[PHuture 2021 - Volume 24]

IPSF- Volume 24

2021

Phuture A Scientific / Educational Publication of IPSF

Editorial Board

Editorial Team DesigningTeam

Tomás Oliveira - PEN and Phuture Editor 2020-2021

Hamsa Hassan - PEN and Phuture Editor 2021-2022

Jyotshana Pokharel - Chairperson of Media and Publications 2021-2022 Mauricio Abel Miranda - Visual and Creativity Committee 2021-2022

Supervising Proofreading Team Team

João Guedes - President 2020-2021

Oussama Madadi - President-Elect 2020-2021

Karima Bennara - Chairperson for Pharmacy Education 2020-2021

Kenneth Bitrus David - Editorial and Translation Coordinator 2020-2021

Phuture 2021

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Letter from the Editor Dear reader, Welcome to the 24th edition of Phuture!

Phuture is the annual scientific publication from the International Pharmaceutical Students’ Federation (IPSF), aimed at promoting research by providing a platform for students and recent graduates to publish research articles, reviews, and abstracts.

On account of the increasing awareness and concern of the human’s impact on Nature, this year’s edition intends to demonstrate the potential that natural products still have in store for us and the necessity to perform more well-design studies to confirm their efficacy and safety (Natural Products in Drug Discovery), to identify some of the emerging environmental pollutants, their impacts on ecosystems, and the strategies to transform/eliminate them (Environmental Contamination, Toxicology, and Remediation), to manipulate living-organism in a responsible manner (Genetically Modified Organisms), and to find reliable alternatives to animal-based testing (New In Vitro Models).

Nature and Science in Harmony - is a necessary balance that we must achieve and researchers have a special role in order to make this achievement possible.

I would like to thank those who participated in the making of this publication, from proofreading, to designing, to supervising. A greater appreciation for the authors who submitted their articles - they are the ones who make this publication possible in the first place.

Apart from the central theme, you may find a Bonus

Viva la Pharmacie!

Section at the end, dedicated to Young Researchers Forum Regional Working Group Papers of 2020 and the winner of EuRO’s Literature Review Competition.

Tomás Oliveira IPSF PEN & Phuture Editor 2020-2021

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Table of Contents

05

Natural Products in Drug Discovery Natural Products in Drug Discovery

08

Phytotherapy

11

Powerful Plant Products Could Be Used in Drug Discovery

13

Diabetes and Medicinal Plants

16

Potential Plants Combinations of Bajakah (Spatholobus suberectus Dunn) and Sungkai (Peronema canescens Jack) Against Coronavirus

Environmental Contamination, Toxicology, and Remediation

19

Pharmaceutical Products in Water

21

The Health Effects of The Plastic Era

23

Bioaccumulation and Distribution of "Forever Chemicals"

Genetically Modified Organisms

25

Genetically Modified Organisms and Their Role in the Environment

28

Brief Approaches on How Genetically Modified Organisms Affected Our Life

New In Vitro Models

30

New in vitro Model (Organ-on-a-chip of the Heart)

Bonus section

34

Climate Change’s Impact on Our Health: How Nature Links to Allergic Respiratory Diseases

37

A Review of the Impact of Climate Change on Human Health and Drugs

44

A Review of the Extent and Strategies for Substandard and Falsified Medicines

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NATURAL PRODUCTS IN DRUG DISCOVERY Noura Mohamed 1 1- EPSF, Egypt | Zagazig University 1- Introduction

Dear Reader,

The Chinese Materia Medica - Shennong Herbal - and Tang Herbal have

Natural products have been used since ancient times throughout history. They have been an important aspect of the traditions of many cultures. Over the ages, many drugs were discovered from natural sources that have made a breakthrough in the pharmaceutical field, starting from antibiotics, anticancer, and

also documented many records of the natural products uses. In ancient Greece, natural products were widely used, with records from Dioscorides - greek physician that wrote Historia Plantarum - and Theophrastus greek philosopher and natural scientist that wrote De materia medica writing about plant’s collection, storage, and usage of medicinal herbs.1,2

antidiabetic drugs. It is stated that a large scale of the approved drugs nowadays is from natural sources. Compared to synthetic drugs, they have a large diversity and complexity, allowing them to be leading in drug discovery. Despite all these advantages and progress, we face many challenges when using them in drug discovery, which have been highlighted in this article.

The use of natural products has not only been used by scientists and physicians over the ages as a medicinal source to treat different diseases but they also have been involved in folklore as traditional medicines. This wide use of natural products is a result of human trials for thousands of years to find sources of food and medicine for survival. There are many examples of natural products used as traditional remedies in different

2- Historical background

cultures, such as the genus Salvia, which exists in southwestern the USA and northwestern Mexico. It was used as an aid for childbirth as male newborn babies were put in the hot Savia ashes, as a belief that these

Over the ages, humanity has greatly depended on nature to get its basic needs (food, clothes, shelter, and medicines).1 Historically, natural products have been widely used for different purposes and have been implemented in folklore since ancient times. They have been the most successful and the best sources of drugs to treat

plants would help babies consistently grow to be the strongest and healthiest members of their tribes and to have immunity to all respiratory ailments for life. Ligusticum scoticum is a plant found in Northern Europe and Eastern North America and was believed to protect the person from daily infection when eaten in the morning.1,2

different diseases and have continued to provide unique structural diversity in comparison to combinatorial chemistry.2 Multiple evidence and records confirm the importance of natural products throughout the ancient ages. Hundreds of clay tablets in cuneiform from Mesopotamia had recorded approximately 1000 plants used for medical purposes, such as Cupressus sempervirens (cypress), Glycyrrhiza glabra (liquorice), and Commiphora spp. (myrrh). Those plants are still used for cough, infections, cold, and inflammation.1,2 Ebers Papyrus, the Egyptian pharmaceutical record, documented more than 700 medical plants that were used as drugs in Egyptian history, ranging from pills, infusion, gargles, to

Apart from plants, also other sources of natural products were used throughout history. They include compounds from plants, microbes (daptomycin), and animals (exenatide and ziconotide), as well as synthetic or semi-synthetic compounds based on natural products (e.g. tigecycline, everolimus, telithromycin, micafungin, and caspofungin).2,6 They have covered a wide range of therapeutic indications (anti-cancer, anti-infective, anti-diabetic), and show a great diversity of fungus, bacterial, marine and algae sources.2,6 Micro and macrofungi have been widely involved in human life for centuries, as Fomitopsis betulina from fungus sources have been used as antiseptic and disinfectants.

ointments.

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The red algae Mastocarpus stellatus and Chondrus crispus were

They show special features in comparison with conventional

well-known as a folk cure for colds, chest infections, sore throat,

synthetic molecules, which is a “double-edged sword”, having both

and tuberculosis.2

advantages and challenges for the drug discovery process. They also

3- Natural products in drug discovery

have a higher molecular mass, a larger number of tetrahedral carbon atoms and oxygen, higher numbers of H-bond acceptors and donors,

Plant-based systems have played an essential role in health care

and greater molecular rigidity in comparison with synthetic

especially during the great advance of science and technology

compounds.5 Natural products are also considered to be a major

nowadays. Based on statistics made in the USA between 1959 and

source of oral drugs. They serve particular biological functions,

1980, community pharmacies in the USA stated that 25% of the

including regulation of endogenous defence mechanisms within the

prescribed drugs were plant extracts or their active ingredients

body, which explains their high efficiency for infectious diseases and

were derived from plant sources.1 Today, about a quarter of the

cancer. Furthermore, they have provided insights regarding efficacy

approved drugs by the Food and Drug Administration (FDA) and

Dear Reader,

and safety, as they were the baseline of traditional medicine. Natural

European Medical Center (EMA) are plant-based. Drug discovery

products are considered a precious treasure enriched with bioactive

from natural sources has greatly revolutionized medicine

compounds covering a wider area compared with synthetic small-

nowadays.

molecule drugs.5

Tetracycline

from

Streptomyces

aureofaciens,

doxorubicin from Streptomyces peucetius, artemisinin from Artemisia afra, and cyclosporin from Tolypocladium inflatum have made a great impact on healthcare.3

4- The advantages of natural products in drug discovery

5- Challenges of using natural products in drug discovery Despite all these advantages and the successful examples in drug discovery, natural products have faced multiple drawbacks that led pharmaceutical companies to reduce natural product drug discovery

Natural products are believed to remain an essential part of

programs.5,6 Natural products screens may involve a large library of

research and development for new, safe, and economical

extracts from different sources, which may not be compatible with

medications. They have a wide structural and chemical diversity, as

traditional target-based assays. Identifying the bioactive compounds

about 40% of the chemical scaffolds that exist in natural products

of interest can be challenging and needs dereplication tools to avoid

are absent in medicinal chemistry nowadays, and that is one of the

the rediscovery of already discovered compounds.5 Getting

reasons for their historical success in drug discovery. Biosynthesis

intellectual property rights for discovery can be an obstacle as

of natural products involves repeated interaction with different

naturally occurring compounds in their original form can not always

enzymes, so the ability of natural products to interact with other

be patented, however, simple derivatives can be patent-protected.

molecules to make an effective drug might be considered

Despite the complexity of natural product structures can be

biologically validated. Many natural products exhibit advanced

advantageous, the generation of structural analogues to study and

binding characteristics compared with synthetics. Nowadays, in

explore structure-activity relationships (SAR) can be challenging,

industrialized nations, about 50% of all prescribed drugs are

especially if the synthetic routes are difficult.5,6

derived or synthesized from natural products, the only available sources for it are animals, plants, and microorganisms. That’s because their constituents’ structural and biological adversity offers a renewable resource for discovering new drugs and biological entities 4 Natural products have played a key role in drug discovery for hundreds of years, especially for cancer and infectious diseases and also in other therapeutic areas, including cardiovascular diseases, such as using statins.

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6- Conclusion The importance of natural products in medicine has been great for centuries, from traditional to industrial uses. They have been implemented in drug discovery for decades, however, there are some challenges and obstacles that hinder their usage, which led the pharmaceutical companies to reduce drug discovery programs based on natural products. On the other hand, many promising drug candidates in the current development are of natural origin.

Technical drawbacks related to natural product research have been decreased, and there have been better opportunities to explore

Dear Reader,

the biological activity of the previously inaccessible sources of natural products, with the increasing acceptance that the chemical diversity of natural products is well suited to provide the core scaffolds for future drugs.6

References 1. Newman, David J., Gordon M. Cragg, and Kenneth M. Snader. "The influence of natural products upon drug discovery." Natural product reports 17.3 (2000): 215-234.

2. Dias, Daniel A., Sylvia Urban, and Ute Roessner. "A historical overview of natural products in drug discovery." Metabolites 2.2 (2012): 303-336.

3. Thomford, Nicholas Ekow, et al. "Natural products for drug discovery in the 21st century: Innovations for novel drug discovery." International journal of molecular sciences 19.6 (2018): 1578.

4. Lahlou, Mouhssen. "The success of natural products in drug discovery." (2013).

5. Atanasov, Atanas G., et al. "Natural products in drug discovery: Advances and opportunities." Nature Reviews Drug Discovery (2021): 1-17.

6. Harvey, Alan L. "Natural products in drug discovery."

Drug discovery today 13.19-20 (2008): 894-901.

Phuture 2021

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PHYTOTHERAPY

Souheib Kirat 1 1- ASEPA, Algeria | Faculty of Medicine of Algiers 3- Examples

1- Introduction

Dear Reader,

Cancer: Green tea extract 2,3,4 Green tea and green tea extracts are widely consumed by patients with

Over the years, we have witnessed the development of a wide

cancer. Yet, overall, there is no proper evidence that green tea or its

variety of drugs that treat a vast and diverse array of diseases,

chemical components slow tumor progression in humans. Conversely,

ensuring the availability of a cure to most pathologies, including

there is some evidence that green tea compounds might interfere with

the rarest and deadliest ones.

anticancer treatment.

Nevertheless, while we praise the advances of modern medicine,

However, some clinical tests prove the effectiveness of green tea in

let us not forget nor neglect the basis and origin of therapeutics -

anticancer treatment since it has been found that green tea polyphenols

traditional medicine, more specifically “phytotherapy”. This

(GTPs) exhibit anticancer effects via the regulation of different cancer-

mysterious therapeutic field has been the subject of numerous

related processes and factors, including DNA methylation, histone

studies, and researchers across the years have been debating its

modification, micro-RNA and proteins regulation. They also play an

utility and value. This article hopes to allow its readers to “unwind

important role in the regulation of apoptosis, growth, invasion, and

the veil” that covers this perplexing mystery.

angiogenesis in various types of malignancies. A recent study showed that GTPs can influence the pathological roles of not only cancer cells,

2- What is Phytotherapy?

but also cancer stem cells. These findings have led to a hypothesis that GTPs have strong anticancer effects in vivo and in vitro.

Phytotherapy is essentially the use of plants to treat the body, facilitating the healing process within the framework of holistic medicine. It is considered both a science and an art, and it includes a vast variety of areas of study. We often associate it with many

Systematic reviews and meta-analyses that pool data from epidemiologic and available clinical trials found possible associations between high levels of green tea consumption (7 cups per day) and reduced risks of prostate, liver, and endometrial cancer. Also, a study conducted in Japan indicated an inverse correlation between green tea consumption and

terms, such as:

prostate cancer (PC) risk, although it did not reach the level of

Herbalism: the study of pharmacognosy and the use of

increasing the frequency, duration, and quantity of green tea

medicinal plants in traditional medicine.

Herb (many definitions exist but we will use the most common one): any type of plant, especially the aromatic ones

consumption could lead to a lower risk of PC. In this study, a hospitalbased 1:2 case-control design (130 cases and 274 hospital controls) was used to investigate the association between green tea consumption and

used in medicine or seasoning.

Holistic medicine: a whole-body approach to healthcare, aiming towards the improvement of health and wellness through the body, mind, and soul, usually combining traditional and alternative medicine.

significance. Conversely, another case-control study in China showed that

PC. Patients whose treatment regimens include bortezomib or radiotherapy should avoid green tea, and all patients with cancer should inform their care team if they are consuming green tea or green tea supplements, as well as any other herbal supplements. It might have some benefits in preventing or curing cancer but it can cause harm if not consumed with caution.

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Cognitive impairment: Ginkgo biloba Clinical studies on the treatment of Alzheimer's disease with Ginkgo biloba leaf extract have been reported since the 1980s, and many clinical studies have been carried out during the following 30 years. However, the benefits of G. biloba on the treatment of Alzheimer's are still controversial.

In 2001, 26 healthy young females and 24 healthy young males were enrolled in a 30-day clinical trial. Then the subjects were assessed on the

Depression: St. John's Wort (Hypericum perforatum)

neuropsychological tests. The tests included the Digit Symbol Substitution Test (DSST), Speed of Comprehension Test (SCT), Symbol Digit Modalities Test (SDMT), Digit Span Test (DST), Trail Making Test (TMT), Rey Auditory

Dear Reader,

Verbal Learning Test (AVLT), Inspection Time (IT), Digit Span Backwards

Hypericum perforatum has made a career as one of the most

Test (DSBT), Working Memory Speed Test (WMST). The validated battery of

prominent and best investigated medical plants during the last

tests was employed to evaluate attention, memory, and work

two decades, with the focus of interest being on its potential as a

performance. The results indicate that DSBT, WMST, and AVLT were

herbal antidepressant. Many other external applications of H.

improved in participants after administration, but the effect was not

perforatum are listed in scientific and popular literature (e.g.

observed on any of the other tests.

smaller wounds, sunburns, blunt traumata, ulcers, varicose,

In 2002, Kennedy and Scholey collaborated on two clinical trials. In

hemorrhoids).

Kennedy’s research, 20 healthy young volunteers received G. biloba, Panax

Several interesting data have been reported about the

ginseng, G. biloba combined with P. ginseng, or placebo. The Cognitive

antidepressant properties of H. perforatum in clinical trials with

Drug Research (CDR) computerized assessment battery and cognitive

different designs. In particular, several antidepressant-controlled

outcome factors were used for evaluating cognitive function. For CDR

trials demonstrated that H. perforatum and its active ingredients -

battery, a statistical difference was only observed in immediate word

hypericin and hyperforin - possess antidepressant properties

recall, numeric working memory, delayed word recalls, and picture

similar to those of tricyclic antidepressants and selective serotonin

recognition reaction time at 6h after administration. Furthermore, the

reuptake inhibitors but with fewer and milder side effects. Anti-

quality of memory and serial 7s responses was improved at 6h after

inflammatory, antimicrobial, and anticancer mechanisms as well as

administration. However, other test items had no statistical difference

stimulation of tissue growth and differentiation have been

between the G. biloba group and placebo. In Scholey’s research, the

reported for these compounds, suggesting a potential benefit of

dosage of G. biloba was adjusted to 120, 240, and 360mg. In the Serial

using this old medicinal plant in skin diseases (e.g. atopic

Threes Task, a statistical difference was only observed in the G. biloba

dermatitis, psoriasis, herpes infections) and skincare.

group at 4h after administration. There was no effect on the Serial Seven

St. John's Wort may exert potent antidepressant effects and

Task at any time point after oral administration. As was shown, using G.

represents an efficacious and safe treatment. However, the current

biloba to treat a plethora of mental illnesses is possible. However, it is not

clinical evidence regarding the efficacy of H. perforatum in other

a miracle worker while there has been a noticeable improvement and

psychiatric and neurodegenerative disorders is not sufficient to

mostly positive results it remains a solution that needs further

draw robust conclusions.

development.

Phuture 2021

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4- Phytotherapy and health systems

6- Conclusion

The usage of phototherapy is different from one country to

We can assume that herbal medicine still has a place in the health

another. For example, South Korea and Japan have fully integrated

department but we must stay alert to the side effects that they may

it into their health insurance coverage. Meanwhile, China, India,

produce while also keeping our doctors in light of what treatment we are

and Nepal placed this field into the traditional medicine services

undertaking.

with the addition of health care coverage.

However, most countries do not fall under the same wavelength of what was previously mentioned, or in simple terms, they do not give any sort of significant attention to herbal treatments. Herbs are much rather a patient’s private choice, and they often are sold

Dear Reader,

as over-the-counter products, though these products may be recommended or prescribed by a wide range of health care practitioners, including general practitioners and naturopathic doctors.

References 1. Hoffman, D. Medical Herbalism: The Science and Practice of Herbal Medicine. Chapter one. 2003.

2. Green Tea and Cancer (cancertherapyadvisor.com) 3. Miyata Y, Matsuo T, Araki K, et al. (2018) Anticancer Effects of Green Tea and the Underlying Molecular Mechanisms in Bladder Cancer.

Medicines (Basel). 2018;5(3):87. doi:10.3390/medicines5030087 4. Miyata Y, Shida Y, Hakariya T, Sakai H. (2019) Anti-Cancer Effects of

5- Health precautions

Green Tea Polyphenols Against Prostate Cancer. Molecules.

2019;24(1):193. doi:10.3390/molecules24010193

Nowadays, phytotherapy is still being used by practically everyone,

5. Wölfle U, Seelinger G, Schempp CM. Topical application of St. John's

mainly due to its diversity of formulations (e.g. lotions, oils, creams,

wort (Hypericum perforatum). Planta Med. 2014 Feb;80(2-3):109-20.

syrups)

doi: 10.1055/s-0033-1351019. Epub 2013 Nov 8. PMID: 24214835

and

usability

(e.g.

skincare,

cancer

treatment,

psychotherapy). However, its validity is still being questioned:

6. Zirak N, Shafiee M, Soltani G, Mirzaei M, Sahebkar A. Hypericum

many arguments limit the general use of herbal treatments, mainly

perforatum in the treatment of psychiatric and neurodegenerative

that there is a lack of actual scientific evidence backing its success

disorders: Current evidence and potential mechanisms of action. J Cell

rate. Also, proof of the possible and highly dangerous toxicity of

Physiol. 2019 Jun;234(6):8496-8508. doi: 10.1002/jcp.27781. Epub

some plants made it quite difficult to gain access to them. For

2018 Nov 21. PMID: 30461013

example, we can mention oleander (Nerium oleander), which is

7. Liu H, Ye M, Guo H. (2020) An Updated Review of Randomized Clinical

known to cause dermatitis.

