Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Reviews
Year : 2008 | Month : October | Volume : 2 | Issue : 5 | Page : 1110 - 1118

Crippled Pharmacovigilance: A Qualm of Medical Profession!

MUDIGANTY S S P*, DANG A**,RATABOLI PV***

*Intern, Goa medical College, Bambolim, Goa. **M.B.B.S Post Graduate student Dept. of Pharmacology, Goa Medical College. ***M.D. (Pharmacology),Assistant Professor, Dept. of Pharmacology Goa Medical College.

Correspondence Address :
Dr. Dang A
Room no. 8, ground floor
Residents hostel (GARD)
Goa medical college
Bambolim, Goa-403202
Mobile no. 09764001983
E-mail address: dramit_gmc@rediffmail.com

Abstract

Drug prescribing is the most essential practice of medical professionals. A single drug to be marketed has to undergo rigorous processes and drug trials before it is labelled as safe for use in humans. However, all the adverse effects and toxicities cannot be elicited in the limited number of volunteers used in the phased trial. A lot of dangerous rare toxicities come to light only when drugs are marketed and prescribed to thousands of people. Drug regulatory bodies should be aware of these facts and take prompt initiatives to withdraw their sale. Similarly useless and irrational combinations flow the markets without any additional benefits to the patient. This review is an attempt to create awareness about drugs that are no longer used due to lack of safety, those once banned but reintroduced, those that are still used despite toxicities and doubtful efficacy and drugs surrounded by controversies.

Keywords

Drug market, banned drugs, bannable drugs, drug toxicity, controversial drugs.

Drugs have become an integral part of medical practice. Presently there are drugs galore available for prescribing by doctors. World drug market has become a cornucopia of drugs(1). The list of available drugs to select from is inexhaustible. Number of these drugs are known to cause hazardous effects in humans, but are still used. Others have been withdrawn voluntarily by some manufacturers.

Clioquinols were once “hot selling” name in the world market. These drugs were however reported to cause SMON (subacute myelo optic neuropathy)(2). Dr. Olle Hanson was a Swedish pediatric neurologist, who actively opposed the use of clioqinols. In opposition to the sale of Mexaform and Enterovioform in the third world countries, over 3000 doctors in Finland, Denmark, Norway, Sweden abhorred the products of Ciba-Geigy. The company suffered huge losses and ultimately withdrew the drugs(3).

An award has been named in honour of Dr. Olle Hanson for people of developing countries actively working in the field of rational drug use. The first Indian recipient of this award is Dr. Mira Shiva.

Discussion

International Scenario: A Timeline Of Events(4)

1901-The vaccine event: Children who were administered Diphtheria vaccine died of tetanus. This was because the horse sera that was used to prepare the anti-toxin was contaminated with tetanus toxin.
1902-The Biologics Control act:is passed to ensure purity and safety of serums, vaccines, and similar products used to prevent or treat diseases in humans.
1906-The food and drugs act:It prohibits interstate commerce in misbranded and adulterated foods, drinks and drugs.
1937-Cough syrup incidence: Elixir of Sulfanilamide, containing the poisonous solvent diethylene glycol, kills 107 people, many of whom were children, dramatizing the need to establish drug safety before marketing and to enact the pending food and drug law.
1938-The Federal Food, Drug and Cosmetics (FDC) Act: This was revision of food and drugs act, 1906 which now also includes cosmetics and therapeutic devices.
1955 - The Cutter incidence(5) : Over 250 polio cases were reported due to the use of two contaminated polio vaccine lots. The vaccine contained live active virus instead of the inactive virus because of a supposedly insignificant change in process. This highlighted the importance of process validation.
1961-Thalidomide disaster: Thalidomide was a drug introduced for sleeping disorders. But when used for treatment of morning sickness in pregnant women it caused severe damage to the foetus. Over 12,000 babies were born with phocomelia (without limbs).
1962-Kefauver-Harris drug amendments: These were to ensure the safety and efficacy of a drug before it is marketed. In testing a new drug the manufacturer must seek informed consent from the subjects. Nowadays the regulators insist that the drug before being tested on humans, must undergo reproductive studies in 2 or 3 animal species.
1968-Drug Efficacy Study Implementation (DESI): Formed by FDA to implement recommendations of the National Academy of Sciences investigation of effectiveness of drugs first marketed between 1938 and 1962.
1972-Over-the-Counter Drug Review: It was started to enhance the safety, effectiveness and appropriate labeling of drugs sold without prescription.
1982-Tylenol Tampering: Deaths resulted due to cyanide poisoning when over-the- counter tylenol was consumed. This occurred due to the tampering on store shelves. Now regulations lay stress on ‘tampering-resistant packaging’.
1987-New guidelines and establishments: To monitor vaccine safety, the NIH (National Institute of Health) established the division of Biologics Control. Today, it’s the Centre for Biologics Evaluation and Research (CBER), now part of FDA.
1989-L-Tryptophan Event: There were 38 deaths and hundreds of less severe reactions due to consumption of a dietary supplement, L-tryptophan which contained a harmful byproduct in excess of normal.
2004-FDA bans dietary supplements: As they contained ephedrine alkaloids and caused increased number of adverse events.
2005-Formation of the Drug Safety Board: The Board will advise the Director, Center for Drug Evaluation and Research, FDA, on drug safety issues and work with the agency in communicating safety information to health professionals and patients.

