a high rate of recurrent and new lesions in the 5-FU and cryosurgery arms. The sustained clearance rate of initially cleared individual lesions was 28% for cryosurgery, 54% for 5-FU and 73% for IMIQ (p <0.011). Sustained clearance of the total treatment field was 4%, 33%, and 73% of patients after cryosurgery, 5-FU, and IMIQ, respectively (p <0.01). The patients in the IMIQ group were judged to have the best cosmetic outcomes (p = 0.0001).

It is important to consider the poor cosmetic outcome of cryosurgery

HISTOLOGICAL EVALUATION Total clearance of AK at test of cure (TOC) was histologically confirmed in 32% (8 of 25) of the cryotherapy group, 67% (16 of 24) of the 5-FU group (p = 0.03) and 73% (19 of 26) of the IMIQ group (p = 0.008). For assessing the clinical diagnosis, the negative predictive value (NPV) was calculated. It was defined as the ratio between the histological and the clinical clearance. The NPVs of the clinical clearance based on histology was 86% in the IMIQ group, 70% in the 5-FU group, and 47% in the cryotherapy group.

TWELVE-MONTH FOLLOW-UP Nonrecurrence of initially cleared lesions was observed 12 months after EOT in seven patients for cryosurgery, 13 patients for 5-FU, and 19 patients for IMIQ. Related to all cleared patients at TOC, this corresponds to ratios of 41%, 57%, and 86% for cryosurgery, 5-FU, and IMIQ, respectively. Sustained clearance of the total treatment field was observed 12 months after EOT in one patient for cryosurgery, eight patients for 5-FU, and 19 patients for IMIQ. Related to all cleared patients at TOC, this corresponds to a ratio of 6%, 35% and 86% for cryosurgery, 5-FU, and IMIQ, respectively. Related to all treated patients (considering in the denominator also those not cleared at TOC) sustained clearance of the total treatment field was observed at that time in 4%, 33% and 73% of patients after cryosurgery, 5-FU, and IMIQ, respectively (p <0.01. Based on the investigator’s assessments 4% of patients in the 5-FU group and the cryosurgery group, 81% of patients in the IMIQ group showed an excellent cosmetic outcome. At ToC the skin surface was of better quality than before treatment in all groups. During follow-up, a better improvement of the skin quality was observed in the IMIQ group. Their skin appearance was better: 83% of the IMIQ group presented with a normal skin surface, 58% of the 5-FU group, and 16% of the cryosurgery group. At ToC, clinical clearance was observed in 68% (17 of 25) of the cryosurgery group, in 96% of the 5-FU group, and in 85% of the IMIQ group, respectively.

used though different methods for the treatment of AKs, namely cryosurgery, 5-FU, and IMIQ, and compared their therapeutic efficiency. They analysed affected skin sites clinically and histologically before and after treatment and followed the patients for 12 months thereafter. Patients were randomised to one of the following three treatment groups: One or two courses of cryosurgery (20–40s per lesion), topical 5-FU (twice daily for four weeks), or one or two courses of topical imiquimod (three times per week for four weeks each).

TREATMENT ALGORITHM Given the increasing incidence of AKs worldwide and the high rates of malignant transformation, it is necessary to search for suitable treatment algorithms for AKs. For the first time, three of the most common therapies were compared in this study: cryotherapy, as the most widely used treatment option and representative for surgical methods; topical applied 5-FU, a frequently used method for chemically destroying all types of AK, and IMIQ, a new alternative that may provide a cure of AK by immunostimulation and observed to have high clearance rates in recent studies. The findings of this study show potential advantages and drawbacks of the investigated treatment options and could be useful in the physician’s decision for the ideal treatment. Based on the clinical assessment, cryosurgery was initially effective in 68% of the 25 treated patients. These results confirm the findings of previous

INSTRUCTIONS:

studies, where no histological examination was performed to confirm the clearance rates after treatment with cryosurgery. In our study, clinically diagnosed clearance was confirmed by histology in only 32% of the patients resulting in a low NPV of 47%. This poor histological outcome seems to be predictive for the long-term clinical outcome with a nonrecurrence of initially cleared lesions in only 28% of patients. Considering the sustained clinical clearance addressing the total treatment field the outcome with only 4% cleared patients after 12 months was even poorer. It is important to consider the poor cosmetic outcome of cryosurgery (only 4% of the patients in the cryosurgery group described it as excellent after 12 months, a similar proportion did so in the 5-FU group, but these figures have to be compared to 81% in the IMIQ group), before opting for this treatment. In particular if multiple AK lesions need to be treated, cryosurgery should be considered secondarily only. The initial therapeutic outcome in the IMIQ group was superior to cryosurgery and comparable to 5-FU. With respect to lesion recurrence and sustained complete clearance rates after 12 months as well as the global cosmetic outcome, it was clearly superior to both comparators. After 12 months the cosmetic outcome was classified as excellent for 81% of the patients. A high NPV of 83% in the IMIQ group confirms the efficacy of IMIQ. Thus, additional biopsies

might be avoided. According to Malvehy (2015), the target for the treatment of AK now needs to be the detection and clearance of all clinical and subclinical lesions across the entire sun-exposed field. It was found by Korman et al (2005) that the only treatment for AK that works by enhancing the immune response against dysplastic cells is 5% imiquimod cream. Ongoing research has recently shown that imiquimod may also act through Toll-like receptor 7 to stimulate rapid synthesis and release of cytokines from monocytes, macrophages, and dendritic cells. Toll-like receptors are receptors that recognise special patterns on immune cell surfaces and are considered essential components of the human innate immune response.

CONCLUSION Imiquimod treatment of AK resulted in superior sustained clearance and cosmetic outcomes compared with cryosurgery and 5-FU. It should be considered as a first-line therapy for sustained treatment of AK. For each of the groups under investigation, the test of cure (ToC) of the treated areas were performed after the end of therapy (ie six weeks after the last cryosurgery, four weeks after last application of 5-FU, and eight weeks after last application of IMIQ) and another skin biopsy was performed either from the most suspicious lesion still present or from the cleared areas. References available on request.

1. Go to www.medicalacademic.co.za 2. Click the tab labelled ‘CPD Portal’ on the far right tab near the top of the page. 3. Select the relevant questionnaire from the list and complete the form. MEDICAL| CHRONICLE MEDICAL CHRONICLE APRIL 2018 47 17


CLINICAL | WOMEN'S HEALTH

CLINICAL

WOMEN’S HEALTH Focus

WOMEN’S HEALTH CPD

WHY BACTERIAL VAGINOSIS IS ALL ABOUT BALANCE

Bacterial vaginosis, an imbalance in vaginal flora characterised by low levels of lactobacilli and an increased frequency of facultatively anaerobic bacteria, is one of the most common reproductive tract infections in women globally.

3 CPD POINTS

the incidence of bacterial vaginosis but women with an intrauterine contraceptive device or system in situ have an increased risk of bacterial vaginosis. BV is the most common cause of unusual vaginal discharge, which develops when the normal environment of the vagina changes. One in three women will get it at some stage. BV is characterised by replacement of the usual lactobacillus-dominated flora with overgrowth of many nonBacterial vaginosis (BV) is the most commonly reported microbiological syndrome among women of childbearing as well organisms. as the lactobacillusage, and anaerobic most frequently occurring condition within the female genital tract. The protective hydrogen peroxide producing lactobacillus species is replaced with Gardnerella vaginalis, obligatory anaerobic Gram negative rods, andapproach Mycoplasma aMobilincus presumptivespecies, treatment smoking, douching, antibiotic treatment for the clinical symptoms of BV, although this V IS CHARACTERISED by a shift hominis. More recently, novel bacteria is practical. another condition, young age of coitarche, idea has been challenged by recent findings. in the vaginal flora from the dominant associated with BV such as Atopobium A probiotic treatment could potentially acquisition of a new sex partner and a recent Ultimately, BV is not caused by the mere lactobacillus to a polymicrobial flora, beenthe discovered by bevaginae used tohave replenish healthy vaginal history of multiple sex partners. Although presence of the potential pathogens (which as well as a thin homogeneous white utilising modern molecular microbiota of women with BV. Ifbiology the various sexual activities are well‐known is common) but rather by their unrestrained discharge, a vaginal pH of greater than 4.5, techniques, writes Machado et al.is incompetence of vaginal lactobacilli risk factors for acquisition of BV, it is not increase in number, often reaching cell a positive amine test, and the presence of Many women self-diagnose and self central to the aetiology of recurrent BV, counts that are 100‐ to 1 000‐fold above the accurate to typify the condition as an STI. clue cells microscopically. BV is associated treat episodes of vaginal infection However, it remains true that, for women then a successful strain replacement with normal bacterial levels of the vagina. with a wide array of health issues, including over the counter treatments may therapy would, in theory, cure thisand condition. who have sex with women, the rate of BV Since BV is essentially a microbial preterm births, pelvic inflammatory disease, subsequently present with a history However, the long‐term colonisation by a of concordance among partners is high. If one imbalance among the constituents of the increased susceptibility to HIV infection, 'recurrent thrush,' never having probiotic strain is a complex processhad and,this so woman has diagnosed BV and symptoms vaginal microbiota, its aetiology involves and other chronic health problems. diagnosis confirmed by microbiological far, the results of clinical trials investigating are present in her partner, treatment of the complex interactions between pathogenic Although the condition is not tests. important confirmof the the use Itofisprobiotics forto treatment BV are partner is reasonable. For women with BV species, endogenous vaginal microbiota, usually serious and is asymptomatic in diagnosis and to ensure a full sexual rather conflicting. who Ithave with men, sexual intercourse the and possibly bacteriophages, but approximately 50% to 75% of women, cansex develop in the vagina and on Bacterial vaginosis (BV) is the to host Dr Corné Brink gynaecologist and health screen been done to exclude The aim of BVhas treatment should be to activity, and consistent the relative contributions of these factors multiple studies havedisorder also associated the maledisease and female genitals. It is a obstetrician from Fourways Life Hospital influences leading vaginal in women concurrent infection. Management preserve the vaginal pH at 4.5 and lowerof use of common condoms may reduce the ratevaginal of unknown. Additionally, the interactions aof diagnosis of BV with a wide range of to are very cause of unusual in Johannesburg, BV is mostly seen in childbearing age, contributing vaginal discharge requires an empathic to prevent the overgrowth of pathogens recurrence. circumcision may reducewill and between factors are modulated a reproductive BV has been dischargeMale – three out of four women women these of reproductive age – fromby 15-42 more thantract 60%disorders. of all vulvovaginal approach with reassurance and until normal vaginal flora is reconstructed riskthrush of BV inatfemale woman’s environment. reported to be according three times more prevalent have some partners. point in their lives. years ofbehaviour age, but and can her be present in older the infections, to Machado psychological support as pH necessary. and maintain normal vaginal (14,15). This inherent complexity, along with the lack among infertile than in fertile women and is The bacteria responsible for and younger women as well. et al. Prevalence rates range from According to Dr Brink, BV isincreased a The relationship between BV and TREATMENT of a reliable animal model, is the likely reason associated with a two‐fold elevated risk of BV do not persist in the male partner, 5%-12% in women in the US and UK bacterial infection, or eventhe more level of vaginal pH has made use of Given its adverse effects on quality of life why the aetiology of BV remains a mystery preclinical pregnancy loss following in vitro and concurrent treatment of the male BV vs THRUSH respectively to as high as 50% in some precisely a shift in the as normal balance vagina acidifier materials an attempt to and the potential for severe adverse effects after decades of research. fertilisation‐embryo transfer. partner does not affect the rate of A vaginal yeast infection, thrush, is African countries. According to the of bacteria in thearea vagina. Thrush is of a build an unsuitable for the growth during pregnancy, it is important to identify relapse. Condom use with male sexual caused by candida albicans. It is Journal of the American Pharmaceutical yeast infection that most often comes pathogens, reasonable. a simple treatment regimen for BV. Ideally, RISK FACTORS AETIOLOGY partners may help reduce the risk of not a sexually transmitted infection Association, prevalence studies have from the gut. “I would say I see 75% of the treatment of choice should be safe, easy Epidemiological studies indicate that Historically, G. vaginalis is thought to have recurrence of BV. Use of hormonal but can sometimes develop after shown that of patients with infections would be Candida and about ANTIBIOTIC THERAPY to use, and effective over a long period of the risk of BV is increased in women of the leading role30%-35% in the infection, making contraception does not increase sexual intercourse. vaginitis present with BV. According 25% BV,” she said. Antibiotic therapy has been shown to be time. Because studies have shown that only African ethnicity. Other risk factors include the niche suitable for colonisation by strict

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References: 1. Wain A. Metronidazole Vaginal Gel 0.75% (MetroGeI-Vaginal®) A Brief Review. Infect Dis Obstet1.Gynecol 2. 2018, Beigi R, Austin M, Meyn et an al. independent Antimicrobialsurvey resistance associated with the treatment of -bacterial Am J Obstet Gynecolpackage 2004;191:1124-1129. References: Impact1998;6:3-7. Rx – January Data on file. ResultsL, of among South African Gynaecologists Februaryvaginosis. 2017 2. Metrogel Approved insert 2001/02/11. 4. Hoosen A. Management vaginal discharge. CME February 2004, Vol.22, No.2. Disease Control Prevention. Sexually Transmitted Diseases Treatment MMWR Recomm RepPharmacological 2015; 64 (No. RR-3):69-72. 3. Centers forMetronidazole Scheduling status: Proprietary name (and dosage form): MetroGel® V Vaginal Gel. Composition: 37.5and mg/5 g. Preservatives: Methyl hydroxybenzoate 0.08%, Guidelines. Propyl hydroxybenzoate 0.02%. classification: A 20.2.6 Antimicrobial:ofmedicines against protozoa. Indications: MetroGel® V is indicated for the treatment of bacterial vaginosis. Registration number: 33/20.2.6/0243. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. S2 Proprietary Scheduling name(South (and African dosageHealth form):Products MetroGel Regulatory V Vaginal Gel. Composition: Metronidazole mg/5 g. on Preservatives: hydroxybenzoate 0.08%, Propyl hydroxybenzoate 0.02%. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insertstatus: as approved by the SAHPRA Authority). Further information37.5 is available request fromMethyl iNova Pharmaceuticals. IN3439/19. A 20.2.6 Antimicrobial: medicines against protozoa. Indications: MetroGel V is indicated for the treatment of bacterial vaginosis. Registration number: 33/20.2.6/0243. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the MCC (Medicines Control Council). Further information is available on request from iNova Pharmaceuticals. IN2658/18.

