Issuu on Google+


Online Submission

IJCP Group of Publications

Volume 23, Number 4, September 2012

Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal CMD, Publisher, Group Editor-in-Chief

from the desk of group editor-in-chief 185 FDA Approves New Colon-Cleansing Drug

KK Aggarwal

Dr Veena Aggarwal MD, Group Executive Editor review article

Anand Gopal Bhatnagar Editorial Anchor

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj

187 Urinary Tract Infections in Women

Cardiology Dr Praveen Chandra Dr M Paul Anand, Dr SK Parashar Paediatrics Dr Swati Y Bhave Dr Balraj Singh Yadav Dr Vishesh Kumar Diabetology Dr Vijay Viswanathan Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh Dentistry Dr KMK Masthan Dr Rajesh Chandna

Clinical study 195 Role of HiOwna, a Polyherbal Health Drink in

Postoperative Convalescence: A Comparative Clinical Study

Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan Journal of Applied Medicine & Surgery Dr SM Rajendran

Brachytherapy in Carcinoma Cervix: Results From a Randomized Study

Ruchi Gaur, OP Singh, Milind Kumar, Aarti K Patel, DN Sharma, GK Rath

212 Phytotherapy for Lower Urinary Tract Symptoms

due to Benign Hyperplasia of Prostate

Tapas Maitra

215 Efficacy of Homeopathic Combination -

BPA Drug in Prehypertension and Hypertension: A Pilot Study

Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

Debashish Roy, Padmanabha Rugvedi

203 Comparison of Low- and High-dose Rate

Gastroenterology Dr Ajay Kumar Dermatology Dr Hasmukh J Shroff

Ramesh Hotchandani, KK Aggarwal

Prachi Garg, KK Aggarwal, Sunita Gupta, Parul Takkar, Mudita Arora


clinical Study

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

221 Evaluation of Creatine Kinase as a Diagnostic

Tool for Thyroid Function

KMDS Panag, Gitanjali, Sudeep Goyal

Printed at New Edge Communications Pvt. Ltd., New Delhi Š Copyright 2012 IJCP Publications Ltd. All rights reserved.

clinical Practice

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

224 Hypocholesterolemic Effects of Lactobacillus

acidophilus as a Dietary Supplement

M Vani, M Shiva Prakash, P Yashoda Devi

Editorial Policies The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

case report 231 Acute Pancreatitis in Pregnancy

Sreelatha S, Vedavathy Nayak, Nataraj

Medilaw 233 Should a Physician Treat another Physician Free?

Note: Indian Journal of Clinical Practice does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

MC Gupta

lighter reading 234 Lighter Side of Medicine

IJCP’s Editorial & Business Offices Delhi

Mumbai

Kolkata

Bangalore

Chennai

Hyderabad

Dr Veena Aggarwal 9811036687 E - 219, Greater Kailash, Part - I, New Delhi - 110 048 Cont.: 011-40587513 editorial@ijcp.com drveenaijcp@gmail.com Subscription Dinesh: 9891272006 subscribe@ijcp.com Ritu: 09831363901 ritu@ijcp.com

Mr. Nilesh Aggarwal 9818421222

Ritu Saigal Sr. BM 9831363901

H Chandrashekar Sr. BM 9845232974

Venugopal Sr. BM 9849083558

Flat 5E, Merlin Estate Geetanjali 25/8 Diamond Harbour Road Kolkata - 700 008 Cont.: 24452066 ritu@ijcp.com

Arora Business Centre, 111/1 & 111/2, Dickenson Road (Near Manipal Centre) Bangalore - 560 042 Cont.: 25586337 chandra@ijcp.com

Chitra Mohan Sr. BM 9841213823 40A, Ganapathypuram Main Road Radhanagar Chromepet Chennai - 600 044 Cont.: 22650144 chitra@ijcp.com

Building No - D 10 Flat No - 43, 4th Floor Asmita Co-operative Housing Society Near Charkop Naka Marvey Road Malad (W) Mumbai 400 095 nilesh.ijcp@gmail.com

Sr.: Senior; BM: Business Manager

H. No. 16-2-751/A/70 First Floor Karan Bagh Gaddiannaram Dil Sukh Nagar Hyderabad 500 059 Cont.: 65454254 venu@ijcp.com


from the desk of group editor-in-chief Dr KK Aggarwal

Padma Shri and Dr BC Roy National Awardee Sr. Physician and Cardiologist, Moolchand Medcity, New Delhi President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS Chairman Ethical Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

FDA Approves New Colon-Cleansing Drug

T

he US Food and Drug Administration (FDA) has approved a new colon-cleansing drug, prepopik (sodium picosulfate, magnesium oxide and citric acid), a dual-acting stimulant and osmotic laxative, for colonoscopy preparation.

A previously available, low-volume oral phospho-soda preparation was removed from the market for safety reasons. The advantage of a small-volume solution (300 ml) for bowel preparation is greater patient compliance, as use of large-volume cleansing preparations may be a deterrent to some patients for having the procedure. Increased use of screening colonoscopy and cleaner bowel allowing high-quality colonoscopy may improve screening rates and cancer detection. The preparation consists of two packets of sodium picosulfate, magnesium oxide and citric acid. In a split-dose regimen, patients dissolve the first packet of powder into water and drink the orange-flavored solution the night before a scheduled colonoscopy, and then do the same for the second packet the morning of the procedure. If that split-dose regimen cannot be performed, patients may also take the drug as a day-before regimen in the afternoon and evening before a colonoscopy. Patients are also advised to drink additional fluids during and after use of the preparation to reduce the risk for fluid and electrolyte imbalance.

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

185


review article 25. Antimicrobial agents: Sulfonamides, trimethoprimsulfamethoxazole, quinolones. Chapter 44. In: Goodman & Gilman’s the Pharmacological Basis of Therapeutics. Hardman, Limbird (Eds.), 10th edition, McGraw-Hill 2001:p.1185. 26. Aizawa N, Wyndaele JJ. Effects of phenazopyridine on rat bladder primary afferent activity, and comparison with lidocaine and acetaminophen. Neurourol Urodyn 2010;29(8):1445-50. 27. Kirwin TJ, Lowsley OS, Menning J. The effects of pyridium in certain urogenital infections. Am J Surg 1943;62(3): 330-5. 28. Pyridium drug description. Available at: www.rxlist.com 29. Deepalatha C, Deshpande N. A comparative study of phenazopyridine (pyridium) and cystone as short-term analgesic in uncomplicated urinary tract infection. Int J Pharm Pharm Sci 2011;3(Suppl 2):224-6. 30. Heifetz CL, Fisher MW. Phenazopyridine-sulfonamide combination antibacterial therapy in mice. Antimicrob Agents Chemother 1973;3(1):134-5. 31. Neter E, Loomis TA. The combined bacteriostatic activity of sulfonamide compounds and pyridium upon B. coli in vitro. Urol Cutaneous Rev 1941;45:295-7. 32. Marcelín-Jiménez G, Angeles AP, Martínez-Rossier L, Fernández SA. Ciprofloxacin bioavailability is enhanced

192

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

by oral co-administration with phenazopyridine: a pharmacokinetic study in a Mexican population. Clin Drug Investig 2006;26(6):323-8. 33. Nazarko L. Bladder pain from indwelling urinary catheterization: case study. Br J Nurs 2007;16(9):511-2, 514. 34. Sulzbach LM. Ask the Experts. Crit Care Nurse 2002;22(3):84-7. 35. Berkey FJ. Managing the adverse effects of radiation therapy. Am Fam Physician 2010;82(4):381-8, 394. 36. Paola FA, Sales D, Garcia-Zozaya I. Phenazopyridine in the management of autonomic dysreflexia associated with urinary tract infection. J Spinal Cord Med 2003;26(4):409-11. 37. Oxybutynin. Available at: http://www.rxlist.com/ditropandrug.htm. 38. Muscarinic receptor agonists and antagonists. Chapter 7. In: Goodman & Gilman’s the Pharmacological Basis of Therapeutics. Hardman, Limbird (Eds.), 10th edition, McGraw-Hill 2001:p.169. 39. Mohammed ZS, Simi ZU, Tariq SM, Ali KR. Bilateral acute angle closure glaucoma in a 50 year old female after oral administration of flavoxate. Br J Clin Pharmacol 2008;66(5):726-7. 40. Lee M, Bozzo P, Einarson A, Koren G. Urinary tract infections in pregnancy. Can Fam Physician 2008;54(6):853-4.


review article

Urinary Tract Infections in Women Ramesh hotchandani*, kk aggarwal**

Abstract Urinary tract infections (UTIs) are one of the most common bacterial infections seen in primary care, second only to infections of the respiratory tract. Women are particularly at risk of developing UTIs because of their short urethra, and certain behavioral factors which include delay in micturition, sexual activity and the use of diaphragms and spermicides. Uncomplicated UTIs are usually treated empirically with antibiotics. However, not everyone diagnosed with a UTI and treated with an antibiotic will necessarily have a bacterial infection. At least one-half of women who suspect that they have UTI actually do. Studies have shown that one in 7 patients given an antibiotic for UTI symptoms will return within 28 days for a further prescription of antibiotic. Also, many UTIs are self-limiting, improving without treatment even when culture is positive. Symptomatic treatment of uncomplicated UTI may be an option which merits further research. Phenazopyridine  is a time-tested urinary tract antiseptic and analgesic that provide symptomatic relief of the pain, burning, frequency and urgency associated with UTI.

Keywords: Urinary tract infections, symptomatic treatment, phenazopyridine, analgesic

U

rinary tract infection (UTI) is defined as the presence of microbial pathogens in the urinary tract with associated symptoms. When it affects the lower urinary tract it is known as cystitis and when it affects the upper urinary tract it is known as pyelonephritis. UTIs are one of the most common bacterial infections seen in primary care, second only to infections of the respiratory tract.1 They are particularly common among the female population with an incidence of about 1% of school-aged girls and 4% of women through child-bearing years. Incidence of infection in females increases directly with sexual activity and child-bearing. In the women, 25-30% of women between 20-40 years of age will get UTIs.2 These infections account for about 8.3 million doctor visits each year.1 UTIs have been well-studied in Sweden and other parts of Europe.3 These studies have shown that one in 5 adult women experience a UTI at some point, confirming that it is an exceedingly common worldwide problem.3 In 2007, approximately 3.9% of office visits in USA were related to symptoms

*Head, Dept. of Nephrology, Moolchand Medcity, New Delhi **Senior Physician and Cardiologist Moolchand Medcity, New Delhi

involving the genitourinary tract.4 Sixty-one percent of all UTIs are managed in the primary care setting. It is also common for these episodes to recur.5 Predisposing factors Women are particularly at risk of developing UTIs because of their short urethra, and certain behavioral factors which include delay in micturition, sexual activity and the use of diaphragms and spermicides which promote colonization of the periurethral area with coliform bacteria. Infection in women most often results from perineal or periurethral bacteria that enter the urethra and ascend into the bladder, often in association with sexual activity, or due to mechanical instrumentation such as catheterization.6 Rates of infection are high in postmenopausal women because of bladder or uterine prolapse causing incomplete bladder emptying; loss of estrogen with attendant changes in vaginal flora (notably, loss of lactobacilli), which allows periurethral colonization with gramnegative aerobes, such as Escherichia coli; and higher likelihood of concomitant medical illness, such as diabetes. Reports worldwide suggest a significant peak in the incidence of UTI for a few months each year in the post summer season. Anderson et al reported a rise in the incidence of UTI in August.7 They attribute this

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

187


review article to hot and humid conditions during these months. In a study by Hasan et al, in a tertiary Indian hospital in New Delhi, rise in the incidence of UTI was reported during the monsoon months i.e. from July to September.8 Clinical Presentation The characteristic symptoms of UTI in the adult are primarily dysuria with irritating voiding symptoms like urinary urgency, frequency, nocturia, painful voiding, bladder discomfort or stranguria which greatly distress the patient. A sensation of bladder fullness or lower abdominal discomfort is usually present. Pain occurring at the beginning of or during urination suggests a urethral site of disease, whereas pain after voiding implies pathology within the bladder or prostate area. Sometimes a patient will relate a history of pain in the suprapubic area.9 Because of the referred pain pathways, even simple lower UTI may be accompanied by flank pain and costovertebral angle tenderness. In the emergency department, however, it is assumed that the presence of these symptoms represents upper UTI. Bloody urine is reported in as many as 10% of cases of UTI in otherwise healthy women; this condition is called hemorrhagic cystitis. Fevers, chills and malaise may be noted in patients with cystitis, though these findings are associated more frequently with upper UTI (i.e. pyelonephritis). Causative Organisms E. coli is by far the commonest cause of uncomplicated community-acquired UTIs in both outpatient and inpatient settings. Other common uropathogens are Enterococcus faecalis, Enterobacter species, Staphylococcus saprophyticus, Klebsiella pneumoniae, Proteus mirabilis and Pseudomonas species.10 Diagnosis Urinalysis is mandatory in all patients who present with dysuria. The gold standard is evaluation of a spun midstream clean-catch urine specimen. Bacteria or pyuria (or both) are usually found in patients with UTI. Leukocyte esterase is 75% sensitive for detection of UTI (although studies done in the emergency department have demonstrated only 48% sensitivity), but 98% specific. Positive nitrite is highly suggestive of a UTI (90% specific), but a negative result does not rule it out (sensitivity is only 30%).6 Urine culture is unnecessary for most patients with consistent

188

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

symptoms and a positive dipstick test, unless any predisposing factors for upper tract or complicated infection (hydronephrosis or atonic bladder) are present.11 Management UTIs can be classified into acute uncomplicated cystitis, acute uncomplicated pyelonephritis, complicated UTI and acute complicated pyelonephritis. Uncomplicated UTIs are usually treated empirically with antibiotics as recommended by primary care guidelines. Antibiotics for empiric treatment of uncomplicated UTI include.9 ďƒœ

ďƒœ

First-line antibiotic: Trimethoprim/sulfamethoxazole in communities with resistance rates for E. coli <20%. Avoid in women who have been treated within six months, as they are more likely to have resistant organisms. Second-line antibiotics or first-line in resistant communities: Fluoroquinolones, such as ciprofloxacin, levofloxacin, norfloxacin and ofloxacin.

Although, antibiotic treatment supports clinical cure in individual patients but also leads to emerging resistance rates in the population. Resistance has increased to various antimicrobials and more than one-quarter of E. coli strains causing acute cystitis are resistant to amoxicillin, sulfa drugs and cephalexin and resistance to co-trimoxazole is now approaching these levels. Resistance to fluoroquinolones is also rising. Akram et al reported ciprofloxacin resistance rates ranging from 47 to 69% among the gram-negative organisms in their study in India.12 High levels of extended-spectrum beta-lactamase (ESBL) producers among gram-negative community-acquired uropathogens is seen in our country. This, along with the alarming rate of resistance to ciprofloxacin, sulfamethoxazole-trimethoprim and amoxicillin, precludes the use of these commonly used antibiotics for empiric treatment of communityacquired UTI in India.13 To prevent resistance, antibiotics should be used judiciously; they should be prescribed for as short a period as possible. Milo and colleagues reviewed 32 randomized controlled trials (with a total of 9,605 patients) comparing three days of oral antibiotic therapy with longer courses for women 18-65 years of age.14 Pregnant women and women with symptoms that suggest upper UTI (e.g., fever, flank pain, vomiting, positive blood cultures) were excluded. For short- and long-term resolution of symptoms, the reviewers found no difference between a 3-day antibiotic course and a course lasting 5-10 days. Longer courses were more


review article effective at clearing the bacteria on follow-up culture but also caused more adverse effects, and it was not clear that bacterial clearance resulted in improved patient-oriented outcomes.14 However, not everyone diagnosed by a general practitioner with a UTI and treated with an antibiotic will necessarily have a bacterial infection. At least one-half of women who suspect that they have UTI actually do.15 Fifty percent of patients consulting with urinary tract symptoms may not have a clinically important infection on culture. In a study by Eshwarappa et al in a South Indian population, only 510 of the 5,564 suspected cases (9.17%) were proved by culture.16 Studies have shown that one in 7 patients given an antibiotic for UTI symptoms will return within 28 days for a further prescription of antibiotic.17 In many patients without additional risk factors, UTI seems to be a self-limiting condition. Studies have shown that many UTIs are self-limiting, improving without treatment even when culture is positive.18 One trial in Belgium has shown that half of the patients were free of symptoms after three days of placebo.19 If the volume of antibiotic prescribing is to be reduced and the increasing problem of resistant organisms addressed, alternative diagnostic and treatment strategies in primary care are needed.20 Symptomatic treatment of uncomplicated UTI may be an option which merits further research.

3-(phenylazo)-, monohydrochloride.24 It is used as a urinary tract antiseptic and analgesic as brief adjuvant therapy for treatment of UTI. Additionally, the drug is used for many urologic problems involving dysuria.25

Mechanism of Action The precise mechanism of action of phenazopyridine hydrochloride is not known. It is excreted in the urine, where it acts as a topical analgesic on the mucosal lining of the urinary tract thus relieving pain, burning, urgency and frequency. However, it does not possess any antimicrobial properties. In a study undertaken recently, it was demonstrated that phenazopyridine directly inhibits the mechanosensitive Aδ-fibers in the normal rat bladder. In this study, the effect of phenazopyridine on afferent nerve activity was evaluated by direct measurement of both Aδ- and C-fibers, and compared the outcome with the effects of a local anesthetic (lidocaine) and of an analgesic (acetaminophen). Intravenous administration of phenazopyridine significantly decreased dosedependently only the Aδ-fibers but not the C-fiber activity. According to the researchers, phenazopyridine exerts its clinical effect in conditions of urinary bladder hypersensitivity by direct inhibition of the mechanosensitive Aδ-fibers.26

Clinical Efficacy

Symptomatic Treatment of Uncomplicated UTI

Analgesic Properties

Symptomatic UTIs are among the most common of bacterial infections.21 Though relatively benign and self-limiting, these irritating voiding symptoms like urinary urgency, frequency, nocturia, painful voiding, bladder discomfort or stranguria greatly distress the patient and have a detrimental influence on patient quality-of-life.22 Symptomatic treatment allows time for microbiological investigation and helps to reduce unnecessary prescribing of antibiotics. A urinary tract analgesic would have an immense reassuring effect on the patient. Phenazopyridine is a urinary tract antiseptic and analgesic that has for long been used to provide symptomatic relief of the pain, burning, frequency and urgency associated with UTI during the first 24-48 hours of therapy.