Trials Testing the Improvement of Cognitive Function of Ginkgo

Generally speaking, herbs can be taken in conjunction with

biloba Extract in Healthy People and Alzheimer's Patients. Front

prescribed drugs. However, this practice must be under

Pharmacol. 2020;10:1688. doi:10.3389/fphar.2019.01688

supervision from a specialist, since not all plants mix well with

Edition. Elsevier. 2012.

normal medications.

A study done on close to 50 patients found that certain herbals (e.g. flaxseed, cranberry, goji berry, chamomile, green tea) can interact with some cardiovascular drugs, promoting bleedingrelated adverse events. While others can even worsen depression (e.g. celery root, mentat).

8. Heinrich, M. Fundamentals of Pharmacognosy and Phytotherapy. 3rd 9. Nelson, Lewis S., and Balick, Michael J. Handbook Of Poisonous and Injurious Plants. 3rd Edition. Springer US. 2020.

10. Herbal Medications and Prescription Drugs Don’t Always Mix (healthline.com) Images taken from the following links: Ginkgo Biloba, Green tea, and Hypericum perforatum. Accessed on July 9th, 2021.

Phuture 2021

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POWERFUL PLANT PRODUCTS COULD BE USED IN DRUG DISCOVERY

Kirollous Raafat 1 1- EPSF, Egypt | Misr University for Science and Technology 1- Introduction

Dear Reader,

Anti-depressants Lucio Recardo et al. found that cinnamic acid found in kiwis and cherries

Plants were used in ancient times in relieving symptoms without knowing

the

active

ingredient.

Now,

with

modern

extraction/isolation techniques and modern imaging techniques, especially NMR and mass spectroscopy, we are able to study the

cause antidepressant effects in tested animals, whereas its analogues ferulic and caffeic acid - were found to decrease the immobility of the tested animals and promote sucrose intake, owing to their action in reducing the oxidative stress in the central nervous system.3 In an experimental study by Weerawan et al. on mice by using a test

structure and the function of active ingredients.

These plant-originated active ingredients can be powerful and, when compared to synthetic drugs, tend to have fewer side effects.

They are widely used for their strong ingredients such as antidepressant, antioxidant, antibacterial, antiviral, anti-inflammatory,

called forced swimming test, they found that the alcohol-induced depression in those mice was decreased when giving those mice Panax ginseng extract G115, due to its activity in increasing the brain-derived neurotrophic factor (BDNF) that was decreased on using alcohol.4

and antifatigue agents, while they also contribute to our future in drug discovery. This article will talk about some traditional plants

Osteoporosis treatment

and healing plants to our brain and a plant with a healing property

A review article by M. Martiniakova et al. reviewed that genistein and

to our microbial gut.

daidzein found in soya beans act by inducing osteoclasts’ apoptosis and, in the case of genistein, promoting osteoblasts’ differentiation and

2- Active ingredients treating different diseases Antimicrobials Basil has two major components - linalool and estragole - which show its antimicrobial activity. However, thyme and oregano show more antimicrobial effects owing to their more powerful ingredients - carvacrol and thymol. They show a strong antibacterial

effect

against

E.

coli,

Staphylococcus,

and

Campylobacter.1 A review article by John et al. demonstrates that

maturation.5

Microbial gut boosters Scazzocchio et al. in their review article revealed that curcumin favours the growth of the beneficial microbial gut, associated with a better defence and metabolism. It was also found that curcumin enhances the intestinal barrier.6

3- “Three Kings”

cannabis also has antimicrobial and anti-biofilm activities against methicillin-resistant Staphylococcus aureus (MRSA), which can be

Ginkgo biloba

used as a preservative because of its cannabinoids as cannabidiolic

M. Martiniakova et al., in their review article on osteoporosis, conducted

acid and ∆9-tetrahydrocannabinol (THC).2

many studies about G. biloba and its effect on the bone: on some animal trials, they found that it improves the osteoblasts’ formation and decreases the bone loss due to its phytoestrogens - quercetin and kaempferol - that now become an available source for the treatment of osteoporosis.5

Phuture 2021

11

Another review article by Franziska Pohl et al. found that,

Ginsenosides can reduce the level of the Beta-amyloid protein in the brain

according

in

(linked to Alzheimer’s progression).11,12 In a study, P. Ginseng was found to

neurodegenerative diseases, G. biloba extract had improved the

have an antifatigue property on some tested mice.11 All that sounds great,

cognitive ability and stabilized it; that was attributed to its two

but still can cause abnormalities, like atrial fibrillation and hypertensive

ingredients which are ginkgolide and bilobalide.7

crisis, and must be cautioned in case of pregnant women.11

Nan Mei et al. in their review article found that G. biloba has a

4- Conclusion

to

some

clinical

trials

they

reviewed

conduction ability in the blood circulation and acts as a powerful

This article exhibited just a few examples that demonstrate plants with

antioxidant, but it was reported that G. biloba extract has an

active substances that can be used in the treatment of all sorts of illnesses.

interaction and induction of the CYP enzymes, so it should not be

There is a need to include plants in drug-designed studies, especially

taken with many drugs. It was reported that G. biloba may have an

because plant-based medicines tend to have fewer side effects.

anti-platelet activity and can induce hepatocellular carcinoma in

Dear Reader,

some rodents, cardiovascular toxicity, and immunotoxin effect (in long-term use).9

References 1. Sakkas H, Papadopoulou C. Antimicrobial activity of basil, oregano, and thyme essential

oils.

J

Microbiol

Biotechnol.

2017;27(3):429-438.

doi:10.4014/jmb.1608.08024

Psidium guajava P. guajava has quercetin and kaempferol (already mentioned above in G. biloba) in treating osteoporosis. In their review, Sumra Naseer et al. found that the flavonoid compounds of P. guajava have anti-microbial properties, especially the methanolic extract. P.

2. Karas JA, Wong LJM, Paulin OKA, et al. The antimicrobial activity of cannabinoids. Antibiotics. 2020;9(7):1-10. doi:10.3390/antibiotics9070406 3. Diniz LRL, Souza MT de S, Barboza JN, Almeida RN de, Sousa DP de.

Antidepressant Potential of Cinnamic Acids: Drug Development. Molecules.

2019;24(4):1-12.

guajava extract can boost immunity and reduces inflammation by

4. Boonlert W, Benya-Aphikul H, Welbat JU, Rodsiri R. Ginseng extract G115

reducing the tumour necrosis factor (TNF). Gallic acid, kaempferol,

attenuates ethanol-induced depression in mice by increasing brain BDNF levels.

galangin, and homogentisic acid in combination can boost the

Nutrients. 2017;9(9):1-9. doi:10.3390/nu9090931

defence and be anti-viral and anti-cancerous agents. Also, the

5. Martiniakova M, Babikova M, Omelka R. Pharmacological agents and natural

great content of vitamin C and other antioxidant agents can

compounds: Available treatments for osteoporosis. J Physiol Pharmacol.

2020;71(3):1-14. doi:10.26402/jpp.2020.3.01

empower the brain.10

6. Scazzocchio B, Minghetti L, D’archivio M. Interaction between gut microbiota and curcumin: A new key of understanding for the health effects of curcumin.

Panax Ginseng P. Ginseng can attribute to relieve the induced ethanol depression

Nutrients. 2020;12(9):1-18. doi:10.3390/nu12092499 7. Pohl F, Lin PKT. The potential use of plant natural products and plant extracts

of mice. The free radicals from smoking, radiation, and alcohol can

with antioxidant properties for the prevention/treatment of neurodegenerative

cause many severe diseases to our brain, ear, and eye. A review

diseases: In vitro, in vivo and clinical trials. Molecules. 2018;23(12).

article by Zubair Ahmed et al. found that P. Ginseng reduces free

doi:10.3390/molecules23123283

radicals and there was an increase in the indigenous antioxidants.

8. Bungau S, Abdel-Daim MM, Tit DM, et al. Health Benefits of Polyphenols and

They reviewed that ginsenosides from P. Ginseng decrease TNF

Carotenoids in Age-Related Eye Diseases. Oxid Med Cell Longev. 2019;2019.

and inhibit the macrophage-derived cytokine causing antiinflammatory effects, meaning that it may contribute to the brain’s

doi:10.1155/2019/9783429 9. Nan Mei. Review of Ginkgo biloba-induced toxicity, from experimental studies to human case reports. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev.

endurance.11 From many clinical trials, P. Ginseng seems to have antiviral (e.g. coxsackievirus B3, enterovirus 71, human rhinovirus 3) and antibiotic (e.g. Clostridium perfringens, Cryptococcus neoformans) activity.11

2017 January 02; 35(1): 1–28. doi: 10.1080/10590501.2016.1278298.

10. Naseer S, Hussain S, Naeem N, Pervaiz M, Rahman M. The phytochemistry and medicinal value of Psidium guajava (guava). Clin Phytoscience. 2018;4(1). doi:10.1186/s40816-018-0093-8 11. Ratan ZA, Haidere MF, Hong YH, et al. Pharmacological potential of ginseng and its major component ginsenosides. J Ginseng Res. 2021;45(2):199-210. Doi:

A clinical study in the review of Zubair et al. promoted that P. Ginseng regulates blood glucose levels in diabetic patients. It can increase blood circulation and stimulate nitric oxide production.

10.1016/j.jgr.2020.02.004 12. Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer’s disease:

A

new

lexicon.

Lancet

Neurol.

2010;9(11):1118-1127.

doi:10.1016/S1474-4422(10)70223-4

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12

DIABETES AND MEDICINAL PLANTS Maria Mohammed Halimeh 1 1- EPSF, Egypt | Cairo University 1- Background on Diabetes

Dear Reader,

Diabetes mellitus (DM) is a metabolic disease that is characterized by high blood glucose levels. The insulin hormone is the key regulator of blood glucose levels inside the body. It helps the body utilize glucose and prevents hepatic glucose production. A high blood glucose level is due to either a deficiency in insulin production or an inability of the body tissues to be sensitive to the presence of insulin. This is called insulin resistance.1 DM is classified into three types: type 1, type 2, and gestational diabetes. Emphasis is placed on the first two types of diabetes. For instance, in type 1 diabetes, there is a destruction of islets beta cells of the pancreases, which results in absence of insulin. However, type 2 diabetes - which is more common - is a result of deficiency of insulin production or insulin resistance. This means that, despite the presence of insulin, the body does not respond to it.

Uncontrolled DM leads to long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels.2,3

2- Why Medicinal Plants?

Antidiabetic drugs from natural origin have always played a major role in the treatment of diabetes type 2 since the early centuries.

This is due to its few side effects compared with synthetic antidiabetics, as synthetic drugs may have many undesirable adverse effects, such as hypoglycemia, coma, and weight gain.4 Using plant-derived compounds has the advantages of being accessible, needing less industrial equipment, and being effective and safe.5

Figure 1. The effect of dysfunction and destruction of beta-cells in the pancreas

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13

3- Mechanism of Action of Medicinal Plants Used in Diabetes

Cinnamon (Cinnamomum spp.) 9,10 Cinnamon, which is derived from a Greek word that means “sweet wood”, comes from the inner bark of tropical evergreen cinnamon trees. It

There are several mechanisms of natural plants in the management of diabetes. For instance, stimulation of insulin secretion from pancreatic beta-cell, reduction of insulin resistance, decrease in glucose (re)absorption, stimulation of glucagon-like peptide-1 (GLP-1), and regulation of insulin signalling that induces gene and protein expression. Recently, the mechanisms of action of different bioactive molecules with antidiabetic properties and

possesses

its

antidiabetic

activity

through

activation

of

the

phosphorylation of insulin receptors (beta subunit) on adipocytes and other cells. This is due to the presence of Cinnamtannin B1, a proanthocyanin isolated from the stem bark of Ceylon cinnamon. As well, it causes an increase in GLUT-4 receptor synthesis and improvement of its membrane translocation, inhibition of pancreatic and intestinal amylase and glucosidase, and an increase in hepatic glycogen synthesis.

phytochemistry have got much more concern than before. These

Dear Reader,

plants might contain bioactive compounds such as glycosides, alkaloids, terpenoids, flavonoids, carotenoids, peptidoglycans, hypoglycin, guanidine, and amino acids, which are approved to have an anti-diabetic effect.6

4- Current plants (Literature review) This review will cover the most important natural plants that are effective in diabetes.

Gurmar (Gymnema Sylvestre) 11 It is known as “gurmar” for its distinct property as a “sugar destroyer”. It is a

Fenugreek (Trigonella foenum-graecum) 7

reputed herb in the Ayurvedic system of medicine. The phytoconstituents

Fenugreek is a plant of the Fabaceae family that is native to India,

responsible for glucose inhibition include triterpene saponins known as

China, and North Africa (Prabhakar and Doble, 2011). Its

gymnemic acids, gymnema saponins, and a polypeptide, gurmarin. It has a

hypoglycemic activity is due to the presence of diosgenin (3b-

well-established antidiabetic activity besides other uses for arthritis,

hydroxy-5-spirostene), and soluble dietary fibre. The mechanism of

diuretic, anemia, osteoporosis, hypercholesterolemia, cardiopathy, asthma,

action starts with the regeneration of pancreatic beta cells and

constipation, microbial infections, indigestion, and anti-inflammatory. It

enhancement of insulin secretion. As well, it has an antioxidant

possesses its activity on blood sugar homeostasis, controls sugar cravings,

effect. 4-Hydroxyisoleucine is a branched-chain amino acid

and promotes regeneration of the pancreas. The extraction of the plant is

derivative that is only found in plants and forms a high content of

used in dietary supplements. As it reduces body weight, blood cholesterol,

the fenugreek seed-free amino acids. This phytochemical causes

and triglyceride levels. It has great prospects in dietary and

stimulation of glucose-dependent insulin secretion that results in a

pharmacological applications.

reduction of insulin resistance in muscle and/or liver.

Garlic (Allium sativum) 8 Garlic is a member of the Amaryllidaceae family that is cultivated all over the world. It has many potential health benefits. In 1550 B.C., antibiotics and pharmacy products were not available, garlic was used for typhus, dysentery, cholera, and influenza. It had potential effects in the treatment of diabetes. Allium sativum contains organosulfur compounds. These compounds reduce blood glucose levels through an antioxidant effect. As well, garlic acts as a hydrogen sulfide donor that controls type 2 diabetes. It decreases lipid profile and HBA1c.

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5- Limitation

4. Chaudhury A, Duvoor C, Reddy Dendi VS, et al. Clinical Review of Antidiabetic Drugs: Implications for Type 2 Diabetes Mellitus

Few of these active compounds from natural sources have been

Management.

approved for clinical use. There is a need for more scientific

doi:10.3389/fendo.2017.00006

progress in the field of converting phytochemicals with

5. Arumugam G, Manjula P, Paari N. A review: Anti diabetic medicinal

antidiabetic activity to clinical drugs as a means of reforming the

plants used for diabetes mellitus. J Acute Dis. 2013;2(3):196-200.

management/treatment of type 2 DM.

doi:10.1016/s2221-6189(13)60126-2

6- The Highlights and Current Challenge Despite the strong data and reports on the efficacy of

Dear Reader,

phytochemicals in diabetes, there is a lack of experimental evidence to assesses their achievement in clinical trials. Therefore, it is significant to exert more efforts in experimental findings to support the use of potential phytochemicals in type 2 DM

Endocrinol

(Lausanne).

2017;8(January).

6. Unuofin JO, Lebelo SL. Antioxidant Effects and Mechanisms of Medicinal Plants and Their Bioactive Compounds for the Prevention and Treatment of Type 2 Diabetes: An Updated Review. Oxid Med Cell Longev. 2020;2020. doi:10.1155/2020/1356893 7. Neelakantan N, Narayanan M, de Souza RJ, van Dam RM. Effect of fenugreek (Trigonella foenum-graecum L.) intake on glycemia: a metaanalysis of clinical trials. Nutr J. 2014;13(1):7. doi:10.1186/1475-289113-7 8. Ansary J, Forbes-Hernández TY, Gil E, et al. Potential Health Benefit of

treatment.

Natural plants and photochemical constituents have shown strong anti-diabetic effects according to many scientific papers and systematic reviews. The use of them as an alternative for synthetic drugs is still under research. The challenge now is to do more clinical trials on the use of these natural plants to estimate their

Garlic Based on Human Intervention Studies: A Brief Overview. Vol 9.; 2020. doi:10.3390/antiox9070619 9. Vinitha M, Ballal M. In vitro Anticandidal Activity of Cinnamomum verum. J Med Sci. 2008;8(4):425-428. doi:10.3923/jms.2008.425.428 10. Medagama AB. The glycaemic outcomes of Cinnamon, a review of the experimental evidence and clinical trials. Nutr J. 2015;14(1):1-12.

efficacy and toxicity in humans.

doi:10.1186/s12937-015-0098-9

References

Tiwari P, Mishra BN, Sangwan NS. Phytochemical and pharmacological

1.Edgerton DS, Kraft G, Smith M, et al. Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.

Front

JCI

insight.

properties of Gymnema sylvestre: An important medicinal plant.

Biomed Res Int. 2014;2014. doi:10.1155/2014/830285

2017;2(6):e91863.

doi:10.1172/jci.insight.91863 2. Diabetes DOF. Diagnosis and classification of diabetes mellitus.

Diabetes Care. 2010;33(SUPPL. 1). doi:10.2337/dc10-S062 3. Skyler JS, Bakris GL, Bonifacio E, et al. Differentiation of diabetes by pathophysiology, natural history, and prognosis. Diabetes.

2017;66(2):241-255. doi:10.2337/db16-0806

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POTENTIAL PLANTS COMBINATIONS OF BAJAKAH (SPATHOLOBUS SUBERECTUS DUNN) AND SUNGKAI (PERONEMA CANESCENS JACK) AGAINST CORONAVIRUS Norhayati Andri Djuhri 1 1- ISMAFARSI, Indonesia | Universitas Airlangga 1- Introduction

Dear Reader,

Through the incoming lymphatic vessels, immune cells and foreign

The immune system is the human's best defense that can support the body's natural ability to defend itself against several pathogens, such as viruses, bacteria, fungi, protozoa, and worms.1,2 The innate immune response can inhibit the virus replication process, promote viral clearance, tissue repair, and induce an adaptive immune response against viruses in the future.3

particles enter the lymph nodes. When they are in the bloodstream, they are transported to tissues throughout the body. They continue the cycle by exercising the ubiquitous foreign antigen surveillance and then gradually returning to the lymphatic system. Immune cells gather, work, and function to confront antigens in the lymph nodes and spleen compartments.7 There are three types of immunity,

At the moment, the world is experiencing a pandemic caused by the SARS-CoV-2 virus, which is the cause of COVID-19. The use of vaccines has begun to be distributed and it is hoped that it can reduce the number of increasing confirmation cases of COVID-19 globally, as of 8 March 2021, there have been 116.521.281 confirmed

namely innate immunity (fast response), adaptive immunity (slow response), and passive immunity (Figure 1). However, when the body first encounters a germ or virus, the immune system may not work properly, and disease can arise. This scenario is what has happened in the case of COVID-19.8

cases of COVID-19, including 2.589.548 deaths.4 The discovery of vaccines gives us hope that there will be therapies for the treatment of COVID-19 for all countries, but other therapies besides vaccines are needed, such as immunity supplements that are potentially effective and minimize side effects, specially the ones that are derived from natural ingredients. This article will consider the use of a combination of two plants native to Asia - Bajakah (Spatholobus suberectus Dunn) and Sungkai (Peronema canescens Jack) - as an additional possible strategy in the treatment of COVID-19.

2- Immune System and SARS-CoV-2 The human body contains an immune system that can protect against various diseases, whether their cause is exogenous (e.g. microorganisms) or endogenous (e.g. neoplasms)5,6 In the immune system, cells that have an important role are white blood cells, which can spread throughout the body through blood vessels. Blood and lymphatic vessels in the body will exchange cells and fluids to activate the lymphatic system to prevent microbes. Lymphatic vessels carry lymph, which contains special compartments where antigens can converge.