42 AUGUST 2019 | MEDICAL CHRONICLE 48 MEDICAL CHRONICLE

MEDICAL CHRONICLE | APRIL 2018 27


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Proprietary name (and dosage form): Pregnavit M Fizzy. Composition: Each capsu Vitamin A, 6 mg Vitamin B1, 3 mg Vitamin B2, 20 mg Vitamin B3, 7 mg Vitamin B5, 5 mg Vita B12, 120 mg Vitamin C, 1000 IU Vitamin D3, 100 mg Calcium, 1 mg Copper (from AAC), 500 Iron (from AAC), 75 mg Magnesium, 2 mg Manganese (from AAC), 1 mg Potassium, 60 µg 10 mg Zinc. Name and business address: iNova Pharmaceuticals (Pty), Co. Reg. No. 1 Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further info request from iNova Pharmaceuticals. Name and business address: iNova Pharmaceuticals ( 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co. is available on request from iNova Pharmaceuticals. IN496/18

Proprietary dosage form):/ Constructed Pregnavitclass). M MAT Fizzy.DecComposition: contains: 1000 IUM Fizzy. Composition: Each capsule contains: 1000 IU Vitamin A, 6 mg Vitamin B1, 3 Reference: 1. Impactname Rx. Script(and data (Vitamins & Minerals 2017. ProprietaryEach name capsule (and dosage form): Pregnavit Vitamin mg Vitamin 3 mg Vitamin B2, 20B6, mg5 μg Vitamin B3, 120 7 mg 5 IUmg Vitamin B6,mg 5 µg Vitamin mg Vitamin B2,A, 206mg Vitamin B3, 7B1, mg Vitamin B5, 5 mg Vitamin VitaminB12, mgVitamin Vitamin C,B5, 1000 Vitamin D3, 100 Calcium, 1 mg Copper (from AAC), 500 μg Folic Acid, 24 mg Iron (from AAC), 75 mg Magnesium, 2 mg Manganese 1 mgC,Potassium, μg Selenium 10 mg Zinc.1Name and business iNovaµg Pharmaceuticals (Pty),mg Co. Reg. No. 1952/001640/07,15E Riley Road, Bedfordview. Tel. No. 011 087 0000. B12, 120(from mg AAC), Vitamin 1000 IU60Vitamin D3,(from 100AAC), mg Calcium, mg Copper (fromaddress: AAC), 500 Folic Acid, 24 www.inovapharma.co.za. available from iNova(from Pharmaceuticals. Name and business iNova Pharmaceuticals Iron (from AAC), Further 75 mginformation Magnesium, 2 on mgrequest Manganese AAC), 1 mg Potassium, 60address: µg Selenium (from AAC), (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information is available on request from iNova Pharmaceuticals. IN496/18 10 mg Zinc. Name and business address: iNova Pharmaceuticals (Pty), Co. Reg. No. 1952/001640/07,15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information available on request from iNova Pharmaceuticals. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information


CLINICAL WOMEN’S HEALTH Focus WOMEN’S HEALTH CPD

She says that while some patients might misdiagnose themselves and use incorrect treatments, most will come for a checkup if their symptoms don’t improve with whichever treatment they are using.

SYMPTOMS Symptomatic BV is characterised by an offensive and homogenous vaginal discharge. The odour is often described as fishy and associated with significant embarrassment and it is frustrating to both patient and clinician due to the lack of curative therapy. However, in about half of microbiologically diagnosed BV

patients are asymptomatic. According to the International Journal of Obstetrics and Gynecology, of the estimated 21 million women infected with BV in the US every year, only about four million will seek treatment, and 50% of women treated will experience a recurrence of symptoms within a year, a consequence of low awareness of this condition. According to Dr Brink, 50%-75% of women with BV will be asymptomatic. “Those with symptoms will usually see an off-white thin homogenous discharge that has a bit of a fishy odour. This fishy smell is often more pronounced after

sexual intercourse,” she said. Women may report psychosexual symptoms with lack of libido and anxiety about infection as a consequence of recurrent episodes of BV and associated malodour. BV can have a substantial negative impact on a woman's quality of life. Stress associated with living with the infection can potentially place a strain on romantic relationships and self-image. It can also have a negative impact on social and physical activities, which can impact productivity at work and/or school. “There are different criteria for diagnosis of BV, but most commonly we will see a change in the pH of the vagina,

with the discharge and a fishy odour when the discharge is mixed with a 10% potassium hydroxide solution. I diagnose it based on Pap smear results or vaginal swabs,” said Dr Brink.

Dr Taheera Hassim, gynaecologist and obstetrician at Netcare Sunninghill Hospital

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Reference:1.1.Impact ThrushRx and Bacterial2018, vaginosis. Association. https://www.fpa.org.uk/sites/default/files/thrush-bacterial-vaginosis-information-and-advice.pdf. Accessed 2018. 3. Thrush and Bacterial vaginosis. Looking References: – September Data onThe file. Family Results ofPlanning a survey of 64 South African gynaecologists, commissioned by iNova and undertaken by a third party in February 2017. 2. Metrogel V approved package March insert, 2000/10/23. after your sexualstatus: health [online] [cited 22 Marchname 2018]; Available from URL:form): http://www.sexualhealthsheffield.nhs.uk/wp-content/uploads/2015/03/thrush-bacterial-vaginosis-information-and-advice.pdf. 4. Ries AJ. Treatment of Vaginal Scheduling S2 Proprietary (and dosage MetroGel V Vaginal Gel. Composition: Metronidazole 37.5 mg/5g. Preservatives: Methyl hydroxybenzoate 0.08%, PropylInfections: Candidiasis, Bacterial Vaginosis, and Trichomoniasis. J Am Pharm Assoc. 1997;NS37:563-9. 5. Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR 2015;64(3):1-137. 6. Hanson JM, McGregor JA, Hillier S, et al. Metronidazole for bacterial vaginosis. A comparison of hydroxybenzoate 0.02%. Pharmacological classification: A 20.2.6 Antimicrobial: medicines against protozoa. Indications: MetroGel V is indicated for the treatment of bacterial vaginosis. vaginal gel vs. oral therapy. J Reprod Med. 2000;45(11):889-96. 7. Wain A. Metronidazole Vaginal Gel 0.75% (MetroGeI-Vaginal®) A Brief Review. Infectious Diseases in Obstetrics and Gynecology 1998;6:3-7. 8. Beigi R, Austin M, Meyn L, et al. Antimicrobial resistance associated with the treatment of bacterial vaginosis. American JournalName of Obstetrics Gynecology 2004;191:1124-9. Registration number: 33/20.2.6/0243. and and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 S2 Proprietary name (and 087 0000.status: www.inovapharma.co.za. Fordosage full prescribing information, to the package insert37.5 asmg/5 approved by the MCC (Medicines Control Council). Further information is available onclassification: request fromA iNova Scheduling form): MetroGel V Vaginal Gel.refer Composition: Metronidazole g. Preservatives: Methyl hydroxybenzoate 0.08%, Propyl hydroxybenzoate 0.02%. Pharmacological 20.2.6 Antimicrobial: medicines against protozoa. Indications: MetroGel V is indicated for the treatment of bacterial vaginosis. Registration number: 33/20.2.6/0243. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, Pharmaceuticals. IN2658/18. 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. IN2900/18.

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28 APRIL 2018 | MEDICAL CHRONICLE 50 MEDICAL CHRONICLE

2018/03/23 13:07 2019/07/05 09:00

RISK FACTORS Epidemiological studies have reported several groups of women at risk of BV. Some of these included risk factors similar to STDs such as young age, black ethnicity, douching, smoking, use of intra-uterine contraceptive devices, multiple sexual partners and recent change of partners. This suggests that a sexually transmissible agent is responsible for the changes of vaginal flora that underpin BV. However, other studies clearly showed that BV also occurs in virgin girls, which indicate that BV is not exclusively sexually transmitted. Also, treatment of male sexual contact of BV cases did not reduce the recurrence adding further evidence against the STDs theory. Women who have sex with women (WSW) have high prevalence of BV and there is an association with high lifetime number of female partners, shared use of sex toys, and oral-anal sex. Bradshaw and colleagues report that the rate of recurrent BV increased two-folds in women with a history of BV, sexual workers, and those who had a regular male sexual partner. Also, the recurrence rate in WSW increased by three-fold, and use of hormonal contraception was protective and recurrence commonly occurs around the time of menstruation. Some of the risk factors for BV include having more than one sexual partner, having changed partners in the last 30 days, having a female sexual


WOMEN’S HEALTH Focus CLINICAL WOMEN’S HEALTH CPD

partner, and douching at least once a month or within the previous seven days. Recurrence of BV after treatment is common and can be increased by personal hygiene practices, such as vaginal douching, that disrupt the normal vaginal flora. Bacterial vaginosis may also be associated with concurrent STIs, commonly Trichomonas vaginalis. Bacterial vaginosis is associated with pelvic infection after induced abortion and in pregnancy with pre-term delivery and low birthweight babies. According to Dr Taheera Hassim, gynaecologist and obstetrician at Netcare Sunninghill Hospital, many women claim that douching makes them feel cleaner, eliminates embarrassing odor and protects them against infection. “The vagina, like many other areas of the body, can cleanse itself. So there is very little reason for a normal, healthy woman to use a vaginal douche. Douching can upset the balance of the vaginal flora and change the vaginal pH, thus predisposing the woman to vaginitis.” Douching changes the balance of natural chemicals in the vagina, which can make it easier for one to get these infections. The vagina cleans itself on the inside with natural fluids. The best way to clean the outside of the vagina is to wash with warm water and gentle, scent-free soap during a bath or shower.

COMORBIDITIES BV is associated with serious health problems, including pre-term birth, spontaneous abortion, pelvic inflammatory disease, endometritis as well as the acquisition and transmission of several sexually transmitted diseases (STDs). Recurrence rates are high. Clinical trials reported a cure rate of 80%-90%, but about 30% of the women taking part in the trials had recurrence within three months. Long-term follow up (mean 6.5 year) showed that 52% of these women had at least one more episode of BV. Although BV was initially thought to be of limited clinical significance, it has since been implicated in a variety of possible consequences including risks of preterm birth and the development of pelvic inflammatory disease, as well as increased risk of upper genital tract infection including possible endometriosis after giving birth, wound infection, increased infection after hysterectomy and chorioamnionitis or intra-amniotic infection. BV has also been linked to an increased transmission of HIV and other sexually transmitted infections.

TREATMENT Treatment is based on the culture and sensitivity of the bacteria, but

INSTRUCTIONS:

Although BV was initially thought to be of limited clinical significance, it has since been implicated in a variety of possible consequences including risks of preterm birth and the development of pelvic inflammatory disease

options can include gels, creams and oral treatments. The two most common prescription medications used for the treatment of BV are metronidazole and clindamycin. Both medications need to be used for multiple days and can be taken in pill form by mouth, or with a gel or cream that is inserted inside the vagina. Oral medication may be more convenient, but causes more side effects. A single-dose medication that is taken by mouth is also available. However, it is often more expensive and is not more effective than metronidazole or clindamycin. Vaginally administered metronidazole has low systemic absorption results in better tolerability with fewer side effects than oral mediation.

VAGINAL GEL Two randomised controlled studies directly compared the efficacy of vaginal (0.75% metronidazole vaginal gel 5g, twice daily for five days) versus oral regimens (500mg twice daily for seven days). The efficacy of vaginal and oral regimens was similar when evaluated two weeks and five weeks after treatment. However, the vaginal regimen was associated with less gastrointestinal complaints (33% vs 52%). Only one study has evaluated the use of oral clindamycin versus intravaginal administration. According to this study, oral administration of

450mg clindamycin three times daily and 2% clindamycin in vaginal cream 5g once daily, for seven days had similar cure rates.

PERSISTENT VAGINAL DISCHARGE It can be difficult to know what to do for women who complain of persistent vaginal discharge with repeated negative STI screen results and negative cervical cytology. When minimal discharge is evident on examination, it is worth discussing again personal hygiene practices and douching, the basis for physiological discharge, and inquiring whether there are psychosexual difficulties as a result of the patient's continued symptoms. If use of spermicides and lubricants is contributing to symptoms, alternative contraception choices should be discussed. An extensive cervical ectropion can cause heavy mucoid discharge, which, if troublesome to a woman with normal cervical smear test results, may be helped by intravaginal acetic acid. Some cases may warrant cryocautery to relieve symptoms. After the menopause, atrophic vaginal changes may predispose women to infective vaginitis. Intravaginal oestrogen replacement, with pessaries or cream, gradually improves the condition of the vaginal epithelium and reduces the susceptibility to infection.