A study was undertaken by Kirwin et al to evaluate the effects of phenazopyridine 500 mg (two tablets thrice-daily) administration in urogenital infections in 118 patients. It was seen that in 65 (55.1%) cases, all the characteristic symptoms of urogenital infections were relieved: Pain on urination was alleviated or abolished in 95.3%; burning on urination was relieved in 93.6%; frequency decreased in 85%, nocturia was eliminated or reduced in 83.7%, with reduction the organized sediment. In the remaining 53 cases, symptomatic relief was also observed in all but a few, although, there was no concomitant reduction in the organized urinary sediment. Phenazopyridine was very well-tolerated with no toxic effects observed during the two weeks of its administration.27

Phenazopyridine Phenazopyridine hydrochloride is an azo dye with local analgesic and anesthetic effects on the urinary tract.23 Chemically, phenazopyridine is 2,6-Pyridinediamine,

Adjuvant to Antimicrobial Therapy in Uncomplicated UTIs Phenazopyridine is compatible with antibacterial therapy and can help to relieve pain and discomfort during the interval before antibacterial therapy controls the infection. Treatment of UTI with

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

189


review article phenazopyridine hydrochloride should not exceed two days because there is a lack of evidence that the combined administration of phenazopyridine hydrochloride and an antibacterial provides greater benefit than administration of the antibacterial alone after two days.28 Efficacy of phenazopyridine when administered along with antibiotics as a short-term analgesic in the treatment of uncomplicated UTIs was demonstrated in a randomized, open label study. It was seen that phenazopyridine, when given with antibiotics such as ciprofloxacin, doxycycline within 48 hours of diagnosis, resulted in marked reduction in urinary symptoms of burning micturition (91%) and pain during voiding of urine (89%).29 Phenazopyridine is widely used as an adjunct to sulfonamides in the treatment of bacterial infections of the urinary tract because of its proven analgesic effect on the mucosa of the urinary tract. It does not alter the effectiveness of sulfonamides against uropathogenic bacterial species in mice.23 The combined bacteriostatic activity of sulfonamide compounds and phenazopyridine upon Balantidium coli has been demonstrated in vitro.30,31 Another study demonstrated that bioavailability of ciprofloxacin is enhanced by oral co-administration with phenazopyridine. This study compared the pharmacokinetic behavior of ciprofloxacin administered alone versus ciprofloxacin plus phenazopyridine. While there were no differences between the two treatments in terms of peak plasma concentration (Cmax) and elimination constant (ke), area under the concentrationtime curve to last measurable concentration (AUCt) and area under the concentration-time curve extrapolated to infinity (AUCâ&#x2C6;&#x17E;) were 35% and 29% higher, respectively, in the combined treatment arm. In addition, a significant delay in tmax (from 1 to 1.5 hours) and a statistical increase of 29% in mean residence time (MRT) were also observed in the combination group. The study concluded that phenazopyridine, when given together with antibiotic (ciprofloxacin) enhances its bioavailability with regard to the amount absorbed and MRT in the body, which is beneficial during treatment.32 Pain due to Bladder Spasms Indwelling urinary catheter is a foreign body and its presence may trigger spasms, or detrusor contractions due to irritation of the trigone area.33 This complication is distressing for the patient. Phenazopyridine hydrochloride helps relieve the pain caused by catheters.34

190

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

Chronic Radiation Cystitis Radiation therapy is an integral part of adjunctive treatment in approximately 66% of cancer patients and its use has increased cancer survival. However, it is associated with chronic cystitis which impairs the cancer survivorâ&#x20AC;&#x2122;s quality-of-life. Phenazopyridine provides symptomatic relief for chronic cystitis associated with radiation therapy.35 Autonomic Dysreflexia Phenazopyridine may be useful in the management of autonomic dysreflexia (AD) associated with UTI. Paola et al have reported a case of a 36-year-old man with tetraplegia and AD triggered by cystitis, who improved both subjectively and objectively following the institution of a 2-day course of phenazopyridine.36 Phenazopyridine vs Other Antispsmodics Urinary antispasmodics such as oxybutynin and flavoxate are muscarinic receptor antagonists and exert beneficial direct relaxant effect on smooth muscle of the urinary tract, with local analgesic and anesthetic effects on the urinary tract.16 However, flavoxate and oxybutynin have anticholinergic effects such as dry mouth, constipation and other anticholinergic effects. Phenazopyridine has a different mechanism of action; it has both local analgesic and anesthetic effects on the urinary tract. Anticholinergics like oxybutynin and flavoxate alter the absorption of some concomitantly administered antimicrobials due to anticholinergic effects on gastrointestinal motility.37 On the other hand, the bioavailability of ciprofloxacin has been shown to be enhanced by oral co-administration with phenazopyridine. Hence, the major limitation in the use of non selective drugs like flavoxate and oxybutynin is often failure to obtain desired therapeutic responses without concomitant side effects. The anticholinergic side effects, though usually not serious, are sufficiently disturbing to decrease patient compliance, particularly during long-term administration.38 Also, the lack of demonstrated effect of flavoxate in placebocontrolled studies makes it difficult to recommend the use of flavoxate and it is definitely not a first-line treatment.39 Safety in Pregnancy Phenazopyridine is currently classified in pregnancy category B. The Collaborative Perinatal Project monitored 50,282 mother-child pairs in which 1,109 exposures anytime during pregnancy and 219 exposures during the first-trimester were documented. Results indicated no increase in the rates of major malformations or any


review article other adverse effects.40 On the other hand, there are no well-controlled studies on use of flavoxate in pregnant women, so it should be used during pregnancy only if clearly needed.

10. Watring NJ, Mason JD. Deciphering dysuria. Emerg Med 2008;40(9):29-34.

Conclusions

11. Car J. Urinary tract infections in women: diagnosis and management in primary care. BMJ 2006;332(7533):94-7.

UTIs are a significant clinical problem. The associated symptoms of burning micturition, pain during voiding and increased frequency of urination can be a source of great discomfort and can greatly affect patients’ quality-of-life. Uncomplicated UTIs are usually treated empirically with antibiotics. However, antibiotics should not be prescribed excessively, particularly in view of the increasing prevalence of antibiotic resistance. Symptomatic treatment is an option which allows time for microbiological investigation and helps to reduce unnecessary prescribing of antibiotics. Phenazopyridine is a urinary tract antiseptic and analgesic that provides symptomatic relief of the pain, burning, frequency and urgency associated with UTI during the first 24-48 hours of therapy and is safe in pregnancy. Other urinary antispasmodics such as oxybutynin and flavoxate are useful but the bothersome anticholinergic side effects, limits their use. References 1.

Pushpalatha KS. Urinary tract infection and management. J Nighting Nursing Times 2008;4(5):28-32.

2.

Wilma JP. Shafers Medical Surgical Nursing. 7th edition, B.I. Publications: New Delhi 2002:p.637-40.

3.

Naber KG, Schito G, Botto H, Palou J, Mazzei T. Surveillance study in Europe and Brazil on clinical aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): implications for empiric therapy. Eur Urol 2008;54(5):1164-75.

4.

Hsiao CJ, Cherry DK, Beatty PC, Rechtsteiner EA. National Ambulatory Medical Care Survey: 2007 summary. Natl Health Stat Report 2010;(27):1-32.

5.

Medina-Bombardó D, Jover-Palmer A. Does clinical examination aid in the diagnosis of urinary tract infections in women? A systematic review and meta-analysis. BMC Fam Pract 2011;12:111.

Examinations. 3rd edition, Walker HK, Hall WD, Hurst JW (Eds.), Butterworths: Boston; 1990.

12. Akram M, Shahid M, Khan AU. Etiology and antibiotic resistance patterns of community-acquired urinary tract infections in J N M C Hospital Aligarh, India. Ann Clin Microbiol Antimicrob 2007;6:4. 13. Kothari A, Sagar V. Antibiotic resistance in pathogens causing community-acquired urinary tract infections in India: a multicenter study. J Infect Dev Ctries 2008;2(5): 354-8. 14. Milo G, Katchman EA, Paul M, Christiaens T, Baerheim A, Leibovici L. Duration of antibacterial treatment for uncomplicated urinary tract infection in women. Cochrane Database Syst Rev 2005;(2):CD004682. 15. Bent S, Nallamothu BK, Simel DL, Fihn SD, Saint S. Does this woman have an acute uncomplicated urinary tract infection? JAMA 2002;287(20):2701-10. 16. Eshwarappa M, Dosegowda R, Aprameya IV, Khan MW, Kumar PS, Kempegowda P. Clinico-microbiological profile of urinary tract infection in south India. Indian J Nephrol 2011;21(1):30-6. 17. Lipman T, Price D. Decision making, evidence, audit, and education: case study of antibiotic prescribing in general practice. BMJ 2000;320(7242):1114-8. 18. Ferry SA, Holm SE, Stenlund H, Lundholm R, Monsen TJ. The natural course of uncomplicated lower urinary tract infection in women illustrated by a randomized placebo controlled study. Scand J Infect Dis 2004;36(4):296-301. 19. Christiaens TC, De Meyere M, Verschraegen G, Peersman W, Heytens S, De Maeseneer JM. Randomised controlled trial of nitrofurantoin versus placebo in the treatment of uncomplicated urinary tract infection in adult women. Br J Gen Pract 2002;52(482):729-34. 20. Christiaens TC, Digranes A, Baerheim A. The relation between sale of antimicrobial drugs and antibiotic resistance in uropathogens in general practice. Scand J Prim Health Care 2002;20(1):45-9.

6.

Litza JA, Brill JR. Urinary tract infections. Prim Care 2010;37(3):491-507, viii.

21. Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA). Clin Infect Dis 1999;29(4):745-58.

7.

Anderson JE. Seasonality of symptomatic bacterial urinary infections in women. J Epidemiol Community Health 1983;37(4):286-90.

22. Ellis AK, Verma S. Quality of life in women with urinary tract infections: is benign disease a misnomer? J Am Board Fam Pract 2000;13(6):392-7.

8.

Hasan AS, Nair D, Kaur J, Baweja G, Deb M, Aggarwal P. Resistance patterns of urinary isolates in a tertiary Indian hospital. J Ayub Med Coll Abbottabad 2007;19(1):39-41.

23. Berkey FJ. Managing the adverse effects of radiation therapy. Am Fam Physician 2010;82(4):381-8, 394.

9.

Wrenn K. Dysuria, frequency, and urgency. Chapter 18. In: Clinical Methods: The History, Physical, and Laboratory

24. Hui JY, Harvey MA, Johnston SL. Confirmation of ureteric patency during cystoscopy using phenazopyridine HCl: a low-cost approach. J Obstet Gynaecol Can 2009;31(9):845-9.

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

191


Clinical study

Role of HiOwna, a Polyherbal Health Drink in Postoperative Convalescence: A Comparative Clinical Study Debashish Roy*, Padmanabha Rugvedi**

Abstract Background: Postoperative nutritional support has a vital role in the management of postoperative convalescence. Oral nutrition uses the physiological route of nutrient intake, is inexpensive and is generally safer, and should be the preferred method of nutritional support, in the presence of a functioning gastrointestinal tract. It also accelerates recovery and reduces postoperative morbidity and overall costs. Objective: To evaluate the clinical efficacy and safety of a polyherbal health drink in the clinical recovery during postoperative convalescence cases. Material and Methods: A comparative clinical trial was conducted in 45 postoperative cases during their convalescence period. The study subjects were randomized into two groups: HiOwna health drink or the comparator health drink. They were instructed to take four tablespoons with warm milk or warm water, twice-daily for one month. Subjects were assessed at entry, and at the end of 15 days and 30 days. At each visit the subjects were evaluated for various parameters of postoperative signs and symptoms. Results: Improvement in the parameters such as hemoglobin (Hb), WBC count and time taken for complete recovery, significant weight gain was quicker and significant in HiOwna group than in the comparator health drink group. HiOwna health drink group showed comparable results with the comparator group with respect to recovery from pain in the incision site and time taken for patient ambulation. Conclusion: HiOwna, a natural health drink supplement may be safe and effective in reducing undesirable sequelae of surgical injury with accelerated recovery and reduction in postoperative morbidity and overall costs.

Keywords: HiOwna, postoperative convalescence

F

rom a metabolic and nutritional point of view, the key aspects of perioperative care include integration of nutrition into the overall management of the patient, metabolic control, reduction of factors which exacerbate stress-related catabolism or impair gastrointestinal function early mobilization.1 Major operations are commonly followed by fatigue and convalescence. The pathogenesis of postoperative fatigue can include sleep disturbances induced by cytokines and opioids in the period while the late fatigue persisting for upto several weeks can depend on loss of muscle tissue and function and deconditioning of cardiovascular response to exercise, as well as level of preoperative fatigue.2 The changes in organ function are thought to be mediated by trauma-induced endocrine metabolic changes and activation of several *Consultant Surgeon Voluntary Health Services Hospital, Adyar, Chennai **Consultant Ayurveda Physician, Vagatma Vaidyashala, Tumkur Address for correspondence Dr Debashish Roy, Consultant Surgeon Voluntary Health Services Hospital, Adyar, Chennai - 32

biological cascade systems (cytokines, complement, arachidonic acid metabolites, nitric oxide, free oxygen radicals, etc.).2 Therapeutic interventions in order to reduce catabolism and loss of muscle tissue and function may include stress reduction, enforced early mobilization, electrical muscle stimulation and early oral nutrition, supported by pain treatment techniques to accelerate restoration of gastrointestinal motility. Furthermore, a variety of nutritional substrates, growth hormone or other growth factors may reduce catabolism and maintain muscle mass.2 Postoperative recovery is dependent on pain, fatigue and traditional recommendations of a long convalescence period. Reduction of the convalescence period is also highly dependent on advice from surgeons and general practitioners, but in the past such information has mostly been restrictive and based on traditions.3 During and after surgical injury, the body responds with profound changes in neural, endocrine and

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

195


clinical study metabolic systems in addition to alterations in organ functions,4 which may be implicated in the development of postoperative complications. All surgical procedures are followed by pain, which may amplify endocrine metabolic responses autonomic reflexes, nausea, ileus and muscle spasm and thereby delay restoration of function. Optimal treatment of postoperative pain is mandatory in order to enhance recovery and reduce morbidity. Much evidence has emerged to demonstrate pronounced trauma-induced alterations in immunological systems. Major surgery causes immunosuppression with reduced delayed hypersensitivity response to recall antigen stimulation, T-cell-dependent antibody response, interleukin-2 (IL-2) production and HLA-DR antigen expression, g-interferon (g-IFN) production and T-cell blastogenesis.5 The clinical consequences of pre- and postoperative immunological changes are increased susceptibility to infective complications.6 Nausea, vomiting and ileus are among the most common postoperative complaints. They are also important determining factors in postoperative rehabilitation. Thus, early enteral nutrition is critical in reducing post-traumatic infective complications7 as well as catabolism.8 Sleep patterns are severely disturbed in postoperative patients, with a decrease in total sleep time, elimination of rapid eye movement (REM) sleep and a marked reduction in slow wave sleep (SWS).9 The pathogenesis of postoperative sleep disturbances is multifactorial, and includes afferent neural stimuli (surgical stress), cytokines, pain, use of opioids and noise and awakenings during monitoring and nursing procedures.10 Traditional perioperative care involves bed rest, even though it is well-known that immobilization may increase the risk of thromboembolic and pulmonary complications. Bed rest also predisposes to orthostatic intolerance and instability during standing, and to an increased loss of muscle tissue and function.11 Early ambulation may improve wound healing12 and rehabilitation in order to improve outcome and may reduce costs.

patients with normal nutritional status have a high-risk of developing septic complications and multiple organ failure. Early enteral nutrition has been claimed to reduce septic complications14-16 and, has been suggested to reduce the rate of multiple organ failure when initiated within 24 hours.17 A National US-Database evaluation also supported the cost-effectiveness of nutritional formulae modulating immune function. In order to reduce resource consumption and total cost, a break even infection rate was also calculated for well-nourished as well as undernourished surgical patients.18 Three randomized controlled trials showed that postoperative immune modulating formulae are effective in both undernourished and well-nourished gastrointestinal cancer patients. In patients undergoing gastrectomy for gastric cancer, early enteral nutrition with immune modulating formula was associated with significantly less wound healing problems, suture failure and infectious as well as global complications.18 It is also found that time to wound closure can be shortened by oral antioxidant and glutamine containing supplements in trauma patients with impaired wound healing.19 In addition to reducing early post-transplant infections by perioperative immunonutrition, the use of such immune-modulating diets over an extended period in patients with advanced liver disease may also ameliorate the malnutrition-induced immune suppression and hyperinflammatory state characteristic of these patients20 with subsequent survival benefit. Whenever possible administration of these supplemented formulae should be started before surgery and continued postoperatively for 5-7 days after uncomplicated surgery.18

It has been suggested that the routine provision of oral dietary supplements in postoperative surgical patients is beneficial with regard to morbidity and length of hospital stay.13

An immunonutritional formula enriched in arginine, fish oil and nucleotides has proven to be beneficial in reducing postoperative infectious complications and length of hospital stay.21-23 Studies of patients given enteral nutrition supplemented with arginine or glycine after major surgery benefited from a faster recovery of immunological parameters, fewer infectious complications and a shorter hospital stay.24 The elimination of ileus allows the early use of enteral nutrition which is an important factor in reducing the risk of infectious complications.25

Oral nutrition by means of oral nutritional supplements and if necessary tube feeding offers the possibility of increasing or ensuring nutrient intake in cases where food intake is inadequate. Trauma

A large variety of nutritional supplements with varying nutrients, flavor and taste are available in the market as per the patient preferences to enhance postoperative nutrition and control postoperative dysfunction.

196

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012


clinical study Aim To evaluate the clinical efficacy and safety of a HiOwna health drink in clinical recovery during postoperative convalescence cases as compared to a standard comparator health drink. Material and Methods A total of 45 postoperative cases during their convalescence period at Voluntary Health Services Hospital, Adyar, Chennai, were evaluated in this comparative clinical trial after the approval from Institutional Ethics committee. Inclusion criteria: Both male and females aged more than 18 years; at least three days following surgery and ambulatory cases were included in the study. Individuals who were already started with oral foods were included in the trial after their consent to participate in the study and who were willing to follow the study rules and responsibility. Exclusion criteria: Postoperative cases advised nil per oral, cases with intestinal obstruction, paralytic ileus, pulmonary embolism or any severe infection, postoperative cases who are critical requiring observation in intensive care unit (ICU), patients with cardiac, hepatic or renal failure or regularly on any treatment or concurrently taking medicines for any illness, etc., those with a strong history of food or drug allergy and subjects not willing to provide informed consent or abide by the requirements of the study.

Study Procedure All eligible cases who were willing to participate in the study were given detailed description about the investigational product, nature and duration of the study. They were also explained their responsibilities after entering the study. Only subjects who met these requirements and signed an informed consent form were included in the study. The investigator retained the original copy of the signed informed consent and the subject received a copy of the signed informed consent. At entry, a detailed medical and surgical history was obtained from all the enrolled subjects. Subsequently, the subjects underwent a simple physical and systemic examination. HiOwna health drink or the comparator health drink was given to all the subjects as per the randomization. They were instructed to take four tablespoons with warm milk or warm water, twicedaily for a period of one month in addition to the regular diet.

The predefined primary endpoints were speedy recovery in postoperative convalescence. The predefined secondary endpoints for short-term safety were assessed by incidence of adverse events, and compliance to the drug therapy.

Follow-up and Assessment Subjects were assessed at entry, and at the end of 15 days and 30 days. At each visit, the subject was evaluated for parameters for time for ambulation, incision site or dressing inspection and weight gain, improvement in hemoglobin (Hb), fever, bowel sounds, stool frequency, pain, nausea/vomiting, appetite. The grading of the other parameters was done as follows: Severe-3, Moderate-2, Mild-1, Disappearance of the symptoms-0. The overall clinical assessment was defined as cured, improved and unchanged.

Adverse Event Assessment At each follow-up visit, the investigator recorded information about intercurrent illness or infections and concomitant medication. All the adverse events reported or observed by patients were recorded with information about severity, date of onset, duration and action taken regarding the study drug. Any adverse effects reported, or observed by the subjects were recorded with information about severity, date of onset, duration and action taken regarding the study drug. Relation of adverse events to study medication was predefined as ‘Unrelated’ (a reaction that does not follow a reasonable temporal sequence from the administration of the drug), ‘Possible’ (follows a known response pattern to the suspected drug, but could have been produced by the subject’s clinical state or other modes of therapy administered to the subject) and ‘Probable’ (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the subject’s clinical state).

Statistical Analysis All values are expressed as compared to ‘At entry’ as mean ± SD. Hb, white blood cells (WBC) count, biochemical parameters were analyzed by paired t-test. Body weight was analyzed by repeated measures of ANOVA using Tukey’s multiple comparison test. Between the group analyses for weight gain, time taken for ambulation and complete clinical recovery was analyzed by unpaired t-test. Pain at the incision site was analyzed by Fisher’s exact test. The minimum level of significance was fixed at p < 0.05. Statistical analysis was performed using

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

197


clinical study Graphpad Prism Software version 4.00 for Windows, San Diego, California, USA.