Figure 1. Innate and adaptive immune system8 Passive immunity has two types: natural immunity, which is received from the mother, and artificial immunity, which is received from vaccines. The skin and inflammatory response begin when the body is affected.9,10

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When the body is affected by a virus, the immune response acts as

Phytochemical studies show that Bajakah contains several types of

an intermediary for protection. B cells, assisted by T cells, will

compounds, namely alkaloids, non-protein amino acids, amines,

differentiate into plasma cells, which then produce special

flavonoids, isoflavonoids, coumarins, phenylpropanoids, anthraquinones,

antibodies for viral antigens. Natural antibodies will neutralize

disesqui and triterpenes, cyanogenic glycosides, and lectins.18 In addition,

efficiently to completely block the virus from entering the host cell

the Chinese use Bajakah as an antiplatelet, to eliminate digestive tract

and limit the progression of the infection that occurs. In contrast, a

disorders,

cellular immune response can be observed in infected cells, which

activity20, and anti-virus.21 There are several bioactive compounds

is mediated by T-lymphocytes. The overall adaptive immune

possessed by Bajakah, namely dihydroquercetin, epicatechin, afrormosin,

response is directed by helper T cells, and cytotoxic T cells play an

cajanin, 3',4',7-trihydroxyflavone, and licochalcone A.22

important role in the cleansing of virus-infected cells.11 Information from SARS-CoV-1 requires exploration of knowledge to

Dear Reader,

understand how SARS-CoV-2 can escape the immune response

menstrual

disorders,

rheumatism19,

anti-inflammatory

4- Sungkai (Peronema canescens Jack)

because data on SARS-CoV-2 is very limited. In particular, 80% of

Sungkai is a plant that is often called sabrang, ki sabrang, sungkai, or sekai.

the SARS-CoV-1 RNA sequences matched the SARS-CoV-2 RNA12,

The Dayak people in East Kalimantan, Indonesia, still use these plants as a

and SARS-CoV-2 showed additional genome regions. Compared to

treatment (e.g. common cold, fever, ringworms) or as a health procedure

SARS-CoV-1 and other coronaviruses, the S protein coronavirus is

(e.g. mouthwash to prevent toothache, for women after giving birth);

longer, namely 20-30 amino acids. Moreover, SARS-CoV-2 has an

people of Lampung use it as an anti plasmodium and fever23, explained

immune avoidance strategy, but an additional mechanism has yet

by the fact that its leaves have bioactivity compound as immunostimulant

to be discovered and the leukocytes (important of the immune

agents, namely terpenoids, polysaccharide, alkaloid, and polyphenol

system) come from lymphocytes that play an important role in the

compounds.24

immune system, namely B lymphocytes and T lymphocytes.13,14

3- Bajakah (Spatholobus suberectus Dunn) Bajakah belongs to the Leguminosae family, which has 18.000 species worldwide. It is used by Chinese people for nearly 1.000 years for the solution of various diseases.15

Figure 3. Sungkai (Peronema canescens Jack)25

The compounds present in Sungkai leaves that have immune system activity are peronemin, sitosterol, isopropanol, phytol, diterpenoids,

Figure 2. Bajakah (Spatholobus suberectus)16,17

flavonoids. In an in vivo study, a dose of 96% alcohol extract of 0.5625 mg/Kg of Sungkai leaves could increase the leukocyte count by 7324/cc or 36% greater than the conventional (Imunos) which only increased the leukocyte count by 23%.26. Leukocytes are very important in the immune system, maintaining body functions against infection, and evaluating bacterial and viral infections. The CD4 and CD8 T cells are also important in controlling viral replication, inflammation, and viral clearance in infected cells.27

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17

6- Conclusion Treatment therapy derived from natural compounds, such as Bajakah (Spatholobus suberectus Dunn) and Sungkai (Peronema canescens Jack) can potential to synergistic to minimize side effects, safe, easy to produce, efficacious because has been proven several studies so that it can realizes the SDGs point 3 “Good Health and Well-being” and supported vaccines and improve the immune system when an infection occurs due to

Table 1. The average count of leukocytes (in pathogens, especially at this pandemic to the treatment of COVID-19. thousands)26 References

5- Challenge

1. https://www.britannica.com/science/immune-system.

Dear Reader,

2. https://www.ncbi.nlm.nih.gov/books/NBK279397/.

3. Kumara A. Role of the Body Immune System Against Corona Virus Attack (Sars-Cov-2) in Human. Researchergate Publication. Published Online 2020.

Natural compounds tend to have a bitter taste and pungent

4. WHO. Coronavirus disease COVID-2019 Report. World Health Organization. Covid19.who.int

aroma, so that if they are made in tablet preparations it will be less

5. https://kidshealth.org/en/parents/immune.html

precise and in capsules, it is relatively expensive. Plus, the solubility

7. Assessing

of an active compound plays a major role in the dissolution or process of dissolving a drug in a solvent and develop formulas to increase the bioavailability.28 Therefore, it is necessary to choose

6. https://www.clinicaltrialsarena.com/analysis/coronavirus-mers-cov-drugs/ the

human

immune

system

through

blood

transcriptomics.

http://www.imgt.org/IMGTeducation/Tutorials/ImmuneSystem/UK/theimmunesystem.pdf 8. Chaussabel D, Pascual V BJ. Assessing the human immune system through blood transcriptomics. BMC Biol. 2010; (8):84.

9. https://www.khanacademy.org/science/high-school-biology/hs-human-body-systems/hs-the-immunesystem/a/hs-the-immune-system-review

the right drug delivery system to overcome this, namely chitosan

10. https://www.health.mil/Military-Health-Topics/Health-Readiness/Immunization-Healthcare/Clinical-Consultation-

nanoparticles can be an option since this method is simple and

11. Swatantra Kumar, Rajni Nyodu, Maurya Vimal K SSK. Host immune response and immunobiology of human SARS-

does not require organic solvents, which can affect the quality of

12. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H et al. Genomic characterization and epidemiology of 2019 novel coronavirus:

active ingredients, is not toxic, and prevents damage to the active ingredients to be encapsulated in chitosan nanoparticles.29

Services/Immunology-Basics CoV-2 infection. In Coronavirus Disease 2019(COVID-19) :43-53. implications for virus origins and receptor binding. Lancet. 2020;395 (10224):565-574.

13. Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pacific J Allergy Immunol. 2020;38(1):1-9. doi:10.12932/AP-200220-0772 14. Susanna Felsenstein, Herbert Jenny A, Mc Namara Paul S HCM. COVID-19: immunology and treatment options. Clin Immunol. 2020;(215):108448.

15. Huang KC. The pharmacology of Chinese herbs. Boca Rat CRC Press. 1993:261.

16. Global Biodiversity Information Facility. Spatholobus suberecetus Dunn. GBIF. Published 2020. Accessed November 3, 2021. https://www.gbif.org/species/2977075 17. BioCrick Science Solution Specialist. Spatholobus suberectus Dunn. Published 2020. Accessed November 3, 2021. https://www.biocrick.com/ 18. Wink, M., & Mohamed G. Evolution of chemical defense traits in the Leguminosae: mapping of distribution patterns of secondary metabolites on a molecular phylogeny inferred from nucleotide sequences of the rbcL gene [J].

Biochem Syst Ecol.2003;31(8):897-917.

19. Huang, W.H., Lee, A.R., Yang C. Antioxidative and anti-inflammatory activities of polyhydroxy flavonoids of Scutellaria baicalensis. Biosci Biotechnol Biochem. 2006;(2371):80.

20. Li, RW., Lin, GD., Myers, SP., Leach D. Anti-inflammatory activity of Chinese medicinal vine plants. J Ethnopharmacol. 2003;5:61-67. doi:10.20944/preprints202003.0226.v1 21. Y Goda, M Shibaya, U Sankawa GY. Inhibitors of prostaglandin biosynthesis from Mucuna birdwoodiana. Chem Pharm Bull. 1987;35:2675-2677.

22. Jiang, S.Y., Huang, K., Liu, W., Fu, F.M., Xu J. Combined AutoDock, and comparative molecular field analysis study on

Figure 4. Illustration of mechanism nanoparticle plants combination with virus

In addition, nanoparticles can increase the saturated solubility

value of a substance, dissolution rate, stability, bioavailability of compounds, and the dosage required to achieve efficient pharmacological effects, in increasing drug stability so that drugs can go directly to the target area, improve absorption of a macromolecular compound, and reduce the irritant effect of active substances on the gastrointestinal tract.30

predicting 5-lipoxygenase inhibitory activity of flavonoids isolated from Spatholobus suberectus Dunn. Zeitschrift Fur Naturforsch C J Biosci. 2015;70(3-4):103-113. doi:10.20944/preprints202003.0333.v1 23. Harmida S, Yuni V. Ethnophytomedical Study in Lawang Agung Village, Mulak Ulu District, Lahat Regency, South Sumatera. J Sains. 2011;14(6):14110.

24. Gresinta E. Potential Test of Etlingera hemisphaerica Leaf against the number of Mus musculus and implementation as a immune system module. Thesis UNIB. Published online 2012.

25. Fajar WH. Sungkai Leaves as an Immunomodulator. Indonesia Portal Information. Published online 2020;28 (April): Article. https://indonesia.go.id/ 26. Yani AP, Putranto AMH. Examination of the Sungkai’s Young Leaf Extract (Peronema canescens ) as An Antipyretic, Immunity, Antiplasmodium, and Teratogenicity Mice. Int J Sci Eng. 2014;7(July):30-34. doi:10.12777/ijse.7.1.30-34 27. Ivashkiv L, Donlin L. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14(1):36-49. doi:10.1038/nri3581 28. Ajazuddin SS. Applications of novel drug delivery systems for herbal formulations. Fitoterapia. 2010;81(7):680.

29. Mardlyati E, Muttaqien S, Setyawati D., Rosidah I, Sriningsih. Preparation and Applications of Chitosan Nanoparticle an Oral Insulin Delivery System. Prosiding in SINAS. Published online 2012:25-30.

30. Mohanraj V, Chen Y. Nanoparticles-A Review. Trop J Pharm Res. 2006;(5):561.

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PHARMACEUTICAL PRODUCTS IN WATER Gabrielle Gimenes Lima 1, Anderson Ferreira Rossatto 2, Larissa Marinho Camillo 3 1- FEBRAF, Brazil | Universidade Mogi das Cruzes 2- FEBRAF, Brazil | Centro Universitário das Faculdades Metropolitanas Unidas 3- FEBRAF, Brazil | Universidade de São Paulo

3- Methodology

1- Introduction

Dear Reader,

A systematic search of the literature published between 2010 and

The incorrect disposal of pharmaceutical products is increasingly becoming a threat to the aquatic ecosystem. When these drugs are incorrectly disposed of, they can reach the aquatic ecosystem and remain active, influencing the marine lives that live in water. Many of these wastes come from hospital wastewater and hospital waste.1,2 These pharmaceutical products can reach the aquatic ecosystem, not only due to incorrect disposal, but also as a result of diagnostic activities, research activities, and drug excretion by patients. An example of the influence of drugs on aquatic lives is in the case of high concentrations of anxiolytic pharmaceutical products, as these

2020 was performed using PubMed and MEDLINE databases. Search terms

comprised

“water”,

“residues”,

“agrochemicals”,

and

“pharmaceuticals”, using articles in English, Spanish and Portuguese to do this Systematic Review. Of all the 18 articles found, we use 6 articles for this discussion of the topic under study. The other articles did not present data consistent with the scope of the research, having their scientific value molded to other themes. The selected articles were publications from ScienceDirect, Springer, and Science.

4- Results

products (benzodiazepines) are difficult to be degraded. Therefore, they can be found in water effluents in significant concentrations

In a study by Arlos et al. (2015), the presence of antiandrogenic

known to cause harmful effects to the marine lives present. The

products used for personal care (triclosan and chlorophene),

effects caused are decreased sociality and a higher feeding rate.1,2

herbicide (atrazine), and representative drugs (carbamazepine,

Another example of this influence is in the case of endocrine

ibuprofen, naproxen, and venlafaxine) were found in significant

disruption and the occurrence of intersex between wild fish. A study

amounts in Grand River watershed in Southern Ontario. These

published in ScienceDirect, shows that this hormonal deregulation

components found in the hydrographic basin may be responsible for

and reproductive effects are related to the presence, in the aquatic

endocrine disruption and the occurrence of intersex in wild fish.

ecosystem, of estrogen and androgen receptor agonists and/or

There is a diversity of contaminants in wastewater effluents, once the

antagonists. These compounds can be found in some treatments and

presence of these contaminants depends on the treatment process

products. In addition to the endocrine effects, there are also changes

and the quality of the effluent.1

in gene expression, changes in energy allocation, and increased

In addition, as demonstrated in an analysis by Afonso-Olivares (2017),

production of steroids.3

the main source of entry into the environment for these contaminants are the wastewater treatment plants (WWTPs). At a

2- Objectives

WWTP in Gran Canaria (Spain), it was found that there was a removal of 80% for most contaminating compounds, except those whose

We conducted a bibliographic review regarding studies focusing on the disposal of pharmaceutical products and waste in water, taking into account rivers and tributaries, in addition to products of hospital origin.

elimination efficiency index reaches, in the best case, only 40%, such as CBZ, FLX, and IBU. The removal of these contaminants and drugs from wastewater by WWTPs is growing, but more research is needed in the area. It is very important that this process is carried out correctly so that there are no environmental risks for the aquatic ecosystem.4

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In the article carried out by Azuma et al. (2015), results were

Our

presented in which, in the effluent waters of Japan’s WWTPs, four

underestimated effects of psychotherapeutic drugs entering aquatic

microbial drugs and one psychotropic drug used for therapeutic

ecosystems and new testing protocols to examine the total environmental

medication were found. Anticancer compounds were also found in

impact of pharmaceutical waste.

results

highlight

the

ecological

importance

of

previously

average concentrations of 32 ng/L in the river water and 245 ng/L in the effluents of the WWTPs. It was found that total energy

In addition, hospital waste and wastewater (as well as sludge) must be

expenditure (TEE) was the main source of anticancer compounds

properly treated and disinfected before disposal. Without disinfection,

and other pharmaceutical products. Ozonation is an effective

they should not be disposed of arbitrarily or used as agricultural fertilizers.

sewage treatment technique in removing these compounds from

The use of any infiltration wells/pits to discharge wastewater and sludge,

water.5

or the discharge into sanitary protection zones of drinking water sources

In the work carried out by Brodin et al. (2013), it was found that

must also be strictly prohibited. In addition, governments must take steps

psychotropic

to improve the management of hospital waste and effluents.

anxiolytic

drugs,

which

contain

Dear Reader,

oxazepam

(benzodiazepine), alters the behavior and feeding of wild

Personnel involved in the disposal of disposable medical supplies must be

European perch, this species showed reduced sociality and a

qualified and strengthened in personal protection. In recent years, many

higher feeding rate, these changes can have ecological and

new advances have also been made in hospital wastes and wastewater

evolutionary consequences. The benzodiazepine compound

treatment technologies, such as radiation disinfection technology, reverse

persists in wastewater effluents, as they are quite resistant to

polymerization disinfection technology, plasma disinfection technology,

photodegradation, and thus persist in aquatic environments.6

and thermal gasification disinfection technology.

5- Discussion

Finally, there is a greater need for longitudinal studies with emphasis on precaution and prevention as well as multi-generational studies in

Environmental contaminants are a worldwide problem and are

humans.

hidden players in health. The aim of this review was to provide

References

greater awareness to the clinician and the general public about the potential consequences of some of these chemicals whose effects

Behavior of Fish from Natural Populations. Science, v. 339, n. 6121, p.

could be transmitted to further generations.1 Effective

protection

from

chemical

1. BRODIN, T. et al. Dilute Concentrations of a Psychiatric Drug Alter

exposures

requires

814–815, 14 Feb. 2013.

governmental leadership, environmental education, and social

2. WANG, J. et al. Disinfection technology of hospital wastes and

action. Thus proper education about these chemicals can help

wastewater: Suggestions for disinfection strategy during coronavirus

individuals limit their exposure to these chemicals (at least to a

Disease 2019 (COVID-19) pandemic in China. Environmental Pollution,

certain extent) in food and water, ultimately alleviating the risk on

v. 262, p. 114665, Jul. 2020.

3. ARLOS, M. J. et al. Distribution of selected antiandrogens and

future generations.1 There is a great demand in the need for constant assessment of

pharmaceuticals in a highly impacted watershed. Water Research, v.

the destination of pharmaceutical products, due to their capacity

72, p. 40–50, Apr. 2015.

for toxicity and contamination in the environment.4

4. AFONSO-OLIVARES, C.; SOSA-FERRERA, Z.; SANTANA-RODRÍGUEZ, J. J.

There is also a need to elucidate the population about the correct

Occurrence and environmental impact of pharmaceutical residues

disposal of medicines and pharmaceutical products, in order to

from conventional and natural wastewater treatment plants in Gran

decrease the amount of waste disposed in rivers and tributaries,

Canaria (Spain). Science of The Total Environment, v. 599-600, p. 934–

giving rise to a collective awareness of the recycling capacity and

943, Dec. 2017.

5. AZUMA, T. et al. Occurrence and fate of selected anticancer,

correct disposal of materials.6

antimicrobial, and psychotropic pharmaceuticals in an urban river in a

6- Conclusion

subcatchment of the Yodo River basin, Japan. Environmental Science

The increase of pharmaceutical waste services in aquatic systems is expected, as pharmaceutical use is expected to increase as they become more available to a growing global population.

and Pollution Research, v. 22, n. 23, p. 18676–18686, 17 Jul. 2015.

6. BRODIN, T. et al. Dilute Concentrations of a Psychiatric Drug Alter Behavior of Fish from Natural Populations. Science, v. 339, n. 6121, p.

814–815, 14 Feb. 2013.

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THE HEALTH EFFECTS OF THE PLASTIC ERA Laura Trevisan Fechner 1 1 - FEBRAF, Brazil | Universidade Federal do Rio Grande do Sul

Dear Reader,

Everyday we are surrounded by products made of plastic: beverage

Mammalian models, mostly mice, turned out to have

bottles, plastic bags, toothbrushes, cosmetics, fabrics and food

some interesting findings regarding plastic consumption.

packaging. Yet, we have insufficient information about how these

Some authors had found pathological alterations in the

plastics can interact with the human organism.

gut

Microplastics (MPs) are plastic particles ranging from sizes of about 5

barrier,

such

as

dysbiosis,

dysfunction

and

inflammation, and lipid accumulation on the liver due to

mm or even less. Due to their small size, they can easily interact with

plastic accumulation., 12, 13, 14 The researchers also tried

different organisms and disperse in air and water. The MPs most

to reproduce these findings in human cells and, not

commonly found are polyethylene terephthalate (PET), followed by

surprisingly, found signs of cytotoxicity at high

polyethylene (PE), polystyrene (PS), and polypropylene (PP), and they

concentrations of MPs.15 16

are usually in the form of a fiber or fragment. 1,2,3 One of the biggest concerns is that persistent organic pollutants

As it is an issue with growing debate, the results are

(POPs), such as organochlorines, bisphenol A, and toxic metals,

finally being achieved: Italian researchers detected the

adsorb unto surfaces of these microplastics and these components

presence of microplastics in 4 of the 6 analyzed placentas,

are capable of generating hormonal and neurological changes.4

totaling 12 microplastics. They also theorized the entry of

Until now, few in vitro and in vivo studies have been carried out to

this substance into the human body through food and

verify the interactions of MPs with human physiological and biochemical functions.

breathing, with the action of M cells, paracellular diffusion, macrophages, and ciliated epithelium, being

Knowing about the most common routes of contamination, such as

carried into the blood by dendritic cells.17

food, the Rapid Alert System for Food and Feed (RASFF) and the European Food Safety Authority (EFSA) have cautioned the presence of MPs in food products. Among them, but not limited to, are foods, such as honey, milk, beer, meats stored in trays, teas, salt (from various

regions

of

the

contaminated).5,6,7,8,9,10

world), There

and is

also

seafood a

(the

World

most Health

Organization’s (WHO) report on “Microplastic in drinking-water” that indicates the necessity of more research about the topic.11

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Previous research, carried out by Schwabl and collaborators,

8. Hernandez, L.M., Xu, E.G., Larsson, H.C.E., Tahara, R., Maisuria, V.B., Tufenkji, N.

analyzed the presence of microplastics as a result of digestion,

Plastic teabags release billions of microparticles and nanoparticles into tea.

finding all samples (n=8) containing about 20 microplastics in 10g

Environ. Sci. Technol. 2019, 53(21), 12300-12310.

of feces, such as polypropylene (PP) and polyethylene

9. Huang, Y., Chapman, J., Deng, Y., & Cozzolino, D. Rapid measurement of

terephthalate (PET).18 The consequences of chronic and acute MPs exposure in the mammalian system are still very unclear.