Underlying gynaecological disease must be considered in all women with unexplained persistent vaginal discharge. Gynaecological neoplasms, such as benign endocervical and endometrial polyps, can present with vaginal discharge, and malignancy needs to be excluded. Referral to a gynaecologist allows for further investigations that may include transvaginal ultrasonography, endometrial sampling, and hysteroscopy. References

1. Myer L et al. Bacterial Vaginosis and Susceptibility to HIV Infection in South African Women. A Nested Case-Control Study. Journal of Infectious Diseases 2005; 192:1372-80 2. Ries, A .Treatment of Vaginal Infections. Journal of American Pharmaceutical Association Vol NS37 No 5 September October 1997 3. Eckert Acute Vulvovaginitis. The New England Journal of Medicine – Clinical Practice. 1 April 2010 4. Chavoustie SE et al. Experts explore the state of bacterial vaginosis and the unmet needs facing women and providers. International Journal of Gynecology and Obstetrics. May 2017 (http://onlinelibrary.wiley.com/doi/10.1002/ ijgo.12114/full) 5. Impact Rx. Script data - September 2017. 6. Metrogel approved package insert 2001/02/11. 7. Hansen, JM. Metronidazole for Bacterial Vaginosis. The Journal of Reproductive Medicine. Volume 45 No 11 / November 2000 8. Hoosen A. Management of vaginal

1. Go to www.medicalacademic.co.za 2. Click the tab labelled ‘CPD Portal’ on the far right tab near the top of the page. 3. Select the relevant questionnaire from the list and complete the form.

MEDICAL| APRIL CHRONICLE 51 MEDICAL CHRONICLE 2018 29


WOMEN’S HEALTH Focus CLINICAL WOMEN'S HEALTH

USING BISPHOSPHONATES IN MANAGING OSTEOPOROSIS Osteoporosis is a common and costly disease, associated with significant morbidity and mortality.

According to the NOFSA guideline for the Diagnosis and Management of Osteoporosis (2017), bisphosphonates are potent inhibitors of osteoclastic bone resorption. The aminobisphosphonates cause a 2%-10% increase in bone mineral density (BMD). The anti-fracture efficacy of the bisphosphonates has been documented in women and men, in most subsets of osteoporosis including glucocorticoid-induced osteoporosis

HOW IT WORKS Bone is in a constant state of remodeling. New bone is laid down by cells called osteoblasts while old bone is removed by cells called osteoclasts. Bisphosphonates strengthen bone by inhibiting bone removal (resorption) by osteoclasts. After menopause, there is an increased rate of bone loss leading to osteoporosis, and ibandronate has been shown to increase bone density and decrease fractures of bones.Ibandronate is one of the bisphosphonate drug treatments which are widely used to reduce the risk of broken bones in people with osteoporosis.

42 JULY 2018CHRONICLE | MEDICAL CHRONICLE 52 MEDICAL

HOW PATIENTS SHOULD USE THEM Documentation of the anti-fracture efficacy of bisphosphonates has been limited to patients at high fracture risk, and their use should, therefore, largely be reserved for those with a BMD T-score ≤-2.5 and/or a prior fracture. Oral bisphosphonates should be taken on an empty stomach with tap water only, and the patient should refrain from reclining. Oral bisphosphonates should not be prescribed to individuals with known upper gastrointestinal disease. Following five years of therapy with a bisphosphonate, the NOFSA guideline suggests that a ‘drug holiday’ be considered in those who are not at very high fracture risk, in order to prevent the unlikely development of atypical fragility fractures (AFFs). This may be particularly applicable to cases of GIOP. An evidence-based (GIOP), in more than 30 RCTs. The relative risk (RR) of vertebral fractures is generally decreased by about 40%–50%, and that of non-vertebral fractures by about 25-35% over periods of three years. Studies on the anti-fracture efficacy of the bisphosphonates have been limited to patients at high fracture risk, being those with a BMD in the osteoporosis range or with prior fracture. Bisphosphonates are generally well tolerated and the only relatively

recommendation on the duration of such a drug holiday cannot be made, other than to say that the patient should clearly be followed up. BMD is usually maintained following the discontinuation of a bisphosphonate, but should be monitored after 18-24 months. In subjects with fractures or a BMD that is still in the osteoporosis range (T-score ≤ -2.5), in those with ongoing risk factors, and in those who responded poorly to treatment (eg BMD decreased markedly and progressively), treatment with a nonbisphosphonate, ongoing treatment with a bisphosphonate or with another bone active drug, should be considered. According to the NOFSA guideline, until further safety and efficacy data become available, it cannot recommend the use of generic bisphosphonates.

common side effect of the oral preparations is upper gastrointestinal discomfort, particularly when the patient reclines within 30-60 minutes of taking the drug. A flu-like syndrome following the intravenous administration of bisphosphonates may occur, but is usually a first-dose phenomenon. According to the NOFSA guideline, bisphosphonates should be regarded as first-line treatment for osteoporosis in postmenopausal women, men and in certain secondary osteoporoses, like

glucocorticoid-induced osteoporosis (GIOP). References

Hough S, Amod A, Ascott-Evans B et al. South African Clinical Guideline for the Diagnosis and Management of Osteoporosis 2017. For the National Osteoporosis Foundation of South Africa. Official supplement to Journal of Endocrinology, Metabolism and Diabetes of South Africa. JEMSDA 2017; 22(1) (Supplement 1). NOS UK: https://nos.org.uk Medicine Net: www.medicinenet.com


CLINICAL WOMENâ&#x20AC;&#x2122;S HEALTH Focus OBESITY

BATTLING THE Obesity is a medical condition that requires intervention.

BULGE *Supplied content

Obesity is a worldwide problem and places a huge burden on healthcare resources and the economy. In SA, a quarter of people are obese. Obesity is a growing pandemic of global concern. Obesity leads to morbidity and mortality. In fact, obesity and overweight constitute the fifth leading risk of global deaths. Negative consequences of obesity include an increased risk of heart disease, diabetes, dyslipidaemia and mortality. It is driven by different factors, and simply following a healthy eating plan alone may not be enough to achieve the desired weight loss in an obese patient. Doctors who ignore obesity and its associated comorbidities, do not broach the topic with patients, and will continue to treat the co-morbid conditions. Even a modest 55%-10% decrease in body weight results in striking health benefits. Obesity increases the risk of death by 50%100%. The risk of mortality already starts to increase with BMI >25kg/ m2. Obese patients are at greater risk of heart disease, type 2 diabetes, dyslipidaemia, stroke and cancers. There is a 25% increase in type 2 diabetes risk with every unit increase in BMI >25kg/m2. Obesity is driven by more than one factor. Food addiction is a recognised condition, and can be just as debilitating as drug addiction. There is also a link between binge eating and obesity. Obese patients may not be able to lose weight and gain control of their eating habits on their own. Cravings, obsessions about food and a failure to cut back despite knowing how harmful it is, are the reality that these patients live with. Appetite and satiety (energy balance) are regulated by hormones that act primarily on the hypothalamus to inform the brain about the status of energy reserves. Phentermine is a centrally acting sympathomimetic amine, and its appetite suppressant effect is generally considered to be exerted through the hypothalamus. It reduces food cravings, which results in weigh loss. Sweet and fatty foods (hyper-palatable food) are positively linked to food cravings and food addiction. The weight loss is progressive. Tolerance does not develop to the product and patients will be more motivated to continue with lifestyle changes and may have a better chance

of long-term success vs a product that achieves slower weight loss. A survey conducted amongst physicians who specialise in the treatment of obesity revealed

that 98% of these specialists use pharmacotherapy, of which 97% preferred to use phentermine. Pharmacotherapy used in conjunction with a healthy diet, exercise

and behaviour changes, is significantly effective in reducing body weight and waist circumference. References available on request.

NEW PACKAGING

S5

S5

MEDICAL CHRONICLE | FEBRUARY 2018 39 MEDICAL CHRONICLE 53


SHE MAY HAVE

44 %

Increase in pregnancy success in patients undergoing IVF1#

45,5 %

Reduction in insulin resistance2

8,4 %

Reduction in

obesity3**

16,4 % Reduction in hirsutism 4**

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POLYCYSTIC OVARIAN SYNDROME & ASSOCIATED INFERTILITY##1-7 *Polycystic ovarian syndrome # IVF - In-vitro fertilisation **Studies were conducted on supplemental Alpha Lipoic Acid only ## Due to PCOS

References: 1. Rago R, Marcucci I, Leto G, et al. Effect of myo-inositol and alpha-lipoic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. J Biol Regulators Homeostatic Agents 2015;29(4):1-11. 2. Genazzani AD, Shefer K, Della Casa D, et al. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J Endocrinol Invest 2018;41:583–590. 3. Carbonelli MG, Di Renzo L, Bigioni M, et al. α-Lipoic Acid Supplementation: A Tool for Obesity Therapy? Curr Pharmaceut Design 2010;16:840846. 4. De Cicco S, Immediata V, Romualdi D, et al. Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin-independent action. Gynecol Endocrinol 2017;33(9):698–701. 5. Sinopol® package insert, February 2019. 6. Cappelli V, Musacchio MC, Bulfoni A, et al. Natural molecules for the therapy of hyperandrogenism and metabolic disorders in PCOS. Eur Rev Med Pharmacol Sci 2017; 21(2 Suppl):15-29. 7. Bellver J, Rodríguez-Tabernero L, Robles A, et al. Polycystic ovary syndrome throughout a woman’s life. J Assist Reprod Genet 2018;35:25 -39. Proprietary name (and dosage form): SINOPOL® granules. Composition: Each sachet contains: Myo-inositol 1 000 mg, Alpha Lipoic Acid 400 mg and Folic Acid 200 µg. Complementary Medicine: Health Supplement. D34.12 Multiple Substance formulation. This unregistered medicine has not been evaluated by SAHPRA for its quality, safety or intended use. Studies as part of the references were not conducted on Sinopol®. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert. Further information is available on request from iNova Pharmaceuticals. IN3397/19.


CLINICAL WOMEN’S HEALTH Focus PRODUCT UPDATE

IMPORTANCE OF

NATURAL BALANCE Mundipharma has launched a new cosmetic range specifically designed for the intimate area. The new range focuses on natural ingredients and prebiotics.

Prebiotics promote the growth of the good bacteria naturally found in the vaginal flora

This TRI-CARE+™ formulation is combined with prebiotics, an innovative concept in intimate care. Prebiotics promote the growth of the good bacteria naturally found in the vaginal flora, which helps keep it healthy by preventing the invasion of unhealthy organisms. This unique combination provides protection from unwanted symptoms associated with pH imbalance. The hypoallergenic, gynaecologically tested and pHbalanced products have no parabens and are colourant free. Mundipharma was recently recognised when it was awarded the Top Gender Empowered Company Award in the Healthcare & Pharmaceuticals category at the recent 2018 Standard Bank Top Women Awards. Mundipharma CEO, Raman Singh, says “Our goal is to share our expertise in this area and educate women about the importance of feminine care.

Women’s issues remain a core part of our philosophy, and we believe that through improvement of women’s health

in particular, we are playing our role in the upliftment and empowerment of women in South Africa.” The Betadine

Daily Intimate Care range of products is currently available at Clicks and other leading pharmacies.

UI

RED 2

PREFERRED BY SOUTH AFRICAN GYNAECOLOGISTS1

EQ

Everything from daily protection, to doctor-recommended treatments for specific issues is now available in the Betadine Intimate Care range. Betadine Daily Intimate Care, incorporates daily foam, wash and intimate wipes, scientifically formulated from natural ingredients to meet daily feminine hygiene needs and support the intimate area’s natural pH balance. The range has a unique TRI-CARE+ formulation combined with prebiotics to provide daily gentle protection and maintain the pH balance of the intimate flora. The formulation contains three natural ingredients: ‘Immortelle’, a natural antioxidant that helps improves skin’s natural moisture; ‘Citrofol (TM) AI’, a natural extract that provides effective odour neutralisation, and ‘Citrofol (TM) SC 50’, a natural emollient that soothes the skin and reduces skin redness and irritation.

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B

metronidazole 0.75%

IS THE MOST COMMON VAGINAL INFECTION, AFFECTING 1 out of 3 WOMEN3,4 5

Metronidazole Gel 0.75 % is a recommended regimen for the treatment of B

Why treat orally when you can treat topically2

Comparable efficacy to oral metronidazole, with lower systemic absorption and improved systemic tolerability6,7

Comparable efficacy to intravaginal clindamycin, with little to no development of resistance8

References: 1. Impact Rx – September 2018, Data on file. Results of a survey of 64 South African gynaecologists, commissioned by iNova and undertaken by a third party in February 2017. 2. Metrogel V approved package insert, 2000/10/23. 3. Thrush and Bacterial vaginosis. Looking after your sexual health [online] [cited 22 March 2018]; Available from URL: http://www.sexualhealthsheffield.nhs.uk/wp-content/uploads/2015/03/thrush-bacterial-vaginosis-information-and-advice.pdf. 4. Ries AJ. Treatment of Vaginal Infections: Candidiasis, Bacterial Vaginosis, and Trichomoniasis. J Am Pharm Assoc. 1997;NS37:563-9. 5. Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR 2015;64(3):1-137. 6. Hanson JM, McGregor JA, Hillier S, et al. Metronidazole for bacterial vaginosis. A comparison of vaginal gel vs. oral therapy. J Reprod Med. 2000;45(11):889-96. 7. Wain A. Metronidazole Vaginal Gel 0.75% (MetroGeI-Vaginal®) A Brief Review. Infectious Diseases in Obstetrics and Gynecology 1998;6:3-7. 8. Beigi R, Austin M, Meyn L, et al. Antimicrobial resistance associated with the treatment of bacterial vaginosis. American Journal of Obstetrics and Gynecology 2004;191:1124-9. Scheduling status: S2 Proprietary name (and dosage form): MetroGel V Vaginal Gel. Composition: Metronidazole 37.5 mg/5 g. Preservatives: Methyl hydroxybenzoate 0.08%, Propyl hydroxybenzoate 0.02%. Pharmacological classification: A 20.2.6 Antimicrobial: medicines against protozoa. Indications: MetroGel V is indicated for the treatment of bacterial vaginosis. Registration number: 33/20.2.6/0243. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. IN2900/18.