Indian Scenario
India has the world’s third largest medical manpower and has one of the best developed pharmaceutical industries among the developing countries, but ironically 1 out of every 5 drugs tested turns out to be sub-standard or spurious. India contributes to about 35% of Asia’s counterfeit drugs(6)(Table/Fig 2). In spite of having 70,000 formulations in market, we fail to have essential life saving drugs. There is uncontrolled proliferation of irrational, useless and sometimes hazardous drug products(7). There is no source for unbiased drug information. The practices of adverse drug reaction (ADR) monitoring and post marketing surveillance (PMS) by the drug manufacturing companies clearly falls short of the expected requirement(8). The latest official update available states that 78 categories of drugs have been banned in India, out of which 15 are individual drugs and 63 are fixed-drug combinations(9)(Table/Fig 1)

Establishment Of Review Committees
1. Hathi Committee-1974(10)

It attempted to formulate an essential drugs list for the first time. It recommended drug price control measures to increase the availability of life saving and essential drugs. The Drug Price Control Order (DPCO) was started in 1979 with three different categories of drugs. Presently, there are only two categories, one which allows a profit margin of 100% and other whose prices are decontrolled. The committee recommended a gradual shift to generic names from brand names.

2. The Lentin Commission Report-1986
Fourteen deaths were reported from J. J. hospital, Mumbai in January 1986. The deaths were totally unrelated to the treatments. The deaths were caused due to the use of diethylene glycol instead of the safer propylene glycol which resulted in acute renal failure. The event was similar to the one which occurred in 1937.

3. Mashelkar Committee-2003
This committee presented a report on comprehensive examination of drug regulatory issues including the menace of spurious drugs.

Drug Product Recall (DPR)(11)
A DPR may be initiated by the Food and Drug Administration (FDA) or by the manufacturer (voluntary recall). A numerical class indicates the degree of consumer hazards associated with the product being recalled.
•Class I: Situation I in which there is a reasonable probability that the use of, or exposure to, a violative product will cause adverse health consequences or death.
•Class II: Situation in which the use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences, or where the probability of serious health consequences is remote.
•Class III: Situation in which the use of, or exposure to, a violative product is not likely to cause adverse health consequences.

Criteria For Banning A Drug/Drug Combination
•Harmful single ingredient preparations.
•Combinations containing harmful ingredients.
•Irrational and untested combinations.
•Food supplements and tonics with inadequate quantity of nutrients.
•Potentially harmful preparations for which safer alternatives of comparable or better efficacy and pricing are available.

Reasons For Banning A Drug/Drug Combination
A drug is introduced into the market for the benefit of consumers. FDA approves a drug only when its safety is proved. However a safe drug need not be harmless. Every drug comes with its own adverse effects. But only when the risk: benefit ratio is low that the drug is approved by FDA.

The Reasons For Banning A Drug Are:
1. Unexpected Problems

The adverse effects of drugs introduced into the market are well known. Morbidity and mortality is more due to known adverse effects rather than unknown adverse effects. Some adverse effects are rare and cannot be elicited by clinical trials which highlight the commonly encountered adverse effects. Severe drug-induced liver diseases is one of the leading causes of banning drugs but is very rare to the extent of 1:5,000 to 1:10,000 exposures or less, which is easily missed in clinical trials and drug is introduced in the market.

2. Excess Toxicity
A drug may show toxicity only after it is introduced in the market and not at the time of clinical trials. The best example would be Cerivastatin (Baycol) which caused severe rhabdomyolysis(12).

3. Availability Of Safer Options
A drug with less adverse effects and greater or similar efficacy is preferred. Terfenadine introduced in 1985 was banned in 1998 due to its implications in causation of cardiac rhythm abnormalities. This was because fexofenadine introduced in 1997 had similar efficacy but no such adverse effects(13).

4. Harmful Interactions
Mibefradil and astemizole were introduced in the market with known dangerous interactions with 3-4 drugs each. Consequently they showed dangerous interactions with other drugs. They were withdrawn due to availability of other safer alternatives.

5. Irrational Use
The safety of thalidomide in pregnant women was not established. Still this drug was used in pregnant women, causing foetal toxicity and children were born with phocomelia. It was clearly mentioned that bromfenac sodium (NSAID) should be used only for a short time as it elevates liver enzymes when used over a long period of time. However it was used for prolonged time period and this resulted in many cases of liver failure.