Furthermore, these MPs can be decomposed into nano sizes

microplastic contamination in chicken meat by mid infrared spectroscopy and chemometrics:

A

feasibility

study.

Food

Control.

2019,

107187.

doi:10.1016/j.foodcont.2020.107187 10. Kutralam-Muniasamy, G., Pérez-Guevara, F., Elizalde-Martínez, I., & Shruti, V. C.

(nanoplastics), potentially entering the circulation system and

Branded milks – Are they immune from microplastics contamination? Sci Total

interacting with albumin and other blood proteins, probably

Environ. 2020, 136823. doi:10.1016/j.scitotenv.2020.136823

modifying drug distribution.

11. World Health Organization. Microplastics in Drinking‐Water; 2019. Accessed

After all this information you might be wondering: what can we, as

on

pharmacists and future pharmacists, do about it? One of the best

https://www.who.int/water_sanitation_health/publications/microplastics‐in‐

ways to act quickly is to encourage the correct disposal of

drinkig‐waTer/en/

medicines and packaging at collection points and even the usage

12. Jin Y., Lu L., Tu W., Luo T., Fu Z. Impacts of polystyrene microplastic on the gut

Dear Reader,

of bioplastics is an alternative. But more: we can explore this field as researchers, clarifying potential interactions that these MPs and NPs have with physiological parameters and medications.

26

Feb

2021.

Available

online:

barrier, microbiota and metabolism of mice. Sci. Total Environ. 2018;649:308–317. doi: 10.1016/j.scitotenv.2018.08.353.

13. Li B., Ding Y., Cheng X., Sheng D., Xu Z., Rong Q., Wu Y., Zhao H., Ji X., Zhang Y. Polyethylene microplastics affect the distribution of gut microbiota and inflammation development in mice. Chemosphere. 2019;244:125492. doi:

References

10.1016/j.chemosphere.2019.125492.

1. Mammo, F.K.; Amoah, I.D.; Gani, K.M.; Pillay, L.; Ratha, S.K.; Bux, F.;

14. Luo T., Wang C., Pan Z., Jin C., Fu Z., Jin Y. Maternal polystyrene microplastic

Kumari, S. (2020). Microplastics in the environment: Interactions with

exposure during gestation and lactation altered metabolic homeostasis in the

microbes and chemical contaminants. Science of The Total

dams and their F1 and F2 offspring. Environ. Sci. Technol. 2019;53:10978–10992.

Environment, 140518. doi:10.1016/j.scitotenv.2020.140518

doi: 10.1021/acs.est.9b03191.

2. Liu, G., Zhu, Z., Yang, Y., Sun, Y., Yu, F., Ma, J., 2019b. Sorption behavior

15. Walczak A.P., Kramer E., Hendriksen P.J.M., Tromp P., Helsper J.P.F.G., van der

and mechanism Journal Pre-proof Journal Pre-proof of hydrophilic

Zande M., Rietjens I.M.C.M., Bouwmeester H. Translocation of differently sized

organic chemicals to virgin and aged microplastics in freshwater and

and charged polystyrene nanoparticles in in vitro intestinal cell models of

seawater. Environmental Pollution 246, 26 –33

increasing

3. Allen, S., Allen, D., Phoenix, V.R., Le Roux, G., Durántez Jiménez, P.,

complexity.

Nanotoxicology.

2015;9:453–461.

doi:

10.3109/17435390.2014.944599.

Simonneau, A., Binet, S., Galop, D., 2019. Atmospheric transport and

16. Hesler M., Aengenheister L., Ellinger B., Drexel R., Straskraba S., Jost C., Wagner

deposition of microplastics in a remote mountain catchment. Nature

S., Meier F., von Briesen H., Büchel C., et al. Multi-endpoint toxicological

Geoscience 12(5), 339 –344.

assessment of polystyrene nano- and microparticles in different biological

4. Lina Fu, Jing Li, Guoyu Wang, Yaning Luan, Wei Dai. Adsorption

models in vitro. Toxicol Vitro. 2019;61:104610. doi: 10.1016/j.tiv.2019.104610.

behavior of organic pollutants on microplastics, Ecotoxicology and

17. Ragusa A et al.; Plasticenta: First evidence of microplastics in human placenta.

Environmental Safety, Volume 217, 2021, 112207, ISSN 0147-6513,

Environ Int. 2021, 146:106274. doi: 10.1016/j.envint.

5. Liebezeit, G., & Liebezeit, E. Non-pollen particulates in honey and sugar. Food Addit Contam Part A, 2013, 30(12), 2136–2140.

18. Schwabl, Philipp et al.; Detection of Various Microplastics in Human Stool: A Prospective Case Series. Ann of Intern Med. 2019, 171. doi: 10.7326/M19-0618.

doi:10.1080/19440049.2013.843025 6. Lusher, A. L., McHugh, M., & Thompson, R. C. Occurrence of microplastics in the gastrointestinal tract of pelagic and demersal fish from the English Channel. Mar Pollut Bull. 2013, 67(1-2), 94–99.

7. Lachenmeier, D.W., Kocareva, J., Noack, D., Kuballa, T. Microplastic identification

in

German

beer-an

artefact

of

laboratory

contamination? Deutsche Lebensmittel-Rundschau. 2015, 111 (10), pp. 437-440.

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BIOACCUMULATION AND DISTRIBUTION OF "FOREVER CHEMICALS" Khaldi Mariah 1 1- ASEPA, Algeria | Université d'Alger 1

Dear Reader,

“Forever Chemicals'' or per- and polyfluoroalkyl substances (PFAS)

For instance, an article published in the chemosphere

are pollutants that have been used in a wide variety of industrial and

journal tells us that sorption coefficient for PFCs derived

commercial applications, including carpeting, upholstery, apparel, floor wax, textiles, firefighting foam, and sealants. PFAS used in

from laboratory experiments when compared to the gross

industries were produced in processes of electro-chemical

distribution between the concentrations of PFCs in

fluorination and telomerization. Lots of research articles have been

surface waters and sediments, demonstrate that applying

published since the year 2000, which mainly dealt with the topics of

lab-based log Koc distribution coefficients can result in a

perfluorooctanesulfonic acid (PFOA) and perfluorooctanoic acid

serious overestimation of PFC concentrations in water

(PFOS) immunotoxicity and hormonal effects. Few articles are dealing with bioaccumulation and the toxic effect of PFOA and PFOS and their fate and distribution in the environment. Biological

and in turn to an underestimation of the residence time of PFOA and PFOS in contaminated soils.4 Irrespective of

monitoring using marine biological tissues (fish, bird, and marine

the dissipation kinetics, the majority of PFOA and PFOS

mammal samples) for time trend surveys has shown that exposure to

from contaminated soils will be transported to

polyfluorinated surfactants (PFS) has increased significantly in the

groundwater and surface water bodies. Therefore,

past few years1 and the concentration of PFS in humans and wild

continuous monitoring and more awareness among

animals living in industrialized areas of North America, Europe, and Asia may increase (2-30 000 ng/mL or ng/g wet weight (ww)). PFS (≤3000 ng/g ww) has also been detected in organisms from the

water-related professionals and researchers of this emerging environmental issue are so important.

Arctic and islands in the ocean.2 Food web analysis has shown that perfluorinated carboxylic acid (PFCAs) and perfluoroalkane sulfonic acids (PFSAs) can bioaccumulate and magnify in marine and freshwater ecosystems. Knowledge gaps with concerning transport, accumulation, biodegradation, temporal/spatial trends and PFS precursors have been identified.4

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Dear Reader,

Figure 1. PFAS-Cycle. There are many ways from which PFAS can contaminate drinking water and marine life. One way is when PFAS and PFAS-containing products are spilled on the ground or into lakes and rivers. PFAS moves easily through the ground, getting into groundwater that may supply drinking water to homes or cities. Or, as the figure shows, PFAS can be released from our homes and industries and enter surface waters directly or through wastewater treatment plants.

PFAS can also be released into the air, where it can be taken up by rain or snow and end up in rivers and lakes.

References

3. Nobuyoshi Yamashita, Kurunthachalam Kannan, Sachi Taniyasu, Yuichi Horii, Gert Petrick, Toshitaka Gamo, National Institute of

1. Fatihah Suja, Biplob Kumar Pramanik, Universiti Kebangsaan Malaysia, RMIT University,

Contamination,

bioaccumulation

and

toxic

effects

Advanced Industrial Science and Technology (AIST), Japan, Wadsworth

of

Center, New York State Department of Health, Department of

perfluorinated chemicals (PFCs) in the water environment, review paper,

Environmental Health and Toxicology, State University of New York at

2009.

Albany, Leibniz-Institute of Marine Sciences, IFM-GEOMAR, West Shore

2. Magali Houde, Jonathan W. Martin, Robert J. Letcher, Keith R. Solomon, and Derek C. G. Muir Department of Environmental Biology, University of Guelph, Guelph, Ontario, Canada, National Water Research Institute, Environment Canada, Department of Public Health Sciences, University of Alberta,

Campus, Germany, Ocean Research Institute, University of Tokyo, Japan, A global survey of perfluorinated acids in oceans, review paper, 2005.

Edmonton, Alberta, Canada, and Canadian Wildlife Service, National Wildlife

4. P.Zareitalabad, J.Siemens, M.Hamer, W.Amelung, Institute of Crop

Research Center, Environment Canada, Ottawa, Ontario, Canada, Biological

Science and Resource Conservation-Soil Science and Soil Ecology,

Monitoring of Polyfluoroalkyl Substances, review paper, 2006.

University of Bonn, Germany, GIQS e.V., c/o Faculty of Agriculture, University of Bonn, Germany, Institute of Bio- and Geosphere (IBG-3; Agrosphere), Forschungszentrum Jülich, Germany, Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in surface waters, sediments, soils and wastewater – A review on concentrations and distribution coefficients, review paper, 2013.

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GENETICALLY MODIFIED ORGANISMS AND THEIR ROLE IN THE ENVIRONMENT Asmaa Maher Ahmed 1, Safa Tamer Mostafa 1, Aya Elsayed Ebied 1, Ammar Yasser Awad 1, Asmaa Zakaria Younes 1, Dena Ezzat Ibrahim 1, Nada Mohamed Abdalaziz 1, Rania Ramadan Mohamed 1, Fatma Abdelmonaim Abdelaziz1 1- EPSF, Egypt | Zagazig University

1- Introduction

Dear Reader,

Nowadays, along with industrial and technological breakthroughs,

3- GMOs concept, production, and importance GMOs are currently used in various applications in agriculture,

environmental pollution has remarkably increased, resulting in a

health, research, and environmental management.

malicious change in our ecosystem. The substances causing this

The technique is mainly done by inserting one or more individual

pollution are mostly dangerous hazardous substances to humans

genes from one species' organism into the DNA of another species'

and other living species as well as non-living things1, and they can

organism.1

be either intentionally or unintentionally released into the

GMOs have a potential role in environmental management especially

environment. Harmful chemicals have been discharged into the

waste management and environmental detoxification. There are two

Earth's air, land, and water over the past few decades as a result of

major

population and industrial growth.2 Air can be contaminated with

bioremediation.7

particulate matter, greenhouse gases, and CO. Water may be contaminated with oil spills among other chemical and biological substances. Also, soils can be contaminated with all kinds of wastes.1 So, to overcome this problem, scientists developed a technique called genetically modified organisms (GMOs) and applied it to the environmental field. GMOs are organisms that have been altered for the production of a desired biological product by recombinant DNA technology or other genetic engineering techniques.

2- History of GMOs

bioremediation

technologies:

phytoremediation

and

A- Phytoremediation Phytoremediation is a technique where scientists use genetically engineered plants to degrade organic and inorganic pollutants preventing them from migration to other environments. There is this fascinating fact that the more pollutants there are the faster the process is. However, there are several phytoremediation approaches all shown and explained in Figure 1.

The United States first launched research and development programs for GM technology in the early 1980s.3 In 1970, the first GMOs made were called “superbug”, they were developed by genetic engineering through plasmid transfer that had the ability to degrade a variety of wastes existing in the form of petroleum chemicals, such as xylene, camphor, hexane, naphthalene, and toluene.4 Since the introduction of GM crops to the market in 1996, there has been an increasing interest in the GMOs technology.5 The state council promulgated the regulation of safety administration of agricultural GMOs on 23 May 2001 and later on 5 January 2002 supporting regulations were issued completing the bio-safety regulation on GMOs.3 In 2013, crops containing this type of technology accounted for 46% of the global cultivation.6

Figure 1. Schematic representation of different phytoremediation approaches by plants under study8

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Achievements in the past decades imply that plant genetic engineering

Like any novel technique, GMOs have their flaws and hazards, like food

can help in the improvement of phytoremediation9, by creating desirable

allergies1; also, animals and plants can be infected from host, recipient

GM plants and GM crops which will reduce the use of chemicals for insect

or vector organism used in GMOs manufacturing process in case of

control and lower pesticide use, resulting in less soil pollution and

bioremediation technique16. Many of the possible risks are associated

safeguard water supplies. Also, it has the ability to increase quantities of

with the use of GMOs in laboratories and industries: potential hazards

food production10,11 and precursors, such as using “Golden Mustard”,

linked with GM work have been identified, including the development

which can produce high levels of beta-carotene, a precursor of Vitamin A

of more infectious microorganisms, the transmission of damaging

used to treat Vitamin A deficiency.3,12,13,14

genetic material, and aggressive genetically modified plants that could colonize the environment. Because of the immense complexity of the

B. Bioremediation

GMOs interactions within our living ecosystems, ecologists claim that it is almost impossible to clearly describe the effects of releasing GMOs

Dear Reader,

Bioremediation involves three stages: biotransformation, which is

into the environment.17

converting

5- The future of GMOs

hazardous

pollutants

into

non-hazardous

ones;

biodegradation, which is basically pollutants breaking down into smaller molecules; and mineralization, which is the transformation of the pollutants into inorganic constituents such as CO2 and H2O. However, it is

In the near future, by using GMOs, scientists will be able to increase

done by using different biological agents (microbes or plants) and their

plant resistance, which will reduce the need for broad-spectrum

enzymes. Among the microbes used, Mycobacterium, Actinobacteria,

insecticides, according to traditional breeding variants. It is predicted

Bacillus, and Pseudomonas are the most commonly used species. Despite

that more GM crops with various stress tolerance genes will also be

the great progress, these procedures are still costly and no single

released. The applications of more precise, rapid, and well-regulated

technique can provide full-scale environmental decontamination.2

technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR) and new breeding technologies, will increase, as they

4- Benefits and risks of GMOs

come under proportionate regulations with the advantage of being science-based and suitable for the purpose. There will be a need for

GMOs offer various merits, including genetic improvement in plants and

more precise, animal-specific, organ-specific, and long-term evaluation

animals to increase their yields. They also expedite plant and animal

processes in terms of safety and health concerns, with special attention

disease diagnosis, vaccine development, as well as improving the quality

to novel toxins, dose, potentially hazardous mixes, and the influence

and quantity of plant and animal products by the introduction of more

on metabolism and other body functions.5,18

nutritional value into them. Genetically modified plant varieties offer various features, including resistance to diseases, production of superior yields with high-quality nutrients, and, more importantly, the generation of products that can not be produced naturally, which is a leap in all agriculture, crop, and genetic sciences. Not only can GMOs produce more efficient outcomes but also it can degrade and detoxify the environmental pollutants in contaminated matrices, like hexane, naphthalene, and toluene.15

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6- Conclusion

6. Brookes G, Barfoot P. Environmental impacts of genetically

By the superfluity of pollution, which is a crisis humans have been facing

carbon

since the 19th century, scientists, in an attempt to overcome this

doi:10.1080/21645698.2015.1025193

problem, are using genetically modified organisms technique that is done

7. Fatih Ozcan, Cansu Telci Kahramanogullari, Nilufer Kocak, Mustafa

by the alteration of the genetic material or by inserting one or more

Yildiz,* IH and ET. Use of genetically modified organisms in Forestry.

individual genes from one species into the DNA of another species that is

Fresenius Environ Bull. 2012;21(August 2016):3443-3447.

more tolerant towards the abiotic stress like drought, cold and heat.

8. Rigoletto M, Calza P, Gaggero E, Malandrino M, Fabbri D.

With concern to the environmental recovery, GMO technology is done

Bioremediation methods for the recovery of lead-contaminated

either by bioremediation - which is the use of microorganisms or plants to

soils: A review. Appl Sci. 2020;10(10). doi:10.3390/app10103528

transform pollutants into CO2 and H2O - or phytoremediation - which is

9. Kotrba P, Najmanova J, Macek T, Ruml T, Mackova M. Genetically

the use of GM plants to degrade environmental pollutants.

modified plants in phytoremediation of heavy metal and metalloid

GM products are currently used around the globe. However, in spite of

soil and sediment pollution. Biotechnol Adv. 2009;27(6):799-810.

the great progress this technology has made, they are still costly and

doi:10.1016/j.biotechadv.2009.06.003

potentially dangerous, but hopefully, in the near future, GM crops with

10. Zilberman D, Holland TG, Trilnick I. Agricultural GMOs-What we

various stress tolerance genes will be used in the application of more

know and where scientists disagree. Sustain. 2018;10(5):1-19.

well-regulated technologies, such as CRISPR and new breeding

doi:10.3390/su10051514

technologies in which great attention will be paid to their effect on all

11. Hails RS. Environmental Impact of Genetically Modified

body functions. Hopefully, we will be there to witness this splendid

Organisms (GMOs). Encycl Life Sci. Published online 2009.

scientific breakthrough.

doi:10.1002/9780470015902.a0003255.pub2

modified (GM) crop use 1996-2013: Impacts on pesticide use and

Dear Reader,

GM

Crops

Food.

2015;6(2):103-133.

12. Dubock A. The politics of Golden Rice. GM Crops Food.

References

2014;5(3):210-222. doi:10.4161/21645698.2014.967570 13. Ricroch A, Chopra S, Fleischer SJ. Plant biotechnology:

1. Shankar S, Shikha. Renewable and Nonrenewable Energy Resources: Bioenergy and Biofuels.; 2017. doi:10.1007/978-981-10-1866-4_9 2. Saxena G, Kishor R, Saratale GD, Bharagava RN. Genetically Modified Organisms

emissions.

(GMOs)

and

Their

Potential

in

Environmental

Management: Constraints, Prospects, and Challenges. Bioremediation Ind Waste Environ Saf. Published online 2020:1-19. doi:10.1007/978-

Experience and future prospects. Plant Biotechnol Exp Futur Prospect. Published online 2014:1-291. doi:10.1007/978-3-31906892-3 14. Obesity P. Nutrition Bytes. Nutrition. 2000;6(1).

15. Example of genetically modified plant (GMP) Bacillus thuringiensis.

16. Steinhäuser KG. Environmental risks of chemicals and genetically

981-13-3426-9_1 3. Du L, Rachul C. Chinese newspaper coverage of genetically modified organisms. BMC Public Health. 2012;12(1). doi:10.1186/1471-2458-

modified organisms: A comparison: Part I: Classification and characterisation of risks posed by chemicals and GMOs. Environ Sci Pollut Res. 2001;8(2):120-126. doi:10.1007/BF02987305

12-326 4. Awasthi MK, Guo D, Awasthi SK, et al. Recent Advances in Phytoremediation of Toxic Metals from Contaminated Sites: A Road Map to a Safer Environment. Vol II.; 2020. doi:10.1007/978-981-13-

17. Ford N, Murphy G. Managing environmental risks from genetically modified organisms: the role of safety training. Environ Manag Heal. 1998;9(3):100-105. doi:10.1108/09566169810222175 18. Tsatsakis AM, Nawaz MA, Tutelyan VA, et al. Impact on

3426-9_4 5. Fontes EMG, Pires CSS, Sujii ER, Panizzi AR. The environmental effects of genetically modified crops resistant to insects. Neotrop Entomol.