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MEDICAL CHRONICLE | OCTOBER 2018 19 MEDICAL CHRONICLE 55


WOMEN’S HEALTH Focus CLINICAL SEXUAL HEALTH

Identification and care of

EXTERNAL GENITAL WARTS External genital warts (EGWs) are one of the most commonly reported sexually transmitted diseases worldwide.

EGWs, also known as condylomata acuminata, are epidermal growths caused by the human papillomavirus (HPV), on the anogenital areas of both females and males (Narsinghani et al 2016). The specific cause of the occurrence of these warts is HPV-induced infection and replication in the lower levels of stratified epithelium, which manifests clinically as warty growths and dysplastic areas of cellular proliferation (Wiley et al 2002). About 50% to 60% of sexually active women aged 18 to 49 years have been exposed to HPV infection, but only 10% to 15% will have genital warts (Narsinghani et al 2016). Although benign, EGWs can cause significant physical discomfort, including inflammation, fissuring, itching, bleeding and dyspareunia, although they are benign growths (Maw 2004). Additionally, they are perceived as cosmetically unacceptable, and can cause psychological distress, anxiety, guilt, anger, loss of self-esteem and relationship problems for patients (Maw 2004). They also create concerns about future fertility and of cancer risk (Lacey et al 2012). There is no certain way to tell who will develop health

problems from HPV and who will not (CANSA 2017). In most cases HPV goes away by itself before it causes any health issues, and most people who become infected with HPV do not even know that they have it (CANSA 2017). Most patients only complain of the presence of the lesions, which are otherwise symptomless, although symptoms can include itching, bleeding, fissuring or dyspareunia (Lacey et al 2012). EGWs can develop months or even years after contracting HPV (CDC 2015). HPV types that cause genital warts can be passed on to another person even in the absence of visible signs of warts (CDC 2015). Sex partners also tend to share HPV, even though signs of HPV such as warts might occur in only one partner or in neither partner (CDC 2015). A vaccine that prevents genital warts (Gardasil) is available for both males and females, but it will not treat existing HPV or genital warts (CDC 2015). This vaccine can prevent most cases of genital warts in persons who have not yet been exposed to wartcausing types of HPV (CDC 2015).

DIAGNOSIS

Diagnosis of anogenital warts is usually made by visual inspection, but can be

ACTINIC KERATOSIS

confirmed by biopsy, which is indicated if lesions are atypical (eg pigmented, indurated, affixed to underlying tissue, bleeding or ulcerated lesions) (CDC 2015). Biopsy might also be indicated in the following circumstances, particularly if the patient is immunocompromised (including those infected with HIV) CDC 2015): • The diagnosis is uncertain • The lesions do not respond to standard therapy • The disease worsens during therapy. Lesions are often found in sites that are traumatised during intercourse and may be solitary, but frequently there will be five to 15 lesions of 1-5 mm diameter (Lacey et al 2012). Warts may also coalesce into larger plaques, but this is more commonly seen with immunosuppression and in diabetes (Lacey et al 2012). Furthermore, anogenital warts may vary significantly in colour, from pink to salmon red, and from white to greyish white to various shades of brown (Lacey et al 2012). Although warts tend to be non-pigmented, pigmented lesions are mostly seen on the labia majora, penile shaft, pubis, groin, perineum and perianal area (Lacey et al 2012).

SUPERFICIAL BASAL CELL CARCINOMA

Because genital warts can be sexually transmitted, patients with genital warts benefit from testing for other STDs and sexual activity should be avoided with new partners until the warts are gone or removed (CDC 2015). HPV might remain present and can still be transmitted to partners even after the warts are gone (CDC 2015).

TREATMENT OPTIONS

Because warts might spontaneously resolve within one year, an acceptable alternative for some persons is to forego treatment and wait for spontaneous resolution (MMWR 2015). That being said, the current treatment options are largely centred upon removal of the warty growths rather than elimination of the underlying viral infection (Yanofsky et al 2012). Since EGW treatments do not remove the viral infection, it is common for genital warts to recur after treatment, especially in the first three months (CDC 2015). Because of this, it is necessary for successful treatments to stimulate the immune system to recognise the virus (O’Mahony 2005). Treatments for genital warts can be classed as either provider- or patient-applied (Maw 2004). Traditionally, genital

EXTERNAL GENITAL WARTS

WITH ALDARA YOUR PATIENTS HAVE EFFECTIVE SUSTAINED CLEARANCE FOR AK, sBCC AND EGW1-4 References: 1. Krawtchenko N, et al. Br J Dermatol 2007; 157(Suppl.2):34-40. 2. Stockfleth E et al. Arch Dermatol/Vol 140, Dec 2004:1542. 3. Gollnick H, et al. Eur J Dermatol 2005; 15(5):374-381. 4. Edwards L, et al. Arch Dermatol 1998; 134:25-30. Scheduling status: S4 Proprietary name and dosage form: ALDARA Cream. Composition: Each 2,0 g cream pump contains 5 % Imiquimod (100 mg). ALDARA Cream Sachet. Composition: Each 250 mg cream sachet contains 5 % Imiquimod (12,5 mg). Preservatives: Methyl hydroxybenzoate 0.2 % m/m, Propyl hydroxybenzoate 0.02 % m/m, Benzyl alcohol 2 % m/m. Pharmacological classification: A 34 Other. Indications: ALDARA Cream is indicated for the topical treatment of superficial basal cell carcinoma (sBCC), and of external genital/perianal warts (condyloma acuminata) and clinically typical, non hyperkeratotic, nonhypertrophic actinic keratosis (AKs) on the face or scalp in adult patients. Registration number: 32/34/0541. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd,. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert approved by the MCC (Medicines Control Council). Further information is available on request from iNova Pharmaceuticals. IN2659/18

14 2019 | MEDICAL CHRONICLE 56 MARCH MEDICAL CHRONICLE 8547L ALD Medical Chronicle Strip ad R.indd 1

2018/03/29 12:17


CLINICAL WOMEN’S HEALTH Focus SEXUAL HEALTH

warts have been treated with providerapplied therapies, often requiring multiple clinic visits for successful wart clearance (Maw 2005). Commonly used physical treatment methods include cryotherapy, trichloroacetic acid, laser and electrocautery but many patients respond extremely well to home therapies with either podophyllotoxin or imiquimod (O’Mahony 2005). This is consistent with the shift in focus over recent years towards topical, patient-applied treatments (Maw 2004). Patients prefer the comfort and dignity of home treatment, and this should be the first-line of treatment for the majority of patients (O’Mahony 2005). Clinician feedback over the years has indicated that patient preference is of major importance and the majority of patients want a treatment they can apply in the comfort of their own homes, as opposed to regular clinic visits (O’Mahony 2005). The most common patient-applied treatments are imiquimod, podophyllotoxin and 5-fluorouracil and of these, only imiquimod and podophyllotoxin are recommended in both Europe and the US (Maw 2004). It is unclear whether treatment of visible genital warts has any effect on transmission of infection, and most currently available treatments do not attempt to treat the underlying problem of viral infection; they only cosmetically remove warts (Maw 2004). Therefore, in contrast to other sexually transmitted diseases, the primary treatment goals associated with EGWs resulting from HPV are to ameliorate symptoms, remove symptomatic warts and minimise psychological sequelae where possible (Maw 2004). Imiquimod Imiquimod is a novel synthetic molecule with potent immune-modifying activities, often formulated in a 5% vanishing cream as Aldara (Slade et al 1998). The molecule does not demonstrate direct antiviral activity, but through induction of cytokines results in immune-based resolution of wart tissue and reduction of viral burden (Slade et al 1998). Phase III trials of imiquimod have demonstrated that patients who experience complete clearance of either new or recalcitrant warts tend to remain clear, possibly related to Th1 immune recognition and memory (Slade et al 1998). Selfapplication, good tolerability and a unique mechanism of action combine to make imiquimod a reasonable firstline therapy for genital warts (Slade et al 1998). The same study found that over 50% of patients rated imiquimod better than cryotherapy, podophyllotoxin and laser therapy (O’Mahony 2001). Recurrence rates are also consistently lower after treatment with imiquimod than they are after podophyllotoxin treatment, even though their efficacy rates for clearing EGWs are similar (Yanofsky et al 2012). Imiquimod has been shown to be effective in many studies, including three randomised, placebocontrolled, double-blind trials in which clearance rates were 37%–52% after

8–16 weeks of treatment (Maw 2004). When considering a broader selection of trials, clearance rates for imiquimod were 33%–72% for up to 16 weeks of treatment (Maw 2004). During the three-month follow-up phase of an imiquimod clinical trial, baseline warts that completely cleared during therapy recurred in 13% of patients who were treated with 5% imiquimod (Edward 2000). Additionally, imiquimod is suitable for all types of external genital warts (keratinised and

non-keratinised), thus making it an ideal choice for first-line therapy (Maw 2004). Studies have indicated that application site reactions were the most common adverse event associated with imiquimod use and were generally mild to moderate (Garland et al 2006). The most frequently reported side-effects include pain, itch, erythema, burning, irritation, tenderness, ulceration and erosion at the application site, but these local reactions are likely related to the beneficial inflammatory response

ALDARA

®

CHANGING THE

NATURE OF

induced by imiquimod (Maw 2004). For the treatment of EGWs, imiquimod 5% is applied at bedtime three times per week for up to 16 weeks (Yanofsky et al 2012). Imiquimod 3.75% cream should be applied once at bedtime, but must be applied every night (CDC 2015). With either formulation, the treatment area should be washed with soap and water six to 10 hours after the application (CDC 2015). References available on request.

WITH ALDARA YOUR PATIENTS HAVE THE FREEDOM OF TREATMENT IN THE PRIVACY OF THEIR OWN HOME1

TREATMENT

EXTERNAL GENITAL WARTS Effective treatment – 40 % total clearance at 4 weeks2 Sustained clearance – 87 % at 3 months follow-up3,4 Significantly reduce HPV viral load – > 98 % to 100 % reduction in wart tissue and clearance of > 75 % in wart tissue5 An ideal choice for first-line therapy6

References: 1. O’Mahony C. Am J Clin Dermatol 2005; 6(4):239-243. 2. Garland SM, et al. Int J STD AIDS 2006;17:448-452. 3. Edwards L. J Am Acad Dermatol 2000; 43 (1 Part 2):S12-S17. 4. Edwards L, et al. Arch Dermatol 1998; 134:25-30. 5. Tyring SK, et al. J Infect Dis 1998; 178:551-555. 6. Maw R. Int J STD AIDS 2004; 15:357-364. Scheduling status: S4 Proprietary name and dosage form: ALDARA Cream. Composition: Each 2,0 g cream pump contains 5 % Imiquimod (100 mg). ALDARA Cream Sachet. Composition: Each 250 mg cream sachet contains 5 % Imiquimod (12,5 mg). Preservatives: Methyl hydroxybenzoate 0.2 % m/m, Propyl hydroxybenzoate 0.02 % m/m, Benzyl alcohol 2 % m/m. Pharmacological classification: A 34 Other. Indications: ALDARA Cream is indicated for the topical treatment of superficial basal cell carcinoma (sBCC), and of external genital/perianal warts (condyloma acuminata) and clinically typical, non hyperkeratotic, nonhypertrophic actinic keratosis (AKs) on the face or scalp in adult patients. Registration number: 32/34/0541. Name and business address of the holder of the certificate of registration: iNova Pharmaceuticals (Pty) Ltd,. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert approved by the MCC (Medicines Control Council). Further information is available on request from iNova Pharmaceuticals. IN2610/18

MEDICAL CHRONICLE | MARCH 2019 57 15 MEDICAL CHRONICLE


CLINICAL

WOMEN'S HEALTH

WOMEN’S HEALTH Focus

FAST-FORWARD TO PAUSE

The symptoms of menopause are being recognised in younger women with more and more frequency.

While its onset can occur for a variety of reasons, menopause leaves an indelible mark on those the condition affects. For most women, the term ‘menopause’ is synonymous with maturity, wisdom, an established family, and a life well lived. However, some women between the ages of 15 and 45 experience early or premature menopause. Under normal circumstances, menopause signifies the end of a woman’s fertile years, which is cause for huge concern in those who enter menopause early and have not yet had children (or completed their families). In this case, fertility clinics can assist childless women to conceive. A distinct difference exists between early and premature menopause, which is directly linked to age. If it strikes before the age of 40, it is considered to be premature menopause, and if it occurs prior to 45 years of age, it is termed early menopause. Either way, there is hope for women experiencing its symptoms or resultant infertility.