Table 1. Demographic Data

Results

Age

The demographic details of the subjects at entry are provided in Table 1. Both the groups were comparable in age, sex and type of surgery at entry. The effect of HiOwna and comparator on parameters of Hb and WBC count is shown in Table 2. In the HiOwna group, Hb significantly increased from 12.80 ± 0.80 at entry to 13.15 ± 0.65 at the end of the study (p < 0.026). The changes in the mean hemoglobin were not significant in the comparator group with mean initial values from 12.59 ± 1.71 at entry to 12.68 ± 1.71, at the end of the study. Results for the mean WBC count (% w.mm) in HiOwna also showed significant changes from the initial 8684 ± 1085 to 8180 ± 695.8 at the end of the study (p < 0.001). The WBC count (% w.mm) also improved from 8325 ± 1910 to 7325 ± 1263 in the comparator group at the end of the study (p < 0.026). The effect of HiOwna on biochemical parameters of serum glutamic pyruvic transaminase (SGPT), serum creatinine and uric acid are shown in Table 3. Mean value of SGPT in the study group at entry was 32.80 ± 2.22 and 33.40 ± 2.63 after the treatment with no significant changes. Mean creatinine value was 0.67 ± 0.21 at entry; after HiOwna administration, the mean creatinine value was 0.73 ± 0.14 with no significant changes. Similarly for uric acid, changes were not significant with initial value of 4.21 ± 0.50 and 4.44 ± 0.77 after the trial. In the comparator group also, the changes were not significant for all the three variables with respective mean values before and after the trial. This establishes the safety of both the formulations. The effect of HiOwna on weight profile is shown in Table 4. In the HiOwna group, the mean weight, which was 55.85 ± 7.09 at entry improved to 57.46 ± 7.5 at Day 15 (p < 0.001) and further improved to 58.15 ± 7.65 at Day 30 (p < 0.001) on continued administration. The mean weight in the comparator group was 61.10 ± 8.24 at entry, which improved to 61.65 ± 7.93 at Day 15. At the end of 30 days, it was improved to 62.45 ± 8.29 as compared to the initial values (p < 0.01). Between-group comparisons for weight gain as shown in Table 5 suggest that the mean weight gain in the HiOwna group on Day 15 was 1.62 ± 1.45 (p < 0.04) as compared to the comparator group, which is 0.55 ± 1.36 on Day 15. On Day 30, the improvements are comparable with no significant changes between the study and comparator groups with mean weight

198

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

Parameters

HiOwna

Comparator

40.80 ± 13.08 44.85 ± 13.04

Number of patients (M,F)

25 (18,7)

20 (14,6)

Meshplasty for hernia

7

5

Plication of the sac in chylous ascites

0

1

Saphenofemoral ligation right for varicose veins

0

1

Sacroplasty for filarial scrotum

0

1

Appendicectomy

4

Cholecystectomy

2 0

Orchidectomy

3

1

Left eversion of sac in hydrocele

0

1

Hemorrhoidectomy

1 4

1

8

4

Type of surgery

Excision of lipoma/ fibroadenoma Others (Hemisectomy, hemi thyroidectomy, wound debridement, gastrectomy, sphincterectomy, etc).

1

0

Table 2. Hematological Parameters Parameter

HiOwna

Comparator

Initial

Final

Initial

Final

Hemoglobin (gm%)

12.80 ± 0.80

13.15 ± 0.65 (p < 0.026)

12.59 ± 1.71

12.68 ± 1.71 (NS)

WBC count (% w.mm)

8684 ± 1085

8180 ± 695.8 (p < 0.001)

8325 ± 1910

7325 ± 1263 (p < 0.026)

Statistical analysis: Paired t-test, Significance as compared to respective initial values; NS: Not Significant.

Table 3. Biochemical/Clinical Chemistry Parameters Parameter

HiOwna Initial

Final

Comparator Initial

Final

SGPT

32.80 ± 2.22

33.40 ± 2.63 30.95 ± 3.58 33.15 ± (NS) 3.25 (NS)

Serum creatinine

0.67 ± 0.21

0.73 ± 0.14 (NS)

0.80 ±0.25

0.83 ± 0.14 (NS)

Uric acid

4.21 ± 0.50

4.44 ± 0.77 (NS)

4.67 ± 0.81

4.62 ± 0.51 (NS)

Statistical analysis: Paired t-test, NS; Not significant.


clinical study Table 4. Weight Profile HiOwna Initial 55.85 ± 7.09

Day 15

Comparator Day 30

57.46 ± 58.15 ± 7.55 7.65 p < 0.001 p < 0.001

Initial

Day 15

Day 30

61.10 ± 8.24

61.65± 7.93

62.45 ± 8.29 p < 0.01

Statistical analysis: Repeated measures of ANOVA followed by Tukey’s multiple comparison test.

Table 5. Weight Gain (kg) Days

HiOwna

Comparator

Significance

Day 15

1.62 ± 1.45

0.55 ± 1.36

p < 0.04

Day 30

2.31 ± 1.55

1.35 ± 1.93

NS

For weight gain on Day 15 and Day 30, between-group analysis was performed using unpaired t-test.

Table 6. Pain in the Incision Site Treatment HiOwna

Comparator

Duration

Patients with pain

Significance

Present

Absent

Day 0

25

0

-

Day 15

2

23

p < 0.0001

Day 30

0

25

p < 0.0001

Day 0

19

1

-

Day 15

1

19

p < 0.0001

Day 30

0

20

p < 0.0001

Table 7. Time Taken for Ambulation and Complete Recovery HiOwna

Comparator Significance

Ambulation (Days)

1.83 ± 0.64

1.44 ± 1.09

NS

Time taken for complete recovery (Days)

8.17 ± 3.20

11.40 ± 3.25

p < 0.002

Statistical analysis: Unpaired t-test for between the group analysis. Statistical analysis: Analysis was performed for within the group analysis using Fisher’s exact test. P values mentioned in the table are with respect to Day 0 observation. No statistical significance was observed for between the group analysis on Day 15 and Day 30.

gain of 2.31 ± 1.55 in study group and 1.35 ± 1.93 in comparator group, respectively. Between-group analysis clearly establishes the beneficial effect of HiOwna over the comparator in terms of weight. The effect of HiOwna and comparator on pain at the incision site is shown in the Table 6. In HiOwna group, 23/25 subjects had no pain on Day 15 (p < 0.0001) and

on Day 30 all the subjects in the group were free from pain in the incision site (p < 0.0001) compared to the initial values. Similarly in the comparator group, 19/20 subjects had no pain on Day 15 (p < 0.0001) and pain was absent in all the 20 subjects by the end of Day 30 (p < 0.0001). The effect of HiOwna on time taken for ambulation and complete recovery after surgery is shown in Table 7. The results were comparable with mean values 1.83 ± 0.64 and 1.44 ±1.09 for study drug and comparator, respectively for ambulation. Time taken for complete recovery was much earlier in the HiOwna group (8.17 ± 3.20) versus (11.40 ± 3.25) in the comparator group (p < 0.002). Overall, HiOwna group exhibited better results with respect to Hb, WBC count and time taken for complete recovery. It also showed significant weight gain as compared to the comparator health drink. HiOwna health drink had comparable results with respect to recovery from pain in the incision site and time taken for patient ambulation. Other parameters like fever, nausea and vomiting, infection at the incision site, appetite were also comparable improvement in both the groups. Overall, the patient compliance was good and no adverse drug reactions were observed or reported with both the health drinks. Discussion The physiological changes after routine major surgery may persist for upto several months in patients receiving established routine care. While no single technique or drug regimen has been shown to eliminate postoperative morbidity and mortality, multimodal interventions may lead to a major reduction in the undesirable sequelae of surgical injury with improved recovery and reduction in postoperative morbidity and overall costs. Oral nutrition being the physiological route of nutrient intake is inexpensive and generally safer, and should be the preferred method of nutritional support, in the presence of a functioning gastrointestinal tract. Energy and protein requirements depend on body composition, clinical status and mobility. A coordinated multidisciplinary team approach to nutritional support can reduce the incidence of feeding complications and improve the overall quality of care. HiOwna is a polyingredient formulation designed to support normal physiological functioning of the nervous and cardiovascular systems, with impaired natural immunity. The principal herb ingredients are Saccharum officinarum, Pisum sativum, Phoenix dactylifera, Emblica officinalis, Piper nigrum. Additional ingredients include skimmed milk powder (kshira), soy protein isolate, maltodextrin, cocoa powder, minerals (calcium,

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

199


clinical study phosphorous, iron, magnesium, zinc, chromium, selenium, molybdenum), vitamins (A, C, D, E, K, B1, B2, B6, B12, niacin, biotin, folic acid and pantothenic acid) and nature identical flavoring substance. The pharmacological actions of the ingredients in the formulation are discussed broadly in the following headings.

Antioxidant Activity The fruits of P. dactylifera are an ideal high-energy food rich in carbohydrates, including dietary fiber and minerals, such as calcium, iron, magnesium, phosphorus, potassium and zinc. Recent studies indicate that the aqueous extracts of dates have potent antioxidant and antimutagenic activity. The antioxidant activity is attributed to the wide range of phenolic compounds in dates including p-coumaric, ferulic and sinapic acids, flavonoids and procyanidins. Growing evidence indicates that diets rich in fruits and vegetables protects against chronic disease such as cardiovascular disease. It follows that P. dactylifera fruits may provide a significant source of daily dietary.26 S. officinarum juice provides antioxidant activity at various levels, and inhibits radical formation by reducing iron complexes, radical scavenging at both primary and secondary stages and in membrane protection (as assayed by lipid peroxidation).27 Multiple micronutrients such as vitamins and minerals when delivered through either supplements or fortified foods had a positive effect on cognitive performance.28

Neuroprotective Activity Oxidative stress has been implicated in cognitive impairment and may be responsible for the development of Alzheimer’s disease (AD) in the elderly. So antioxidants with acetylcholinesterase inhibitory properties may have beneficial effects in AD. Vitamin C, present in E. officinalis, is also a good antioxidant. The neuroprotective effect of E. officinalis may be due to antioxidant and acetylcholinesterase inhibitory property.29

Adaptogenic Activity Adrenal glands contain large amounts of ascorbic acid and cortisol, which are relatively decreased due to stress. The fruit of E. officinalis has been shown to have adaptogenic activity.30

help in the digestion and absorption of dietary fats. P. nigrum also protects against the gastric damage caused by gastric irritant agents, which might be related to the inhibition of gastric motor activity and the stimulation of prostaglandin synthesis.32 This is indicative of its gastroprotective activity. Dietary piperine, by favorably stimulating the digestive enzymes of pancreas, enhanced the digestive capacity and significantly reduced the gastrointestinal food transit time, enhanced the bioavailability of a number of phytochemicals by inhibitory influence on enzymatic drug biotransforming reactions in the liver. The bioavailability-enhancing property of piperine is also partly attributed to increased absorption as a result of its effect on the ultrastructure of intestinal brush border.33 E. officinalis fruit extract contains tannins, gallic acids, alkaloids, phenolic compounds, amino acids and carbohydrates, and is reported in having gastroprotective activity.34

Immunomodulatory Activity Amla (E. officinalis) was effective against the cytotoxic effects of chromium-induced oxidative damage of murine macrophages and resulted in an enhanced cell survival, decreased free radical production and higher antioxidant levels similar to that of control cells. Further, chromium (VI) treatment resulted in decreased phagocytosis and γ-IFN production, while Amla inhibited chromium-induced immunosuppression and significantly restored both phagocytosis and γ-IFN production by macrophages.35 These findings suggest the cytoprotective and immunomodulatory potential of E. officinalis fruit. In another in vitro study, Amla relieved the immunosuppressive effects of chromium on lymphocyte proliferation and even restored the IL-2 and γ-IFN production considerably.36 An experimental study conducted on mice demonstrated that the aqueous extract of E. officinalis was very effective in reducing cyclophosphamide-induced suppression of humoral immunity.37 All the above studies indicate the immunomodulatory potential of E. officinalis. Skimmed milk powder has been well-documented in its action of improving immunity by increasing the level of the biotransformation of IgG to IgA.38

Enhancement of Nutrient Absorption and Gastroprotective Activity

Other Functions

P. nigrum, which is a rich source of piperine increased bile secretion in experimental studies.31 Hence, it may

Juice of S. officinarum/refined sugar enhances Hb levels in blood.39 Milk can be described as one of the most

200

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012


clinical study nutritionally complete foods available. The (skimmed) milk contains protein that is helpful in improving better growth and repair, improves Hb levels, promoting healthy skin and provides energy.40 Pea (P. sativum) is rich source of crude protein (23%), carbohydrate (54%) and contains trigonelline. Pea has laxative activity and is used as dietary source. Pea protein is a rich source of crude fiber, minerals and amino acids that include arginine, histidine, leucine and methionine. Pea protein, a rich source of highly digestible protein, has very low levels of antinutritional factors. This unique property of pea protein provides better nutritional benefits compared to other protein supplements.41,42 The ingredients of HiOwna provide balanced nutrition and help in promoting overall health by their nutritive, energy-boosting, digestive, antioxidant and immunomodulatory properties. P. dactylifera is a good source of nutrients and is a potent antioxidant. P. nigrum improves digestion and enhances nutrient absorption from the gastrointestinal tract. E. officinalis has potential immunomodulatory activity and protects from repeated infections. In addition to the unique botanicals, HiOwna also contains various essential macro- and micronutrients, which meet the nutritional demand required at various stages of physiological requirement. Proteins, carbohydrates and fats provide energy, promote growth and development and regulate body functions. Vitamins and minerals lead to beneficial effect on meeting the additional nutritional requirement at various stages.

properties. The macro- and micronutrients in HiOwna meet the nutritional demand required at various stages of physiological requirement. The immunomodulatory activity enhances body immunity as evident by absence of postoperative secondary infections and healing of the incision wound. Therefore, it can be concluded that HiOwna, a natural health drink supplement may be safe and effective in reducing undesirable sequelae of surgical injury with accelerated recovery and reduction in postoperative morbidity and overall costs. References 1.

Weimann A, Braga M, Harsanyi L, et al. ESPEN (European Society for Parenteral and Enteral Nutrition). ESPEN Guidelines on Enteral Nutrition: Surgery including organ transplantation. Clin Nutr 2006;25(2):224-44.

2.

Kehlet H. Multimodal approach to control postoperative pathophysiology and rehabilitation. Br J Anaesth 1997;78(5):606-17.

3.

Kehlet H, Dahl JB. Anaesthesia, surgery, and challenges in postoperative recovery. Lancet 2003;362(9399):1921-8.

4.

Bessey PQ. Metabolic response to critical illness. In: Scientific American Surgery. Wilmore DW, Cheung LY, Harken AH, Holcroft JW, Meakins JL, (Eds.), Scientific American Inc: New York, 1995:p.1-31.

5.

Nielsen HJ. The effect of histamine type-II receptor antagonists on posttraumatic immune competence. Dan Med Bull 1995;44(2):162-74.

6.

Wakefield CH, Carry PD, Foulds S, Monson JR, Guillou PJ. Polymorphonuclear leukocyte activation. An early marker of the postsurgical sepsis response. Arch Surg 1993;128(4):390-5.

7.

Moore FA, Feliciano DV, Andrassy RJ, McArdle AH, Booth FV, Morgenstein-Wagner TB, et al. Early enteral feeding, compared with parenteral, reduces postoperative complications. The results of a meta-analysis. Ann Surg 1992;216(2):172-83.

8.

Ziegler TR, Gatzen C, Wilmore DW. Strategies for attenuating protein-catabolic responses in the critically ill. Annu Rev Med 1994;45:459-80.

9.

Rosenberg J, Wildschiedtz G, Pedersen MH, von Jessen F, Kehlet H. Late postoperative nocturnal episodic hypoxaemia and associated sleep pattern. Br J Anaesth 1994;72(2):145-50.

Conclusion The present study clearly shows that HiOwna, a polyherbal health drink supplement is effective in accelerating postoperative recovery. The improvement in the postoperative parameters like Hb, WBC count and time taken for complete recovery, significant weight gain was much quicker and significant in HiOwna group than with the comparator health drink. It had comparable results with respect to recovery from pain in the incision site and time taken for patient ambulation including fever, nausea and vomiting, infection at the incision site, appetite. Overall patient compliance was good and no adverse drug reactions observed or reported with both the health drinks. The efficacy of HiOwna can be attributed to the synergistic actions of the potent herbs and micro- and macronutrients. The ingredients of HiOwna provide balanced nutrition and promote overall health by their nutritive, energy boosting, digestive, antioxidant and immunomodulatory

10. Rosenberg-Adamsen S, Kehlet H, Dodds C, Rosenberg J. Postoperative sleep disturbances - mechanisms and clinical implications. Br J Anaesth 1996;76(4):552-9. 11. Harper CM, Lyles UM. Physiology and complications after bed rest. J Am Geriatr Soc 1988;36(11):1047-54. 12. MacFie J, Woodcock NP, Palmer MD, Walker A, Townsend S, Mitchell CJ. Oral dietary supplements in pre- and postoperative surgical patients: a prospective and randomized clinical trial. Nutrition 2000;16(9):723-8. 13. Moore FA, Moore EE, Jones TN, McCroskey BL, Peterson VM. TEN versus TPN following major abdominal trauma-

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

201


clinical study reduced septic morbidity. J Trauma 1989;29(7):916-22; discussion 922-3.

its protective role against radiation induced DNA damage. Food Chem 2008;106(3):1154-60.

14. Kudsk KA, Croce MA, Fabian TC, Minard G, Tolley EA, Poret HA, et al. Enteral versus parenteral feeding. Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215(5):503-11; discussion 511-3.

28. Eilander A, Gera T, Sachdev HS, Transler C, van der Knaap HC, Kok FJ, et al. Multiple micronutrient supplementation for improving cognitive performance in children: systematic review of randomized controlled trials. Am J Clin Nutr 2010;91(1):115-30.

15. Takagi K, Yamamori H, Toyoda Y, Nakajima N, Tashiro T. Modulating effects of the feeding route on stress response and endotoxin translocation in severely stressed patients receiving thoracic esophagectomy. Nutrition 2000;16(5):355-60. 16. Kompan L, Kremzar B, Gadzijev E, Prosek M. Effects of early enteral nutrition on intestinal permeability and the development of multiple organ failure after multiple injury. Intensive Care Med 1999;25(2):157-61. 17. Plank LD, McCall JL, Gane EJ, Rafique M, Gillanders LK, McIlroy K, et al. Pre- and postoperative immunonutrition in patients undergoing liver transplantation: a pilot study of safety and efficacy. Clin Nutr 2005;24(2):288-96. 18. Blass SC, Goost H, Tolba RH, Stoffel-Wagner B, Kabir K, Burger C, et al. Time to wound closure in trauma patients with disorders in wound healing is shortened by supplements containing antioxidant micronutrients and glutamine. A PRCT. Clin Nutr 2012;31(4):469-75. 19. Braga M, Gianotti L, Radaelli G, Vignali A, Mari G, Gentilini O, et al. Perioperative immunonutrition in patients undergoing cancer surgery. Results of a randomized double-blind phase 3 trial. Arch Surg 1999;134(4):428-33. 20. Senkal M, Zumtobel V, Bauer KH, Marpe B, Wolfram G, Frei A, et al. Outcome and cost effectiveness of perioperative enteral immunonutrition in patients undergoing elective upper gastrointestinal tract surgery: a prospective randomized study. Arch Surg 1999;134(12):1309-16. 21. Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA 2001;286(8):944-53. 22. Tilg H, Wilmer A, Vogel W, Herold M, NĂślchen B, Judmaier G, et al. Serum levels of cytokines in chronic liver diseases. Gastroenterology 1992;103(1):264-74. 23. Desborough JP. The stress response to trauma and surgery. Br J Anaesth 2000;85(1):109-17. 24. Kehlet H. Acute pain control and accelerated postoperative surgical recovery. Surg Clin North Am 1999;799(2): 431-43. 25. Anja Kort, Line Lydom, Henriette Askar. Can postoperative nutritional therapy influence the convalescent period for patients who have undergone radical cystectomy. Research Project Plan, EAUN 2011. 26. Hong YJ, Tomas-Barberan FA, Kader AA, Mitchell AE. The flavonoid glycosides and procyanidin composition of deglet noor dates (Phoenix dactylifera) J Agric Food Chem 2006;54(6):2405-11. 27. Kadam US, Ghosh SB, De S, Suprasanna P, Devasagayam TP, Bapat VA. Antioxidant activity in sugarcane juice and

202

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

29. Gargi Nag, et al. Acetylcholinesterase inhibitory activity of Terminalia chebula, Terminalia bellerica and Emblica officinalis and some phenolic compounds. Int J Pharm Pharm Sci 2011;3(3):121-4. 30. Azmathulla S, Hule A, Naik SR. Evaluation of adaptogenic activity profile of herbal preparation. Indian J Exp Biol 2006;44(7): 574-9. 31. Ganesh Bhat B, Chandrasekhara N. Effect of black pepper and piperine on bile secretion and composition in rats. Nahrung 1987;31(9):913-6. 32. Al-Moflehi A, Al-Haider AA, Mossa JS, Al-Sohaibani MO, Rafatullah S, Quresh S. Inhibition of gastric mucosal damage by piper nigrum (black pepper) pretreatment in Wistar albino rats. Pharmacogn Mag 2005;1(2):64-8. 33. Srinivasan K. Black pepper and its pungent principlepiperine: a review of diverse physiological effects. Crit Rev Food Sci Nutr 2007;47(8):735-48. 34. Khan KH. Roles of Emblica officinalis in medicine - a review. Bot Res Int 2009;2(4):218-28. 35. Sai Ram M, Neetu D, Deepti P, Vandana M, Ilavazhagan G, Kumar D, et al. Cytoprotective activity of Amla (Emblica officinalis) against chromium (VI) induced oxidative injury in murine macrophages. Phytother Res 2003;17(4):430-3. 36. Sai Ram M, Neetu D, Yogesh B, Anju B, Dipti P, Pauline T, et al. Cytoprotective and immunomodulating properties of Amla (Emblica officinalis) on lymphocytes: an in-vitro study. J Ethnopharmacol 2002;81(1):5-10. 37. Haque R. Bin-Hafeez B, Ahmad I, Parvez S, Pandey S, Raisuddin S. Protective effects of Emblica officinalis Gaertn. in cyclophosphamide-treated mice. Hum Exp Toxicol 2001;20(12):643-50. 38. Pham TT, et al. Effects of Skim Milk Powder Supplementation to Soy Yogurts on Biotransformation of Isoflavone Glycosides to Biologically Active Forms during Storage. World Academy of Science, Engineering and Technology 49. 2009 39. Arcanjo FP, Pinto VP, Arcanjo MR, Amici MR, Amâncio OM. Effect of a beverage fortified with evaporated sugarcane juice on hemoglobin levels in preschool children. Rev Panam Salud Publica 2009;26(4):350-4. 40. Anonymous. The health benefits of Milk. http://www. dairyco.org.uk/media/22091/the_health_benefits_of_ milk-whole_semi-milk_july_07.pdf. 41. Sri Bhava Mishra. Bhavaprakasa Nighantu. Chaukhamba Sanskrit Sansthan. Varanasi. 6th edition 1984:p.649-50. 42. Anonymous. Nutralys pea protein - The good for your protein. Roquette 2008:p.1-18.


clinical Study

Comparison of Low- and High-dose Rate Brachytherapy in Carcinoma Cervix: Results From a Randomized Study Ruchi Gaur*, OP Singh**, Milind Kumar*, Aarti K patelâ&#x20AC; , DN Sharma*, GK Rath*

Abstract Purpose: We are reporting results of a randomized study with the aim to compare the results of low-dose rate (LDR) versus high-dose rate (HDR) brachytherapy in locally advanced carcinoma cervix patients. Material and methods: Sixty cases of carcinoma of uterine cervix in Stage IIB-IIIB (FIGO) were included from a period of January 2002 to March 2003 and were randomized into HDR brachytherapy (6 Gy/fraction for 4 sessions) or LDR brachytherapy (27 Gy/single session) arm after completion of external beam radiotherapy (50 Gy/25#/5 weeks). Results: In HDR arm, 16/30 (53.33%) patients experienced complete response. In LDR arm, complete response was experienced by 13/30 (43.33%) of patients. Locoregional control in HDR group was 54.54%, 57.14% and 71.42% at 6, 9 and 12 months, respectively. Locoregional control in LDR group at 6, 9 and 12 months was 45%, 63.63% and 42.85%, respectively. Conclusion: The results of our study indicate that LDR and HDR groups are similar in locoregional control in the management of carcinoma uterine cervix. HDR brachytherapy can safely substitute LDR brachytherapy applications.