2002;31(4):497-513. doi:10.1590/s1519-566x2002000400001

environment, ecosystem, diversity and health from culturing and using GMOs as feed and food. Food Chem Toxicol. 2017;107:108121. doi:10.1016/j.fct.2017.06.033

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BRIEF APPROACHES ON HOW GENETICALLY MODIFIED ORGANISMS AFFECTED OUR LIFE Ahmed Elfitory 1 1- EPSF, Egypt | October 6 University 1- Introduction

Dear Reader,

In August 2013, a research field of Golden Rice managed by the Philippine Government's IRRI, and other public sector partners were attacked by anti-GMO activists.“Golden Rice” expresses high levels of beta-carotene (a precursor of vitamin A) thanks to its modified genetic properties. After 25 years’ bench work in the laboratory, Golden Rice designed a cheap and effective way to deliver a dietary source of vitamin A for developing areas of the world, which had finally reached the point where field trials were practical. Although different in many ways from the 2011 CSIRO break-in, the 2013 incident triggered strong condemnation by the scientific community, though that reaction failed to achieve consensus among public voices. The fundamental reason for the failure is the continuing lack of a comprehensive understanding of current agricultural problems and the nature of genetically modified organisms (GMOs). In this review, starting with the history of GMOs, we address the motivation for GMOs (including GM foods), their benefits and risks, as well as the impact of recent technology developments on GMO/GM foods.

3- New innovation in GMOs in the exposition of technological gap, demand lag, and trade The nexus of innovation and trade is commonly analyzed in terms of technological gaps and market-share gains for innovating countries.

However, this relationship may not hold under certain circumstances - as in the case of genetically modified organisms. Based on a firm heterogeneity model, this study investigates the role of technological gaps and demand lags in the case of international trade in goods after the emergence of a “highly scrutinized” or “distrusted” technology. The demand lag may be understood as the difference between techniques employed by producers in exporting countries and levels of acceptance or compatibility in destination markets.

Likewise, a technological gap is the difference between techniques employed by late-movers and those used by leading countries. By means of a gravity equation, we empirically estimate these effects based on the bilateral trade of soybeans between 1995 and 2012.

Results indicate that both technological gaps and demand lags reduce trade by similar magnitudes. Thus, producing countries

2- History

should carefully weigh the negative effects of falling behind and of approving varieties not approved for importation in destination

The genesis of DNA modification technology can be traced back to 1944,

markets.

when scientists discovered that genetic material could be transferred between different species. Several hallmark papers paved the way to the modern science of molecular biology.

In 1954, Watson and Crick

discovered the double-helix structure of DNA, and the “central dogma” -

4- Effect of GMO regulations on gene therapy clinical trials - Industry’s position paper

DNA transcribed to messenger RNA, translated to protein - was established. Nobel Laureate Marshall Nirenberg and others had

The Alliance for Regenerative Medicine (ARM) and other industry

deciphered the genetic code by 1963. In 1973, Cohen et al. developed

groups are urging regulators to consider gene therapy requirements

DNA recombination technology, showing that genetically engineered

in upcoming reforms, because some advanced therapy medicinal

DNA molecules could be transferred among different species.

products, such as gene therapies, contain GMOs, and as such, require additional approvals before clinical trials can commence.

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According to a new position paper from ARM and other industry groups,

An experiment was conducted in which subjects in the experimental

the GMO application and clinical trial approval process in some EU

group tasted cheeses, one of which was labeled as “produced using

member states places a “significant burden” on gene therapy medicinal

GMOs.” The cheeses were selected in a way that ensured that the

products (GTMP) clinical trials, ultimately delaying patient access to

subject had a sensory preference for the GMO cheese. A control group

“potentially transformative medicines”. It adds that “these GMO

tasted cheeses that were unlabeled. After the tasting, subjects

regulations actually hinder the start of clinical trials for gene therapy

completed a conjoint analysis task about cheese, in which the type of

products in Europe, despite all the advances that have been made for the

starter culture used was one of the attributes. Subjects also were

regulation of advanced therapies”, quoting Anne-Virginie Eggimann, vice

administered a set of items measuring attitude towards the use of

president of regulatory affairs. Eggimann explained that many companies,

GMOs in food production. Results showed that for the subjects in the

which are primarily based in the US, when trying to initiate clinical trials

experimental group (who believed that they had tasted a GMO cheese,

for gene therapy products in the EU, run into several issues because the

with which they had a positive sensory experience):

requirements for GMOs are complex.

1. attitude towards GMO in food production was less negative

Reader, 5-Dear Challenges facing GMOs

2. type of starter culture used had less impact on their buying intentions with regard to cheese than for subjects in the control group

A. Arable land decrease FAO predicted that the finite amount of arable land available for food production per person will decrease from the current 0.242ha to 0.18ha by 2050. This problem confounds those of population growth and malnutrition. Yet, our ability to bring additional acreage under cultivation seems limited. The alternative is the greater yield per acre, which in turn must come from greater agriculture inputs, such as fertilizer, water, pest and weed control – and/or genetic improvement. This scenario is compounded by several complicating factors: 1. The increased demand and feedstock production 2. Accelerated urbanization 3. Land desertification, salinization, and degradation 4. Climate change

7- Conclusion Farmers have benefited from being able to reduce insecticide use when growing GM crops that are resistant to diseases and insects and reduce crop loss associated with these pests. Crop loss to disease and insects could be economically devastating to growers worldwide, and GM crops that provide protections from such losses continue to be desirable to growers. GM crops that help address nutritional needs or consumer preferences will likely continue to be produced in the future as the latest research has shown GMO ingredients and products are safe to consume and are associated with very little to no health risk for the public. However, consumer acceptance is still low and many feel

5. Water resource limitation

that consumers have a right to know if there are GMO ingredients in their food and want them clearly identified on food labels. Soon

B. Population expansion The expansion of population is one of the major contributors to undernourishment around the world. In 2016, the U.N. FAO reported that

consumers will be able to identify when a product contains GMOs. References

795 million people in the world were undernourished, among which 780

1. Zhang, C., Wohlhueter, R., & Zhang, H. (2016). Genetically modified foods: A critical

million people in developing regions. Therefore, the eradication of hunger

review of their promise and problems. Food Science and Human Wellness, 5(3), 116–123. doi:10.1016/j.fshw.2016.04.002

should be a priority of policy-making.

2. Oliveira, P. R. S., Silveira, J. M. F. J. da, & Bullock, D. S. (2019). Innovation in GMOs,

6- Attitudes towards the use of GMOs in food production European consumers are skeptical towards GMOs in food production, and

technological gap, demand lag, and trade. Agribusiness. doi:10.1002/agr.21622 3. GMO regulations a ‘significant burden’ on gene therapy clinical trials. Article from Outsourcing-Pharma.com, writen by Melissa Fassbender, October 2017.

their willingness to buy such products is low. Previous research also

4. Grunert, K. G., Bech-Larsen, T., Lähteenmäki, L., Ueland, Ø., & Åström, A. (2004).

shows that these attitudes are quite resistant to attempts to change them

Attitudes towards the use of GMOs in food production and their impact on buying

by giving additional information. The aim of the study was to investigate if positive sensory experience with a GMO-based food product would influence consumers' attitude towards the use of GMOs in food

intention: The role of positive sensory experience. Agribusiness, 20(1), 95–107. doi:10.1002/agr.10086 5. What Are GMOs? Article from the Division of Agriculture, University of Arkansas, written by Jamie I. Baum, Amanda McWhirt, and others, 2017.

production.

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NEW IN VITRO MODEL (ORGAN-ON-A-CHIP OF THE HEART) Enas Ezzat 1 1- EPSF, Egypt | Misr University for Science and Technology 2-Object

1- Introduction

Dear Reader,

The development of organs-on-chip (OoC) has revolutionized in vitro cell-culture experiments by allowing a better mimicry of human

The heart is one of the most important organs in the human body,

physiology and pathophysiology, which has consequently led

actively pumping blood through the vascular network to supply

researchers to gain more meaningful insights into disease

nutrients to and remove wastes from all other organs, thereby

mechanisms. Several models of hearts-on-chips and vessels-on-chips

maintaining the biological system's homeostasis. Huge efforts have

have been demonstrated to recapitulate fundamental aspects of the

been made over the last few decades to engineer functional cardiac

human cardiovascular system in the recent past. These 2D and 3D

tissues for heart regeneration using biomimetic approaches. More

systems include synchronized beating cardiomyocytes in hearts-on-

recently, progress has been made toward transforming knowledge

chips and vessels-on-chips with layer-based on structures and the

gained from cardiac tissue engineering into physiologically relevant

inclusion of physiological and pathological shear stress conditions.

microfluidic human heart models (e.g. heart-on-chips) for drug

The opportunities to discover novel targets and to perform drug

discovery applications.4 Lab-on-a-chip systems may be the solution,

testing with chip-based platforms have been substantially enhanced.

allowing the creation of a heart muscle model and the growth of

However, certain technical and biological challenges remain, making

cardiac cells in conditions similar to those found in vivo.

the global utilization of OoCs to tackle unanswered questions in

Microsystems can also be used successfully to differentiate stem cells

cardiovascular science still rather challenging.1 Extensive preclinical

into heart cells. It will help better understand of proliferation and

examination and validation of potential therapeutic compounds are

regeneration ability of these cells.5

required prior to their clinical evaluation and approval. This process is time-consuming (approximately ten years), extremely costly (approximately two billion dollars), and has low efficiency (<20%).

Some drug nominees have shown preclinical success, while they were ineffective and sometimes deadly in the clinic. For example, encainide and flecainide as class I antiarrhythmic agents showed a great role at suppressing irregular cardiac pacing in preclinical trials in 1980.2 Making human tissues on a chip allows for more accurate, repeatable, real-time, and ideally high-throughput measurements of tissue behavior and function in pharmaceutical applications. Human tissue models can be scaled based on organ size in the body.

Therefore,

drug

toxicity

or

effectiveness

using

metabolite

concentrations in the model and understanding physiological ratios of blood surrogate to cells, the efficacy of human tissue models can

Figure 1. Heart’s anatomy

be extrapolated to the entire human body.3

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Dear Reader,

Figure 2. Blood’s pathway throughout the heart

Table 1. Examples of materials used in the production of OoC platforms and their advantages/disadvantages

B.The heart is a muscular pump that serves two functions: 1. to collect blood from the tissues of the body and pump it to the lungs; 2. to collect blood from the lungs and pump it to all tissues of the body.

The human heart is located in the protective thorax, posterior to the sternum and costal cartilages, and rests on the superior surface of the diaphragm. The heart is positioned obliquely in the thorax, two-thirds to the left of the midline. It is located between the pleural cavities in a space known as the middle mediastinum, which is defined as the space inside the pericardium, the covering that surrounds the heart. The inner and outer layers of this serous membrane are separated by a lubricating fluid.

Because of the fluid, the inner visceral pericardium can "glide" against the outer parietal pericardium.6

3- Materials and methods of manufacturing

Figure 3. Examples of manufacturing of OoC16

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4- Heart-on-chip disease models

A 5.2- Cardiac fibrosis In the scope of cardiac fibrosis, Kong et al. were able to recreate increased extracellular matrix (ECM) components, such as collagen and fibronectin, and increases tissue stiffness.12 Although several factors have been implicated in orchestrating the fibrotic response, tissue fibrosis is dominated by one central mediator: transforming growth factor (TGF).13 TGF secretion is sustained, resulting in a continuous cycle of growth factor signaling and dysregulated matrix turnover. Despite abundant evidence from fibrosis animal models and human biopsies supporting a central role for TGF in tissue fibrosis, modulating

Dear Reader,

TGF function to attenuate or reverse fibrosis is fraught with difficulties. For example, attempts to block TGF-β signaling using antagonists to the type I activin receptor-like kinase 5 (ALK5) have failed to reach clinical studies, owing mainly to

Figure 4. Examples of hearts-on-chips16

safety concerns.14

A rise in the biological complexity of their organisms control over the microenvironment and the cultured cell types permits the recreation of relevant aspect of a certain ailment. Among the various documented heart-on-a-chip platforms, models to address cardiac ischemia, cardiac fibrosis, and cardiotoxicity can be discovered, while many other promising technologies are still being developed.

5.1- Ischaemia Figure 5. Development and characterization of the human In ischemia, the abrupt interruption of blood flow results in the

cardiac fibrosis-on-a-chip (hCF-chip) model. Render of the hCF-

accumulation of metabolic by-products and a reduction in oxygen supply

chip

to the tissue.

microtissues indicates fibrosis affects human cardiac tissue

Cardiomyocytes contraction is affected locally as a result of this. Using

function. Average tissue stiffness was assessed by atomic force

patterned electrodes in a heart-on-a-chip device, Liu et al. were able to mimic the hypoxic microenvironment and track the action potential changes in the cell culture over time.11

containing

3

microwells.

Characterization

of

the

microscopy at the endpoint (average ± SEM, p=0.029, n=3).

Comparative transcriptomic analysis between control and fibrotic tissues shows recapitulation of a fibrotic signature. Heat map showing unsupervised clustering of selected fibrosisrelevant

genes.

Treatment

with

the

anti-fibrotic

drug

pirfenidone significantly decreases tissue stiffness and BNP secretion but does not alter other parameters. Schematic of the drug treatment timeline.12

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5.3- Cardiac toxicity

Reference

Surprisingly, the vast majority of heart-on-chip devices reported in the literature

state

cardiotoxicity

as

their

primary

goal.

Although

cardiotoxicity has a variety of etiologies, two common trends can be found in these gadgets: An investigation of the toxic effects that specific drugs have on cardiac cells.

The toxic effect produced by the co-cultured cells from other organs (e.g liver).

The aforementioned models, of course, make use of cardiac cells, a scarce

Dear Reader,

resource, given that primary cardiomyocytes proliferate poorly in vitro.

This major cell source bottleneck is gradually being overcome with the introduction of human iPSC-CMs.15

5.4- Atherosclerosis

1. Ribas, J., Sadeghi, H., Manbachi, A., Leijten, J., Brinegar, K., Zhang, Y., Ferreira, L. and Khademhosseini, A., 2016. Cardiovascular Organ-on-a-Chip Platforms for Drug Discovery and Development. Applied In Vitro Toxicology, 2(2), pp.82-96.

2. Huh D, Kim H, Fraser J et al. Microfabrication of human organs-on-chips. Nat Protoc. 2013;8(11):2135-2157. Doi:10.1038/nprot.2013.137.

3. Microfluidic Cell Culture and Its Application in High-Throughput Drug Screening: Cardiotoxicity Assay for hERG Channels – Xiaojing Su, Edmond W. K. Young, Heather A. S. Underkofler, Timothy J. Kamp, Craig T. January, David J. Beebe, 2011.

SAGE Journals. https://journals.sagepub.com/doi/abs/10.1177/1087057110386218.

Published 2021. Accessed May 31, 2021.

4. 2. Zhang Y, Aleman J, Arneri A et al. From cardiac tissue engineering to heart-on-a-chip: beating challenges.

Biomedical Materials.

2015;10(3):034006. doi:10.1088/1748-6041/10/3/034006 5. 3. Jastrzebska E, Tomecka E, Jesion I. Heart-on-a-chip based on stem cell biology.

Biosensors and Bioelectronics.

2016;75:67-81. doi:10.1016/j.bios.2015.08.012.

6. Anthony J Weinhaus, Kenneth P Roberts Handbook of cardiac anatomy, physiology, and devices, 51-79, 2005 1. Sudo R, Chung S, Zervantonakis I et al. Transport‐mediated angiogenesis in 3D epithelial coculture. The FASEB Journal. 2009;23(7):2155-2164. doi:10.1096/fj.08-122820.

2. M. L. McCain, A. Agarwal, H. W. Nesmith, A. P. Nesmith, K. K. Parker, Biomaterials 2014, 35, 5462.

3. Bhattarai N, Edmondson D, Veiseh O, Matsen F, Zhang M. Electrospun chitosan-based nanofibers and their cellular compatibility. Biomaterials.

2005;26(31):6176-6184. doi: 10.1016/j.biomaterials.2005.03.027.

4. Douezan S, Dumond J, Brochard-Wyart F. Wetting transitions of cellular aggregates induced by substrate rigidity. Soft Matter. 2012;8(17):4578. doi:10.1039/c2sm07418d.

5. Liu H, Bolonduro O, Hu N et al. Heart-on-a-Chip Model with Integrated Extraand Intracellular Bioelectronics for Monitoring Cardiac Electrophysiology

Figure 6. Examples of vessels-on-chips16

6- Conclusion The field of OoC is growing, and an increasing number of academic groups and companies are becoming active in the development of OoC systems. All these OoC systems have different layouts and interfaces, which prevents them from being easily connected, interchanged, or compared. Overall, the use of OoC system is rapidly moving from basic science to

under Acute Hypoxia. Nano Lett. 2020;20(4):2585-2593. Doi: 10.1021/acs.nanolett.0c00076 6. Mastikhina O, Moon B, Williams K et al. Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug testing.

Biomaterials.

2020;233:119741.

Doi: 10.1016/j.biomaterials.2019.119741.

7. 6. Wong M, Staszewsky, Latini R. Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure. ACC Current Journal Review. 2004;13(9):26. doi:10.1016/j.accreview.2004.08.034 8. 7. Westra I, Oosterhuis D, Groothuis G, Olinga P. Precision-cut liver slices as a model for the early onset of liver fibrosis to test antifibrotic drugs. Toxicol Appl Pharmacol. 2014;274(2):328-338. doi:10.1016/j.taap.2013.11.017.

9. Savoji H, Mohammadi MH, Rafatian N, Toroghi MK, Wang EY, Zhao Y, Korolj A, Ahadian S, Radisic M. Cardiovascular disease models: a game changing paradigm in Drug discovery and screening. Biomaterials 2019; 198:3–26.

10. Valentina Paloschi, Maria Sabater-Lleal, Heleen Middelkamp, Aisen Vivas, Sofia Johansson, Andries van der Meer, Maria Tenje, Lars Maegdefessel, Organ-on-a-chip technology: a novel approach to investigate cardiovascular diseases, Cardiovascular Research, 2021;, cvab088, https://doi.org/10.1093/cvr/cvab088

translational research to validate results from genomic studies and provide better models for drug testing, paving the way for personalized medicine.

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CLIMATE CHANGE’S IMPACT ON OUR HEALTH: HOW NATURE LINKS TO ALLERGIC RESPIRATORY DISEASES Priyanka Patel 1 1- BPSA, United Kingdom | University of Brighton Abstract

Dear Reader,

2- Materials and methods

The impact of climate change on healthcare is a widespread imminent problem which is being brought to light due to the progression of the climate crisis. In particular, allergic respiratory diseases (ARDs) such as asthma, allergic rhinitis, and hay fever are exacerbated by climate changes like extreme weather conditions, pollen grains, and greenery. The majority of studies focused on the impacts of these changes and the way by which they influence the prevalence of ARDs. Human and plant migration are also important factors in the increase in ARDs. There is a great deal of correlation shown between the factors being explored in the review. However, the studies show limits such as countries and settings in which they have been conducted. As this is an ever-changing field, there is a wide scope for multiple studies and further niche studies to be developed from the current studies.

This study is a systematic review of existing literature that has been sourced from a variety of research libraries. The studies reviewed and discussed in this literature had to adhere to the following criteria in order to be considered: 1. Written originally in English 2. Published in 2020 and onwards 3. Focusses on allergic respiratory diseases 4. Discusses plants or pollen in detail These criteria ensure the studies discussed are correctly interpreted, relevant, and discuss the current knowledge and findings within this field. 22 articles were reviewed and 7 of these were used (either excluded due to repetition of information or unsuitable as per parameters).

1- Introduction

3- Results

This literature review aims to focus on the impacts of climate change

The majority of studies determined that pollen grains and air pollutants

on nature, with a particular focus on plants, as well as the

in the atmosphere have increased due to climate change. Climate

subsequent impact on patient health. Allergic respiratory diseases

change has a multitude of effects but the most notable are on weather

are arguably one of the most affected disease groups by the ongoing

conditions and temperature extremes. There are a variety of

climate crisis. There are a number of studies discussed which explore

environmental implications which contribute to the occurrence and

the way in which the climate crisis is, directly and indirectly,

exacerbation of ARDs. The results of this literature review identify these

increasing the number of patients with asthma, allergic rhinitis, and

as being temperature extremes, indoor and outdoor air quality, and

hay fever amongst other ARDs.

urbanisation.

The objective of this study is to determine the key contributing

To detail this further, one key environmental occurrence which has

factors to disease onset and exacerbation, as well as highlight the

increased in prevalence due to climate change is thunderstorms.

key considerations for healthcare professionals.

Thunderstorms were found to be a major contribution in exacerbating ARDs, with a key relationship being identified between thunderstorms and asthma. Another idea that has been consistently found throughout a number of studies is the impact of decreasing biodiversity.