SYMPTOMS

Early or premature menopause is characterised, for the most part, by symptoms identical to those experienced during natural menopause. The well-documented night sweats, hot flushes, insomnia, headaches, joint or muscle pain, and mood swings are indicators that the sufferer could be going through ‘change of life’. Weight gain and a change in body shape may also be signs of menopause, along with anxiety, depression, cravings, forgetfulness, atrophic vaginitis, and a low libido. The leading cause of these symptoms is a dramatic reduction of oestrogen levels, which brings about a variety of changes to many of the body’s functions. This sudden decrease can occur as a result of the following factors: • Premature ovarian failure: This condition causes the ovaries of women to stop functioning properly, which can be due to the fact that they either stop producing eggs or no longer secrete the hormones needed to ovulate. • Surgical menopause: This refers to the purposeful decision taken to force women into menopause for specific health reasons such as endometriosis,

32 JULY 2017 | MEDICAL CHRONICLE 58 MEDICAL CHRONICLE

polyps, or ovarian cancer. Surgical procedures such as an oophorectomy) or hysterectomy can cause oestrogen levels to drop suddenly, causing the early or premature onset of menopause. • Cancer treatment: Chemotherapy or radiation can destroy healthy ovarian cells, leading women to enter temporary or permanent early menopause. • Autoimmune disorders: In this case, the body sees itself as an invader and develops antibodies to fight itself, including the ovaries. • Genetics: 5% of women echo their mother’s experience and enter menopause at the same age. • Infections: Diseases such as mumps and TB can infect ovaries, thereby shaking hormonal balances, although this is very rare. Early or premature menopause may also bring along with it various health risks such as osteoporosis, colon and ovarian cancer, periodontal (gum) disease, tooth loss, as well as the development of cataracts. It is for this reason that patients who are experiencing the aforementioned

symptoms would be well advised to undergo tests sooner rather than later.

TREATMENT

While there is no cure for menopause, early, premature or otherwise, great strides have been made in the treatment thereof. Hormone therapy is an extremely effective treatment option and may alleviate the symptoms of early or premature menopause, occasionally including infertility. Those concerned that they may be inflicted with the condition need simply to undergo a test that measures oestradiol levels, or alternatively follicle stimulating hormone levels, as well as the measurement of the ovarian reserve. Treatment for menopause depends on many things, including how bad the menopausal symptoms are, the patient’s overall health and their preferences. It may include lifestyle changes or hormone therapy. Hormone replacement therapy (HRT) prevents health problems and discomfort associated with diminished circulating oestrogens and progesterone hormone levels. This series of drugs, designed to artificially

boost hormone levels, consist mainly of oestrogen, progesterone or progestins and sometimes testosterone. Several major studies have questioned the health benefits and risks of hormone therapy. According to the Revised Global Consensus Statement on Menopausal Hormone Therapy (2016), menopausal hormone therapy (MHT) includes a wide range of hormonal products and routes of administration, including tibolone (where available) or conjugated estrogens/bazedoxifene, with potentially different risks and benefits. However, evidence regarding differences in risks and benefits between different products is limited. The type and route of administration of MHT should be consistent with treatment goals, patient preference and safety issues and should be individualised. The dosage should be titrated to the lowest appropriate and most effective dose. Duration of treatment should be consistent with the treatment goals of the individual, and the benefit/ risk profile needs to be individually reassessed annually. This is important in view of new data indicating longer duration of vasomotor symptoms in some women. The use of custom-compounded hormone therapy is not recommended because of lack of regulation, rigorous safety and efficacy testing, batch standardization, and purity measures. Current safety data do not support the use of systemic MHT in breast cancer survivors, although discussions, in selected women and in conjunction with each woman’s oncologist, may occur for compelling reasons after nonhormonal or complementary options have been unsuccessful. Most HRT is prescribed as tablets as they are highly effective in combating physical and emotional symptoms and they are easily available. Transdermal skin patches have become popular. These patches release low dosages of hormones that are absorbed through the skin.

CONCLUSION

A diagnosis of the condition does not carry dire consequences and there is much that can be done to alleviate its symptoms and overcome fertility challenges. References available on request.


CLINICAL WOMEN’S HEALTH Focus WOMEN'S HEALTH CPD

COCS: IMPACT OF OESTROGEN TYPE ON CV SAFETY

The following CPD article describes the cardiovascular safety and effectiveness results of the oral contraceptive E2V/DNG from the International Active Surveillance Study on the Safety of Contraceptives and the Role of Estrogens (INAS-SCORE).

As combined oral contraceptives (COCs) have been further developed over the past decades, their ethinylestradiol (EE) content has been reduced. However, reducing the EE dose also led to a less favourable control of bleeding. Based on the lower impact of estradiol (E2) and estradiol valerate (EV) on the hepatic system and subsequently on haemostatic parameters compared to ethinyl estradiol it is assumed that E2 and E2V are associated with a similar or even lower risk of cardiovascular events, including venous (VTE) and arterial thromboembolism. In 2012, an E2V-based COC was introduced to the market that appears to combine both reliable contraception and an acceptable bleeding profile. This regimen consists of a dynamic dosing regimen with a 26-day active tablet phase followed by two placebos: Two tablets with 3mg EV, five tablets with 2mg DNG and 2mg EV, 17 tablets with 3mg DNG and 2mg EV, and two tablets with 1mg EV, and two placebos. The dynamic dosing regimen aims to ensure that sufficient oestrogen levels are available during the first half of the cycle in which endometrial proliferation is promoted under the influence of estrogens. Shortening the hormone-free interval from the conventional seven days to only two days and extending the oestrogen phase at the end of the progestogen phase are expected to be beneficial for cycle control, tolerability and effectiveness. The INAS-SCORE study was conducted as a phase IV commitment to the European regulatory authorities. Three COC user groups - users of preparations containing DNG/ EV, users of other COCs (oCOC) and users of levonorgestrel-containing COCs (LNG) -

were followed throughout the study. The International Active Surveillance study, “Safety of Contraceptives: Role of Estrogens” (INAS-SCORE) investigated the cardiovascular risks associated with the use of a COC containing dienogest and estradiol valerate (DNG/ EV) compared to established COCs in a routine clinical setting. The study design was transatlantic, prospective, noninterventional cohort study conducted in the US and seven European countries with three exposure groups: New users of DNG/EV, other oCOC users, and levonorgestrelcontaining COC users. All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. The primary objective was to evaluate the serious cardiovascular events (SCE), particularly venous thromboembolic (VTEs) events. The secondary objectives were to evaluate effectiveness of ovulation inhibition, as well as return to fertility after stopping contraception. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. Real-world evidence is important to connect clinical trial data to routine

clinical practice settings; it helps reflect priorities to ensure a well-rounded clinical development and market access plan that includes not only RCTs but also more pragmatic research in real clinical practice. These aspects are well recognised by the pharmaceutical industry, reflecting the need for a change in focus toward demonstrating the value of a new medicine in routine clinical practice settings. Study designThe INAS-SCORE trial was a large, real-world study (also referred to as a real-life study) designed to fill this gap and provide real-world data comparing dienogest/estradiol valerate (DNG/EV) with other COCs in a representative population. The INASSCORE study was conducted as a phase IV commitment to European regulatory authorities and was funded with an unconditional grant from Bayer AG. A robust study of more than 50 000 new COC users was actively monitored for up to five years for the occurrence of rare or unexpected adverse outcomes possibly related to COC exposure. The population of the INAS-SCORE study is representative of realworld clinical practice. It enrolled all consenting women who required a new

More specific inclusion or exclusion criteria were not stipulated, because of the non-interference nature of the study design.

prescription for a COC, and could be attributed to one of the following groups: Comprehensive data collection and quality control. Baseline data were recorded via selfadministered questionnaires • Information was collected: - State of health - Medical history - Medication history - History of COC use - Potential prognostic factors for serious diseases, particularly cardiovascular disease. To prevent loss to follow up, participants provided their addresses and phone numbers, as well as back-up contacts and contact information for their primary care physicians and/or gynaecologists. Baseline questionnaires were completed in the physicians' offices and checked by the physicians or their co-workers. Follow-up assessments for each woman were scheduled every six months for the first two years and annually thereafter. • Follow-up questionnaires addressed occurrence of adverse events - In particular serious adverse events and cardiovascular events • Reasons for discontinuing OC use or for switching to another hormonal contraceptive were requested if applicable. Questionnaires were collected in each country by local study teams • These teams reviewed the questionnaires for completeness, plausibility and consistency of responses. Missing or inconsistent information was clarified with women by phone In a second quality control step, the central study team at ZEG (Berlin)

1

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This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. Health Supplements do not replace a healthy diet and lifestyle. For more information, speak to your healthcare professional. Reference: 1. Mahan, L.K. et al. Krause’s Food and the Nutrition Care Process. 13th edition. United States of America. Saunders, an imprint of Elsevier Inc. 2012. ENERGY: p516. DEFENCE: p88, 516. MENTAL VITALITY: p961-962. Proprietary name (and dosage form): StaminoGro® Woman Tablets. Composition: Each tablet contains: 93.75 mg L-Arginine, 75 mg L-Glutamine, 37.5 mg Glycine, 25 mg L-Lysine, 22.5 mg L-Ornithine,450 μg Beta-carotene,15 μg Selenium (AAC), 50 mg Vitamin C, 30 IU Vitamin E, 10 mg Zinc, 250 μg Folic Acid, 0,75 mg Vitamin B1, 1,25 mg Vitamin B2, 6 mg Vitamin B3, 6 mg Vitamin B5, 10 mg Vitamin B6, 6 μg Vitamin B12, 100 mg Calcium, 400 IU Vitamin D3, 20 μg Biotin, 4,1 mg Choline, 500 μg Copper (AAC), 70 mg Magnesium, 1 mg Manganese, 5mg Iron (AAC). Name and business address: iNova Pharmaceuticals (Pty) Ltd Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma. co.za. Further information available on request from iNova Pharmaceuticals. IN513/18

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CLINICAL WOMEN’S HEALTH Focus WOMEN'S HEALTH CPD subjected all data to electronic and manual plausibility checks • Protocol driven credibility: For the analysis, classification of all VTEs were verified by independent blinded adjudication • Three independent medical experts reassessed all decisions made by the medical review group to minimise classification bias • They reviewed all available information on reported events • Brand names, dose, regimen and composition of hormonal contraceptives were anonymised • The adjudicators performed reviews independently of each other and

without knowing the judgment of other adjudicators or medical review group • Events were classified as confirmed if that was the judgment of at least one adjudicator.

STRENGTHS OF THE STUDY

1. A large, international, real-world, prospective, comparative cohort study 2. Availability of important confounder information (e.g. BMI and family history of cardiovascular outcomes) 3. Validation of outcomes of interest and exposure of relevant cases 4. Comprehensive follow-up procedure and very low loss to follow-up 5. Independent blinded adjudication of

critical outcomes 6. Relevant statistical analyses 7. Study population with baseline characteristics similar to OC users under routine clinical conditions 8. Reproducibility of typical time pattern of VTE risk 9. Supervision by an independent Safety Monitoring and Advisory Council 10. Scientific independence from study funder.

WEAKNESSES OF THE STUDY 1. Observational studies are associated with a potential for bias, and residual confounding can never be entirely eliminated - therefore the ability to

Finding the right pill can take longer than finding the right man For many women, finding the right pill can be a long journey. Qlaira® delivers a derivative of natural estradiol in unique combination with dienogest.1,2,3 Suitable for women 18-50 years of age,4 Qlaira® offers benefits beyond contraception:

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HWaS - Hormone withdrawal associated symptoms

CINGULATE 11188

References: 1. Fruzzetti F, Trémollieres F, Bitzer J. An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest. Gynecol Endocrinol 2012;28(5):400-408. 2. Palacios S, Wildt L, Parke S, et al. Efficacy and safety of a novel oral contraceptive based on oestradiol (oestradiol valerate/dienogest): A Phase lll trial. Eur J Obstet & Gynecol & Reproductive Biology 2010;149:5762. 3. Qlaira® Package Insert 2011. 4. Alessandra Graziottin (2015): The shorter, the better: A review of the evidence for a shorter contraceptive hormone-free interval. Eur J Contraception and Reproductive Health Care. Published online http://dx.doi.org/10.3109/13625187.2015.1077380 5. Micks E, Jensen JT. Estradiol valerate and dienogest: a novel four-phasic oral contraceptive pill effective for pregnancy prevention and treatment of heavy menstrual bleeding. Women’s Health 2011;7(5):513-524. 6. Sitruk-Ware R, Nath A. Characteristics and metabolic effects of estrogen and progestins contained in oral contraceptive pills. Best Practice & Research Clinical Endocrinology & Metabolism 2013;27:13-24. 7. Junge W, Mellinger U, Parke S, et al. Metabolic and haemostatic effects of estradiol valerate/dienogest, a novel oral contraceptive. Clin Drug Investig 2011;31(8):573-584. 8. Ahrendt HJ, Makalova D, Parke S, et al. Bleeding pattern and cycle control with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial of estradiol valerate/dienogest and ethinyl estradiol/levonorgestrel. Contraception 2009;89(5):436-444. 9. Caruso S, Agnello C, Romano M, et al. Preliminary study on the effect of four-phasic estradiol valerate and dienogest (E2V/DNG) oral contraceptive on the quality of sexual life. J Sex Med 2011;8(10):2841-2850. S3 Qlaira® Tablets. The 28-day pack contains 2 tablets each containing 3 mg oestradiol valerate and 5 tablets each containing 2 mg oestradiol valerate and 2 mg dienogest and 17 tablets each containing 2 mg oestradiol valerate and 3 mg dienogest and 2 tablets each containing 1 mg oestradiol valerate and 2 placebo tablets. RSA Reg. No.: 43/18.8/0591. Namibia: NS2 ; Reg. No.: 13/21.8.2/0154. Bayer (Pty) Ltd. Reg. No.: 1968/011192/07. 27 Wrench Road, Isando, 1609. Tel. +27 11 921 5000. For full prescribing information, please refer to the package insert approved by the Medicines Regulatory Authority. L.ZA.MKT.WH.01.2016.0944.