Keywords: Low-dose rate brachytherapy, high-dose rate brachytherapy, carcinoma cervix

C

arcinoma of uterine cervix is considered the disease of women of developing world and is the most common malignancy seen in Indian woman. The majority of patients in India present with advanced stage of disease for which platinum-based concurrent chemoradiation is the standard of care currently accepted worldwide. Hence, in management of vast majority of cases of carcinoma cervix, radiation therapy plays integral role. The curative potential of radiation therapy in the management of carcinoma cervix is greatly enhanced by use of intracavitary brachytherapy. Hence, a combination of external beam megavoltage irradiation along with intracavitary brachytherapy is considered mandatory for proper and adequate delivery of radiation dose. The success of brachytherapy is attributed to the fact that there is delivery of a high radiation dose directly to the tumor, while sparing the surrounding normal tissues due to a rapid dose fall-off. *Dept. of Radiotherapy, AIIMS, New Delhi **Dept. of Radiotherapy, Gandhi Medical College, Bhopal â&#x20AC; Dept. of Radiotherapy, JNCH & RC, Bhopal Address for correspondence Dr Milind Kumar Dept. of Radiotherapy, IRCH, AIIMS, New Delhi - 110 029 E-mail: drmilindkumar@yahoo.com

Cervical carcinoma has traditionally been treated with low-dose rate (LDR) brachytherapy, with radium source, which was subsequently replaced by cesium-137 (137Cs). LDR lies in the range of 0.4-2 Gy/ hour (0.6-3.33 cGy/minute), whereas the HDR is defined when the dose rate above 12 Gy/hour (above 20 cGy/min). High-dose rate (HDR) brachytherapy was developed to overcome potential disadvantages of LDR brachytherapy (radiation exposure to medical staff, prolonged treatment time, mandatory hospitalization and applicator movement). HDR brachytherapy machines initially utilized cobalt-60 (60Co) source. Miniature iridium-192 (192Ir) source design technology has revolutionized the design of remote after loading equipment and these new 192Ir stepping sources have given strength, to the concept of treatment of carcinoma cervix by fractionated HDR-brachytherapy. There are nearly three decades of experience comparing HDR to LDR brachytherapy in the treatment of cervical cancer. LDR treatment is considered radiobiologically more sound as because of continuous exposure of the cancer cells causing noncell cycle specific killing and also decreased risk of late normal toxicity, and increased repair capacity of normal tissues. HDR employs

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

203


clinical study high- dose/fraction in a relatively short-time and there is a concern for late toxicity. But, the overwhelming advantages of HDR are computerized optimization of dosimetry, less risk of radiation exposure for medical personnel and also less chances of organ motion during radiation delivery. Most of the data comparing LDR versus HDR results emerged from west, whereas the majority of cases are in developing countries. We have few studies from India in this regard, most notably by Patel et al, but overall there is paucity of data from Indian population. Hence, this study was designed to compare the shortterm result of HDR and LDR brachytherapy in the management of carcinoma cervix in terms of toxicity and disease free status at one year in our set-up. Material and Methods

Patient Characteristics This study was conducted in Dept. of Radiotherapy of Hamidia Hospital, Gandhi Medical College, Bhopal and Jawaharlal Cancer Hospital, Bhopal and 60 cases of carcinoma cervix in Stage IIB-IIIB (International Federation of Gynecology and Obstetrics [FIGO]) were included from a period of January 2002 to March 2003. A detailed history was taken and a thorough local and systemic examination was conducted. The following investigations were done in all the patients: Hemogram, renal function tests, liver function tests, blood sugar estimation, chest X-ray, ultrasound abdomen and pelvis, cystoscopy, sigmoidoscopy, intravenous pyelogram (IVP). Contrast-enhanced CT scans were done as optional investigation. Patient were staged on the basis of FIGO staging system, along with ultrasonographic or IVP findings to rule out hydronephrosis. Criteria for inclusion in the study were: Age <65; FIGO Stage IIB-IIIB histologically proven squamous cell carcinoma, and Karnofsky performance status >40.

Treatment Patients were randomized in two separate groups named ‘A’- HDR group and ‘B’- LDR group such that each consisted of 30 patients. All the patients received pelvic external beam radiotherapy by using megavoltage beam on telecobalt by two parallel opposed A-P portals with Source Axis Distance (SAD) technique, so that 50 Gy in 25 # was delivered in 5-week duration (daily-dose 200 cGy/fraction/day) and midline shield was done after 40 Gy. Patients with anteroposterior separation >20 cm were treated using four fields for external beam radiotherapy in both the groups.

204

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

Concurrent chemotherapy with injection cisplatin 50 mg was also added to the treatment in suitable cases. HDR brachytherapy after completing EBRT 4 # on weekly interval 6 Gy/session/to Point A were given to patient in Arm ‘A’. LDR brachytherapy after completing external beam radiotherapy was given in single session of 27 Gy, depending on dose distribution after application to patients in Arm ‘B’ patients. The treatment of both group completed in 7-8 weeks approximately which is considered as ideal. During the whole course of the treatment, patients were closely observed for radiation reaction and acute toxicities and managed accordingly.

Response Assessment The patients were assessed at one month after completion of treatment, then at every third month interval for one year. Local failure was defined as pelvic failure below the L5 (fifth lumbar vertebra) vertebral space, and this was either biopsy-proven or clinically determined. Metastases failures included all other extrapelvic sites and again were either, biopsyproven or clinically determined. Response criteria were used as per World Health Organization (WHO) guidelines. Late side effects were defined as sequelae reported three months from completion of radiotherapy and were recorded for the sites bladder; bowel, vagina, skin and other were graded as Radiation Therapy Oncology Group (RTOG) criteria. All patients were regularly evaluated to ascertain treatment tolerance. Analgesics, antipyretics, laxative, hematinics, appetizers, antacids, antiemetics and hemostatic, etc. were advised to the patients as per their requirement. Blood transfusions and IV fluids were given to patients in condition of anemia and dehydration. Results This study comprised of 60 patients of carcinoma cervix, enrolled in Dept. of Radiotherapy, Hamidia Hospital, Gandhi Medical College and in Jawaharlal Cancer Hospital, Bhopal from January 2002 to March 2003. Majority of patients belonged to 5th decade of life and were from rural background. Maximum cases belonged to Stage IIIB in both groups, 60% in HDR arm and 73.33% in LDR arm.


clinical study The gross pathology of lesion was almost similar in both groups. Ulcerative and infiltrative lesions accounted for very less number of the total cases and growth was almost often proliferative in both the groups. Histopathologically all cases were of squamous cell carcinoma with varying degree of differentiation.

follow-up and 45% were found disease free. At nine months follow-up, for HDR arm, eligible patient were 30, 14 (46.66%) came for follow-up and eight (57.14) were found disease free. In LDR arm, at the same follow-up, eligible patients were 25, 11 (44%) reported for follow-up and seven (63.63%) were found disease free.

The frequent symptoms in both the groups were bleeding per vaginum associated with discharge per vaginum.

In 12 months follow-up, in HDR arm, eligible patient were 22 (73.33%), seven came for follow-up and 5 (71.42%) was found disease free, whereas in LDR arm patients, 16 were eligible, 7 (43.75%) patient came for follow-up and three (42.85%) were found disease free.

After completion of treatment in HDR arm, 16/30 (53.33%) patients experienced complete response (CR), 7/30 (23.33%) had partial response (PR) and 7/30 (23.33%) had stable or progressive disease (SD/PD). In LDR arm, complete response was experienced by 13/30 (43.33%) of patients, whereas 5/30 (16.66%) had partial response and 12/30 (40%) had stable or progressive disease. Overall response and disease free status are tabulated in Table 1 and 2.

Table 1. Overall Response Grade of response

Patients in both groups were followed up at three monthly intervals till 12 months. At the follow-up at six months in HDR arm, only 22 could report for follow-up and 54.54% were found to be disease free. In LDR arm, at the same follow-up, out of 29 patients, 20 reported for

Group A (HDR arm)

Group B (LDR arm)

No.

%

No.

%

Complete response

16

53.33%

13

43.33%

Partial response

7

23.33%

5

16.66%

Stable + progressive disease

7

23.33%

12

40%

Table 2. Disease Free Status at Follow-up Duration of follow-up in months

Group A (HDR arm) Eligibility

No. of pt. follow-up

Disease free follow-up

Eligibility

No. of pt. follow-up

Disease free follow-up

Six months

30

22

12

29

20

9

(73.33%)

(54.54%)

(96.66%)

(68.96%)

(45%)

Nine months

30

Twelve months

Group B (LDR arm)

14

8

25

11

7

(46.66%)

(57.14%)

(83.33%)

(44%)

(63.63%)

22

7

5

16

7

3

(73.33%)

(31.8%)

(71.42%)

(53.33%)

(43.75%)

(42.85%)

Table 3. Acute Effects Complications

Grades

Gastrointestinal

III

Genitourinary

Rectal

Group A (HDR)

Group B (LDR)

No.

%

No.

%

-

-

-

-

IV

-

-

-

-

I

1

3.33%

3

10%

II

-

-

1

3.33%

III

-

-

1

3.33%

I

2

6.66%

1

3.33%

II

-

-

1

3.33%

III

-

-

2

6.66%

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

205


clinical study Table 3 shows frequency of occurrence of acute complications during and after therapy. None of the patient in both the groups had suffered from moderate or severe gastrointestinal toxicity. In LDR arm, 10% patient had mild, genitourinary toxicity, one patient had Grade II and 1 had Grade III toxicity. In HDR group, none of the patient had Grade II or III toxicity. In LDR arm, one patient had Grade II and two patients had severe rectal reactions, whereas none of rectal reactions were noted in HDR arm. Table 4 shows late complication after treatment. In HDR arm, 76.66% patient developed, synechie in the vagina, after treatment. In LDR arm, 66.66% patient had vaginal synechie. In both the groups, one patient developed vesicovaginal fistula (VVF) as complication during follow-up. DISCUSSION Carcinoma of uterine cervix is the commonest malignancy seen among the Indian women. According to National Cancer Registry Report, 20011 carcinoma cervix remains the most common neoplasm among Indian females in most parts of India except in Delhi and Mumbai, where carcinoma breast is leading one. According to various estimates India bears one-fifth of the global burden of the disease, with approximately 1,30,000 new cases a year.2 It accounts for approximately 35% of all malignancies in females and 74% of all gynecological tumors, in our department. As noticed by patients, subjective response was very encouraging in both the groups, in this study. Almost every patient experienced relief from presenting symptoms, this may be due to control of infections, bleeding and pain. Overall objective response, after full treatment, was as follows: In Group A (HDR arm) 16/30 (53.33%) patients had CR, 7/30 (23.33%) had PR and 7/30 (23.33%) had SD/PD response. In Group B (LDR arm) 13/30 (43.33%) Table 4. Late Effects Complications

Group A

Group B

No.

%

No.

%

Vaginal fibrosis

23

76.66%

20

66.66%

VVF

1

3.33%

1

3.33%

RVF

-

-

-

-

Cystitis Proctitis

206

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

patients had CR, 5/30 (16.66%) had PR and 12/30 (40%) had SD/PD. We would briefly compare our response rates and toxicity rates with other trials. Shigematsu et al,3 reported patients with Stage II and III disease treated with the HDR technique had a higher one year local control rate (90% with HDR vs 77% with LDR). Hareyama et al4 reported, complete response 83% in HDR group and 79% in LDR group with Stage I-III patients. Patel et al5 reported local control rate, 79.7% in LDR group and 75.8% in HDR group for Stage I-III patients. Petereit et al6 compared HDR and LDR, brachytherapy in cancer cervix and found overall pelvic control, 71% in HDR group and 82% in LDR group. In this study, stage-wise response rate in both the groups are also compared, it shows that in both the groups, patients with IIB disease responded in better way than to Stage IIIB disease: 66.66% patients with Stage IIB disease in Group A had complete response, whereas in Stage IIIB, 44.44% had complete response. In LDR group, Stage IIB disease, 75% patient had complete response, whereas in Stage IIIB disease only, 32% patient had complete response. It is observed in this study that with HDR, response is better in both Stages IIB and IIIB. When complete and partial response rate is combined together, it is seen that patient with IIIB diseases responded better in Group A than in Group B. It is proved by literature that higher growth rate (more in Stage III disease) is more responsive with HDR therapy. In the series of Akine et al7 local control rate was 83% in LDR group and 71% in HDR group, for Stage IIB disease and 61% and 64%, respectively for Stage IIIB disease. In the series by Kuipers8 the local control rate in LDR group was 89% versus 85% in HDR group for Stage II and 62% versus 70% for Stage III patients, respectively. Patel et al5 reported local control rate 78.5% and 76.3%, respectively for Stage II and III in LDR group and 75.6 versus 71.2% for Stage II and III in HDR group. Daniel et al5 also noted pelvic control rate in HDR was 80% versus 78% in the LDR group for Stage II, and 44% versus 75% for Stage III patients, respectively. Thus, the local control rates with HDR brachytherapy are as good as those achieved with conventional LDR brachytherapy. Observations regarding disease free follow-up was noted at 6, 9 and 12 months. In Group A, disease free


clinical study follow-up was 54.54%, 57.14% and 71.42% at 6, 9 and 12 months, respectively. In Group B, it was noted as 45%, 63.63% and 42.85% at 6, 9 and 12 months, respectively. In the present study, observation regarding complication rates shows, that there was no significant moderate-tosevere gastrointestinal toxicity seen in any of the study group. In HDR group, none of the patient reported to have moderate-to-severe genitourinary and rectal complications. In LDR group two patients (6.66%) had moderate severe genitourinary toxicity and three patients (10%) had moderate-to-severe rectal toxicity. Patel et al5 observed, incidence of overall rectal complication, 19.9% versus 6.9%, in LDR and HDR groups, respectively, more severe Grade 3-4 complication were not significantly different between the two groups, (2.4% vs 0.4, respectively). Bladder morbidity in both the group was similar. Review of literature has shown that for the individual institutions, the complication rates are comparable between LDR and HDR groups, except for the series by Cikarić 9 who noted complication rates, significantly higher in LDR group. Late complication was recorded in terms of vaginal fibrosis only, in both the groups which indicates that patients need frequent dilatation, in both LDR and HDR. One patients in both the groups developed VVF. As these patient had type C response it seems that VVF is not a complication of therapy but it is due to progressive disease. Two patients in LDR group had distant failure, one developed multiple liver metastases and one developed multiple lung secondaries during their follow-up. There have been numerous clinical studies comparing HDR and LDR brachytherapy for the treatment of carcinoma of uterine cervix. The treatment technique and the dose fractionation schedules used in different institutions too have been greatly variable. Review of literature showed that with HDR, the dose/fraction at Point ‘A’ varied from 3 to 10 Gy, the number of fractions from 2 to 13 and the treatment of fractions/week varied from 1 to 3.10 Dose rate ranges have been broadly classified into three groups, low, medium and high (Table 5).11 The most comprehensive comparison to date was that conducted by Orton,12 in his survey of some 56 institutes who had of both LDR and HDR. He reported fraction

numbers between 4 and 6 with dose/fraction in the region of 7.5 Gy, of HDR compared with LDR treatment of about 78 hours delivered at 0.85 Gy/hr; analysis of the results suggested that survival at HDR was at least as good as LDR and perhaps a little better and that HDR produced significantly less radiation toxicity. This clinical evidence strongly suggests that provided a suitable dose/fraction is chosen and the HDR is given in 4-6 fractions then results can be obtained which are biologically comparable to LDR. Patel et al PGI Chandigarh,5 did a prospective randomized clinical trial, with 482 cancer cervix with different stages. Two hundred forty-six patients were treated by LDR 137Cs and 236 by HDR 60Co therapy. Stage for stage to local control rates in the LDR group and HDR group were similar i.e. 79.7% and 75.8%, respectively. The 5-year survival figures in LDR and HDR group were also comparable. In Stage I, it was 73% for LDR patients and 78% for HDR patients, for Stage II it was 62% and 64%, respectively and for Stage III it was 50% and 43%. The only statistically significant difference was found in the incidence of overall rectal complications which was 19.9% for LDR and 6.4% for HDR group. However, the more severe Grade 3-4 complications were not significantly different. The bladder morbidity in both the groups was similar. Lorvidhaya et al13 did a retrospective analysis of 1,992 patients of cancer cervix and suggested that results of HDR brachytherapy as per pelvic control and survival rates are comparable to LDR series. Orton et al14 suggested that HDR brachytherapy may be radiobiologically superior to LDR brachytherapy, due to slow repair of late responding normal tissue cells. Hareyama et al4 did a randomized clinical trial on 132 patients with Stage II or IIIB of cancer cervix. They concluded that pelvic control or acturial complication rates were comparable between HDR and LDR groups. The difference between disease specific survival rates for HDR and LDR was not statistically significant for Stage II or III, although in Stage II, patient treated Table 5. Dose Rate Ranges Dose rate definition after Corbett11 Low-dose rate

0.4-2 Gy/hr

Medium-dose rate

2-12 Gy/hr

High-dose rate

12 Gy/hr (but usually in the range of 150 Gy/hr)

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

209


clinical study Table 6. Recent Trials Comparing LDR vs HDR Brachytherapy for Carcinoma Cervix Study

No. of patients (LDR/HDR)/ Median FU

LDR arm

HDR arm

LDR arm

HDR arm

Comments

Narayan et al15

217 (90/127)/4.1 years

60%

60%

55%

55%

No diff.

al16

160 (103/ 57)/4 years

60%

55%

78%

76%

No diff.

al17

308 (190/118)/70 moLDR/33 mo - HDR

69%

55%

73%

56%

16% (LDR) vs 8% (HDR) rectal complication probability

70.9%

68.4%

69.9%

69.9%

Gž complications 2.8% LDR vs 7.1% in HDR

Falkenberg et Ferrigno R et

Lertsanguansinchai 237(109/112), 40.2 mo et al18 LDR and 37.2 mo - HDR

Overall survival

with LDR appeared to have a better survival rates than those treated with HDR. The trial reported by Narayan et al15 has shown comparison of 3D image guided HDR brachytherapy application with the traditional LDR treatment. The outcome is summarized along with other recent trials15-18 in Table 6. The treatment outcome was similar in both arms. They showed slight lowering of Grade II toxicity in HDR arm though overall difference was not statistically significant. The limitation of our data is small number of patients and unsatisfactory duration of follow-up. Conclusion HDR brachytherapy is now an established alternative to conventional LDR brachytherapy for the treatment of the cancer cervix. In this small series with shortterm results no clinical superiority of HDR in terms of response and toxicity was found over LDR though it was observed that tolerance and compliance to the therapy was better in HDR group, than to LDR group. This may be because of easy OPD-based procedure, short procedure time (less need to dilate os, due to thin applicator) short (15 min vs 15 hours) treatment time (less psychological load to the patient and less difficulty keeping the precise positioning of applicators). Despite these advantage and favorable results with HDR brachytherapy, the entire therapeutic potential can only be exploited if there is availability of modern therapy planning systems and sufficient well-trained support staff. References 1.