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Overall, a significant amount of literature builds on the idea that

Climate change and weather differences can affect the amount of

pollen count and air pollutants, such as nitrogen dioxide and

pollen and allergens in the environment too. Climate change leads to

particulate matter, can have direct impacts on our respiratory tract

longer and earlier pollen seasons. Atmospheric fungal spore counts

and thus on the prevalence of ARDs.

are linked to significant asthma admission increases and ER visits.1

4- Discussion

Pollen and mould allergens are able to trigger the release of pro-

ARDs have dramatically increased in prevalence over the last few

adhere to pollen grain surfaces changing their morphology as well as

decades5 and this can largely be related to the ongoing climate

their allergenic potential.3

inflammatory and immunomodulatory mediators that accelerate the onset of IgE-mediated sensitisation and of allergy. Air pollutants

crisis. Climate change can result in hot and cold temperature extremes which have direct impacts on human respiratory health. A

A key concern highlighted in numerous studies is the spread of these

study by Deng et al1 outlines that extreme heat conditions can

pollen grains. Changes in wind patterns mean pollen and pollutants

stimulate

nerves,

are transported over longer-distance. Air pollutants such as nitrogen

whereas increases in cold weather can lead to decreased pulmonary

dioxide, sulphur dioxide, particulate matter, and diesel exhaust

circulation and lung perfusion. In addition, cold temperature can

particles can increase respiratory tract permeability, facilitate allergen

induce bronchial hyperactivity and tracheal smooth muscle

penetration into mucous membranes, and cause interaction with the

contraction, and exercise in cold air is associated with

cells of the immune system. Airway inflammation increases the

bronchoconstriction and airway hyper-responsiveness. However, as

permeability of airways which means pollutants overcome the

knowledge of the extensive effects of climate change is increasing

mucosal barrier and allergenic response is enhanced.3

and developing, a number of studies are shifting the focus onto

To further this, an increase in carbon dioxide in the atmosphere leads

factors such as the implications of temperature on other

to faster and larger growth of plants thus there is a rise in pollen and

environmental factors.

an increase in intensity. Plants show improved photosynthesis and

Several studies have discussed the wider environmental impact in

reproductive effects and produce more pollen. There are two key

particular relation to weather events like thunderstorms. During a

groups of plants C3 and C4: C3 grasses are temperate and increase in

thunderstorm, pollen grains in the environment rupture due to

winter then bloom in spring; C4 grasses are subtropical and grow and

osmotic shock and thereby release their content into the

bloom in summer and early fall. Allergic sensitivity to subtropical

atmosphere.6 Particularly in the first half an hour of a thunderstorm

pollen exists with climatic and geographic differences.3

during pollen season, a high concentration of pollen-related

A study on the impact of residential greenness focussed on whether

allergenic material is dispersed in the environment and thus inhaled.

planting greenery in urban areas could help offset the negative

Raindrops containing pollen or moulds can break up into

impacts of urbanisation and decrease environmental factors such as

microdroplets which then carry these allergens deeper into the

air pollution.4 There are many studies linked to the idea that

airways.5 In addition, thunderstorms tend to take place in spring and

exposure to green spaces can significantly influence human health.

summer when pollen levels are high to begin with. Rainwater

Short-term benefits are vegetation removing air pollutants and

promotes the release of these particles which can be inhaled.

improving air quality. Green areas are characterised by biological

Studies show that pollen grains become concentrated at ground

diversity and a variety of species and ecosystems. However, Deng et

level due to storms, which then provokes allergenic particle release

al explains that plant migration can expose people to new plant

in respirable size after water absorbance and rupture by osmotic

types and new aeroallergens. Another study describes how climate

shock.1

change has brought about a drastic reduction in our planet’s

Dear Reader, thermosensitive

bronchopulmonary

C-fibre

biodiversity.5 Other studies relating to this field present contradicting ideas and thus this is an area that requires further research and studies.

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The impact of climate change on indoor and outdoor mould gets little attention in comparison to things like pollen. After a severe flood, there are increased levels of microbes and mould growth in houses and more mould spores in the atmosphere.1 Indoor allergens such as pets, moulds, and house dust mites can contribute to the onset and aggravation of ARDs.7 The magnitude of mould influenced by climate change is not known.

In addition to plant migration, human migration is an interesting factor that has many effects on climate change and thereby the prevalence of ARDs. Human migration involves exposure to a different set of allergens including housing condition, indoor and

Dear Reader,

outdoor contamination, and diet.1 The impacts of these environmental factors and the subsequent respiratory implications are seen throughout the world in both developed and developing countries. High microbial exposure, such as on farms, is shown to have protective roles against ARDs. There is a concept called “healthy immigration effect” that describes the lower occurrence of these diseases and better health in those who immigrate to countries like the USA and Canada. Age during migration also plays a role in the risk of developing ARDs.5 The main role of the industrial process is due to pollutants, however, the industrial process also releases plant allergens into the atmosphere thus exacerbating ARDs. Indoor nitrogen dioxide is derived from gas-fuelled cooking and heating. All of these factors are key considerations in regards to determining the effect of climate change on ARDs.

5- Conclusion

References 1. Deng, S. Z., Jalaludin, B. B., Antó, J. M., Hess, J. J., & Huang, C. R. (2020). Climate change, air pollution, and allergic respiratory diseases: a call to action for health professionals. Chinese medical journal,

133(13),

1552–1560.

https://doi.org/10.1097/CM9.0000000000000861 2. Demain, J.G., Choi, YJ. & Oh, JW. The Impact of Climate Change on the Pollen Allergy and Sporulation of Allergic Fungi. Curr Treat Options Allergy 8, 60–73 (2021). https://doi.org/10.1007/s40521020-00277-5 3. D’Amato, G, Chong‐Neto, HJ, Monge Ortega, OP, et al. The effects of climate change on respiratory allergy and asthma induced by pollen and mold allergens. Allergy. 2020; 75: 2219– 2228. https://doi.org/10.1111/all.14476 4. Giuliana Ferrante, Federica Asta, Giovanna Cilluffo, Manuela De Sario, Paola Michelozzi, Stefania La Grutta. The effect of residential urban greenness on allergic respiratory diseases in youth: A narrative review. World Allergy Organization Journal, Volume

13,

Issue

1,

2020,

100096.

ISSN

1939-4551.

https://doi.org/10.1016/j.waojou.2019.100096.

5. Wenping Lei, Chengguo Liu, Lina Pan, Can Peng, Jiaqi Wang, Hui Zhou. (2021) Screening of probiotic Lactobacilli with potential anti-allergic activity based on hyaluronidase inhibition and degranulation of RBL-2H3 cells in vitro. LWT 140, pages 110707. https://doi.org/10.1080/17476348.2020.1794829 6. D’Amato G., D’Amato M. (2020) Thunderstorms During Pollen Season as Risk Factors for Allergic Respiratory Diseases and Severe Asthma. In: Akhtar R. (eds) Extreme Weather Events and Human Health. Springer, Cham. https://doi.org/10.1007/978-3-

In conclusion, the current focus of numerous studies is on the weather and pollen changes due to climate changes. This literature review has briefly discussed how air pollutants are generally increased due to climate change, how pollutants and other factors can affect us biologically, and the impact of human and plant

030-23773-8_20 7. Eguiluz‐Gracia, I, Mathioudakis, AG, Bartel, S, et al. The need for clean air: The way air pollution and climate change affect allergic rhinitis

and

asthma.

Allergy.

2020;

75:

2170–

2184.

https://doi.org/10.1111/all.14177

migration. There are further details regarding thunderstorms, extremes of temperature, and indoor vs outdoor pollutant impacts.

In terms of gaps in the field, the majority of studies focus on countries such as the USA and Canada, thus a more globalised approach would provide further data and trends. Also, in the current climate there is scope for studies on the impact of the pandemic and whether wearing masks or spending time indoors has had an influence on the various factors discussed in this study. In addition, further studies should be undertaken to determine solutions for patients and equip healthcare professionals with knowledge on the subject.

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A REVIEW OF THE IMPACT OF CLIMATE CHANGE ON HUMAN HEALTH AND DRUGS Karima Bennara, Alison Ekwere Williams, Olaoue Damilola Quazeem, Adeola Bamisaiye, Nahal Shamisiezadeh, Annabeth Korkor Ocansey, Amira Elgendy Young Researchers Forum, International Pharmaceutical Students Federation

Abstract

Background

Dear Reader,

Climate change means the long-term shift in global or regional climate patterns. Climate change is now a major concern, especially in colder countries. It has various consequences for sea-level changes, plant life, and human societies and their well-being.

Changed climate associated with the enhanced Greenhouse Effect may lead to drug-related health impacts through modifying storage conditions, increasing heat stress from medication-induced heat intolerance, and influencing pharmacokinetics, drug quality, and supply chain.

This review aims to examine how climate change affects drugs, as well as the economic aspects of climate change and how it affects pharmaceutical

companies,

by

following

a

critical

and

comprehensive literature review process on published articles with keywords “Heat Waves”, “Drug Shelf life”, “Drug storage conditions”.

The articles were sourced from PubMed, Google Scholar, and WHO databases.

Our climate has been measurably changing for the past 100 years. It may indeed be the most significant health threat of the twenty-first century, and consequently tackling climate change may be the greatest health opportunity. The impacts of climate change on human health are varied and coming more into focus. Direct effects, such as heatwaves, severe weather, drought, and flooding, are apparent and frequently in the news. Indirect or secondary effects, such as changes in ecosystems and the impact on health, are less obvious. It is these changes in ecosystems that may have the

Earth’s climate is now changing faster than at any point in the history of modern civilization, primarily as a result of human activities.

Impacts related to climate change are evident across regions and in many sectors important to society, such as human health, agriculture and food security, water supply, transportation, energy, ecosystems, and are expected to become increasingly disruptive in the coming decades.

According to the WHO, climate change is impacting human lives and health in a variety of ways. It threatens the essential ingredients of good health, clean air, safe drinking water, nutritious food supply, and safe shelter, and has the potential to undermine decades of progress in global health. Between 2030 and 2050, climate change is expected to cause approximately 250 000 additional deaths per year, as a result of malnutrition, malaria, diarrhea, and heat stress alone.

Medicines and health products are important for addressing health problems and improve the quality of life. However, evidence in the literature on how the changing climate may affect the quality, availability, accessibility, and affordability of medicines is very scarce.

This research aims to use a critical point of view, to reflect and elaborate on the ways in which climate change can affect all these aspects of medicines and medicines use.

Method

greatest impact on allergic and respiratory diseases.30 This review will also explore some of the ways that climate change,

This research used a critical and comprehensive literature review

current and predicted, influences human health, with greater

process by developing research questions based on the aim of the

emphasis on respiratory diseases.

research and critically evaluate what is existing in the literature to answer the research question. This topic is not quite famous, however,

Key Words: Heatwaves, Drug shelf life, Drug storage conditions

some books and articles are available.

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Introduction

The release of greenhouse gases causes global warming and climatic variations affect human health. The Northern Hemisphere has severe

The planet earth faces unimaginable changes in climatic patterns as a result of the interaction between natural and anthropogenic forces. The contribution of volcanic eruption19, fossil fuel burning22, deforestation23 towards the observed climatic changes have raised growing concerns in recent years. The humanistic, psychological, economic, and health impacts of climate change have been studied and accounted for24-26 but only a few studies have however studied the impact of climate change on drug effectiveness. Studies also show higher temperatures affect the availability of clean air, safe

Dear Reader,

drinking water, and food, worldwide.

winters and heatwaves, strong storm winds raise the risk of illness related to low temperatures such as hypothermia and frostbite and lowering resistance to respiratory infection. The change in climate is associated with the change in pharmaceutical use, and it affects the ecosystems'

functions

and

structures.

The

elevated

drug

consumption is due to the availability of cheap generic drugs, the increase of the global population, the current depression epidemic, obesity, and the aging demographics of many western and developing nations.2 The ecotoxicological effects of pharmaceuticals and their metabolites

Climate change affects human health by various pathways as shown in Figure 1.

in the environment are under examination as the routine sewage treatment process does not remove the pharmaceuticals completely.

Their presence causes damaging consequences exerted on biota, such as the deaths of millions of vultures on the Indian subcontinent due to exposure to the nonsteroidal anti-inflammatory drug (NSAID) diclofenac, and the fish feminization cases associated with excreted components of women's contraceptive pills. Besides, the global spread of antibiotic resistance in the environment.3-5 Non-communicable diseases represent about two-thirds of all global diseases. If the climate continues to change, the number of affected people will increase by the hundred thousands worldwide.6 Heatwaves' intensity and frequency during summertime have caused thousands of deaths across Europe in the recent decade, harming particularly those with cardiovascular and cerebrovascular diseases.

The treatment of cardiovascular disease involves a cocktail of drugs

Figure 1. Pathways on how climate change affects human health1 Since the mid-20th century, global temperature increases due to the emissions of greenhouse gases, such as carbon dioxide, methane, and nitrous oxides. According to "Intergovernmental Panel on Climate Change 2007", the mean surface temperature rises 0.74ºC between 1906 and 2005 and if not properly addressed, the atmospheric concentrations of carbon dioxide will reach 500 to 1100 ppm by 2100 that increases the mean surface warming of 1.1 to 6.4ºC by the end of the 21st century.2

that often include diuretics to reduce blood pressure, salicylates and antiplatelets to decrease blood clotting, and statins to tackle high cholesterol. Those prone to cerebrovascular disease need similar treatment as cardiovascular disease, although anticoagulants are most used after an ischemic stroke. During heat waves, people spend time outdoors prone to sunburns, so they use anti-inflammatory medications such as cortisone (steroidal). The long-time exposure to sunlight causes actinic keratoses of the skin, and in some cases, squamous-cell carcinoma develops, requiring chemotherapeutic antimetabolites.6 In hotter weather, the use of deodorants and detergents increases.

On the other hand, with erratic rainfall patterns, if individuals neglect hygiene, infections will occur and the person is vulnerable to dermatitis caused by the mite Sarcoptes scabiei or conjunctivitis and trachoma caused by Chlamydia trachomatis (gram-negative bacteria), which respectively require anthelmintics and antibiotics.2

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Heat - Although the predicted range of temperature increases falls

1- Climate change and health

within the range of 1.4-58°C this is only a global average. There could indeed be local variations in certain parts of the globe that will

Human-induced climate change will impact societies and their

exceed this range. In general, when evaporation exceeds water

health in many ways. The chain that creates the effect is composed

absorption by the soil, increased temperatures are a prelude to

of three distinctive steps: climate change impact, changes in the

drought. Drought can have several direct and indirect effects on

environmental system that determine human health, and impacts

ecosystems that may lead to a variety of problems, like changes in

on human health.

vector abundance if that vector breeds in dry river beds, leading to a

To give an idea of the potential uncertainties that may exist with

proliferation of a disease-carrying species; drier than normal

each of the levels of the “climate chain”, the following is a summary

conditions tend to decreased crop production and generate famine

of potential variations that could occur:

and malnutrition; reduction in the quality of water supply leads to

Greenhouse gas emissions (which create climate change) may

malnutrition and increased risk of infection due to water-related

be much higher than expected due to increased demand from

illnesses; displacement of people from regions of drought lead to

Third World countries.

transmission of regional diseases to areas that have little/no

Climate change impacts may be more severe and more

immunity from those diseases.

geographically spread than first envisaged.

Extreme weather events - Increased atmospheric energy will

Human health may deteriorate, in general, due to the changing

inevitably lead to a greater chance of more extreme weather events

climate change conditions of the next century (poorer diets due

such as hurricanes, tornadoes, typhoons, and storms in general.

to lack of foods and lack of access to appropriate health drugs

These events themselves can cause local, regional, and national

and clean water).

problems simply from their sheer destructive nature (e.g. loss of

Certain genetic pools may become more susceptible to different

infrastructure). In addition, these large events can decimate crops

diseases in an unforeseen way as climate changes increase.

instantly, exposing local and national populations to famine

Disease vectors may react differently and more radically than

conditions and associated levels of malnutrition. Hurricanes are large

expected (in a warmer and wetter world).

atmospheric disturbances that can span thousands of kilometers in

Dear Reader,

width. When they form they have the ability to pull in the local atmosphere (from the central eye of the storm) and eject it many hundreds or thousands of kilometers away (at the outer edges of the storm system). This very mechanism is thought to be a good way of spreading disease-bearing organisms from one region to another in a sort of conveyor-belt/escalator mode. Thus, communities that have little or no immunity to a certain type of disease may be inadvertently exposed to new diseases from many thousands of kilometers away.

El Niño - When the specific climate event known as El Niño operates, usually every 3-7 years, in the Pacific region, quite often an after-

It is clear that future climate may not mirror the past climate and as

effect of this perturbation is an outbreak of cholera in the Peruvian

such will require special adaptive responses. The climate change

coastline region. It seems that El Niño, which is associated with a

indicators mentioned in the previous section will generate quite

large mass of unusually warm water moving from central Pacific to

specific environmental factors that will in turn affect the health of

north-eastern Pacific regions, allows the creation of masses of algae

populations

these

to move into coastal waters off Peru. The creation of the mass of

mechanisms are direct, while others will operate in a more

algae allows the cholera bacteria to multiply in favourable conditions

complicated and indirect manner. The more specific environmental

off the coast and invariably infects the local fishing communities,

factors caused by climatic changes include the following range of

usually within six months of the onset of El Niño.

through

various

mechanisms.

Some

of

effects:

Phuture 2021

39

Flooding - Climate change will inevitably bring about an

Climate change also raises the risk of a variety of infectious diseases,

increased chance of flooding by virtue of the fact that the

including those transmitted by water, food, and vectors such as

atmosphere will be able to retain ever greater amounts of water,

malaria and dengue. Globally, there are great concerns about the

which when released may create flash-flood conditions in river

impacts of climate change on the “big two” - malaria and dengue -,

floodplains. Damage caused by flood waters can be substantial

which have now perhaps become the “big five” - malaria, dengue,

and this can lead to the onset of diseases such as typhus and

yellow fever, chikungunya, and zika. These diseases are significant

cholera. Mosquito populations can either be rapidly increased

causes of morbidity and mortality globally.31

due to the wet conditions occurring in normally dry areas or in

Climate and weather impact transmission cycles of vector-borne

some cases can rapidly decrease, due to the destruction of

pathogens directly by effects of temperature on the duration of the

breeding sites caused by violent floodwaters. Thus outbreaks of

extrinsic incubation period of pathogens in insect vectors, which is a

malaria and dengue fever are quite common after a major flood

crucial factor determining whether or not insect-borne diseases can

in the tropical regions of the world, where conditions are ripe

persist or not.31

Dear Reader, for breeding mosquitoes.7

Although it would appear that winter respiratory infections should

2- Climate change and respiratory diseases

decrease with increasing global temperature, the relationships are more complex. Fluctuating temperatures affect the incidence and mortality of respiratory infections. This is especially true among older

Government worldwide and international organizations, such as the

adults and children, who are both more vulnerable to daily

World Health Organization and the European Union, are facing a

temperature oscillations. It appears that the metabolism of children

growing problem of respiratory effects induced by gaseous and

does not adapt as well as adults to heat stress and temperature

pollutants particulate. In addition, climate change may significantly

variations.30

worsen health inequities within and among countries and put

Several reports have linked infection outbreaks directly or indirectly

additional stress on poorer groups.

to climate change. Health effects of climate change include an

Climate change, mediated by greenhouse gases, causes adverse

increase in the prevalence of allergic respiratory diseases,

health effects in the most vulnerable patient populations, such as

exacerbations of chronic obstructive lung disease, premature

the elderly, children, and those in distressed socioeconomic strata.

mortality, and declines in lung function. Climate change modifies the

Climate change produces a number of changes to the natural and

production and dispersion of chemical and biological components of

built environments which are a direct contributor to hospital

atmospheric air pollution. These changes, including global warming

admissions and mortality from chronic and respiratory diseases, such

induced by human activity, have an impact on the biosphere, human

as asthma and allergic respiratory conditions.30-32

health, and the environment. Hence researchers are expecting a shift

Climate alterations may directly or indirectly affect the incidence and

towards more prescription and use of antihistamines, lozenges, and

severity of respiratory infections by affecting the vectors and the

cough suppressants.

host immune responses. Changing weather patterns already affects

3- Climate change and drugs

some respiratory infections.30 The increment in atmospheric ozone levels and other reactive oxides

The continuous advancement in pharmacotherapy over the last few

can augment deleterious health effects on humans. Increasing

decades have projected and placed global response to infectious and

temperatures and altered rainfall patterns, along with the changing

non-infectious disease in good lights20 (Jain et al, 2017), with

frequency and severity of extreme weather patterns, which include

promises of continuous paradigm shift. Without a doubt, the

extreme heat, floods, and storms, can increase the number of people

effectiveness and appropriateness of drugs remain key to the

affected with asthma. As a direct result of changes in the production

successful implementation of all pharmacotherapeutic plans. Drug

and dispersion of pollen, there has been an increased prevalence of

pharmacokinetics, the integrity of the supply chain, the quality of

allergic respiratory disease and asthma over the past decades. In

drugs procured, and patients’ adherence are important determinants

addition, long-term continuous exposure to high levels of O3 may

of drug effectiveness and clinical efficacy27 (Jin et al, 2008).

reduce lung function in adults and children and contribute to the

Therefore, it becomes imperative to assess the impacts of climate

increasing prevalence of both asthma and chronic obstructive

change on these determinants in a bid to draw relevant correlations

pulmonary disease (COPD), and cardiovascular diseases.32

between climate change and drug effectiveness.