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infer causation is limited. 2. Risk estimates close to unity may not allow differentiation between causation, bias and confounding.

HOW CAN THE METHODOLOGY FROM THE INAS-SCORE STUDY HELP INFORM CLINICAL PRACTICE? 1. The INAS-SCORE study provides comparative data showing the shortand long-term cardiovascular risks associated with COCs in a real-world setting 2. The real-world nature of this study means clinicians can be confident that these data reflect routine clinical practice, adding important information to that derived from clinical studies

RESULTS

To date, there were no studies available investigating the cardiovascular safety of combined oral contraceptives not containing ethinylestradiol.

PRIMARY OBJECTIVE

To assess cardiovascular risks of shortand long-term use of DNG/EV and of other COCs in a study population that is representative of actual users of individual preparations. The following outcomes were assessed: • Venous thromboembolism e.g. (deep venous thrombosis & pulmonary embolism) • Arterial thromboembolism (acute myocardial infarction and cerebrovascular accidents). All other serious cardiovascular events were also analysed. In a real-world study, the treatment cohorts are usually not comparable due to selected prescribing based on patient characteristics. Therefore, the cohorts need to be adjusted for potential risk factors at baseline to allow a valid comparison (compare like with like). The hazard ratios without adjustments are called ‘crude hazard ratios’, those with these adjustments are called ‘adjusted hazard ratios. In total, 47 venous thrombotic events (European study population) were confirmed in the study. The risk seen in the primary data set, as defined by the European Medicines Agency (EMA), found no indication that there was an increased risk of dienogest/estradiol valerate compared to other COCs (combined oral contraceptives) or to levonorgestrel-containing combined oral contraceptives. In contrast, a decrease in risk was found, which was statistically significant when compared to all other combined oral contraceptives. Also, when the venous thromboembolic risk of dienogest/estradiol valerate was compared to levonorgestrel-containing COCs, a decrease in risk was found, which was not statistically significant. Arterial events were also investigated in our study. Lower incidences of arterial events in the dienogest/ estradiol valerate group was found when


CLINICAL WOMEN’S HEALTH Focus WOMEN'S HEALTH CPD • 9 ischaemic strokes • 1 transient ischaemic attack • 2 peripheral ATEs. Incidence rate for serious cardiovascular events was lower for DNG/EV compared to other COCs, including LNG-containing COCS: Primary analysis - European study population • 233 serious cardiovascular events. The point estimate of the adjusted hazard ratio for the comparison of DNG/ EV versus oCOCs was 0.6 with an upper 95% confidence limit of 0.96, indicating statistical significance.

CONCLUSIONS

The INA-SCORE study provides comparative data showing the shortand long-term cardiovascular risks associated with COCs in a real-world setting. The real-world nature of this study means clinicians can be confident that these data reflect routine clinical practice, adding important information to that derived from clinical studies.

compared to other combined oral contraceptives, including the direct comparison of dienogest/ estradiol valerate to levonorgestrelcontaining COCs. Based on the data from this very large and robust dataset, it can be stated that the cardiovascular risk of dienogest/estradiol valerate is similar if not even lower compared to other combined oral contraceptives, including levonorgestrel-containing oral contraceptives. Results: Contraceptive effectiveness As a secondary objective the INASSCORE study also investigated the effectiveness of dienogest/estradiol valerate on ovulation inhibition, and return to fertility compared to other combined oral contraceptives under routine clinical practice. Based on the primary dataset, as defined by the European Medicines Agency (EMA), it was found that all combined oral contraceptives are efficacious. However, the contraceptive effectiveness of dienogest/estradiol valerate seems to be even better than other combined oral contraceptives, including levonorgestrelcontaining combined oral contraceptives. The results found a reduction of contraceptive failure compared to levonorgestrel-containing COCs (combined oral contraceptives) of almost two, which was also statistically significant. When compared to all other COCs, a borderline statistically significant decrease in contraceptive failure was found. In summary dienogest/estradiol valerate is at least as efficacious as other combined oral contraceptives on the market.

RETURN TO FERTILITY

Barnett et al (2016) sought to estimate the real-use contraceptive effectiveness of the DNG/EV combined oral contraceptive compared to others were slightly lower compared to other COCs. This was to be expected due to the different age profiles of the cohorts and because fecundity decreases with age. Crude pregnancy rates for DNG/ EV users overall was slightly lower compared to other COC cohorts. This difference disappeared after ageadjustment. Accordingly, no difference was seen when analysis was limited to women aged 25-34 years. Likewise, no significant difference in pregnancy rates was seen between contraceptive types when results were stratified for parity.

CARDIOVASCULAR OUTCOMES AND SAFETY

The incidence rates for VTE, ATE and serious cardiovascular events were lower for DNG/E2V compared to oCOC and LNG. The primary statistical analysis (European data set) of these outcomes yielded HR adj of 0.4 for VTE and 0.6 for serious cardiovascular events for the comparison of DNG/EV vs oCOC. The primary analysis was based on the European population. The European regulatory authorities requested that an additional analyses be based on the European cohort alone (primary analysis), since uptake of DNG/EV was low in the US. To compensate, follow up in Europe was extended. Incidence rate for confirmed VTE was lower with DNG/EV compared to other COCs, including LNG-containing COCs. A similar or even lower risk of

confirmed VTE was observed with DNG/ EV compared to LNG-containing COCs or other COCs. Incidence rate for ATE was lower for DNG/EV compared to other COCs, including LNG-containing COCs. COMBINED US AND EUROPEAN COHORTS - 18 ATE were observed: • 4 acute myocardial infarctions • 10 ischaemic strokes • 2 transient ischaemic attacks • 2 complete thromboses of a peripheral artery. Incidence rate for ATE was lower for DNG/EV compared to other COCS, including LNG-containing COCs: Primary analysis - European study population - 15 ATE were observed: • 3 acute myocardial infarctions

The INAS-SCORE study tells us that: • COCs have excellent contraceptive effectiveness with typical use. • DNG/EV is associated with a similar or even lower risk of contraceptive failure compared to oCOC or LNG-containing COCs (European cohort). • Pregnancy rates after cessation of COC use with the intention of becoming pregnant are high. The study results tell us that a COC containing DNG/EV is associated with a similar or even lower cardiovascular risk compared to LNG-containing COCs in routine clinical practice.

References

Barnett C, Hagemann C, Dinger J et al. Fertility and combined oral contraceptives – unintended pregnancies and planned pregnancies following oral contraceptive use – results from the INAS-SCORE study, The European Journal of Contraception & Reproductive Health Care. 2016;DOI: 10.1080/13625187.2016.1241991. Dinger J, Minh T, Heinemann K. Impact of estrogen type on cardiovascular safety of combined oral Contraceptives. Contraception 94. 2016:328-339.

The INAS-SCORE Study

CPD questionnaire on pg 52. Complete online: www.medicalchronicle.co.za/cocs-impact-of-oestrogen-type-on-cv-safety/ MEDICAL CHRONICLE MEDICAL CHRONICLE | JULY 2017 61 21


CLINICAL | WOMEN'S WOMEN’S HEALTH Focus

HEALTH

Folate – Benefits beyond

NTD prevention

The most well-known use of folic acid is its role in preventing neural tube defects (NTD) during pregnancy. However folate, with its dynamic effects on red blood cell production and DNA methylation, affects numerous bodily functions and is beneficial for much besides pregnancy.

F

OLIC ACID IS IMPORTANT for functioning of the nervous system at all ages (Reynolds 2002). Folic acid

is a B vitamin essential for the integrity and function of DNA, relative deficiency of which may occur in conditions such as

pregnancy and hyper-proliferative or chronic inflammatory disorders (Gisondi et al 2006). Folate and the metabolically related

Enhance your patients’ outcome 4

2 Methionine in return produces S-adenosylmethionine2

1 5 Methyl-THF is required to convert homocysteine to methionine1

3

Folic acid taken with anti-depressant medication improves the treatment outcomes of patients4

Improved HAM-D# scores 6.8 vs 11.7 in placebo group*4

YAZ® Plus is the only combined oral contraceptive with these 4 indications:4 • Oral contraception • Improved folate status*

• Treatment of moderate acne vulgaris* • Treatment of PMDD symptoms*

* 500 mcg folic acid + 20 mg fluoxetine daily # Hamilton depression rating scale

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CINGULATE 13865

*In women seeking oral contraception; PMDD – Premenstrual Dysphoric Disorder; The efficacy of YAZ® Plus for PMDD was not assessed beyond 3 cycles. YAZ® Plus has not been evaluated for

treatment of PMS. †Metafolin® (Levomefolate calcium) is licensed and supplied by Merck & Cie, Switzerland. Metafolin® is a registered trademark of Merck KGaA, Germany. References: 1. WHO: Conclusions 1. Mahan, L.K. et al. Krause’son Food and the Nutrition CareBProcess. 13th edition. UnitedNutr States of America. Saunders, an imprint of Elsevier Inc.2012. Folate. A, Maron al. National Institute ofReferences: a WHO Technical Consultation folate and vitamin Food Bull 2008;29(2 Suppl):S238-244. 2. Diefenbach K, P82-85.2. TrummerBradley D, Ebert F, etM.D al. etEE-drospirenone-levomefolate calcium versus EE12 deficiencies. of Health. The Treatment Hyperhomocysteinemia. Annu Rev 2009 [cited 2016 14] 20 ; 60:39–54. from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716415/pdf/nihms-84951.pdf.4. 3. Mischoulon drospirenone + folic ofacid: folate status during 24Med.[Online]. weeks of treatment and Oct over weeks Available following treatment cessation. Int J Womens Health 2013;5:149-163. 3. EFSA Panel on Dietetic Products, Nutrition and D. Update and Critique of Natural Remedies as Antidepressant Treatments. Obstet Gynecol Clin North Am. [Online]. 2009 [cited 2016 Oct 14] ; 36(4): 789–807. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19944301. Allergies Opinion the substantiation of health claims to folate and bloodtrial. formation 79), homocysteine metabolism 80), energy-yielding metabolism 4. Coppen (NDA). A, Bailey Scientific J. Enhancement of the on antidepressant action of fluoxetine by folic acid: arelated randomised, placebo controlled Journal of(ID Affective Disorders. 2000 (60): 121–130. 5.(ID National Institute of Health. Folate dietary (ID 90), function of the immune system (ID 91), function of blood vessels2016 (ID April 94, 175, 192), cell (ID 193), and maternal tissue growth during pregnancy (ID 2882) pursuant to Article 13(1) of Regulation (EC) No 1924/20061. EFSA Journal supplements fact sheet. [Internet]. 2016 [updated 20; cited 2016 Octdivision 14]. Available from: https://ods.od.nih.gov/factsheets/FolateHealthProfessional. 2009;7(9):1213. 4. YAZ® Plus package insert, 2014. YAZ® Plus Tablets. The 28-day pack contains 24 hormone-containing pink film-coated tablets each with 3 mg drospirenone, 0,020 mg ethinyloestradiol Proprietary name (and dosage form): Folic Acid Forte Tablets. Composition: Each tablet contains: 500 μg Folic Acid, 3 mg Vitamin B1, 5 mg Vitamin B2, 18 mg Vitamin B3, 15 mg Vitamin B5, 24 mg Vitamin B6, 24 μg Vitamin (as betadex clathrate) and 0,451 mg levomefolate calcium (equimolar to 0,400 mg folic acid), plus 4 hormone-free light orange film-coated tablets each with 0,451 mg levomefolate calcium. RSA Reg. No.: B12, 200 mg Vitamin C. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information is 45/21.8.2/0534. No.: E13025/05/2018. For full prescribing information, please refer to the professional information approved by SAHPRA. Bayer (Pty) Ltd. Reg. No: 1968/011192/07. 27 Wrench Road, available on requestMauritius from iNova Reg. Pharmaceuticals. IN266/17 Isando. 1609. Tel. 011 921 5000. L.ZA.MKT.11.2017.2136

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NEURAL TUBE DEFECTS NTDs are congenital abnormalities of the brain and spinal column that cause serious mortality and morbidity (Moussa et al 2016). Research has indicated that folate levels are low in 75% of women of childbearing age (McDowell et al 2008). In neonates, infants, children, and adolescents, inborn errors of folate transport and metabolism are associated with a variety of overlapping syndromes, which are influenced by age of clinical presentation, and include (Reynolds 2002): • Developmental delay • Cognitive deterioration • Motor and gait abnormalities • Behavioural or psychiatric symptoms • Signs of/failure of demyelination • Seizures. The molecular requirements for neural tube closure are complex (Moussa et al 2016). Neural development occurs early in embryogenesis (by six weeks of gestation), when the majority of women are not aware of their pregnancy (Moussa et al 2016). In the foetus the relation between maternal folate status and the risk of neural tube defects is well established: clinical trials have shown that periconceptual preventive treatment with 400 mcg or higher of folic acid significantly reduces the risks of such defects (Reynolds 2002). Beginning in 1998, the Food and Drug Administration (FDA) required the addition of folic acid (a form of folate) to all enriched breads, cereals, flours, corn meal, pasta products, rice and other cereal grain products sold in the United States (McDowell et al 2008). Blood folate data from the National Health and Nutrition Examination Surveys (NHANES) has subsequently documented improvements in the folate status of the US population after folate fortification was implemented (McDowell et al 2008). This is particularly important since the majority of pregnancies in most countries are unplanned (Moussa et al 2016).