National Cancer Registry Programme: Consolidated Report of the population based cancer registries 1990-1996. ICMR 2001.

2.

IARC (International Agency for Research on Cancer) Scientific Publication No. 143, 1997.

210

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

Disease free survival

Toxicity

3.

Shigematsu Y, Nishiyama K, Masaki N, Inoue T, Miyata Y, Ikeda H, et al. Treatment of carcinoma of the uterine cervix by remotely controlled afterloading intracavitary radiotherapy with high-dose rate: a comparative study with a low-dose rate system. Int J Radiat Oncol Biol Phys 1983;9(3):351-6.

4.

Hareyama M, Sakata K, Oouchi A, Nagakura H, Shido M, Someya M, et al. High-dose-rate versus lowdose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial. Cancer 2002;94(1): 117-24.

5.

Patel FD, Sharma SC, Negi PS, Ghoshal S, Gupta BD. Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial. Int J Radiat Oncol Biol Phys 1994;28(2):335-41.

6.

Petereit DG, Sarkaria JN, Potter DM, Schink JC. Highdose-rate versus low-dose-rate brachytherapy in the treatment of cervical cancer: analysis of tumor recurrence - the University of Wisconsin experience. Int J Radiat Oncol Biol Phys 1999;45(5):1267-74.

7.

Akine Y, Arimoto H, Ogino T, Kajiura Y, Tsukiyama I, Egawa S, et al. High-dose-rate intracavitary irradiation in the treatment of carcinoma of the uterine cervix: early experience with 84 patients. Int J Radiat Oncol Biol Phys 1988;14(5):893-8.

8.

Kuipers T. High-dose-rate intracavity irradiation results of treatment. In: Brachytherapy. Mould RF (Ed.), 1984. Leersum. The Netherlands: Nucletron Trading BV 1985: p.169-75.

9.

CikariÄ&#x2021; S. Radiation therapy of cervical carcinoma using either HDR or LDR afterloading: comparison of 5-year results and complications. Sonderb Strahlenther Onkol 1988;82:119-22.

10. Fu KK, Phillips TL. High-dose-rate versus low-dose-rate intracavitary brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 1990;19(3):791-6. 11. Corbett PS. Brachytherapy in carcinoma of the cervix: The state of the art. In: Brachytherapy HDR & LDR. Martine Z AA, Orton CG, Mould RF (Eds.), Nucletron: Columbia 1990:p.100-9. 12. Orton CG, Seyedsadr M, Somnay A. Comparison of high


clinical study and low dose rate remote afterloading for cervix cancer and the importance of fractionation. Int J Radiat Oncol Biol Phys 1991;21(6):1425-34. 13. Lorvidhaya V, Tonusin A, Changwiwit W, Chitapanarux I, Srisomboon J, Wanwilairat S, et al. High-dose-rate afterloading brachytherapy in carcinoma of the cervix: an experience of 1992 patients. Int J Radiat Oncol Biol Phys 2000;46(5):1185-91. 14. Orton CG. High-dose-rate brachytherapy may be radiobiologically superior to low-dose rate due to slow repair of late-responding normal tissue cells. Int J Radiat Oncol Biol Phys 2001;49(1):183-9. 15. Narayan K, van Dyk S, Bernshaw D, Rajasooriyar C, Kondalsamy-Chennakesavan S. Comparative study of LDR (Manchester system) and HDR image-guided conformal brachytherapy of cervical cancer: patterns of

failure, late complications, and survival. Int J Radiat Oncol Biol Phys 2009;74(5):1529-35. 16. Falkenberg E, Kim RY, Meleth S, De Los Santos J, Spencer S. Low-dose-rate vs. high-dose-rate intracavitary brachytherapy for carcinoma of the cervix: The University of Alabama at Birmingham (UAB) experience. Brachytherapy 2006;5(1):49-55. 17. Ferrigno R, Nishimoto IN, Novaes PE, Pellizzon AC, Maia MA, Fogarolli RC, et al. Comparison of low and high dose rate brachytherapy in the treatment of uterine cervix cancer. Retrospective analysis of two sequential series. Int J Radiat Oncol Biol Phys 2005;62(4):1108-16. 18. Lertsanguansinchai P, Lertbutsayanukul C, Shotelersuk K, Khorprasert C, Rojpornpradit P, Chottetanaprasith T, et al. Phase III randomized trial comparing LDR and HDR brachytherapy in treatment of cervical carcinoma. Int J Radiat Oncol Biol Phys 2004;59(5):1424-31.

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

211


clinical Study

Phytotherapy for Lower Urinary Tract Symptoms due to Benign Hyperplasia of Prostate Tapas Maitra

Abstract Phytotherapy, the use of plant extracts is long established in France and Germany, and so products containing extracts of Serenoa repens and Pygeum africanum, among others, have a market share of upto 50% of all preparations used for the treatment of symptomatic benign prostatic hyperplasia (BPH). In these countries, plant extracts are prescribed drugs, their costs being totally or partially reimbursed by the healthcare system, in contrast to the UK, where they are neither approved nor reimbursed. More commonly used medicines for BPH are a-blockers (reduce smooth muscle tone at bladder neck and adenoma) and 5a-reductase inhibitors (reduce the volume of adenoma), but in sexually active patients 5a-reductase inhibitors reduce the libido. Although, these plant extracts help to reduce lower urinary tract symptoms (LUTS) due to BPH but their use is limited and controversial because of the lack of established mechanism of action, efficacy and safety. Clinical trials of large scale, long duration with controlled group is not available.

Keywords: Phytotherapy, lower urinary tract symptoms, benign prostatic hyperplasia

P

hytotherapy is thought to have its roots in Chinese herbal medicine, a practice that has evolved during the past 5,000 years. Traditional medicine (also known as indigenous or folk medicine) and phytotherapy continue to play a central role in the healthcare of about one-third of the world’s population in developing countries and accounts for 80% of primary healthcare in Africa due to the lack of essential medicine.1 According to some US urologists, 50-90% of newly referred patients with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) have already tried or are using some form of alternative medicine at the time of their presentation. ‘Natural agents’ are commonly believed to be devoid of any side effects and are thought to might be as efficacious as synthetic and chemical products. Another factor for increased use of phytotherapeutic agents in the United States is the availability and ease with which consumers can obtain them. They are readily available in supermarkets, food stores, pharmacies. Due to patient demand, urologists have to be familiar Associate Professor Dept. of Urology North Bengal Medical College, Sushrutanagar, West Bengal Address for correspondence Dr Tapas Maitra SUBINA, Sarat Bose Road, Hakimpara, Darjeeling, Siliguri, West Bengal - 734 001 E-mail: urmi_811@yahoo.com

212

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

with these agents, their advantages and disadvantages, side effects, proposed mechanism of action, interaction with other drugs. Origin of some of the commonly used phytotherapeutic agents is given in Table 1. Proposed Mode of Action The proposed mechanism of action of many products has yet to be elucidated, although antiestrogenic and proapoptotic effects have been reported for some preparations, along with inhibition of 5a-reductase activity (see Table 2). Proposed active constituents of plant extracts are phytosterols, phytoestrogens, free fatty acids, lectins, flavonoids, plant oils and polysaccharides. In 1994, US Food and Drug Congress expanded the definition of ‘Dietary supplement’ to include herbal medicine, botanicals and other forms of phytotherapy.2 Before the passage of the act, few queries regarding these agents have to be addressed like: 

Bioavailability of these agents

Correct dosages and duration of therapy

Is there a dose dependency?

Standardization of the amount of active ingredient in each pill Is the mechanism of action clearly understood?


clinical study Table 1. Origin of Phytotherapeutic Agents Used for LUTS due to BPH Common term

Source

American dwarf palm, saw palmetto

Fruit

South African star grass

Root

Pine

Root

Spruce

Root

African plum tree

Bark

Stinging nettle

Root

Rye

Pollen

Pumpkin

Seeds

Table 2. Proposed Mechanism of Action of Phytotherapeutic Agents Mechanism of action Inhibition of 5α-reductase activity

Extract Serenoa repens

Antiestrogenic effect

Pygeum africanum

Antiandrogenic effect

Serenoa repens

Induction of apoptosis Interference with prostaglandin metabolism

Serenoa repens Pygeum africanum

Inhibition of proliferative growth factor

Urtica dioica

Decrease of sex hormone binding globulin

Urtica dioica

Alteration of cholesterol metabolism

Pygeum africanum

Common Phytotherapeutic Compounds Use

African Plum Tree Extracts from the bark of the African plum tree (Pygeum africanum) are widely used in France and US. The extract is believed to have anti-inflammatory and antiestrogenic effect as well as it inhibits fibroblast proliferation. Eleven constituents have been identified in the crude extract, including high levels of myristic acid, which is thought to affect membrane fluidity directly and to reduce the contact between propagating free radicals and unsaturated lipid substances, thereby slowing the process of hydrolysis and membrane degradation.3 Ishani et al4 examined 18 doubleblind clinical trials of P. africanum (n = 1,562) and assessed physician reported symptom improvement, nocturia, Qmax, post-void residual (PVR). Studies were methodologically difficult to perform. The meta-analysis showed that men receiving P. africuanum were more than twice as likely as those receiving placebo to be rated by their physician as

having symptom improvement (65% P. africanum group versus 30% placebo group; n = 430). Nocturia was decreased by 19% in three separate trials in man taking P. africanum over those taking placebo (n = 325), Qmax was increased by 23% in the P. africanum group in four studies (n = 363) compared with placebo. Finally, in two studies (M-264), PVR decreased by 24% in those taking P. africanum.4

Saw Palmetto The extract from the berries of the American dwarf palm (Serenoa repens) are the most popular plant-based products used in the treatment of symptomatic BPH.5 In Germany alone, >30 different products contain S. repens.5 Permixon (Pierre Fabre, Burlats, France), an n-hexane liposterolic extract of the saw palmetto berry, is the most common form of S. repens. The action of permixon is considered to be through uncompetitive inhibition of 5a-reductase resulting in lower level of dihydrotestosterone (DHT) formation from testosterone in the prostate gland.6 Lower level of DHT and higher level of testosterone have been identified in the prostates of permixontreated BPH patients, however, superficially at variance with an action as a 5a-reductase inhibitor, no significant effect on serum PSA or prostate volume has been demonstrated in several studies.7 The data on several potential mechanisms of action of S. repens are often confusing and contradictory and many of the effects described have only been demonstrated in vitro, often with considerably higher dosages of the extract than are recommended for clinical treatment. The commonly recommended dose of S. repens is 320 mg daily, often divided into two doses. A dose of 160 mg of permixon twice-daily seems to be as efficacious as two pills of 160 mg once-daily. Apart from occasional gastrointestinal side effect no significant side effects have been reported with the extract, in contrast to most other medical or surgical approaches.

Pumpkin Seed Pumpkin seed extracts (Cucurbita pepo) are usually used in combination with other extracts in the management of BPH. The use of pumpkin seed extracts in the management of LUTS due to BPH is common in Germany. The seeds contain a sweet, oily substance composed of linolic acid sterols, selen magnesium and carotinoid, the mechanism of action is thought to be antiandrogenic and antiphlogistic.8 Cont’d on page 220... Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

213


Clinical Study

Efficacy of Homeopathic Combination - BPA Drug in Prehypertension and Hypertension: A Pilot Study Prachi Garg*, KK Aggarwal**, Sunita Gupta†, Parul Takkar‡, Mudita Arora¶

Abstract Aims and objectives: The primary objective of the study was to evaluate and document the evidence-based efficacy and safety of the study drug in lowering blood pressure (BP). The secondary objectives included efficacy of the study drug in improving symptoms, quality-of-life (QOL) and biochemical parameters including treadmill and Doppler echocardiography. Study design: Phase IV post-marketing/surveillance study. Material and methods: Thirty-five subjects with prehypertension and hypertension (Stage 1 and Stage 2), attending the OPDs and camps of Heart Care Foundation of India were enrolled for the nonplacebo-controlled prospective study. The subjects were given homeopathic combination BPA (study drug) in liquid dosage for 12 weeks. Baseline clinical and biochemical parameters, treadmill test and Doppler echocardiogram were compared with the same parameters at the end of 12 weeks. Sixteen subjects completed the study. Results: There was a mean fall in systolic BP (SBP) of 15.75 mmHg and mean fall in diastolic BP (DBP) of 10.31 mmHg without any side effects. This significant decline in BP was evident from 4th week onwards. There was an appreciable increase in the exercise tolerance as evident by the 8.6% increase in metabolic equivalents (METs) and 8.2% increase in exercise time. No significant changes were observed in systolic or diastolic function parameters on Doppler echocardiography at three months. There was decrease in blood sugar from 96.5 ± 13.938 at baseline to 92.56 ±12.329 at 12 weeks (p = 0.046). Serum uric acid levels also decreased from 5.681 ± 0.8998 at baseline to 6.031 ± 0.8822 at 12 weeks (p = 0.053) suggesting a beneficial effect of the combination on insulin resistance (IR). There were positive changes in the QOL as assessed by SF36 Questionnaire. The average Rand score improved from 54.53 ± 21.9991 to 77.55 ± 10.493 at 12 weeks (p < 0.001). All data are presented as mean ± standard deviation (SD). Conclusion: The results of the study showed that the study drug can be safely used as monotherapy in patients with prehypertension or hypertension with no complications.

Keywords: Homeopathic combination BPA, prehypertension, hypertension

H

ypertension is the commonest cardiovascular disorder, posing a major public health challenge to population. The prevalence of hypertension among adults in developed countries is 25%. A similar prevalence has also been observed in developing countries ranging from 10 to 20%.1 It has been shown that there were 972 million people living with hypertension worldwide in the year 2000, and it is estimated that this number will escalate to more than 1.56 billion by the year 2025.2 Around two-thirds of those people with hypertension worldwide were living in developing countries (639 million) in 2000, and this number is projected to rise to three-quarters living in developing countries (1.15 billion) by 2025.3 Hypertension is an important independent predictor of cardiovascular disease (CVD), cerebrovascular *Clinical Associate, Internal Medicine, Moolchand Medcity, New Delhi **Senior Consultant Cardiologist, Heart Care Foundation of India, New Delhi †Consultant Homeopath, New Delhi ‡Statistician ¶Senior Manager, Clinical Research and Product Development Bakson Drugs and Pharmaceutical Pvt. Ltd., New Delhi

accidents and death.4 The prevalence of hypertension has been increasing in India, both in rural and urban regions.4 The prevalence of prehypertension in India is also increasing. This implies accompanying raise in other CVD risk factors in the Indian population.5 In India, CVDs are estimated to be responsible for 1.5 million deaths annually. Indeed, it is estimated that by 2020, CVDs will be the largest cause of mortality and morbidity in India.3 Trials completed within the last five years clearly indicate that overall cardiovascular risk is reduced by blood pressure (BP) lowering to levels below 140/90 mmHg. Greater cardiovascular risk reduction is not seen, however, by driving BP to levels well below 130/80 mmHg. This is true across the spectrum of cardiorenal risk with few exceptions, stroke prevention possibly being one.6 Antihypertensive drugs work in different ways to lower BP. Some drugs lower BP by removing extra fluid and salt from the body (e.g. diuretics). Others lower BP by slowing down the heartbeat (e.g. b-blockers), or by relaxing, widening or preventing the narrowing of

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

215


clinical study blood vessels (e.g., angiotensin-converting enzyme [ACE] inhibitors, calcium channel blockers [CCBs]). A review has described the main homeopathic medicines whose center of action includes the heart, especially medicines commonly used in mother tincture form for hypertension.7 The study drug is a combination of seven drugs8-15 used for reducing high BP. They are well-known homeopathic medicines and help relieve associated symptoms of BP too. The drugs included are Rauwolfia serpentina 2X (5.00% v/v), Viscum album 3X (1.00% v/v), Crataegus oxyacantha 2X (1.00% v/v), Arnica montana 3X (0.25% v/v), Valeriana officinalis 3X (0.50% v/v), Melilotus alba 3X (0.25% v/v), Cactus grandiflorus 3X (0.25% v/v), Excipients q.s. and alcohol (7.00% v/v). Aims and objectives Primary objective: To evaluate and document the evidence-based efficacy and safety of the study drug in lowering BP. Secondary objectives: 

To assess the efficacy of the study drug in relieving symptoms associated with hypertension. To assess the efficacy of the study drug in improving quality-of-life (QOL) in hypertensive subjects. To assess the improvement or changes, if any, in necessary investigations performed at the beginning and end of study especially lipid profile, treadmill test and Doppler echocardiograms.

Material and Methods

Study Design A phase IV post-marketing/surveillance study was done to delineate additional information on long-term benefits, optimal use and any side effects after approval of the study protocol from the Ethics Committee. The duration of the study was 15 months (October 2010 to December 2011). Subjects with prehypertension or hypertension without target organ damage attending the OPD and camps of Heart Care Foundation of India were included in the study. A total of 67 subjects were screened. There were 32 screen failures. A total of 35 subjects were enrolled, out of whom 16 subjects completed the study. There were 19 dropouts (lost to follow-up). Informed consent was obtained from each study subject. The study drug was dispensed in 30 ml bottle pack duly labeled as per the Drug Authority requirements. No placebo was used during the study. It was a nonrandomized nonblind open study.

216

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

Inclusion Criteria  

Adults of both sexes aged 25-75 years. Newly diagnosed or subjects with prehypertension (diastolic BP [DBP] 80-89 mmHg and systolic BP [SBP] 120-139 mmHg) of less than one year duration. Patients with stage 1 (SBP >140 and <160 and DBP >90 and <100 mmHg) and Stage 2 (SBP >160 and DBP >100 mmHg) hypertension. All subjects were subjected to a washout period of two weeks. Written informed consent for the use of the study drug as stand-alone treatment and necessary investigations.

Exclusion Criteria 

Known secondary hypertension

Body mass index (BMI) >35 kg/m2

Pregnant and lactating women

Poorly-controlled hypertension and/or complications

Target organ damage

Diabetes

Abnormal lab screening: Hemoglobin (Hb) <75% of lower limit, serum cholesterol >300 mg/dl

Abnormal resting ECG

Pre-existing chronic debilitating illness

Subjects on hormonal contraceptives, steroids or nonsteroidal anti-inflammatory drugs (NSAIDs)

Investigations Complete blood count (CBC), lipid profile, fasting blood sugar, serum creatinine, serum uric acid, serum glutamic pyruvic transaminase (SGPT), routine urinalysis, treadmill test and Doppler echocardiography were done at baseline and after 12 weeks of treatment.

Drug Dose Protocol Each subject was given 20 drops of the study drug diluted with 30 ml water twice-daily. Patients who were intolerant to the study drug were instructed to start with 10 drops of the study drug diluted with 30 ml water twice-daily and increase the dose gradually to 15 and than 20 drops.

Follow-up The subjects were clinically assessed every week and their BP readings were recorded. Investigations were done at baseline and after 12 weeks of treatment (completion of the study period).


clinical study Statistical Methods

Fall in Diastolic BP

Statistical analysis was done using the SPSS statistical package (version 17.0). Results are expressed as mean ± standard deviation (SD). Paired test was used to compare normally distributed continuous variables from pre- and post-intervention. BP values over time within the groups were analyzed using repeated measures analysis of variance (ANOVA) followed by Bonferroni’s post-hoc testing; p < 0.05 was considered statistically significant.

There was statistically significant mean fall in DBP of 10.31 mmHg from 0 to 12 weeks (95% CI 5.57 to 15.05) (p < 0.001) (Table 2 and Fig. 2). Post-hoc tests using Bonferroni correction revealed that the reduction in DBP values was again significant from the 4th week onwards.