Phuture 2021

40

3.1- Drug quality and supply chain A range of climate-related storage requirements was found in the membrane-introduction mass spectrometry (MIMS) analysis. Many medications should be stored below a certain temperature (very often 25°C or 30°C). Further, some medications should not only be stored below a certain temperature (or within a certain temperature range) but must also not be refrigerated. Medications were also found that have these requirements and have to be kept at a constant temperature. In addition to temperature requirements, some medications require storage in a dry environment. These

Dear Reader,

storage requirements have been determined from laboratory and field studies that have shown both quantitative and qualitative changes in medications stored outside such conditions. The influence of geography has also been highlighted by Dietz et al.8 These authors state that “since the shelf life of a drug depends on the storage conditions it is kept under until use, as much as on the choice of suitable packaging, the shelf life of one and the same medicinal product may vary from one country to another depending on the climate”.

Vanakoski

and

Seppälä

also

state

that

“changes

in

the

physicochemical properties of transdermal patches, sweating and increased humidity of the skin may contribute to the release and diffusion of transdermally administered drugs”. Klein-Schwartz and Oderda have highlighted a number of physiological changes in the elderly that may influence absorption, distribution, metabolism, and excretion. Such changes may make the elderly particularly vulnerable to climate-induced pharmacokinetic changes. This group is of particular significance given that Australia, like many other countries, has an aging population. The trend towards retirement to warmer climes may also amplify this effect in the elderly. Photosensitivity refers to an abnormal cutaneous response involving the interaction between photosensitising substances and UV radiation. Many medications are photosensitising substances. Indeed, a search of the MIMS database for photosensitivity as an adverse reaction resulted in the listing of 174 products. The study by Bjellerup and Ljunggren14 serves as a good example of one examining medication-induced photosensitivity. These authors investigated differences in the phototoxic potency of two tetracyclines - doxycycline and lymecycline. Tetracyclines are often prescribed for young patients, as

3.2- Pharmacokinetics

they are the medications of choice in Chlamydia infections and acne.

Although lymecycline showed only a slight and, at most, low significance increase in erythema compared with placebo,

Certain medications may predispose individuals to excessive heat strain by altering physiologically or behaviourally thermoregulatory functions. Clark and Lipton divided medications into those that impair heat loss and those that increase endogenous heat production. The area of heat exposure and medications and, more specifically, the effects of hyperthermia on pharmacokinetics, have been reviewed recently by Vanakoski and Seppälä. Heat exposure can influence medication absorption, distribution, and elimination.

For example, studies of transdermally or subcutaneously absorbed medications indicate that total medication absorption and plasma medication concentrations can substantially increase during heat exposure. Heat-induced local vasodilatation and acceleration of skin

doxycycline showed a substantial and highly significant increase in erythema. Gocke has recently reviewed the influence of UV radiation on medications used in the control of psychoses, including schizophrenia and mania. It was concluded that UV irradiation of such medications produces reactive free radicals that possess DNA damaging properties. A number of commonly used antibiotics have also been studied and found to exhibit strong superoxide radical generation in the presence of UV radiation. A number of oral antidiabetics and diuretics have also been studied and some have resulted in phototoxic effects after UVA exposure. McMichael et al. have discussed photosensitising medications of relevance to the eye.

Ocular effects range from cataractogenesis to erythemal reactions.9

blood flow appear to be the main mechanisms leading to this change in absorption.

Phuture 2021

41

4- Economic impact of climate change

Natural disasters come with unique health needs such as mental

Climate change has negative consequences on health and it is

health, risk of outbreaks such as cholera, malnutrition, disruption of

projected that by 2030, this could directly cost 2-4 billion USD per

established chains of drug distribution (which has a strong

year.35 According to the Economic Cooperation and Development

detrimental effect on full supply commodities, like in HIV/AIDS

(OECD), by 2060, outdoor pollution could cost healthcare 176 billion

drugs), inability to access water, sanitation and hygiene, inability to

USD annually, rising from 21 billion USD in 20152. There are also

access basic healthcare, which can worsen chronic conditions such as

other costs associated with climate change, such as the cost of

hypertension and diabetes. Natural disasters also threaten food

mitigation, those associated with natural disasters, and costs due to

security45,46, leading to malnutrition. This could have huge

loss of economic productivity.

implications on the health of infants and children.

Vector-borne diseases such as malaria, dengue fever, yellow fever,

By looking at the expected trends in disease patterns in the coming

schistosomiasis,

to

years, we can predict that pharmaceutical products will be

increase.37,38 As the climate changes, the geographical area over

responsible for health care expenditures. Since climate change will

which vectors can survive will expand and increased transmission of

impact health negatively, there is an inevitable economic cost

vector-borne diseases is expected.38 Spending on vector control is

accompanying these expected changes. There are a number of

expected to rise, since climatic conditions will now favor their

pharmaceuticals expected to be in high demand. This includes those

survival. Vector control measures could be viable strategies to

used for respiratory conditions like asthma, allergies, drugs used in

mitigate some impact of climate change. Hence, government and

cardiovascular diseases, antimicrobial agents, and analgesics.47

individual spending in this area will increase.

Indirect cost due to lost working days per year is estimated at 3.7

Malaria, a vector-borne disease, is known to be a major public health

billion USD by 2060 from the current 1.2 billion.36 Also, up to 3.3%

concern in Africa, accounting for about 81% of global malaria cases

loss from the global gross domestic product (GDP) per year is

in 2010.39 This could imply significant economic costs for countries

expected48 Cost of mitigation might include the cost of research into

where malaria is endemic. A study involving 25 African countries,

the discovery of new vaccines and increasing vaccine coverage, in

estimated that malaria spending could increase by greater than 20%

order to curb infectious diseases which are expected to increase due

in some countries due to climate change.40 This could have

to climate change. Growing rates of resistance will also increase drug

profound effects on children under 5 years and pregnant women,

discovery research.

and

leishmaniasis

are

also

Dear Reader,

expected

since these groups are usually hit the hardest by malaria.

Additionally, it is estimated that the cost due to loss of productivity due to malaria is 12 billion USD in Africa, annually.42 Likely, outbreaks secondary to natural disasters and vector-borne diseases will contribute to a higher rate of infectious diseases.37 This expected rise in infectious diseases carries an additional cost with it.

Antimicrobial resistance (AMR) is known to be associated with increased healthcare spending caused by prolonged hospitalization, the need for second or third-line antimicrobials, which are usually

Conclusion

more expensive and could be more toxic. This could impose

Global climate change has already resulted in a wide range of

significant economic burden particularly in Africa due to the large

impacts across every region of the world and many sectors of the

burden of infectious diseases.42 The global economic implications

economy that are expected to grow in the coming decades.

of AMR by 2050 could be up to 100 trillion USD.43

Thousands of studies conducted by researchers around the world have documented increases in temperature at Earth’s surface, as well

Natural disasters such as drought, floods, wildfires are expected to

as in the atmosphere and oceans. Many other aspects of global

occur more frequently. Thereby affecting vulnerable communities

climate are changing as well. Human activities, especially emissions

and their livelihood, pushing them further into poverty. It is

of heat-trapping greenhouse gases from fossil fuel combustion,

estimated that 100 million people could be pushed into extreme

deforestation, and land-use change, are the primary driver of the

poverty due to climate change.44

climate changes observed in the industrial era.

Phuture 2021

42

The terms "adaptation" and "mitigation" are two important terms

23. Longobardi P, Montenegro A, Beltrami H, Eby M. Deforestation Induced Climate Change: Effects of Spatial Scale. PLoS ONE. 2016;11(4): e0153357. doi:10.1371/journal.pone.0153357

that are fundamental in the climate change debate. Climate

24. Burke M, González F, Baylis P. et al. Higher temperatures increase suicide rates in the United States and

mitigation is any action taken to permanently eliminate or reduce

Mexico. Nature Clim Change. 2018; 8, 723–729. https://doi.org/10.1038/s41558-018-0222

the long-term risk and hazards of climate change to human life and

https://doi.org/10. 1016/j.aogh.2015.08.008.

property. Climate adaptation refers to the ability of a system to

25. Levy B, Patz J. Climate change, human rights, and social justice. Ann. Glob. Health. 2015;81, 310–322.

26. Ciesielski T. Climate Change and Public Health. New Solut. 2017;27(1):8-11. doi:10.1177/1048291117691075 27. Jin J, Sklar GE, Min Sen Oh V, Chuen Li S. Factors affecting therapeutic compliance: A review from the

adjust to climate change in order to moderate potential damage,

patient's perspective. Ther Clin Risk Manag. 2008;4(1):269-286. doi:10.2147/tcrm.s1458

take advantage of opportunities, or cope with the consequences.

pharmacokinetics. Clin Pharmacokinet. 1998;34(4):311-322. doi:10.2165/00003088-199834040-00004

Strategies for mitigation and adaptation can create co-benefits for

28. Vanakoski J, Seppälä T. Heat exposure and drugs. A review of the effects of hyperthermia on 29. Klemsdal T, Gjesdal K, Bredesen J. Heating and cooling of the nitroglycerin patch application area modify the plasma level of nitroglycerin. Eur J Clin Pharmacol 1992; 43: 625-8

both individual and community health, by reducing non-climate-

30. Mehdi Mirsaeidi , Hooman Motahari, Mojdeh Taghizadeh Khamesi , Arash Sharifi , Michael Campos , and

related health hazard exposure and by encouraging health-

03, 2016.

Dean E. Schraufnagel .Climate Change and Respiratory Infections.Annals of the American Thoracic Society.June 31. Nicholas H. Ogden.Climate change and vector-borne diseases of public health significance.FEMS

promoting behaviors and lifestyles.49

Microbiology Letters.19, October 2017

Pharmacists and pharmacy students have a crucial role in raising

32. Maureen George, PhD, RN, AE-C, FAAN1, Jean-Marie Bruzzese, PhD2, & Lea Ann Matura, PhD, RN,

public awareness on the impact of climate change on drugs,

33. Climate Change and Air Pollution: Effects on Respiratory Allergy Gennaro D'Amato,Ruby Pawankar,Carolina

Dear Reader,

stressing its risk on human health and possible mortality resulting in

CRNPFAAN.Climate Change Effects on Respiratory Health:Implications for Nursing.May 13, 2017 Vitale,Maurizia Lanza,Antonio Molino,Anna Stanziola,Alessandro Sanduzzi,Alessandro Vatrella,and Maria D'Amato.Allergy Asthma Immunol Res. 2016 Sep;8(5):391-395.

ignoring such issues.

34. M D ’Amato, L Cecchi, Isabella Annesi-Maesano, G. d’Amato. News on Climate Change, Air Pollu-tion, and

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A REVIEW OF THE EXTENT AND STRATEGIES FOR SUBSTANDARD AND FALSIFIED MEDICINES Alison Ekwere Williams, Olanrewaju Popoola, Mariam Medhat, Saurabh Mamtani, Gulshan Madhur, Mark Odhiambo, Priscilla Owusu-Mensah Young Researchers Forum, International Pharmaceutical Students Federation

Abstract Reader, Dear

Substandard medicines are authorized medical products that do not meet their required (national or international) standards or

Substandard and falsified medicines are a global health concern

specifications or both, while falsified medicines, on the other hand, are

negatively affecting individuals, the public, the pharmaceutical

products that deliberately or fraudulently misrepresent their identity,

industry and governments all over the world. This review aims to

composition or source medical products.1,2 These medicines are

examine the global prevalence of substandard and falsified

everywhere in licensed markets, unlicensed markets, ungoverned

medicines and their impact on health and the health system,

websites, social media platforms or smartphone applications.3 They

including socio-economic impacts and strategies for curbing this

can be detected through examination of packaging for spelling errors,

menace. A literature review of published articles between January

checking for manufacture and expiry dates, checking medicine smell,

2000 and May 2020 was done with keywords “substandard”,

colour and visual inspection and verification services like the European

“counterfeit”, and “falsified medicines”. Articles were sourced from

Union logo for the online sale of medicines.4,5 Substandard and

Pubmed, WHO databases and Google Scholar. There are reports of

falsified drugs are reported all over the world. About 10% of all

substandard and falsified medicines from all WHO Regions with

medicines in the world are either substandard or falsified.2

noticeable prevalence in the African Region. These medicines have

Substandard and falsified medicines may contain lethal contaminants,

been reported to cause death, antimicrobial resistance, increasing

an overdose or a subtherapeutic dose, could harm patients, cause

prevalence of diseases, and loss of confidence in the health system.

adverse drug events, prolong disease and probable death. The use of

Increased patient spending, loss of productivity, strain of limited

these medicines as prophylactic drugs increase infectious disease

health systems resources, and loss of government revenue are major

prevalence through widespread transmission as well as antimicrobial

socio-economic implications of substandard and falsified medicines.

resistance due to subtherapeutic antibiotic doses.1,2 Treatment failure

An increase in criminal sanctions, global harmonization of drug

caused by these medicines could make the public lose confidence in

regulatory authorities, and appropriate education of health care

the healthcare system, medicines and vaccines.2 This review aims to

professionals and patients on how to prevent, detect, and respond to

examine the global prevalence of substandard and falsified medicines,

reported cases of substandard and falsified medicines are strategies

their impact on health and the health system including the socio-

that can be implemented to curb the menace of these medicines.

economic impacts and strategies for curbing the menace of

Registered pharmacists and pharmacy students play critical roles in

substandard and falsified medicines.

addressing this global health issue.

Method

Key Words: substandard, counterfeit, falsified medicines, strategies A literature review of published articles between January 2000 and May

Background

2020 was done with keywords "Substandard" “Counterfeit “and

Substandard and falsified medicines are a global threat negatively

"Falsified Medicines". Articles were sourced from PubMed, WHO

affecting individuals, health systems, economy and governance.

databases and Google Scholar.

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1- Substandard Counterfeit and Falsified Medicines - A Global View There have been reports of substandard counterfeit and falsified medicines in all regions of the world. It is estimated that about 30% of drugs sold in some parts of Latin America, Asia and Africa are falsified. In 2020, the World Health Organization reported 9 different falsified chloroquine products from Niger, Cameroon and the Democratic Republic of Congo.4 Additionally, some anti-tuberculosis

The United States Food and Drug Administration (FDA) reported falsified botulinum toxin-A (Botox) in 2015. About 15 cases of falsified medicines were reported in the United Kingdom between 20052011.16 These existing evidence in the literature shows that the substandard and falsified medicines issues are a global health challenge.

2- Impact of Substandard and Falsified Medicines on Mortality

medicines (isoniazid and rifampicin) failed basic quality testing from pharmacies in Angola, Brazil, China, Democratic Republic of Congo,

The total deaths documented due to counterfeit medicines are

Egypt, Ethiopia, Ghana, India, Kenya, Nigeria, Russia, Rwanda,

thought to be underestimated because this information is only

Thailand, Turkey, Uganda, Tanzania and Zambia.7

reported when counterfeit drugs are seized and a causal relationship

In Africa, packets of the antimalarial artemether/lumefantrine and

between the deaths and the counterfeit drug is established.

anthelmintic mebendazole tablets were detected with no

Additionally, in poorly resourced countries, deaths caused by

artemether,

active

substandard and falsified are not reported in public health statistics.

pharmaceutical ingredients.2,6 In 2011, 64% of antimalaria medicines

Thus, the overall death toll attributable to counterfeit medicines is

in Nigeria were found to be falsified.8 In Ghana, 348 antibiotic

unknown. However, there are various incidents reported globally.17

samples were analysed and 66.38% of all the samples were

Substandard and falsified antimalarials have contributed significantly

substandard. The substandard samples contained less than 90% or

to the malaria burden in Nigeria. A study in 2019 reported that 11.8%

more than 110% of the dose of the active ingredients than the label

of artemisinin-based combination therapy (ACTs) in Nigeria were

claimed.9 A study conducted in the Democratic Republic of Congo

either substandard or falsified and they are responsible for 12,300

illustrated

representing

deaths annually in Nigeria.18 The WHO estimates that in Africa, about

artemether/lumefantrine, amoxicillin powders for suspension, and

169,000 children could die annually from pneumonia treated with

paracetamol tablets were of poor quality.10 Also, 26.7% of 90

substandard and falsified medicines.1

samples of cardiac medicines from the Democratic Republic of Congo

Similarly, in Southeast Asia, the death toll is much larger. In 2001,

were found to be substandard.11 A study that tested 506 medicine

China reported 192,000 deaths attributed to counterfeit medicines.19

samples from the Democratic Republic of Congo reported that 5.1%

A substandard cough medication was found to be the cause of death

of medicines stated to be produced in Europe, 17.7% of medicines

for 33 out of 36 children in India. The affected children were all

stated to be produced in Asia and 22.2% of medicines stated to be

treated with a substandard over-the-counter cough syrup just prior

produced in Africa were substandard.12 A study in Mongolia in the

to their deterioration in health, leading to acute kidney failure. In

Western Pacific Region analysed 1770 drug samples and estimated

2008, 84 children died after consuming teething syrup contaminated

that 10.1% (179) samples were substandard. The prevalence of

with diethylene glycol.20 Cough syrup adulterated with diethylene

substandard products was observed to be three times higher for

glycol became a global concern, resulting in 109 deaths in Nigeria,

locally

236 deaths in Bangladesh, 26 deaths in Argentina and 85 deaths in

Dear Reader, lumefantrine,

that

27%

manufactured

of

mebendazole

239

products

tested

(18.6%)

or

samples

than

other

for

imported

counterparts (6.1%).13 An increasing number of substandard and

Haiti.21

falsified medicines have been reported in both Canada and the United Kingdom.14 In Europe, the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) reported a 10 fold increase in the report of defective poor-quality medicines from 2001 to 2011.3 In 2012, contaminated prednisolone was responsible for fungal infection in about 700 individuals and caused at least 61 deaths in the United States of America.15

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Western countries are not exempt from this issue. In the United States, adulterated heparin was found to be the cause of the death of 81 patients. Manufacturers were found guilty of using an oversulfated structurally similar product, chondroitin sulphate, because it reduced production cost significantly.17

4. Impact of Substandard and Falsified Medicines on Prevalence of Diseases Vaccines save 2-3 million lives per year by preventing diseases.

Substandard and falsified vaccines can reverse this scenario by

Most of the incidents involving health damage caused by falsified medicines were reported or published from the North American region followed by Southeast Asia and Africa. Although Asia is the most significant contributor to fake medicines with India and China being the biggest manufacturers, the number of incidents reported was higher in North America. This could be due to poor public health

Dear Reader,

administration and a weak national reporting system in less developed countries.17,19,22 Counterfeit drug manufacturers use hazardous chemicals which are identical to active pharmaceutical ingredients. These chemicals could be poisonous and fatal if

increasing mortality due to failure to prevent life-threatening diseases such as meningitis and rabies.23,25 In 2015, falsified Neisseria meningitides type C vaccines were linked to 8580 cases of meningitis C in Niger and nearly 600 people died.2 The widespread prevalence of falsified vaccines may lead to a rampant rise in cases of preventable infectious diseases and this will also increase the demand for antimicrobial medicines. The increase in demand for antimicrobials could then be exploited by illegal drug traders to sell substandard and falsified medicines, which may have fatal consequences.2

administered to a patient.17 With these advancements, mortality rates are only likely to increase as counterfeit drugs are becoming more difficult to combat.