S-adenosylmethionine facilitates the synthesis of neurotransmitters including: dopamine & serotonin3

YAZ® Plus is the first low-dose combined oral contraceptive which also with Metafolin®† an essential Vitamin B, which provides enriched requires a range of health benefits and supports future family plans.1,2,3 Vitamin B121

B-vitamins, vitamin B12 and riboflavin, have attracted much scientific and public health interest in recent years (McNulty and Scott 2006).

This article is a synopsis of a CPD article that you can find on www.medicalacademic.co.za 2017/03/14 1:27 PM

2019/04/02 13:59


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References: 1. IMS:TPM Data (A11A, A11B, A11E, V6D, V3X / Constructed Class). MAT Oct 2017. 2. Gross, M and Klein, S. [Internet]: Fish Oil Triglycerides vs. Ethyl Esters [updated 2016; cited 2017 Aug 25]. Available from: http://www.bewellassociates.com/wpcontent/uploads/2013/08/Triglyceride_Fish_Oils.pdf. 3. Puremax.com [Internet]: Health benefits-Omega 3 during pregnancy [cited 2017 Jun 27]. Available from: http://www.puremax.com/home.aspx?d=content&s=154&r=316. Proprietary name (and dosage form): PregOmega® Plus Tablets and Soft Gel Capsules. Composition: Each fish oil soft gel capsule contains: 822 mg Pharmaceutical Grade Fish Oil (derived from tuna and deep marine fish oil) providing: 260 mg DHA, 91 mg EPA. Each calcium tablet contains: 500 mg Calcium, 400 IU Vitamin D3 and 125 mg Magnesium. Each vitamin & mineral tablet contains: 2 666 IU Vitamin A, 3 mg Vitamin B1, 2 mg Vitamin B2, 10 mg Vitamin B3, 1 mg Vitamin B6, 2 μg Vitamin B12, 50 mg Vitamin C, 100 IU Vitamin D3, 230 mg Calcium, 0,15 mg Copper (AAC), 500 µg Folic Acid, 15 mg Iron (AAC), 0,5 mg Magnesium, 0,05 mg Manganese (AAC), 0,025 mg Molybdenum (AAC), 0,84 mg Potassium, 0,085 mg Zinc. Name and business address: iNova Pharmaceuticals (Pty) Ltd, Co. Reg. No. 1952/001640/07, MEDICAL CHRONICLE 63 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. Further information available on request from iNova Pharmaceuticals. IN354/17


CLINICAL | WOMEN'S WOMEN’S HEALTH Focus

HEALTH

Optimising treatment

for bacterial vaginosis

Bacterial vaginosis (BV) is the most commonly reported microbiological syndrome among women of childbearing age, as well as the most frequently occurring condition within the female genital tract.

B

V IS CHARACTERISED by a shift in the vaginal flora from the dominant lactobacillus to a polymicrobial flora, as well as a thin homogeneous white discharge, a vaginal pH of greater than 4.5, a positive amine test, and the presence of clue cells microscopically. BV is associated with a wide array of health issues, including preterm births, pelvic inflammatory disease, increased susceptibility to HIV infection, and other chronic health problems. Although the condition is not usually serious and is asymptomatic in approximately 50% to 75% of women, multiple studies have also associated a diagnosis of BV with a wide range of reproductive tract disorders. BV has been reported to be three times more prevalent among infertile than in fertile women and is associated with a two‐fold elevated risk of preclinical pregnancy loss following in vitro fertilisation‐embryo transfer.

the clinical symptoms of BV, although this idea has been challenged by recent findings. Ultimately, BV is not caused by the mere presence of the potential pathogens (which is common) but rather by their unrestrained increase in number, often reaching cell counts that are 100‐ to 1 000‐fold above the normal bacterial levels of the vagina. Since BV is essentially a microbial imbalance among the constituents of the vaginal microbiota, its aetiology involves complex interactions between pathogenic species, endogenous vaginal microbiota, the host and possibly bacteriophages, but the relative contributions of these factors are unknown. Additionally, the interactions between these factors are modulated by a woman’s behaviour and her environment. This inherent complexity, along with the lack of a reliable animal model, is the likely reason why the aetiology of BV remains a mystery after decades of research.

AETIOLOGY Historically, G. vaginalis is thought to have the leading role in the infection, making the niche suitable for colonisation by strict anaerobes that are largely responsible for

RISK FACTORS Epidemiological studies indicate that the risk of BV is increased in women of African ethnicity. Other risk factors include low socioeconomic status, cigarette

smoking, douching, antibiotic treatment for another condition, young age of coitarche, acquisition of a new sex partner and a recent history of multiple sex partners. Although various sexual activities are well‐known risk factors for acquisition of BV, it is not accurate to typify the condition as an STI. However, it remains true that, for women who have sex with women, the rate of BV concordance among partners is high. If one woman has diagnosed BV and symptoms are present in her partner, treatment of the partner is reasonable. For women with BV who have sex with men, sexual intercourse influences disease activity, and consistent use of condoms may reduce the rate of recurrence. Male circumcision may reduce the risk of BV in female partners. TREATMENT Given its adverse effects on quality of life and the potential for severe adverse effects during pregnancy, it is important to identify a simple treatment regimen for BV. Ideally, the treatment of choice should be safe, easy to use, and effective over a long period of time. Because studies have shown that only 11% of women have a normal vaginal flora,

a presumptive treatment approach is practical. A probiotic treatment could potentially be used to replenish the healthy vaginal microbiota of women with BV. If the incompetence of vaginal lactobacilli is central to the aetiology of recurrent BV, then a successful strain replacement therapy would, in theory, cure this condition. However, the long‐term colonisation by a probiotic strain is a complex process and, so far, the results of clinical trials investigating the use of probiotics for treatment of BV are rather conflicting. The aim of BV treatment should be to preserve the vaginal pH at 4.5 and lower and to prevent the overgrowth of pathogens until normal vaginal flora is reconstructed and maintain normal vaginal pH (14,15). The relationship between BV and increased level of vaginal pH has made the use of vagina acidifier materials as an attempt to build an unsuitable area for the growth of pathogens, reasonable. ANTIBIOTIC THERAPY Antibiotic therapy has been shown to be effective at eradicating bacterial vaginosis

New Feminine packaging same quality product you know and trust • Equivalent clinical cure rates to other recommended treatment options1,2 References: 1. Wain A. Metronidazole Vaginal Gel 0.75% (MetroGeI-Vaginal®) A Brief Review. Infect Dis Obstet Gynecol 1998;6:3-7. 2. Beigi R, Austin M, Meyn L, et al. Antimicrobial resistance associated with the treatment of bacterial vaginosis. Am J Obstet Gynecol 2004;191:1124-1129. Scheduling status: Proprietary name (and dosage form): MetroGel® V Vaginal Gel. Composition: Metronidazole 37.5 mg/5 g. Preservatives: Methyl hydroxybenzoate 0.08%, Propyl hydroxybenzoate 0.02%. Pharmacological classification: A 20.2.6 Antimicrobial: medicines against protozoa. Indications: MetroGel® V is indicated for the treatment of bacterial vaginosis. Registration number: 33/20.2.6/0243. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. IN3439/19.

42 | MEDICAL CHRONICLE 64 AUGUST MEDICAL2019 CHRONICLE


CLINICALWOMEN’S | WOMEN'S HEALTH HEALTH Focus with intravaginal clindamycin, and this is considered to be serious enough to have implications for the future use of clindamycin for pelvic infections. This has wide implications, since a vast number of bacteria comprise the vaginal flora that are potentially exposed to the effects of vaginal antibiotics and resistance mechanisms are transmissible between different species of bacteria. CONCLUSION The aetiology of BV remains uncertain, and hence effective treatment strategies

are by nature imprecise. However, a high degree of success has been achieved by antibiotic treatments such as metronidazole and clindamycin, of which metronidazole is the preferred treatment since it is associated with a lower rate of resistance and reoccurrence of symptoms. In choosing between oral and topical metronidazole, the topical treatment has clear benefits, since it is associated with fewer side effects, is just as effective and does not require a prescription. References available on request.

This is a synopsis of a longer, CPD-accredited article available on www.medicalacademic.co.za

RED 2

PREFERRED BY SOUTH AFRICAN GYNAECOLOGISTS1

EQ

METRONIZADOLE VS CLINDAMYCIN Metronidazole or clindamycin, orally or as a vaginal gel or cream, are first-line treatments for BV. Metronidazole is a nitroimidazole with activity against anaerobic organisms, while clindamycin, a macrolide, has a broad spectrum of activity against a variety of microbes including aerobic and anaerobic organisms. However, metronidazole is widely considered to be the most effective antibiotic treatment for BV. Clindamycin cream is also available on prescription only. Metronizadole has limited activity against vaginal Lactobacillus species, a preferred characteristic for an antibiotic used to treat vaginal infections.

metronidazole helps to restore vaginal lactobacilli colonisation, and clinical studies have demonstrated a 61% increase in the growth of vaginal lactobacilli one week after treatment. In comparison, treatment with clindamycin only showed 11% growth of lactobacilli. This inability to re-establish lactobacilli may lead to treatment failure during the course of BV treatment. Intravaginal clindamycin is associated with significant and sustained anaerobic resistance after treatment, studies have found. Resistance appears to persist in the majority of women (80 %) treated

UI

during pregnancy and reduce the risk of late miscarriage. The 2015 Centers for Disease Control and Prevention (CDC) recommended treatments for BV include oral metronidazole taken twice a day for seven days, five days of an intravaginal metronidazole gel, or seven days of an intravaginal clindamycin cream.

R N O SC

A probiotic treatment could potentially be used to replenish the healthy vaginal microbiota of women with BV Despite treatment with either metronidazole or clindamycin, similar percentages of women (approximately 10 to 15%) fail therapy after 1 month. The proportion of women who relapse also increases over time. The recurrence rate of BV is approximately 30% at 3 months and approximately 50 to 80% at 1 year following therapy with either drug. Current therapy for managing recurrent BV is repeated treatment with antibiotics. An obvious problem and important health issue associated with repeated exposure to the same antibiotic is resistance of those microbes targeted by the drug, which can result in an alteration of flora and possible persistence of BV-associated pathogens. Resistance to metronidazole, despite its use for over 3 decades, is rare. Recent studies have shown an emergence of clindamycin-resistant genital organisms among clinically relevant bacteria, including group B streptococci. In a study of 119 premenopausal, nonpregnant women aged 18 to 45 with a clinical and Gram stain diagnosis of BV, it was determined that treatment with clindamycin and treatment with metronidazole for BV result in different microbiological patterns following therapy. While both topical metronidazole and clindamycin yielded similar clinical responses to treatment, metronidazole may be superior to clindamycin based on the low level of resistance and its capacity to eradicate anaerobic gramnegative rods from the vagina. Intravaginal

IPT

R

SHE DOESN’T HAVE TIME TO LET B ACTERIAL AGINOSIS (B ) GET HER DOWN EMPOWERING WOMEN vaginal gel

B

metronidazole 0.75%

IS THE MOST COMMON VAGINAL INFECTION, AFFECTING 1 out of 3 WOMEN3,4 5

Metronidazole Gel 0.75 % is a recommended regimen for the treatment of B

Why treat orally when you can treat topically2

Comparable efficacy to oral metronidazole, with lower systemic absorption and improved systemic tolerability6,7

Comparable efficacy to intravaginal clindamycin, with little to no development of resistance8

References: 1. Impact Rx – September 2018, Data on file. Results of a survey of 64 South African gynaecologists, commissioned by iNova and undertaken by a third party in February 2017. 2. Metrogel V approved package insert, 2000/10/23. 3. Thrush and Bacterial vaginosis. Looking after your sexual health [online] [cited 22 March 2018]; Available from URL: http://www.sexualhealthsheffield.nhs.uk/wp-content/uploads/2015/03/thrush-bacterial-vaginosis-information-and-advice.pdf. 4. Ries AJ. Treatment of Vaginal Infections: Candidiasis, Bacterial Vaginosis, and Trichomoniasis. J Am Pharm Assoc. 1997;NS37:563-9. 5. Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines, 2015. MMWR 2015;64(3):1-137. 6. Hanson JM, McGregor JA, Hillier S, et al. Metronidazole for bacterial vaginosis. A comparison of vaginal gel vs. oral therapy. J Reprod Med. 2000;45(11):889-96. 7. Wain A. Metronidazole Vaginal Gel 0.75% (MetroGeI-Vaginal®) A Brief Review. Infectious Diseases in Obstetrics and Gynecology 1998;6:3-7. 8. Beigi R, Austin M, Meyn L, et al. Antimicrobial resistance associated with the treatment of bacterial vaginosis. American Journal of Obstetrics and Gynecology 2004;191:1124-9. Scheduling status: S2 Proprietary name (and dosage form): MetroGel V Vaginal Gel. Composition: Metronidazole 37.5 mg/5 g. Preservatives: Methyl hydroxybenzoate 0.08%, Propyl hydroxybenzoate 0.02%. Pharmacological classification: A 20.2.6 Antimicrobial: medicines against protozoa. Indications: MetroGel V is indicated for the treatment of bacterial vaginosis. Registration number: 33/20.2.6/0243. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information, refer to the package insert as approved by the SAHPRA (South African Health Products Regulatory Authority). Further information is available on request from iNova Pharmaceuticals. IN2900/18.