Results

Fall in Systolic BP Means of SBP starting from 0 week to the 12th week were analyzed. There was statistically significant (p < 0.001) mean fall in SBP of 15.75 mmHg at 12 weeks (95% confidence interval [CI] 9.25 to 22.25) (Table 1 and Fig. 1). Post-hoc tests using Bonferroni correction revealed that the reduction in SBP values was significant from 4th week onwards.

There was a statistically significant improvement in metabolic equivalents (METs) from 11.54 ± 1.82 at baseline to 12.53 ± 2.05 at 12 weeks (p < 0.001), which amounted to an average increase of 8.6% per patient in METs. The observed mean difference was 0.95 minutes (95% CI ‒1.39 to ‒0.51) (Table 3 and Fig. 3). There was a statistically significant mean gain of exercise time of 0.82 minutes (95% CI ‒1.25 to ‒0.38). The gain was from 9.84 ± 1.78 minutes at baseline to 10.65 ± 1.78 minutes at 12 weeks (p = 0.001). This amounted to an average increase of 8.2% per patient in exercise time (Table 4 and Fig. 4). Table 2. Fall in Diastolic BP

Table 1. Fall in Systolic BP SBP

Improvement in Treadmill Parameters

Number of patients

Mean

Standard deviation

Week 0

16

146.25

9.83

Week 1

16

135.75

9.74

Week 2

16

138

14.17

Week 3

16

134.06

Week 4

16

Week 5

16

Week 6

Change from Week 0 (%)

Number of patients

Mean

Standard deviation

Change from Week 0 (%)

Week 0

16

95.44

7.92

 

–7.18%

Week 1

16

86.69

7.49

–9.17%

–5.64%

Week 2

16

85.69

10.21

–10.22%

12.89

–8.34%

Week 3

16

86.69

7.49

–9.17%

131.75

9.03

–9.91%

Week 4

16

85.06

7.64

–10.88%

133.69

13.46

–8.59%

Week 5

16

87.06

7.84

–8.78%

16

132.63

12.92

–9.31%

Week 6

16

84.63

10.58

–11.33%

Week 7

16

131.88

11.01

–9.83%

Week 7

16

86.38

7.94

–9.49%

Week 8

16

131.81

10.37

–9.87%

Week 8

16

85.38

10.06

–10.54%

Week 9

16

134.75

11.13

–7.86%

Week 9

16

89.06

9.70

–6.68%

Week 10

16

131.44

10.84

–10.13%

Week 10

16

85.25

6.06

–10.68%

Week 11

16

133.88

13.65

–8.46%

Week 11

16

86.94

8.43

–8.91%

Week 12

16

130.5

11.97

–10.77%

Week 12

16

85.13

8.76

–10.80%

100 95 90 85 80 75 70 65 60

DBP

Mean values

Mean values

SBP 160 150 140 130 120 110 100

DBP

0

1

2

3

4

5

6

Weeks

Figure 1. Reduction in SBP.

7

8

9 10 11 12

0

1 2

3

4

5 6 7 Weeks

8

9 10 11 12

Figure 2. Reduction in DBP.

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

217


clinical study Table 3. Increase in METs at Three Months METs

Number of patients

Mean

Standard deviation

Baseline

14

11.54

1.82

Three months

14

12.53

2.05

P value <0.001 

METs

15 Mean values

12 9

6 3 0

Baseline

3 months

Figure 3. Increase in METs at three months.

Table 4. Increase in Exercise Time at Three Months Exercise time

Number of patients

Mean

Standard deviation

Baseline

14

9.84

1.78

Three months

14

10.65

1.78

P value 0.001

Baseline

3 months

Mean values

Figure 4. Increase in exercise time at three months.

Echo Parameters There was no statistical significant change in Echo parameters after three months of treatment. 

218

No significant differences were observed in the means of aortic diameter (Ao) at baseline (29.86 ± 3.44) and after three months (29.54 ± 3.35) (p = 0.682). The observed mean difference was 0.32 (95% CI ‒1.31 to 1.95). There was no significant difference in the means of left atrial (LA) diameter at baseline (28.92 ± 3.80) and after three months (28.49 ± 3.35) (p = 0.529). The observed mean difference was 0.43 (95% CI ‒0.98 to 1.83). There were no significant differences in the means of LV septum at baseline (9.78 ± 1.29) and after three months (9.77 ± 1.17) (p = 0.969). The observed mean difference was 0.01 (95% CI ‒0.69 to 0.72). There was no significant difference in the means of posterior wall thickness at baseline (9.78 ± 1.29) and after three months (9.77 ± 1.17) (p = 0.969). The observed mean difference was 0.01 (95% CI ‒0.69 to 0.72).

Biochemistry

Exercise time 14 12 10 8 6 4 2 0

There was no significant difference in the means of left ventricular (LV) end-diastolic dimension at baseline (40 ± 4.81) and after three months (39.08 ± 4.43) (p = 0.156). The observed mean difference was 0.93 (95% CI ‒0.39 to 2.24).

No significant differences were observed in the means of E/A (ratio of mitral E-wave velocity to mitral A-wave velocity) at baseline (1.15 ± 0.32) and after three months (1.10 ± 0.34) (p = 0.535). The observed mean difference was 0.05 (95% CI ‒0.11 to 0.19). There were no significant differences in the means of E/E’ ratio (ratio of early mitral inflow to early mitral annular velocity) at baseline (9.03 ± 1.97) and after three months (9.22 ± 2.5) (p = 0.788). The observed mean difference was 0.19 (95% CI ‒1.65 to 1.27).

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

There was no significant difference in the means from baseline to the end of study for Hb (14.406 ± 1.3463 at baseline and 14.106 ± 1.3102 at 12 weeks [p = 0.193]); erythrocyte sedimentation rate (ESR) (15.69 ± 13.553 at baseline and 16.25 ± 8.497 at 12 weeks [p = 0.847]); serum creatinine (0.888 ± 0.1854 at baseline and 0.85 ± 0.1838 at 12 weeks [p = 0.315]); SGPT (51.38 ± 40.516 at baseline and 44.63 ± 19.677 at 12 weeks [p = 0.534]); total cholesterol (183.88 ± 39.16 at baseline and 194.25 ± 35.21 at 12 weeks [p = 0.191]); low-density lipoprotein (LDL) cholesterol (122.56 ± 36.30 at baseline and 127.20 ± 29.25 at 12 weeks [p = 0.476]); VLDL cholesterol (25.66 ± 8 at baseline and 28.48 ± 10.59 at 12 weeks [p = 0.209]); high-density lipoprotein (HDL) cholesterol (42.38 ± 9.14 at baseline and 41.38 ± 8 at 12 weeks [p = 0.403]) and triglycerides (128.31 ± 40.01 at baseline and 142.31 ± 53.15 at 12 weeks [p = 0.213]). Blood sugar decreased at three months (96.5 ± 13.938 at baseline and 92.56 ± 12.329 at 12 weeks [p = 0.046]). A similar decrease was seen in the serum uric acid levels (5.681 ± 0.8998 at baseline and 6.031 ± 0.8822 at 12 weeks [p = 0.053]). Both these changes suggested a beneficial effect on the insulin resistance (IR). There was no change in BMI (28.62 ± 5.69 at baseline and 28.32 ± 5.83 at 12 weeks [p = 0.160]).


clinical study Changes in QOL Questionnaire16

Change in QOL was assessed by SF36 and each subject was scored before and after completion of study. The average Rand score improved from 54.53 ± 21.9991 at baseline to 77.55 ± 10.493 at 12 weeks (p < 0.001).

Safety Evaluation

2.

Chockalingam A, Campbell NR, Fodor JG. Worldwide epidemic of hypertension. Can J Cardiol 2006;22(7):553-5.

3.

Bansal SK, Saxena V, Kandpal SD, Gray WK, Walker RW, Goel D. The prevalence of hypertension and hypertension risk factors in a rural Indian community: A prospective door-to-door study. J Cardiovasc Dis Res 2012;3(2): 117-23.

4.

Yadav S, Boddula R, Genitta G, Bhatia V, Bansal B, Kongara S, et al. Prevalence & risk factors of prehypertension & hypertension in an affluent north Indian population. Indian J Med Res 2008;128(6):712-20.

5.

Asmathulla S, Rajagovindan D, Sathyapriya V, Pai BK. Prevalence of prehypertension and its relationship to cardiovascular disease risk factors in Puducherry. Indian J Physiol Pharmacol 2011;55(4):343-50.

6.

Cunnane RT, Bakris GL. Hypertensive goals in patients with coronary artery disease. Curr Cardiol Rep 2012 Aug 14. [Epub ahead of print]

7.

Holland L. Cardiovascular medicines. British Homeopathic Journal 1994;83(4):223-9.

8.

Circosta C, De Pasquale R, Samperi S, Pino A, Occhiuto F. Biological and analytical characterization of two extracts from Valeriana officinalis. J Ethnopharmacol 2007;112(2):361-7.

9.

Mojiminiyi FB, Owolabi ME, Igbokwe UV, Ajagbonna OP. The vasorelaxant effect of Viscum album leaf extract is mediated by calcium-dependent mechanism. Niger J Physiol Sci 2008;23(1-2):115-20.

No serious adverse events were reported during the entire course of the study. Discussion In a review17 of short-term studies on antihypertensives including CCBs, diuretics, ACE inhibitors, a-blockers, b-blockers, angiotensin II receptor blockers, the change in SBP and DBP was a negative value ranging from –2 to even –12 points, which is comparable to that observed in the current study with mean fall in SBP of 15.75 mmHg and mean fall in DBP of 10.31 mmHg without any side effects observed during the entire study duration. The change however was observed for over a period of 12 weeks with a statistically significant fall observed from 4th week onwards, so the study drug can be used safely used for prehypertension, Stage 1 hypertension and for Stage 2 excluding hypertensive emergencies and urgencies. There were appreciable increase in METs by 8.6% and exercise time by 8.2%, though no change was observed in echo parameters as duration of observation was just 12 weeks during which a change in echo is not expected as the trends go in other such studies. Conclusion The results of the study showed that the study drug can safely be used as monotherapy in patients with prehypertension or hypertension without complications. This is only a preliminary study and more data needs to be collected for further collaboration. A prolonged study for a period of at least six months to one year is needed for an in-depth analysis of the medicine.

Acknowledgment The study product BPA (Bee Pee Aid) was supplied by Bakson Drugs and Pharmaceuticals Pvt. Ltd.

Disclaimer It was an independent study and not influenced by any market forces.

References 1.

Kokiwar PR, Gupta SS, Durge PM. Prevalence of hypertension in a rural community of Central India. JAPI 2012;60:26-9.

10. Shamon SD, Perez MI. Blood pressure lowering efficacy of reserpine for primary hypertension. Cochrane Database Syst Rev 2009;(4):CD007655. 11. Miller AL. Botanical influences on cardiovascular disease. Altern Med Rev 1998;3(6):422-31. 12. Jones AO. Cactus grandiflorus in some forms of heart disease. Br Med J 1890;1(1515):70-1. 13. Norred CL, Zamudio S, Palmer SK. Use of complementary and alternative medicines by surgical patients. AANA J 2000;68(1):13-8. 14. Robin Murphy. Rauwolfia serpentina, Viscum album, Crataegus, Arnica montana, Valeriana, Melilotus alba, Cactus grandiflorus. In: Lotus Materia Medica. 2nd edition, (revised), 2009:p.172-6, 307-11, 556-9, 1117-20, 1465-7,1855-8. 15. William Boericke. Rauwolfia serpentina, Viscum album, Crataegus, Arnica montana, Valeriana, Melilotus alba, Cactus grandiflorus. In: Pocket Manual of Homeopathic Materia Medica and Repertory. 9th edition 2005:p.76-9, 137-9, 237-8, 427-8, 664-5, 677-8, 1072. 16. Bulpitt CJ, Fletcher AE. The measurement of quality of life in hypertensive patients: a practical approach. Br J Clin Pharmacol 1990;30(3):353-64. 17. Effective Health Care. Bulletin on the effectiveness of health service interventions for decision makers. Effectiveness of antihypertensive drugs in black people. 2004:8(4).

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

219


clinical study ...Cont’d from page 213 One trial examined the efficacy of pumpkin seed extract alone. In this placebo-controlled, year-long study, 476 patients were randomly assigned to receive placebo or 500 mg/day of seed extract. Although, there was an identical effect in both groups in Qmax, quality-of-life, and PVR at study end, the group that received phytotherapy showed a decrease in International Prostate Symptoms Score (IPSS) (6.7 points) over the placebo group (5.5 points). This 1.2 point is statistically significant.9

3.

Dreikorn K, Borkowsi A, Braeckman J, et al. Other medical therapies. In: Proceedings of the fourth International Consultation on Benign Prostatic Hyperplasia (BPH) 1997. Denis L, Griffiths K, Khoury S, et al (Eds.), Plymouth: Plymbridge Distributor 1998:p.633-59.

4.

Ishani A, MacDonald R, Nelson D, Rutks I, Wilt TJ. Pygeum africanum for the treatment of patients with benign prostatic hyperplasia: a systematic review and quantitative meta-analysis. Am J Med 2000;109(8): 654-64.

5.

Dreikon K, Lowe F, Braeckman J, et al. Other medical therapies. In: Proceedings of the 5th International Consultation on Benign Prostatic Hyperplasia. Denis L, Griffiths K, Khoury S, et al (Eds.), Plymouth. Plymouth Distributors, 2001.

6.

Bayne CW, Donnelly F, Ross M, Habib FK. Serenoa repens (Permixon): a 5 alpha-reductase types I and II inhibitornew evidence in a coculture model of BPH. Prostate 1999;40(4):232-41.

7.

Strauch G, Perles P, Vergult G, Gabriel M, Gibelin B, Cummings S, et al. Comparison of finasteride (Proscar) and Serenoa repens (Permixon) in the inhibition of 5-alpha reductase in healthy male volunteers. Eur Urol 1994;26(3):247-52.

8.

Levin RM, Riffaud JP, Bellamy F, Rohrmann D, Krasnopolsky L, Haugaard N, et al. Effects of tadenan pretreatment on bladder physiology and biochemistry following partial outlet obstruction. J Urol 1996;156(6): 2084-8.

9.

Madersbacher S, Berger I, Ponholzer A, Marszalek M. Plant extracts: sense or nonsense? Curr Opin Urol 2008;18(1):16-20.

CONCLUSION Uncontrolled studies with low patient numbers and of short duration, not performed according to accepted standards and guidelines, are of questionable value. Meta-analysis are only acceptable if the quality of the studies included is assessed and shown to be appropriate. Due to the widely controversial and partly insufficient ‘hard’ data about the efficacy of phytotherapy for the treatment of LUTS due to BPH, the International Consultation on BPH were reluctant to recommend phytotherapy. However, a review of the role of phytotherapy in the management of LUTS due to BPH is needed. REFERENCES 1.

Mahady GB. Global harmonization of herbal health claims. J Nutr 2001;131(3 Suppl):11205-35.

2.

Young AL, Bass IS. The Dietary Supplement Health and Education Act. Food Drug Law J 1995;50(2):285-92.

220

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012


Clinical Study

Evaluation of Creatine Kinase as a Diagnostic Tool for Thyroid Function KMDS Panag*, Gitanjali*, Sudeep Goyal**

Abstract Thyroid disorders are very commonly affecting the general population, even the persons residing in non goitrous areas are no exception. Currently used tests for the assessment of thyroid functions (throid-stimulating hormone [TSH], tri-iodothyronine [T3] and throxine [T4]) are not sometimes sufficient to clearly make out the diagnosis as T3 and T4 levels are affected by so many other nonspecific conditions. The present study was done to evaluate the role of alternative biochemical parameter creatine kinase (CK) in diagnosing thyroid disorders. Sixty hypothyroid and 40 hyperthyroid patients were compared with 50 age, sex and sociocoeconomic status matched healthy controls. FT3, FT4 and TSH levels were measured by ELISA method and CK levels were measured by modified IFCC method. In hypothyroid patients, significant increase in CK levels was found as compared to control group (190 ± 40 IU/l in hypothyroid patients and 100 ± 70 IU/l in control group). A negative correlation was also found between FT3 and CK (r = –0.51; p < 0.005). In patients of hyperthyroidism, the levels of CK were found to be on the lower side. It was concluded that CK measurements may be useful as alternative diagnostic tool for the diagnosis of thyroid function disorders, which may be not only because of prevalence of muscular dystrophies in thyroid disorders but also due to role of FT3 in gene expression.

Keywords: Thyroid disorders, creatine kinase, diagnostic tool

T

hyroid gland is located in the neck, anterior to trachea. It consists of two lobes that are connected by an isthmus. The gland produces hormones which play a great role in control of basal metabolic rate (BMR), general body metabolism, growth, development and tissue differentiation. Thyroid dysfunction is one of the most common endocrinological disorders. Consequently, abnormalities of these hormones frequently involve many organ systems producing diverse clinical signs and symptoms which are generally nonspecific. Thus confirmation of a provisional diagnosis of thyroid disorder rests largely upon biochemical parameters.1 The commonly used parameters for assessment of thyroid function are estimation of thyroid stimulating hormone (TSH), total tri-iodothyronine (T3), total thyroxine (T4), free T3 (FT3) and free T4 (FT4). Out of these TSH has been accepted as the initial screening test. This is because serum level of TSH has been

*Dept. of Biochemistry GGS Govt. Medical College, Faridkot, Punjab **Dept. of Anesthesia, PGIMS Rohtak, Haryana Address for correspondence Dr Gitanjali Backside Civil Vet. Hospital, Sikhan Wala Road, Prem Nagar Kotkapura, Faridkot - 151204, Punjab E-mail: gitanjaligoyal@yahoo.co.in

documented to reflect the integrative action of thyroid hormone on the tissue most sensitive to circulating thyroid hormones, the pituitary.2 However, the abnormal TSH level necessitates the use of other indicators of thyroid status including total and FT3 and T4. None of these parameters have proven to be ideal as their measured levels tend to vary in conditions like pregnancy, use of oral contraceptives, protein wasting diseases, liver disease, certain drugs and heparin, etc.3 The inherent limitations of these parameters necessitate the establishment of alternate markers and enzymes like transaminases, lactate dehydrogenase (LDH) and creatine kinase (CK). Among these, CK has shown promising results as a diagnostic tool for thyroid disease. Serum CK was first used as a diagnostic aid in progressive muscular dystrophy.4 It has since then become important clinical marker for muscle damage. The serum CK levels in healthy individuals depend on age, race, lean body mass and physical activity.4-6 Musculoskeletal disorders often accompany thyroid dysfunction. In addition to well-known observation that musculoskeletal disorders are common in patients with hypothyroidism, they are also observed in thyrotoxicosis and level of CK is altered in both these conditions.7 In recent years, studies have been conducted

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

221


clinical study to establish a relationship of CK levels in thyroid diseases.8 Skeletal muscle is affected by hypothyroidism more profoundly in cases of overt hypothyroidism and less so when subclinical hypothyroidism is present.9,10 Thus, it follows that assay of CK activity in serum may prove to be valuable in screening of thyroid disorders and in the present study, we tried to evaluate the role of CK as an alternative diagnostic tool in patients of thyroid disorder. Material and Methods The study was done at GGS Govt. Medical College, Faridkot, Punjab. The study group comprised of 100 patients randomly selected from patients coming for thyroid function tests in the biochemistry diagnostic laboratory. There were 60 hypothyroid cases and 40 hyperthyroid cases. Fifty age, sex and socioeconomic status matched persons were taken as controls. Exclusion criteria was taken to rule out other diseases which can alter the results of study like cardiovascular, neuromuscular involvements, recent cerebral stroke, gross hepatic or renal dysfunction and pulmonary infarction. All patients were screened for any drug history, especially drugs which can affect CK or thyroid hormone levels. Recent history of intramuscular injections, strenuous exercise was ruled out. Informed written consent was obtained for venipuncture. Venous blood was withdrawn for investigations taking all aseptic precautions. Serum was separated and investigated either immediately or it was preserved at 2-8°C for upto three days for CK measurement. FT3 and FT4 were measured by competitive enzymelinked immunosorbent assay (ELISA). TSH was measured by quantitative ELISA using Monobind kits. CK was measured by modified International Federation of Clinical Chemistry (IFCC) method based on the principle that ATP formed by reaction of CK on creatine phosphate and ADP reacts with glucose to form glucose 6 phosphate, which reduces NADP to NADPH. The rate of reduction of NADP to NADPH is measured at 340 nm. Results The present study was conducted to evaluate the levels of CK in hypothyroid and hyperthyroid patients. The study and control groups were compared according to age, sex distribution and routine investigations were done which showed insignificant results. Table 1 shows the levels of the four parameters TSH, FT3, FT4 and CK in control and study groups.