Medicines used to treat non-communicable diseases are also affected. WHO reported that 15.8% of total products reported to the

3- Impact of Substandard and Falsified Medicines on Antimicrobial Resistance (AMR)

Global Surveillance and Monitoring System as substandard and falsified medical products were used for non-communicable conditions such as diabetes, cancer, mental health and cardiovascular conditions.2 This may lead to an increase in mortality caused by non-

AMR occurs when the subtherapeutic concentration of antimicrobials

communicable diseases.

kills only a portion of susceptible pathogens. The pathogens that

5- Impact of Substandard and Falsified Medicines on the Healthcare System

survive mutate and become resistant to the antimicrobial agent.

These mutant variants then reproduce rapidly and transfer the mutations that confer the resistance. This, in turn, results in the establishment of drug-resistant colonies, making infections difficult to treat.1

failure and often results in prolonged illness and eventually death.

AMR may be directly linked to the use of substandard and falsified medicines.1 Around 90% of the antimalarials in Africa were found to be falsified.23 Concurrently, not less than 116,000 deaths occur annually in Africa due to antimalarial resistance.24 The continuous use of substandard and falsified anti-tuberculosis drugs may result in an exponential rise of multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) infection.7

The use of substandard and falsified medicines may lead to treatment The poor population in low and middle-income countries are highly affected by these consequences and hence they are more prone to be the target of counterfeit medicines. Treatment failure, adverse drug events and prolonged illnesses caused by substandard and falsified medicines could result in the loss of public confidence in health professionals and health care facilities. This could further result in them refusing vaccination, not taking treatment as prescribed and seeking alternative treatment from unlicensed personnel.2,26 If the sale and use of substandard and falsified medicines are not controlled, they could ultimately result in an increase in chronic disorders, and large outbreaks of preventable infectious diseases all at the same time.

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6- Economic and Socio-economic effect of 6.4- Impact on Pharmaceutical Industries Substandard and Falsified Medicines

Pharmaceutical industries lose about $10 billion to $200 billion

Substandard and falsified medicines have a direct economic and

annually to the sales of substandard and falsified medicines.1,18,27-

socio-economic impact on the individual patients, health systems,

29 In 2010, the pharmaceutical industry in the United States lost an

pharmaceutical industries and the government.1

estimated $75 billion in revenue to falsified medicines.8,28 The revenue lost to the sale of substandard and falsified antimalarials in

6.1- Increased patient’s spending

Nigeria is estimated at $892 million annually.18 Pharmaceutical industries also have to bear the cost of substandard

Treatment failure, drug toxicity and adverse drug events caused by substandard and falsified medicines will increase the patient’s out-of-

Dear Reader,

pocket spending. This is due to further laboratory investigations, additional medical care, and prolonged stay in the hospital, increasing admission costs. Patients that have lost confidence in the healthcare system will incur additional travel expenses in search of

drugs being recalled from the market.2 The increased cost of production due to the incorporation of anti-counterfeiting technologies

into

products

and

packaging

are

borne

by

pharmaceutical companies.30 Poor health outcomes associated with falsified medicines can make patients lose trust in the genuine pharmaceutical product that was falsified.27,31 The brand and reputation of a pharmaceutical

quality healthcare.1

company may also suffer from unquantifiable damage due to

6.2- Loss of Productivity

counterfeiting.30 Pharmaceutical industries invest about 15% to 17% of their revenue

Prolonged illness caused by these medicines leads to loss of productivity as the affected patient is unable to work. This negatively impacts businesses and the wider economy and may further contribute to the vicious cycle of poverty. Falsified medicines account for the loss of more than 750,000 jobs in the United States.8

on research and development (R&D), to discover and develop novel pharmaceutical products. When these products are falsified, the incentives on innovation and creativity are lost.8 This theft of intellectual property may limit investment in pharmaceutical research and development.8,30

Antimicrobial Resistance caused by substandard and falsified antimicrobials may lead to prolonged recovery time and increase the loss of productivity. Adverse drug events and secondary infection(s) caused by the prophylactic failure may result in the premature death of the affected individual.1

6.3- The Strain on Health Systems Resources The use of substandard and falsified medicines may cause premature death leading to a waste of human effort and health care resources.

This waste causes a strain on the health care system which is oftentimes overburdened due to limited resources, especially in low and middle income earning countries.1,27 Health care systems’ resources are further strained as a result of repeated therapy, increased disease prevalence and transmission of drug-resistant infections associated with the use of substandard and falsified medicines.1 Health care systems also bear the cost of increased outpatients’ visits resulting from drug toxicity and adverse drug events associated with these medicines.

6.5- Loss of Government Revenue National governments also lose hundreds of millions of tax revenue to the trafficking and smuggling of substandard and falsified medicines. East African countries reported an estimated $500 million dollar unremitted taxes associated with substandard and falsified medicines.31 Also, resources that should be focused on developing the health sector and other aspects of the economy are redirected towards curbing the menace of substandard and falsified medicines. Profit from the sales of falsified medicines are sometimes used to fund criminal and terrorist organisations like Al-Qaeda further increasing the threat to good health and well-being.32

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7- Factors causing persistence of Substandard and Falsified Medicines Limited access to safe and efficient medicines, bad governance, weak technical capacity, internet gateway, complex supply chain, poor detection and reporting culture are some reasons substandard and falsified medicines have thrived. This could either be due to quality medicines being unaffordable, unavailable or due to patients’

There are so many unlicensed online traders with fake accounts who have managed to avail falsified and substandard medicines to consumers at cheaper prices. Most government regulatory bodies have failed to recognize these online dealers. This may be attributed to a lack of proper insight through information and communication technology. Some have also managed to succeed with their deeds after corrupting the regulatory agencies.2 The existence of a weak technical deficit coupled with poor oversight

preference.

The affordability of high-quality medical products could be another reason for the persistence of these substances and falsified medicines. High-quality medicines have a higher cost of production

Dear Reader,

than substandard and falsified ones. The high cost of safe and effective medicines compels people who cannot afford them to go for the cheap and easily affordable substandard products sold by unlicensed distributors and on the internet.33 Some medical practitioners purchase and dispense poor-quality drugs all in an

of regulatory authorities has contributed to the persistence of substandard and falsified medicines. Lack of adherence to Good Manufacturing Practices in industries, poorly equipped laboratories, lack of well-trained staff, lack of standard transportation facilities and proper tracking procedures also contribute to the availability of these medicines.2,35

7.1- Neglect of Good Manufacturing Practice

attempt to maximize profit.2 Also, safe and effective medicines are sometimes unavailable in the

This can be either accidental or deliberate. Companies may not train

market. This could be due to poor health infrastructure, poor drug

their staff due to the fear of incurring extra costs. Small companies

inventory management, poor regulation of medicines, porous drug

which are suppliers of domestic markets in India have been reported

supply chain and unpredictable surges in medicine demand due to

to produce substandard medicines because of their inability to afford

wars, natural disasters and pandemics.2,34 Slow manufacturing

standard equipment and the use of bad water for manufacturing.35

process, theft and mishaps in the supply chain disrupt the

The high cost of quality ingredients and chemical standards have also

distribution of quality medical products. This creates loopholes in

limited the implementation of GMP.36

the supply chain which is swiftly filled by the suppliers of

7.2- Complex supply chain

substandard and falsified medicines. Poor communication between health regulators and law enforcement agencies also permits the availability of these illegal products into the markets.2

The total process of manufacturing, packaging and distribution of medical products to the desired consumers may be complicated. A

In other instances, the patient’s preferences also come in. It was

country that supplies the excipient may be different from the one

reported that some women use misoprostol - a drug used to treat

manufacturing the products. A company may repackage and brand a

peptic ulcers - to terminate pregnancy in its early stage because

product for clients and customers in another different country. This

they could not afford or access safe and effective contraceptives.

complexity involves a higher turnover of products passing through

This has led to an increase in the manufacturing of falsified

many hands and international borders creating several loopholes for

contraceptives, as well as misoprostol.2 Bad governance also

the illegal and unethical practice to come in.2,34

contributes to the prevalence of substandard and falsified medicines. Some governments have failed to strengthen their medicines regulatory authorities leading to poor inspection and regulation of manufacturing procedures and storage warehouses.

Cases of poor ethical and corrupt practices between the regulatory officials, unscrupulous manufactures and suppliers have also been reported. The sales of falsified medicines are encouraged when poor legislation fails to ensure appropriate criminal penalties and punishments of offenders.8,35

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7.3- Low detection levels, lack of knowledge 8.1- Prevention and poor reporting culture Prevention has to do with hindering the production and distribution Most of the licensed manufacturers have failed to take action in

of substandard and falsified medicines. To do this, there must be

cases where their reputations have been damaged by the

proper education and awareness about these products, there must

falsification of their products.37

be ready access to safe and effective medicines and quality

Some medical personnel lack awareness of substandard and falsified

manufacturing and distribution standards must be adhered to.

medical products, how to detect them and how to report them.38

Education and awareness of patients, health professionals and other

Lack of appropriate testing equipment, chemical standards, trained

stakeholders are the first and crucial steps in prevention. It aims at

personnel and adequate funding has limited testing, detection and

providing accurate and balanced information on the risks of

reporting of substandard and falsified medicines especially in low

substandard and falsified medical products, providing measures to

and middle-income earning countries.2

avoid them, how to spot them and how to report them.

Dear Reader,

Access to safe and effective medicines must also be guaranteed.

Limited access to affordable, quality medical products contributes to the prevalence of substandard and falsified medicines. WHO combats this by improving access to quality medical products through its WHO’s Essential Medicines Programme, and active partnerships with

8- Strategies implemented to solve Substandard and Falsified Medicines The WHO’s Global Surveillance and Monitoring System (GSMS) reports that the prevalence of falsified and substandard medicines is likely to increase unless serious, well-resourced efforts are made to tackle the issue. Coordinated participation between national and regional governments, global organizations, private and non-profit sectors and civil society is needed to tackle the problem of substandard

and

falsified

medicines.

Pharmacovigilance,

others in the field of global health such as United Nations Children’s Fund (UNICEF), Global Alliance for Vaccines and Immunization (GAVI) and other partners.2 Manufacturers, distributors, health care professionals and other stakeholders must ensure appropriate technical and professional standards. WHO’s Department of Essential Medicines and Health Products works with countries and expert committees to create, develop and implement standards that will ensure only quality products are delivered across the global supply chain.

8.2- Detection

collaboration between different disciplines, and collaborations between health authorities and law enforcement agencies are also

The detection of substandard and falsified medicines in the global

very necessary.2

supply chain requires a high level of awareness by all stakeholders,

The Safety and Vigilance Unit of the WHO’s Essential Medicines and

prompt sharing of information across countries and organizations,

Health Products Department aims to strengthen national and global

and appropriate technology (e.g. barcode authentication technology,

responses in three areas:

track and trace technology, mobile applications) to detect such

1. Improving affordable access to quality, safe and effective

products. Trained personnel and equipped laboratories are essential to carry out appropriate testing and inspection of medicines. The

medical products; 2. Strengthening governance and regulatory capacities;

WHO has established systems to help in the detection of such

3. Improving technical capability.

products. WHO developed smartphone applications for health

The WHO’s GSMS aims to support WHO Member States in

professionals to take pictures of suspicious products and send them

minimizing the public health risks posed by substandard and

to regulatory authorities for authentication.2

falsified medical products. In achieving this goal, it supports countries with appropriate public-health-focused investigation and response to incidents involving substandard and falsified medical products. WHO tackles substandard and falsified medicines using a three-pronged strategy of prevention, detection and response.2

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8.3- Response

Implementation of global harmonization of drug regulatory authorities to enhance transparency, detection and reporting of cases of substandard and falsified medicines. This will make the complex

Good governance and swift action on National and International

global supply chain more secure.42

Drug regulation agencies are important. Once poor quality medicines are detected, appropriate investigations to detect the source of the medicines should be done. Reports should be communicated with the appropriate bodies. Pharmaceutical companies should also be alerted and product recalls should be initiated when necessary. Appropriate criminal sanctions should also be applied and published by national or regional drug regulatory

Health professionals should be educated on how to examine medicines for particulate contamination, spelling and packaging errors. They should also be aware of how to report suspicious cases for investigation. The public should also be educated on the health implications and possible fatality associated with the use of substandard and falsified medicines.3

authorities.2,39

8.4Examples Reader, of strategies put in place by Dear different countries

9- Substandard and Falsified Medicines and COVID-19 The COVID-19 pandemic has disrupted the global supply chain and

In Germany, the Official Medicines Control Laboratory (OMCL) controls the quality of medicines in the supply chain by engaging in chemical, and laboratory analysis of product samples. They create awareness on substandard and falsified medicines and new trends used by illicit suppliers and distributors.39

may lead to a surge in substandard and falsified medicines. Initiatives must be implemented to ensure easy access to safe and effective medicines. Following the approval of COVID-19 treatments and vaccines, a global coordinated production, secure distribution chains, and post-market surveillance will be needed to ensure that these

Italy, Belgium, Poland, and other countries in Europe, have adopted

treatments and vaccines are not substandard or falsified.43

the Falsified Medicines Directive (FMD) to detect falsified medicines.

The FMD requires medicines packaging to carry a unique identifier (barcode) and tamper-proof seals which will be used to verify their authenticity. The information contained in the barcodes is uploaded to secure databases like the European Medicine Verification System (EMVS). The barcodes are scanned to verify the authenticity of each medicine.40 The United States Food and Drugs Authority helps to ensure, prevention, detection and reporting of poor-quality medicines. The United States Agency for International Development (USAID) works

10- Limitations to the study Our critical literature review was limited by the lack of comprehensive data and global reports on substandard and falsified medicines.

Limited data is available on the estimated economic and socioeconomic impact of substandard and falsified medicines. There are also limited reports from national drug regulatory agencies on substandard and falsified medicines.

with medicines regulatory bodies of different countries to ensure the development of local capacity that will ensure the distribution of safe and effective medicines. The United States Pharmacopeia (USP) works with pharmaceutical manufacturers to ensure compliance with acceptable standards.41

8.5- Other strategies that can be put in place Criminal sanctions on the trade, manufacture and distribution of substandard and falsified medicines should be increased to make the punishment for such act commensurate with the crime committed.30

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11- Conclusion and Recommendations

12. Khurelbat D, Dorj G, Sunderland B, et al. A cross-sectional analysis of falsified, counterfeit and substandard medicines in a low-middle income country. BMC Public Health. 2020;20:743. https://doi.org/10.1186/s12889-02008897-x 14. Schäfermann S, Hauk C, Wemakor E, et al. Substandard and Falsified Antibiotics and Medicines against

This review identifies that substandard and falsified medicines are a global threat to health, economics and good governance. Over the

Noncommunicable Diseases in Western Cameroon and North-eastern Democratic Republic of Congo. Am J Trop Med Hyg. 2020:1-15. https://doi.org/10.4269/ajtmh.20-0184 15. Sammons MH, Choonara I. Substandard medicines: a greater problem than counterfeit medicines? BMJ

years, strategies have been implemented at the international level

Paediatrics Open. 2017;1:e000007. doi:10.1136/ bmjpo-2017-000007.

by the WHO and at the national level by national regulatory

injections. N Engl J Med. 2013;368:1598–609.

authorities of individual countries. However, these strategies must

16. Smith RM, Schaefer MK, Kainer MA, et al. Fungal infections associated with contaminated methylprednisolone 17. Abril JL, Holt DW, Wilson RR. Falsified Medicines in the European Union and North America: What are we doing to Protect Public Health? J Pharmacovigil. 2016;4:213. doi:10.4172/2329-6887.1000213.

be strengthened and appropriate actions must be carried out.

18. Loewenberg S. Combating counterfeit drugs. Lancet. 2008;371(9624):1551.

Further awareness should be created on the potential harm caused

antimalarial medications in Nigeria. PLoS ONE. 2019;14(8):e0217910. https://doi.org/10.1371/journal.pone.0217910.

by substandard and falsified medicines. Health care professionals and patients should be educated on how to identify these medicines

19. Beargie SM, Higgins CR, Evans DR, Laing SK, Erim D, Ozawa S. The economic impact of substandard and falsified 20. Wertheimer A, Chaney N, Santella T. Counterfeit Pharmaceuticals: Current Status and Future Projections. J Am Pharm Assoc. 2003;43(6):710-718.

21. Schep LJ, Slaughter RJ, Temple WA, Beasley G. Diethylene glycol poisoning. Clin Toxicol. 2009;47(6):525-535.

22. Rahman M, Yoshida N, Tsuboi H, Tomizu N, Endo J, Miyu O, Akimoto Y, Kimura K. The health consequences of

Dear Reader,

and how to report them. Manufacturing companies should be highly

falsified medicines- A study of the published literature. Trop Med Int Health. 2018;23(12):1294-1303.

regulated to conform to national and international standards.

23. World Health Organisation. Growing threat from counterfeit medicines. Geneva, Switzerland: World Health

Adequate laws and commensurate punishments should be enforced

May 2020.

to ensure justice is served to the illicit traders and distributors of

Organization. https://www.who.int/bulletin/volumes/88/4/10-020410/en/. Published April 4th 2010. Accessed 19 24. Kelesidis T. Falagas M. Substandard/Counterfeit Antimicrobial Drugs. Clin Microbiol Rev. 2015;28(2):443-464.

25. Lubell Y, Dondorp A, Guérin P, Drake T, Meek S, Ashley E, Day N, White N, White L. Artemisinin resistance –

substandard and falsified medicines.

modelling the potential human and economic costs. Malar J. 2014;13(1):452.

Pharmacists play a critical role in the curbing of this menace from

qualitative study. BMJ Open. 2014;4(1), 004279.

26. Wheelock A, Miraldo M, Parand A, Vincent C, Sevdalis N. Journey to vaccination: a protocol for a multinational

the production point to the patient level. Pharmacists are in the

27. Gostin L, Buckley G, Kelley P.. Stemming the Global Trade in Falsified and Substandard Medicines. JAMA. 2013;309(16):1693.

perfect position to strongly recommend patients to only buy from

28.Ozawa S, Evans DR, Bessias S, Haynie DG, YemekeTT, Laing SK, Herrington JE. Prevalence and Estimated Economic

registered pharmacies and to educate them about how to avoid

Meta-analysis. JAMA Network Open. 2018;1(4):6-10.

being sold falsified medicines, what to look out for in packaging and

Burden of Substandard and Falsified Medicines in Low-and Middle-Income Countries. A Systematic Review and 29. Przyswa E. Counterfeit Medicines and Criminal Organisations. IRACM. 2013:14.

30. World Economic Forum. Global Risks 2011, Sixth Edition, An Initiative of the Risk Response Network. Geneva,

highlight the potential dangers and possible mortality associated

Switzerland: World Economic Forum; 2011:111.

with these medicines. They can also monitor and report adverse

Institute. 2018:20-36.

drug reactions, which can help raise the profile of any falsified

31. Acri, Kristina ML. Pharmaceutical Counterfeiting: Endangering Public Health, Society, and the Economy. Fraser 32. Aminu N, Sha'aban A, Abubakar A, Gwarzo M. Unveiling the peril of substandard and falsified medicines to public health and safety in Africa: Need for all-out war to end the menace. MA@PoC. 2017;1(1): e145-e154.

33. Findlay B. Counterfeit drugs and national security. The Stimson Center. 2011.

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Rocksville,

United

States

of

America;

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Phuture 2021 A Scientific / Educational Publication of IPSF IPSF is an international non-governmental, non-political, non-religious and non-profit umbrella organisation for pharmacy student organisations and represents more than 500,000 pharmacy and pharmaceutical science students and recent graduates from over 100 countries worldwide. IPSF was founded in 1949, making IPSF the oldest faculty-based student organisation in the world.

IPSF initiatives focus on the areas of public health, pharmacy education, and professional development. Initiatives include multiple public health campaigns, research on issues in pharmacy education and workforce development, the Student Exchange Programme, organising international and regional events, and publication of the IPSF newsletters in pharmacy education and student exchange, among other responsibilities.

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@INTERNATIONAL PHARMACISTS STUDENTS FEDERATION 2021