9762J MET GP AD R.indd 1

2019/07/05 09:00

MEDICAL CHRONICLE | AUGUST 2019 65 43 MEDICAL CHRONICLE


WOMEN’S HEALTH Focus

Get the folic acid facts! What you need to know about this wonder vitamin1

HELP MANAGE HER

PCOS

SYM

16,4 % Reduction in hirsutism 1**

Folic acid, which is also known as vitamin B9, occurs naturally as folate1 and is a vitamin that everybody needs2. Folate is found in certain fruits, vegetables, and nuts2. Folic acid is the man-made form of folate, and is available as a vitamin supplement.1, 2

45,5 %

Reduction in insulin resistance2

obesity3**

44 %

S

TR

ES

S

IN

F

31 IN

LITY*

REFERENCES: 1. Parent 26. Get Fit with Folic (2009) at https://www.parent24. com/Fertility/Getting_pregnant_old/health_safety/Get-fit-withfolic-20090406 2. U.S. Department of Health & Human Services. Office on Women’s Health. Folic Acid (2018) at https://www. womenshealth.gov/a-z-topics/folic-acid 3. CDC. Folic Acid (2018) at https://www.cdc.gov/ncbddd/ folicacid/about.html 4. Livestrong.com. Is Folic Acid Good for Men (2018) at https:// www.livestrong.com/article/268031-fruits-and-vegetablescontaining-folic-acid/ 5. Very Well Family. The Importance of Folic Acid in Female and Male Fertility (2019) at https://www.verywellfamily.com/folicacid-for-female-and-male-fertility-1959878 6. Everyday Health. What is Folic Acid (B9)? (2015) at https:// www.everydayhealth.com/drugs/folic-acid 7. Guidelines for Maternity Care in South Africa 2007 – Department of Health Republic of South Africa (2007)

Reduction in

Increase in pregnancy success in patients undergoing IVF4#

E

DISCLAIMER: This editorial has been commissioned and brought to you by iNova Pharmaceuticals. Content in this editorial is for general information only and is not intended to provide medical or other professional advice. This unregistered medicine has not been has not been evaluated by the SAHPRA for its quality, safety or intended use. Health supplements do not replace a healthy diet and lifestyle. For more information speak to your healthcare professional. Further information is available on request from iNova Pharmaceuticals. Name and business address: iNova Pharmaceuticals (Pty) Ltd. Co. Reg. No. 1952/001640/07. 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www. inovapharma.co.za. IN703/19

8,4 %

TI

66 MEDICAL CHRONICLE

The South African Department of Health recommends 5mg of folic acid per day, ideally taken from three months prior to conception and throughout pregnancy7. Many multivitamins will contain folic acid2. Check the label on the pack to make sure that it contains the recommended daily value of folic acid3. A supplement such as Folic Acid Forte, provides 500 micrograms of folic acid, along with Vitamins B1, B2, B3, B5, B6, B12 as well as Vitamin C. This supplement, which is suitable for vegetarians, meets the usual recommended daily intake1. Folic Acid Forte can be taken once a day with a meal. As with any vitamin supplements, it is important to make sure that these do not interact with any medications that you are taking as well as to ensure that your folic acid levels are not too high6. Always speak to your doctor or pharmacist about what supplements you should be taking.

ER

ERE WE FOUND out more about this indispensable wonder vitamin1. Folic Acid is perhaps best known as a supplement taken by pregnant women to protect unborn babies against serious birth defects2, such as spina bifida1. These neural tube birth defects happen in the first few weeks of pregnancy, often before a woman knows she is pregnant. Since statistically about half of all pregnancies are unplanned, experts recommend that all women of reproductive age need to get enough folic acid even if they are not trying to fall pregnant2, 3. It is essential to take some sort of folic acid supplement during, or ideally before pregnancy, as women who only obtain folic acid through their diet, do not have sufficient levels of folate concentration in their blood1. Folic acid might also help prevent other types of birth defects and early pregnancy loss (miscarriage)2. Essentially, folic acid helps the body to produce new cells and keep existing ones healthy4. In expectant mothers, folic acid helps to create new red blood cells (maternal erythropoiesis) and it aids foetal and placental growth1.Insufficient intake of folic acid can also lead to a type of anemia called folate-deficiency anemia2. Some people may be surprised that folic acid is also a very important vitamin for men4. Folic acid deficiency can lead to difficulty concentrating, exhaustion, heart palpitations, headaches, irritability and respiratory issues4. Folic acid, like all B vitamins, is important for the growth of the cells that form hair, skin, and nails. Having adequate levels of folic acid in your body may also improve growth of these tissues6. Because folate is water-soluble and leaves your body every time you urinate, folate deficiency can be quite common. This is why certain foods are fortified with folic acid, as well as why is it recommended that adults consume at least 400 micrograms (mcg) of folic acid per day4. In South Africa, most store bought breads are fortified with folic acid. Many cereals are also enriched with folic acid1. Naturally, folate levels are higher in foods such as lentils, beans, spinach, asparagus, broccoli1, orange and orange juice, nuts, poultry, meat, whole grains2 and avocado4.

OX I D AT I V

H

H

POL

FORMULATION

4,5

References: 1. De Cicco S, Immediata V, Romualdi D, et al. Myoinositol combined with alpha-lipoic acid may improve the clinical an

2. Genazzani AD, Shefer K, Della Casa D, et al. Modulatory effects of alpha-lipoic acid (ALA) administration on insulin sensitivity in obese P for Obesity Therapy? Curr Pharmaceut Design 2010;16:840-846. 4. Rago R, Marcucci I, Leto G, et al. Effect of myo-inositol and alpha-lipoi Homeostatic Agents 2015;29(4):1-11. 5. Sinopol® package insert, February 2019. 6. Cappelli V, Musacchio MC, Bulfoni A, et al. Natural m 7. Bellver J, Rodríguez-Tabernero L, Robles A, et al. Polycystic ovary syndrome throughout a woman’s life. J Assist Reprod Genet 2018;35:2

Proprietary name (and dosage form): SINOPOL® granules. Composition: Each sachet contains: Myo-inositol 1 000 mg, Alpha Lipoic Acid 400 mg This unregistered medicine has not been evaluated by SAHPRA for its quality, safety or intended use. Studies as part of the references were not Co. Reg. No. 1952/001640/07, 15e Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. For full prescribing information,


WOMEN’S HEALTH Focus

Easing those dreaded

MPTOMS

PMS symptoms

It affects over 90% of women in varying degrees, some suffering so badly that they have to miss work or school, while for others symptoms are milder1. In fact 5-10% of women describe their symptoms as severe or disabling2.

P

BRING BACK BALANCE

Helps to correct imbalances linked to

LYCYSTIC OVARIAN SYNDROME & ASSOCIATED INFERTILITY##1-7 *Polycystic ovarian syndrome # IVF - In-vitro fertilisation **Studies were conducted on supplemental Alpha Lipoic Acid only ## Due to PCOS

nd endocrine features of polycystic ovary syndrome through an insulin-independent action. Gynecol Endocrinol 2017;33(9):698–701. PCOS patients. J Endocrinol Invest 2018;41:583–590. 3. Carbonelli MG, Di Renzo L, Bigioni M, et al. α-Lipoic Acid Supplementation: A Tool ic acid on oocyte quality in polycystic ovary syndrome non-obese women undergoing in vitro fertilization: a pilot study. J Biol Regulators molecules for the therapy of hyperandrogenism and metabolic disorders in PCOS. Eur Rev Med Pharmacol Sci 2017; 21(2 Suppl):15-29. 25 -39.

g and Folic Acid 200 µg. Complementary Medicine: Health Supplement. D34.12 Multiple Substance formulation. t conducted on Sinopol®. Name and business address of applicant: iNova Pharmaceuticals (Pty) Limited. refer to the package insert. Further information is available on request from iNova Pharmaceuticals. IN3396/19.

REMENSTRUAL SYNDROME (PMS) is a condition that affects a woman’s emotional and physical health and behaviour during certain days of the menstrual cycle3. PMS generally starts 5 to 11 days before menstruation and typically goes away once menstruation begins3. Even though PMS is so common and can affect a women’s quality of life to such an extent2, it is still fairly misunderstood and untreated2. For the millions of women affected, the symptoms are very real1, 2. Breast swelling and tenderness, abdominal bloating and weight gain are experienced by approximately 65 to 72% of women while cravings for sweets, an increased appetite, headaches, dizziness or fainting and fatigue are reported to affect 24 to 35% of women. Nervousness, mood changes, irritability and anxiety affect 66 to 75% of women2 while 23 – 37% of women say that they experience crying, depression, forgetfulness, confusion and insomnia2. The cause of PMS is unknown although many researchers believe that it could be related to a change in both sex hormone and serotonin levels at the beginning of the menstrual cycle3. Some vitamin and mineral deficiencies are also thought to worsen certain PMS symptoms, including deficiencies in Magnesium, Vitamin B6, Vitamin E and Zinc2. Due to the complexities of PMS, there is no single effective treatment but some studies have shown that certain vitamin and minerals may help to ease certain symptoms1, 2. Furthermore, some women find that using evening primrose oil for premenstrual syndrome (PMS) and breast pain may be effective4. Evening primrose oil is the oil from the seed of the evening primrose plant and is used as a dietary source of essential fatty acids4. In fact, results of a study published in 2010 in the Alternative Medicine Review found that Evening Primrose Oil used in combination with Vitamin E may improve breast pain or tenderness5, a symptom which itself is said to affect 70% of premenopausal women at some point in their lives4. Primeve Plus® is South Africa’s number 1 Evening Primrose Oil supplement6 and contains Magnesium, Vitamin B6, Vitamin E and Zinc. The addition of Vitamin B6 may help with PMS symptoms, including moodiness, irritability, forgetfulness and anxiety1 while magnesium may also help relieve some PMS symptoms1. Some other tips that may relieve certain PMS symptoms include regular exercise, getting enough sleep

and choosing healthy foods. It is also advisable to avoid foods that contain too much caffeine, salt and sugar in the two weeks leading up to your period1. Studies have also shown that calcium, which is found in foods such as milk, cheese and yogurt, may help reduce some PMS symptoms including fatigue and depression1. Primeve Plus® is especially designed for women and may alleviate some of the symptoms associated with PMS and menopause as well as assist in the maintenance of overall female health, including healthy hair, nails and skin. It can be taken by children from 9 years old. Go to https://www.primeveplus.co.za for more information. Up to 5% of women of childbearing age suffer from premenstrual dysphoric disorder (PMDD), a health problem similar to PMS with more serious that may require medication or other treatments7. Speak to your doctor if your PMS symptoms are severely affecting your quality of life. DISCLAIMER: This article is for information and educational purposes only and is not intended to provide medical or other professional advice. Studies as part of the references were not conducted on Primeve Plus. This unregistered medicine has not been evaluated by the South African Health Products Regulatory Authority for its quality, safety or intended use. For more information on your medical condition and treatment options, speak to your healthcare professional. Further information is available on request from iNova Pharmaceuticals. Name and business address: iNova Pharmaceuticals (Pty) Ltd. Co. Reg. No. 1952/001640/07. 15E Riley Road, Bedfordview. Tel. No. 011 087 0000. www.inovapharma.co.za. IN749/19 REFERENCES: 1. Office on Women’s Health. Premenstrual Syndrome (2018) at https://www.womenshealth.gov/menstrual-cycle/ premenstrual-syndrome (Website accessed on 20 June 2019) 2. Dean C, Steinberg SK, Sylvester WH, Medical Management of Premenstrual Syndrome. Adapted from: Abraham GE National Factors in the Etiology of the Premenstrual Tension Syndromes. J Reprod Med 1983; 28(7):446-464 at https://www.ncbi.nlm.nih.gov/pubmed/21267135 (Website accessed on 20 June 2019) 3. Healthline – Premenstrual Syndrome (PMS) (2016) at https://www.healthline.com/health/premenstrualsyndrome (Website accessed on 20 June 2019) 4. Web MD. Evening Primrose Oil (2018) at https://www. webmd.com/vitamins/ai/ingredientmono-1006/eveningprimrose-oil (Website accessed on 20 June 2019) 5. Pruthi, S. et al. Vitamin E and evening primrose oil for management of cyclical mastalgia: a randomized pilot study. Alternat Med Rev 2010; 15(1):59-67 at https://www.ncbi.nlm.nih.gov/pubmed/20359269 (Website accessed on 20 June 2019) 6. IMS:TPM Data (V3X, G2X and D11A/ Constructed Class). MAT Jan 2017. 7. Office on Women’s Health. Premenstrual dysphoric disorder (PMDD) (2018) at https://www.womenshealth.gov/menstrualcycle/premenstrual-syndrome/premenstrual-dysphoricdisorder-pmdd (Website accessed on 21 June 2019)

MEDICAL CHRONICLE 67


Profile for New Media B2B

Women's Health  

Dear healthcare professional, Welcome to Medical Chronicle’s Women’s Health digibook, sponsored by iNova. Women’s Health has been in the sp...

Women's Health  

Dear healthcare professional, Welcome to Medical Chronicle’s Women’s Health digibook, sponsored by iNova. Women’s Health has been in the sp...