222

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

Table 1. Comparison of the Clinical Parameters between the Study and the Control Groups Parameter

Control

Hypothyroid

Hyperthyroid

FT3 (pg/dl)

2.8 ± 0.64

1.4 ± 0.41

5.82 ± 2.39

FT4 (ng/ml)

1.30 ± 0.17

0.82 ± 0.20

3.5 ± 1.8

TSH (mIU/l)

2.50 ± 0.80

20.11 ± 13.57

0.18 ± 0.18

100 ± 70

190 ± 40

60 ± 30

CK (IU/l)

The mean values of FT3 and FT4 in hypothyroid patients were 1.4 ± 0.41 pg/dl and 0.82 ± 0.20 ng/ml respectively. TSH levels were 20.11 ± 13.57 mIU/l. The mean values of FT3 and FT4 in hyperthyroid patients were 5.82 ± 2.39 pg/dl and 3.5 ± 1.80 ng/ml respectively. TSH level was 0.18 ± 0.18 mIU/l. The mean value of FT3 and FT4 in control patients was 2.8 ± 0.64 pg/dl and 1.3 ± 0.17 ng/ml, respectively. TSH level was 2.50 ± 0.80 mIU/l. The CK values in the three groups were 190 ± 40, 60 ± 30 and 100 ± 70 IU/l in hypothyroid, hyperthyroid and normal individuals, respectively. Discussion The study was done to evaluate the role of CK as a supportive parameter for diagnosing hypothyroid or hyperthyroid individuals. The levels of CK are found to be significantly higher in patients of hypothyroidism as compared to normal individuals which may be because of skeletal muscle involvement in thyroid disorders. Hekimsoy et al in a study conducted in 2005, found that skeletal muscle is affected by hypothyroidism more profoundly in cases of overt hypothyroidism as compared to subclinical hypothyroidism. Also, there was positive correlation between CK and TSH (r = 0.432; p = 0.04), a negative correlation was found between FT3 and CK (r = –0.556, p = 0.002).11 Giampietro et al in 1984, found myoglobin and CK to be the best indicators of hypothyroid myopathy, since they are sensitive for the early detection of muscle involvement due to metabolic disorder and are closely correlated to the metabolic condition of patients.12 Scott et al in a study conducted in 2002 showed that thyroid hormone replacement therapy resulted in resolution of clinical symptoms and a marked reduction in CK levels in a patient with progressive proximal weakness and serum CK level of over 29,000 IU/l. Such a high serum CK level in a patient with hypothyroidism underscores the importance of assessing thyroid function in patients with weakness, regardless of serum CK levels, even when systemic symptoms and signs of hypothyroidism are minimal or absent.13 In case studies, patients with hypothyroidism solely presented


clinical study with symptoms of myositis and very high levels of CK which resolved after treatment for hypothyroidism14 and in a patient of Grave’s disease, patient developed myalgia with high level of CK after total thyroidectomy, the features were normalized after treatment and again reappeared after treatment was stopped.15 These studies clearly show that muscular involvement was there in thyroid disorders. In hypothyroid patients with decrease in serum T3, there is significant increase in CK and this may be in fact used as a parameter for screening hypothyroid patients.16 In the present study, similar results were found showing increased levels of CK in hypothyroid patients and decreased CK in hyperthyroidism. Also, there was a negative correlation between FT3 and TSH. Some authors suggest direct role of T3 at the regulation of gene expression. It has been shown to induce or repress production of different proteins by increasing or decreasing transcription.17,18 Authors have studied thyroid hormone-dependent gene expression in differentiated embryonic stem cells which were induced or repressed in response to T3. Very high levels of FT3 have been documented to inhibit protein synthesis.19 It is concluded from these findings that measurement of CK may act as a good tool to diagnose hypothyroidism not only because of well-documented muscular dystrophy in thyroid patients but also because of negative correlation between FT3 and CK possibly mediated at the level of gene expression. References 1.

Saha M, Sarkar P, Chattopadhyay R, Mukhopadhyaya M, Bhowmick K. Role of creatine kinase and its coenzymes as surrogate markers of thyroid function. IJMB 2009;13(2): 10-4.

2.

Spencer CA. Strategy for use of serum thyrotrophin vs. free thyroxine measurement in thyroid testing. AACC Endo 1991;10:9-17.

3.

Whitley RJ. Thyroid functions. In: Teitz Fundamentals of Clinical Chemistry. 5th edition, Burtis CA, Ashwood ER (Eds.) WB Saunders 2001:p.842.

6.

Meltzer HY. Factors affecting serum creatine phosphokinase levels in the general population: the role of race, activity and age. Clin Chim Acta 1971;33(1): 165-72.

7.

Cakir M, Samanci N, Balci N, Balci MK. Musculoskeletal manifestations in patients with thyroid disease. Clin Endocrinol (Oxf) 2003;59(2):162-7.

8.

Finsterer J, Stöllberger C, Grossegger C, Kroiss A. Hypothyroid myopathy with unusually high serum creatine kinase values. Horm Res 1999;52(4):205-8.

9.

Hekimsoy Z, Oktem IK. Serum creatine kinase levels in overt and subclinical hypothyroidism. Endocr Res 2005;31(3):171-5.

10. Sakaki T, Fujioka Y, Akagami T, Masai M, Shimizu H, Sakoda T, et al. Cardiac wall motion abnormalities observed in a patient with transient hyperthyroidism. Jpn Heart J 2004;45(6):1071-7. 11. Hekimsoy Z, Oktem IK. Serum creatine kinase levels in overt and subclinical hypothyroidism. Endocr Res 2005;31(3):171-5. 12. Giampietro O, Clerico A, Buzzigoli G, Del Chicca MG, Boni C, Carpi A. Detection of hypothyroid myopathy by measurement of various serum muscle markersmyoglobin, creatine kinase, lactate dehydrogenase and their isoenzymes. Correlations with thyroid hormone levels (free and total) and clinical usefulness. Horm Res 1984;19(4):232-42. 13. Scott KR, Simmons Z, Boyer PJ. Hypothyroid myopathy with a strikingly elevated serum creatine kinase level. Muscle Nerve 2002;26(1):141-4. 14. Madhu SV, Jain R, Kant S, Prakash V, Kumar V. Myopathy presenting as a sole manifestation of hypothyroidism. J Assoc Physicians India 2010;58:569-70. 15. Shaheen D, Kim CS. Myositis associated with the decline of thyroid hormone levels in thyrotoxicosis: a syndrome? Thyroid 2009;19(12):1413-7. 16. Prakash A, Lal AK, Negi KS. Serum creatine kinase activity in thyroid disorders. JK Sci 2001;9(1):25-6. 17. Tsai MJ, O’Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 1994;63:451-86.

4.

Ebashi S, Toyokura T, Momoi H, Sugita H. High creatine phosphokinase activity of sera of progressive muscular dystrophy patients. Bioch J Tokyo 1959;46:103.

18. Liu YY, Brent GA. Thyroid hormone-dependent gene expression in differentiated embryonic stem cells and embryonal carcinoma cells: identification of novel thyroid hormone target genes by deoxyribonucleic acid microarray analysis. Endocrinology 2005;146(2):776-83.

5.

Rosalki SB. Enzyme assays in diseases of the heart and skeletal muscle. J Clin Pathol Suppl (Assoc Clin Pathol) 1970;4:60-70.

19. Granner DK. Thyroid hormones. In: Harper’s Biochemistry. 25th edition, Murray RK, Granner DK, Mayes PA, Rodwell VW (Eds.) Appleton & Lange 2000:p.565.

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

223


clinical practice

Hypocholesterolemic Effects of Lactobacillus acidophilus as a Dietary Supplement M Vani*, M Shiva Prakash**, P Yashoda Devi*

Abstract To study the effect of supplementation of Lactobacillus acidophilus on lipid profile in hypercholesterolemia individuals. Thirty hypercholesterolemia subjects (15 men and 15 women) with ages ranging between 42-53 years old were included in the study and the intervention was performed for a period of 60 days. During the intervention all 30 subjects were divided into three groups comprising of 10 individuals in each group. Group A and B were given 10 × 106 and 20 × 106 viable L. acidophilus organisms and Group C served as a nonsupplemented group. However, they were on medication to lower the cholesterol levels. Fasting blood samples were drawn initially at 0, 30 and after 60 days of supplementation, analyzed for lipid profile which included total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol. All the recruited subjects completed the study. Comparisons were made on lipid profile at different time periods i.e., 0, 30 and after 60 days of treatment. The supplementation of either 10 × 106 or 20 × 106 viable L. acidophilus showed significant reduction in cholesterol, triglycerides and increase of HDL cholesterol levels. The supplementation of L. acidophilus is found to be beneficial in altering the levels of lipid profile in hypercholesterolemic subjects.

Keywords: Lactobacillus acidophilus, cholesterol, triglycerides, dietary supplements

O

ne of the major modifiable risk factor for coronary heart disease (CHD) mortality is elevated plasma cholesterol concentration.1 Data from epidemiological and nutritional studies indicate that high concentration of total serum cholesterol and low-density lipoprotein (LDL) cholesterol correlate to the incidence of CHD. Hypercholesterolemia has been implicated to be the primary and important causative factor in underlying CHD.3 The increase in the incidence may be due high intakes of saturated fat or animal fat, which is found to be one of the major dietary factors in hypercholesterolemia.4 Other associated factors were found to be smoking, hypertension, diabetes mellitus, sedentary lifestyles, excess weight and stress.5 It was shown there is coherence with higher levels of cholesterol and the prevalence of ischemic heart disease in both women and men.6 A reduction in high serum cholesterol levels can reduce the risk of CHD. *Dept. of Food and Nutrition, Acharya NG Ranga Agricultural University, Rajendra Nagar, Hyderabad **Assistant Director, National Institute of Nutrition (ICMR) Jamai-Osmania Tarnaka, Hyderabad Address for correspondence Dr M Shiva Prakash Assistant Director (Scientist - D) National Institute of Nutrition (ICMR), Jamai-Osmania Tarnaka, Hyderabad - 500 007

224

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

It was demonstrated that healthy people having cholesterol levels within the normal range had a reduction in the risk of future cardiovascular events.7 Further, it was suggested that the rate of coronary events is reduced by raising high-density lipoprotein (HDL) cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.8 Hence, there is an urgent need to develop intervention programs for the treatment of hypercholesterolemia through dietary modifications, weight reduction and drugs. Drugs used to treat hypercholesterolemia include cholestyramine resin, cholesterol hydrochloride, niacin, gemfibrozil, probucol and lovastatin and they work by different mechanisms in reducing the serum cholesterol concentration.9-11 However, these are associated with side effects which include gastrointestinal discomfort and also have an impaired systematic absorption. Dietary management is the cornerstone in the management of high blood cholesterol concentration. Several findings have shown that low fat vegetarian diet or a diet high in cereal fiber, fruits and vegetables can reduce the risk of hypertension, dyslipidemia and cardiovascular disease.12,13 There is a necessity for a dietary rather than a drug approach to be focused keeping in mind the use of drugs, which are associated


clinical practice with side effects. A number of studies on probiotics have demonstrated the beneficial effects on human health especially in controlling the lipid profile.14,15 Therefore, the present study was taken to see the effect of a commercially and locally available strain of Lactobacillus acidophilus. L. acidophilus belongs to the genus Lactobacillus. L. acidophilus is a homofermentative species, fermenting sugars into lactic acid. Generally, L. acidophilus strains are considered to have probiotic characteristics. These strains are commercially used in many dairy products, sometimes together with Streptococcus thermophilus and Lactobacillus delbrueckii in the production of acidophilus-type yogurt and a typical Indian dahi (curd). Some strains of L. acidophilus have been studied extensively for health effects and found to be effective in decreasing pediatric diarrhea, intestinal bowel syndrome, toxic amines and lactose-intolerance by helping lactose digestion.16 The serum hypocholestrolemic effect of probiotic bacteria such as L. acidophilus has attracted much interest in medical research recently.17,18 Few studies have shown that some strains of Lactobacillus could lower cholesterol content.19,20 For the past several decades, there has been increasing interest in understanding the mechanisms of cholesterol reduction by probiotics, but very recently one study reported that the gene ccpA, which encodes catabolite control protein A, plays an important role in cholesterol reduction by probiotic bacteria.21 Some strains of L. acidophilus were found to secrete bile salt hydrolase, which catalyzed the hydrolysis of glycine- or taurineconjugated bile salts into amino acid residues and free bile salts.22 Another mechanism suggested for cholesterol reduction is that L. acidophilus incorporates some of the cholesterol into cellular membranes, and that results in cholesterol being less available for the absorption from the intestine into the blood.23 Most of the studies for cholesterol reduction in serum by using L. acidophilus and other strains were carried out with rats as experimental animals, but this study investigated in human volunteers. Material and Methods

Bacterial Cultures L. acidophilus (strain no. UBLA-34) was obtained from Unique Biotech Limited, Hyderabad, Andhra Pradesh, India. The strain L. acidophilus UBLA-34 was finally made to 10 × 106 CFU/g and 20 × 106 CFU/g. The L. acidophilus was supplemented as powder form.

Subjects Thirty hypercholesterolemia subjects were selected from the Endocrinology Research Centers of Hyderabad city, Andhra Pradesh, India. The age group ranged between 42-53 years (15 males and 15 females). Subjects with serum cholesterol levels of >200 mg/dl i.e., 200-240 mg/dl were included in the study. The L. acidophilus strain no. UBLA-34, obtained from Unique Biotech Limited located at Hyderabad, was used for supplementation. The subjects were explained about the risk of hypercholesterolemia and the beneficial role of the supplement L. acidophilus and informed consent was obtained before the commencement of the study. The Institutional Ethical Committee approval was obtained before the commencement of the study. The subjects were advised not to take high cholesterol diet i.e. fried foods, butter, ghee, egg yolk, etc. During the experimental period they were restricted and advised to avoid smoking, consumption of alcohol but to continue their habitual diet along with L. acidophilus as a supplement to their diet. The subjects were advised to take L. acidophilus at two dosage level i.e., 10 × 106 (Group A) and 20 × 106 (Group B) viable organisms along with their diet. A structured schedule was used to record their habitual dietary pattern, physical activity, smoking and drinking habits, etc.

Laboratory Investigations Blood samples were collected for lipid profile analysis at 0, 30 and 60 days. Total cholesterol was estimated by enzymatic method of Ciberman.24 Triglycerides were estimated using glycerol phosphate oxidase (GPO) method of Fossati and Lorenzo25 HDL was estimated by enzymatic method of Demacker and Hifman.26 Results The physical examination and initial blood sample reports showed that all the subjects were healthy without signs of liver disease, renal disease and diabetes (Table 1). The results from Table 2 reveal that in Groups A and B, supplementation with L. acidophilus for 30 days, the serum total cholesterol levels were significantly decreased and subsequently after 60 days the values further decreased significantly in both 10 × 106 and 20 × 106 viable L. acidophilus supplementation, respectively (p < 0.001). This decrease in trend was found to be similar to that of Group C i.e., subjects that was on medication with cholesterol lowering drugs.

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

225


clinical practice Table 1. Characteristics of the Subjects Studied Particulars

Female (n = 15)

Male (n = 15)

Total

%

No.

%

No.

%

7 8

46.7 53.3

6 9

40.0 60.0

13 17

43.3 56.7

6 8 1 0

40.0 53.3 6.7 0

3 4 6 2

20.0 26.7 40.0 13.3

9 12 7 2

30.0 40.0 23.3 6.7

13 1 1

86.7 6.7 6.7

0 8 7

0 23.3 46.7

13 9 8

43.3 30.0 26.7

11 4

73.3 26.7

12 3

80.0 20.0

23 7

76.7 23.3

8 6 1

53.3 40.0 6.7

6 9 0

40.0 60.0 0

14 15 1

46.7 50.0 3.3

15 0 0 0

100.0 0 0 0

1 1 8 5

6.7 6.7 53.3 33.3

16 1 8 5

53.3 3.3 26.7 16.7

13 2

86.7 13.3

14 1

93.3 6.7

27 3

90.0 10.0

Age 42-47 years 48-53 years Education Upto 10th 10-12th Graduation Postgraduation Occupation Housewife Service Business Per capita income/month (ì ) 3,000-4,000 >4,000 Habitual diet Vegetarian Nonvegetarian Ovo-vegetarian Other habits Nonalcoholic, nonsmoking Nonalcoholic, smoking Nonsmoking, alcoholic Alcoholic, smoking BMI (kg/m2) 25-30 30-31

Table 2. Total Cholesterol Levels of Hypercholesterolemia Subjects before and after L. acidophilus Supplementation for Different Groups at Different Time Periods Category

Dosage of L. acidophilus supplemented

Serum cholesterol levels (mg/dl) Mean values ± SD (n = 10) 0 day

After 30 days

After 60 days

F value

Level of significance

Group A

10 x 106 viable organisms/ day/individual

228.1a ± 6.4

214.1b ± 6.0

203.5c ± 9.6

89.42

p < 0.001

Group B

20 x 106 viable organisms/ day/individual

229a ± 7.7

208.1b ± 8.9

197.5c ± 5.6

487.03

p < 0.001

Group C

Nil (on medication)

233.5a ± 12.8

208.7b ± 14.5

197.9c ± 12.7

217.89

p < 0.001

NB: Difference in the superscript indicate statistical significance at different time points at p < 0.001.

The triglyceride levels were also significantly lowered in Group A and B at 30 and 60 days supplementation, which was on par with the results of medication group. Table 3 and with respect to HDL cholesterol, in Group A, the levels were significantly increased only after 60 days of supplementation (p < 0.001), whereas in Group B with 20 × 106 L. acidophilus

226

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

supplementation it was found that there was a significant increase even after 30 days and as well as 60 days (Table 4). Discussion The present data suggest that serum cholesterol and triglycerides decreased significantly with a significant


clinical practice Table 3. Triglyceride Levels of Hypercholesterolemia Subjects before and after L. acidophilus Supplementation for Different Groups at Different Time Periods Category

Dosage of L. acidophilus supplementation

Triglyceride levels (mg/dl) Mean values ± SD (n = 10) 0 day

After 30 days

After 60 days

F value

Level of significance

Group A

10 x 106 viable organisms/day/ individual

251.9a ± 36.1

245.5b ± 36.6

241.2c ± 36.1

165.16

p < 0.001

Group B

20 x 106 viable organisms/ day/individual

282.6a ± 43.6

275.5b ± 43.4

268.6c ± 43.6

193.61

p < 0.001

Group C

Nil (on medication)

287.6a ± 59.2

271a ± 82.4

263.3c ± 80.0

56.57

p < 0.001

NB: Difference in the superscript indicate statistical significance at different time points at p < 0.001.

Table 4. HDL Cholesterol Levels of Hypercholesterolemia Subjects before and after L. acidophilus Supplementation for Different Groups at Different Time Periods Category

Dosage of L. acidophilus supplementation

HDL cholesterol levels (mg/dl) Mean values ± SD (n = 10) 0 day

After 30 days

After 60 days

F value

Level of significance

Group A

10 x 106 viable organisms/day/ individual

41.3a ± 2.2

42.2ab ± 1.9

42.6bc ± 1.7

8.40

p < 0.01

Group B

20 x 106 viable organisms/day/ individual

41.6a ± 2.2

42.3b ± 2.5

43.1c ± 1.9

12.62

p < 0.001

Group C

Nil (on medication)

40.8a ± 1.8

41.8b ± 2.16

42b ± 1.7

9.59

p < 0.001

NB: Difference in the superscript indicate statistical significance at different time points at p < 0.001.

increase in HDL cholesterol. The reason for the hypocholesterolemic effect of L. acidophilus might be due to inhibition of 3-hydroxy, 3-methylglutaryl coenzyme A reductase, which is a rate limiting enzyme in endogenous cholesterol biosynthesis in the body and also by deconjugation of bile acids in the intestine which is an important mechanism in reducing the cholesterol concentrations.27 Increased deconjugation of bile acids could also result in the greater excretion of bile salts from intestinal tract which stimulates the synthesis of replacement of bile salts from cholesterol, thus providing the potential to reduce the cholesterol levels in the body.28 The effect of lactobacilli on triglycerides could be due to the action of lipase from the lactobacilli, which breaks the larger molecular fats into simple and easily digestible substrates i.e., fatty acids and glycerol.29 The effect of Lactobacillus on LDL, VLDL and HDL cholesterol was unsettled in the present study. Earlier, it was reported that a probiotic mixture of L. acidophilus and S. faecalis decreased the synthesis of cholesterol in the liver and increased the loss of steroids in rats.30 Further, it was suggested that L. acidophilus can enhance the reduction of serum cholesterol in rats that had been fed a high

cholesterol diet, probably through alteration in the enterohepatic circulation of bile acids.31 The present results indicate that the observed hypocholesterolemic effect is somehow dependent on the presence of the bacteria in the product. An increase in HDL cholesterol may be due to fermentation of the microflora. An ability of certain strains of lactobacilli to assimilate cholesterol in the presence of bile acids has been demonstrated and suggests a possible association between gut microflora and cholesterol absorption.32 The viability of fermenting bacteria strain in the human gut and ultimately the ability to colonize the small intestine, where most of the absorption of cholesterol takes place, could be expected to be important for the effect. Conclusions From this study, it can be concluded that 20 × 106 L. acidophilus viable organisms/day/individual for a period of 60 days is more effective and beneficial in bringing out remarkable changes in serum lipid profile than 10 × 106 viable organisms/day/individual for the same functional parameters. Further studies are necessary to understand the sustaining to understand of

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

229


clinical practice the Lactobacillus supplementation after with drawing from patients. Also such studies underline for the beneficial effects of supplementation of L. acidophilus as a food supplement to control the abnormal lipid levels of the hypercholesterolemic subjects. These observations along with physical exercise to the patients may prove beneficial in minimizing the rate of CHDs.

Acknowledgments We convey our thanks to Dr (Mrs) M Ratna Sudha, Managing Director of M/S Unique Biotech Limited, Hyderabad, Andhra Pradesh, India for providing us the L. acidophilus (strain no. UBLA-34) which was given as supplement in this study.

REFERENCES

10. Insull W Jr. Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review. South Med J 2006;99(3):257-73. 11. Florentin M, Liberopoulos EN, Elisaf MS. Ezetimibeassociated adverse effects: what the clinician needs to know. Int J Clin Pract 2008;62(1):88-96. 12. Anderson JW, Hanna TJ. Impact of nondigestible carbohydrates on serum lipoproteins and risk for cardiovascular disease. J Nutr 1999;129(7 Suppl):1457S-66S. 13. Mozaffarian D, Kumanyika SK, Lemaitre RN, Olson JL, Burke GL, Siscovick DS. Cereal, fruit, and vegetable fiber intake and the risk of cardiovascular disease in elderly individuals. JAMA 2003;289(13):1659-66. 14. Gilliland SE, Nelson CR, Maxwell C. Assimilation of cholesterol by Lactobacillus acidophilus. Appl Environ Microbiol 1985;49(2):377-81.

1.

Shipley MJ, Pocock SJ, Marmot MG. Does plasma cholesterol concentration predict mortality from coronary heart disease in elderly people? 18 year follow up in Whitehall study. BMJ 1991;303(6794):89-92.

2.

Gupta R, Joshi P, Mohan V, Reddy KS, Yusuf S. Epidemiology and causation of coronary heart disease and stroke in India. Heart 2008;94(1):16-26.

16. Sanders ME, Klaenhammer TR. Invited review: the scientific basis of Lactobacillus acidophilus NCFM functionality as a probiotic. J Dairy Sci 2001;84(2):319-31.

3.

Singh RB, Rastogi V, Niaz MA, Ghosh S, Sy RG, Janus ED. Serum cholesterol and coronary artery disease in populations with low cholesterol levels: the Indian paradox. Int J Cardiol 1998;65(1):81-90.

17. Park YH, Kim JG, Shin YW, Kim SH, Whang KY. Effect of dietary inclusion of Lactobacillus acidophilus ATCC 43121 on cholesterol metabolism in rats. J Microbiol Biotechnol. 2007;17(4):655-62.

4.

Ockene IS, Nicolosi R. Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med 1998;338(13):917; author reply 918-9.

5.

Verschuren WM, Jacobs DR, Bloemberg BP, Kromhout D, Menotti A, Aravanis C, et al. Serum total cholesterol and long-term coronary heart disease mortality in different cultures. Twenty-five-year follow-up of the seven countries study. JAMA 1995;274(2):131-6.

18. Mathara JM, Schillinger U, Guigas C, Franz C, Kutima PM, Mbugua SK, et al. Functional characteristics of Lactobacillus spp. from traditional Maasai fermented milk products in Kenya. Int J Food Microbiol 2008; 126(1-2):57-64.

6.

Lindblad U, Langer RD, Wingard DL, Thomas RG, Barrett-Connor EL. Metabolic syndrome and ischemic heart disease in elderly men and women. Am J Epidemiol 2001;153(5):481-9.

7.

Chow C, Cardona M, Raju PK, Iyengar S, Sukumar A, Raju R, et al. Cardiovascular disease and risk factors among 345 adults in rural India - the Andhra Pradesh Rural Health Initiative. Int J Cardiol 2007;116(2):180-5.

8.

Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/ Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279(20):1615-22.

9.

Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of highdensity lipoprotein cholesterol. Veterans Affairs HighDensity Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341(6):410-8.

15. Klaver FA, van der Meer R. The assumed assimilation of cholesterol by Lactobacilli and Bifidobacterium bifidum is due to their bile salt-deconjugating activity. Appl Environ Microbiol 1993;59(4):1120-4.

19. Adebawo OO, Banjoko Y, Osilesi T. Evaluation of the hypocholesterolemic effect of Lactobacillus acidophilus fermented maize meal (ogi) in rats. FASEB J 2008;22: 1092-7. 20. Sridevi N, Vishwe P, Prabhune A. Hypocholesteremic effect of bile salt hydrolase from Lactobacillus buchneri ATCC 4005. Food Res Int 2009;42(4):516-20. 21. Lee J, Kim Y, Yun HS, Kim JG, Oh S, Kim SH. Genetic and proteomic analysis of factors affecting serum cholesterol reduction by Lactobacillus acidophilus A4. Appl Environ Microbiol 2010;76(14):4829-35. 22. Corzo G, Gilliland SE. Measurement of bile salt hydrolase activity from Lactobacillus acidophilus based on disappearance of conjugated bile salts. J Dairy Sci 1999;82(3):466-71. 23. Noh DO, Kim SH, Gilliland SE. Incorporation of cholesterol into the cellular membrane of Lactobacillus acidophilus ATCC 43121. J Dairy Sci 1997;80(12):3107-13. 24. Lieberman LL. A method for the estimation of serum cholesterol. Clin Chem 1958;2:26-30. 25. Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 1982;28(10):2077-80.

Contâ&#x20AC;&#x2122;d on page 232...

230

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012


case report

Acute Pancreatitis in Pregnancy Sreelatha S*, Vedavathy Nayak**, Nataraj†

Abstract Acute pancreatitis is a rare event in pregnancy, which can have a high maternal mortality and fetal loss. Gallstone disease is thought to be responsible for about 70% of these cases. We report a case of a 28-year-old woman, who presented with severe pain confined to the upper abdomen, which was radiating to the back. Investigation undertaken led to the diagnoses of acute pancreatitis.

Keywords: Acute pancreatitis, pregnancy, pancreatitis in pregnancy

A

cute pancreatitis is a rare event in pregnancy, occurring in approximately one in 1,000 to one in 3,333 pregnancies. Pregnancy-related hematological and biochemical alterations influence the interpretation of diagnostic tests and assessment of severity of acute pancreatitis. As in any other disease associated with pregnancy acute pancreatitis is associated with greater concerns as it deals with two lives rather than just one as in the nonpregnant population. Gallstone disease is thought to be responsible for about 70% of these cases. With early recognition and better supportive treatment of acute pancreatitis as well as improvements in maternal and perinatal care, maternal and perinatal mortality dramatically appears to be improved over the past two decades. When properly managed acute pancreatitis in pregnancy does not carry a dismal prognosis as in the past. CASE REPORT A 28-year-old G2P1L1 woman was admitted on 10/6/2012 at 36 weeks of gestation with severe pain confined to the upper abdomen, which was radiating to the back since the previous day. Patient also complained of fever, nausea and vomiting. On examination, pulse rate was 102/min, BP was 110/60 mmHg. Temperature was 100.2oF and respiratory rate was 22/min. Per abdominal examination revealed epigastric tenderness with

*Associate Professor **Assistant Professor †Senior Resident Dept. of Obstetrics and Gynecology, ESICMC and PGIMSR, Rajajinagar, Bangalore

guarding. Uterus was 36 weeks gravid size, relaxed. Fetal heart tones were at 140/min. Laboratory tests done on the day of admission showed a white blood count of 13,600/mm3, and a platelet count of 200,000. Liver function tests showed raised alkaline phosphatase - 217 mg/dl (ref: 35-104 mg/dl) Lactate dehydrogenase was 322 mg/dl (ref: 135-214 mg/dl). Random blood sugar and renal function tests were within normal limits. Serum amylase was 2,339 IU/l (ref: <90 IU/l), lipase 853 IU/l (ref: 8-57 IU/l), calcium 8.7 mg/dl (ref: 8.5-11 mg/l), triglycerides 282 mg/dl (ref: <150 mg/dl) and uric acid 4 g/dl (ref: 2.4-6.7 mg/dl). Urine analysis was normal. Abdominal ultrasonography showed a single live intrauterine fetus of 36 weeks ± 2 days GA with normal cardiac activity and adequate liquor. The gallbladder was distended. The pancreas could not be visualized due to obscuration by bowel shadows. As patient was in severe abdominal pain, patient was shifted to the intensive care unit (ICU). She was managed by nil orally, nasogastric aspiration, intravenous fluids, antibiotics, analgesics, antipyretics and total parenteral nutrition with strict fetal monitoring. The patient improved with this treatment and was shifted back to the antenatal ward after three days. Patient went into spontaneous labor seven days after admission. She delivered a healthy live baby vaginally by vertex presentation on 19/6/2012. Ultrasound done on the 5th postnatal day showed a bulky head of the pancreas with heterogeneity suggestive of acute pancreatitis. Patient was discharged on the 6th postnatal day in good condition.

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

231


case report DISCUSSION Acute pancreatitis during pregnancy is rarely encountered and can have a high maternal mortality and fetal loss. Pancreatitis can occur during any trimester but around 52% of cases are found in the third trimester; it is rarely seen in the postpartum period. Acute pancreatitis following medical abortion is also reported. Gallstones are the most common etiological factor. The relaxant effect of progestogens in pregnancy leading to atony of the biliary tract, bile stasis in the duodenum and reflux may be a contributing factor. Hyperlipidemia is the second most common causative agent. Pregnancy increases the level of serum cholesterol and triglycerides and causes biliary stasis thus inducing the formation of gallstones. Hypertriglyceridemia may also directly cause acute pancreatitis. Genetically, a mutation in the lipoprotein lipase gene (Glutamine4,21 Lysine) causing hypertriglyceridemia-induced pancreatitis in pregnancy has also been reported. Primary hyperparathyroidism is a rare cause of pancreatitis during pregnancy. Clinically, acute pancreatitis is characterized by tenderness in the epigastrium, which can be mild to incapacitating and associated with nausea, vomiting and abdominal distension. The pain may radiate to the back, can be exacerbated by meals or by lying down, and can be relieved by leaning forward. Associated signs include low-grade fever, tachycardia and hypotension. The biochemical investigations required to establish a diagnosis of acute pancreatitis include complete blood count, serum triglycerides, calcium and liver function tests. An elevated serum amylase level has a diagnostic sensitivity of 81% and adding serum lipase increases the sensitivity to 94%. However, amylase levels do not correlate with disease severity. The treatment of pancreatitis in pregnancy should be conservative as far as possible with delaying the

definitive treatment until after delivery. Management includes nil orally, nasogastric aspiration, intravenous fluids, antispasmodics, antibiotics and total parenteral nutrition. Endoscopic sphincterotomy with fetal shielding with the help of a lead apron may be helpful in treating a gallstone-induced pancreatitis. The second trimester is thought to be the ideal time for endoscopic sphincterotomy to avoid any possible teratogenic effects of radiation. Fetus monitoring should be strictly done during the course of this treatment. The second trimester is also the optimum time for the patient to undergo any surgical intervention. Cholecystectomy after endoscopic sphincterotomy should be considered in gallstones induced pancreatitis in pregnancy with recurrent attacks. It is advisable to wait rather than undertake any surgical intervention until delivery, if the patient develops uncomplicated pancreatitis in the third trimester of pregnancy. Complications such as pseudocysts should be surgically managed in the post partum period. Suggested Reading 1.

Ko C. Biliary sludge and acute pancreatitis during pregnancy. Nat Clin Pract Gastroenterol Hepatol 2006;3(1):53-7; quiz following 57.

2.

Hallberg P, Hallberg E, Amini H. Acute pancreatitis following medical abortion: case report. BMC Womenâ&#x20AC;&#x2122;s Health 2004;4:1.

3.

Pitchumoni CS, Yegneswaran B. Acute pancreatitis in pregnancy. World J Gastroenterol 2009;15(45):5641-6.

4.

Tang SJ, Rodriguez-Frias E, Singh S, Mayo MJ, Jazrawi SF, et al. Acute pancreatitis during pregnancy. Clin Gastroenterol Hepatol 2010;8(1):85-90.

5.

Hernandez A, Petrov MS, Brooks DC, Banks PA, Ashley SW, Tavakkolizadeh A. Acute pancreatitis and pregnancy: a 10-year single center experience. J Gastrointest Surg 2007;11(12):1623-7.

...Contâ&#x20AC;&#x2122;d from page 230 26. Emacker PNM, Hifmans AGM. Estimation of HDL cholesterol by enzymatic method. Clin Chem 1980;26(13):1775-80. 27. Bongaerts GP, Severijnen RS, Tangerman A, Verrips A, Tolboom JJ. Bile acid deconjugation by Lactobacilli and its effects in patients with a short small bowel. J Gastroenterol 2000;35(11):801-4. 28. Walker DK, Gilliland SE. Relationship among bile tolerance, bile salt deconjugation, and assimilation of cholesterol by Lactobacillus acidophilus. J Dairy Sci 1993;76(4):956-61. 29. El-Sawah MM, Sherief AA, Bayoumy SM. Enzymatic properties of lipase and characteristics production by

232

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

Lactobacillus delbrueckii subsp. bulgaricus. Antonie Van Leeuwenhoek 1995;67(4):357-62. 30. Fukushima M, Nakano M. Effects of a mixture of organisms, Lactobacillus acidophilus or Streptococcus faecalis on cholesterol metabolism in rats fed on a fat- and cholesterol-enriched diet. Br J Nutr 1996;76(6):857-67. 31. Kiessling G, Schneider J, Jahreis G. Long-term consumption of fermented dairy products over 6 months increases HDL cholesterol. Eur J Clin Nutr 2002;56(9):843-9. 32. Mohan JC, Arora R, Khalilullah M. Preliminary observations on effect of Lactobacillus sporogenes on serum lipid levels in hypercholesterolemic patients. Indian J Med Res 1990;92:431-2.


medilaw

Should a Physician Treat another Physician Free? DM Singh

Q. In my opinion, a physician should treat another physician free. If a physician charges for his/ her services despite you identifying as a fellow physician then the payment receipt must be sent to the Medical Council along with a complaint to take necessary action against the offending doctor however senior he or she may be. Do you agree?

Ans. I do not agree for the following reasons: 

There is no law that a physician should treat another physician free. The MCI Code of Ethics Regulations, 2002, merely state as follows: “4.1. RESPONSIBILITIES OF PHYSICIANS TO EACH OTHER––A physician should consider it as a pleasure and privilege to render gratuitous service to all physicians and their immediate family dependants.” The above regulation is not mandatory. The behavior prescribed is optional on the part of the physician concerned and depends upon whether or not the individual concerned considers it as a pleasure and privilege to render gratuitous service. Such behavior cannot be enforced by law in the absence of a law.

In the circumstances, the medical council has no business to entertain the complaint or to hold that the physician concerned breached the regulations by charging fees or to punish him for the same. The complaint is likely to fail. I suggest that if you doubt my opinion, you may consider sending such a complaint against a physician to the state medical council concerned. If at all the SMC holds the doctor guilty, I will defend him free of cost by filing an appeal before the MCI and, in the unlikely situation that the appeal fails, I will file a WP in the HC against the MCI free of cost. Please also consider the fact that if a physician provides free service to a fellow physician, this in no way prevents the latter from filing a consumer complaint, police complaint and medical council complaint against the treating physician. Please appreciate that the highest amount of compensation awarded so far against a physician was in a case where another physician’s wife was the patient. Dr Kunal Saha got ` 1.7 crore for the death of his wife because of wrong treatment by another doctor. BTW, I admire Dr Saha for the perseverance in exposing the medical negligence in this case and going upto the SC.

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

233


lighter reading

Human Value

A Horoscope for The Workplace

Life is full of ups and downs. It is easy to lose hope and confidence. This little story helps us to realize that no matter what happens, we remain valuable as individuals. A well known speaker started off his seminar by holding up a $20 bill. In the room of 200, he asked, “Who would like this $20 bill?” Hands started going up.

Laugh a While

An Inspirational Story

Lighter Side of Medicine

He said, “I am going to give this $20 to one of you but first, let me do this.” He proceeded to crumple the dollar bill up. He then asked, “Who still wants it?” Still the hands were up in the air.

“My friends, no matter what I did to the money, you still wanted it because it did not decrease in value. It was still worth $20. Many times in our lives, we are dropped, crumpled, and ground into the dirt by the decisions we make and the circumstances that come our way. We feel as though we are worthless. But no matter what has happened or what will happen, you will never lose your value. You are special – Don’t ever forget it!”

—Dr GM Singh

“Idleness is an inlet to disorder, and makes way for licentiousness. People that have nothing to do are quickly tired of their own company.” —Jeremy Collier

Quotes

“Well,” he replied, “What if I do this?” And he dropped it on the ground and started to grind it into the floor with his shoe. He picked it up, now all crumpled and dirty. “Now who still wants it?” Still the hands went into the air.

Middle Management/Department Management/ ”Team Leads” Catty, cut-throat, yet completely spineless, you are destined to remain at your current job for the rest of your life. Unable to make a single decision you tend to measure your worth by the number of meetings you can schedule for yourself. Best suited to marry other “Middle Managers,” as everyone in your social circle is a “Middle Manager.”

“No task is more difficult than systematic hypocrisy.” —Edward George

“If you have zest and enthusiasm you attract zest and enthusiasm. Life does give back in kind.” —Norman Vincent Peale

Dr. Good & Dr. Bad Situation:

A patient came with an eGFR of 15.

—Ms Ritu Sinha

ILLUSION

Hold till proper investigations are done

©IJCP Academy

Go for immediate dialysis

Lesson:

A study published in December 2010 in the Canada Medical Association Journal shows that starting dialysis too soon may increase the risk of death. Dr KK Aggarwal

234

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012


Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767). Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so. The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript. Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper. Covering letter –

– –

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper. Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors. Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript – Three complete sets of the manuscript should be submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures). –

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

All pages should be numbered consecutively beginning with the title page.

departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used. – The title should be of no more than 80 characters and should represent the major theme of the manuscript. A subtitle can be added if necessary. – A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included. – The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page. – A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text. Summary – The summary of not more than 200 words. It must convey the essential features of the paper. – It should not contain abbreviations, footnotes or references. Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives. Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others. – Ethical guidelines followed by the investigations should be described. Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected. – Method of selecting the sample (cases, subjects, etc. from the statistical universe). – Method of allocating the subjects into different groups. – Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the

Confidence intervals for the measurements should be provided wherever appropriate.

Results These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

237


Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution. Examples of common forms of references are: Articles

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat. – All photomicrographs should indicate the magnification of the print. – Special features should be indicated by arrows or letters which contrast with the background. – The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen. – Color illustrations will be accepted if they make a contribution to the understanding of the article. –

Do not use clips/staples on photographs and artwork.

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected

Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes. Q. J. Expt. Physiol. 1955;40:89-111.

2. Total number of pages ________________________

Books

5. Special requests _____________________________

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

6. Suggestions for reviewers (name and postal address)

Articles in Books

2.____________

2._ _______________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________

3._ _______________

4.____________

4._ _______________

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends – These should be typed double spaces on a separate sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text. –

238

The legend must include enough information to permit interpretation of the figure without reference to the text.

Indian Journal of Clinical Practice, Vol. 23, No. 4, September 2012

summary, etc.)_______________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Indian 1.____________Foreign 1._ _______________

7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e- Issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal

Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash, Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com



IJCP_September