6. Failure Of Other Risk Management Options
To highlight the risks associated with a particular drug FDA educates health care professionals through letters (Dear doctor letters) and labeling changes, sometimes new warnings which are placed in black box (black box warnings). Labels are attached specifically for patients mentioning adverse effects and how to detect/avoid them. Drugs are placed in ‘second line’ list – i.e. they are to be used only if other treatments fail. Some drugs are placed in category of restricted distribution, wherein they are made available only in certain conditions(Table/Fig 3).

Drugs surrounded by controversies – to use or not to use?

1. Rosiglitazone (Thiazolidinedione Antidiabetic)

In May 2007, the New England Journal of Medicine (NEJM) published an analysis linking rosiglitazone to increased risk of heart attacks. The meta-analysis reviewed 42 studies and found patients taking rosiglitazone to be at a 43% higher risk of heart attacks and a 64% elevated rate of cardiovascular death(17). However analysis of the 42 studies showed that 40 of them were small and all these put together did not yield statistically significant difference for Myocardial Infarction (MI) between groups. Of the 42 studies included 30 were unpublished and none of them were designed to address MI as either primary or secondary endpoint(18). Thus the presently available data are not conclusive and henceforth United States Food And Drug Administration (US FDA) has not withdrawn the drug but asked for strict review and some changes have been made on the prescription label(19). Undoubtedly, data, if confirmed would be of significant concern since patients with diabetes are already at an increased risk of heart disease.

2. Gatifloxacin (Fluoroquinolone Antibiotic)
According to a March 2006 article in NEJM about 2 Canadian studies, one of every 100 patients who take gatifloxacin were hospitalized for either hypoglycaemia or hyperglycaemia(20). On May 1, 2006, the consumer advocacy group Public Citizen asked FDA to ban this drug(21). On April 27, 2006 Bristol-Myers Squibb Co. announced that it would stop selling their brand of gatifloxacin (Tequin)(22).

3. Telithromycin (Ketolide Antibiotic)
On March 21 2006, the Annals of Internal Medicine reported three cases of liver problems associated with telithromycin(23). The drug has been associated with liver damage, liver failure and hepatitis. In mid-May 2006 FDA recommended that a black box warning should to be added to the telithromycin label, stating that “severe, life threatening, and in some cases fatal” liver toxicity has been reported in patients put on this drug(24). In February 2007, FDA has recommended this drug only for Community Acquired Pneumonia (CAP)(25).

4. Alendronate (Bisphosphonate)
Recent studies have shown a possible link between using alendronate and developing osteonecrosis of the jaw (ONJ)(26). ONJ can be very painful and may lead to infection, breakdown of the jaw bone, oral ulceration and osteomyelitis. FDA has advised the manufacturers to include a warning in the drug label to highlight this serious side effect(27).

5. Pergolide And Carbergoline (Antiparkinson’s Dopaminergic Agonists)
On March 2007 FDA announced that pergolide would be withdrawn from the market on account of two separate studies published in January 2007 in NEJM which concluded that patients put on pergolide and carbergoline are four to seven times more likely to suffer from heart valves’ damage than patients on alternative drug therapy(28).

6. Tegaserod (Serotonin agonist for Irritable Bowel Syndrome)
FDA has asked Novartis to suspend the sales of tegasarod (Zelnorm) following analysis of trial data showing adverse side effects such as heart attack and stroke(29). Recently in March 2007, Novartis agreed to voluntarily suspend the sales of their brand Zelnorm.

7. Rosuvastatin (Hypolipidemic)
During clinical trials patients taking 80 mg dose of rosuvastatin began to show signs of muscle weakness, rhabdomyolysis and kidney damage, and this dose was discontinued. A new analysis of post marketing safety still suggests that this statin is more likely to cause Adverse Drug Reactions (ADRs) than the other statins(30). .

8.Rimonabant (Antiobesity drug)
This drug sold in 18 countries and promoted for marketing in USA by Sanofi-Aventis, is likely to cause adverse psychiatric reactions including suicidal thoughts and actions, neurological problems and seizures(31). US FDA approval is still under consideration.

9. Sparfloxacin (Fluoroquinolone)
Reports suggest higher incidence of QT prolongation (2.1 %) as compared to 0.6 % for cefaclor and suggestions are increasing to label this drug as bannable.

10. Propofol (General Anaesthetic)
FDA has issued alerts about several patients experiencing chills, fever and body aches after receiving propofol(32). FDA is currently investigating the various reasons for these acute febrile reactions.

Similarly, few other drugs like ezetimibe and simvastatin for their harmful effects on liver and nesiritide for its kidney failure reports(33) are under strong controversies presently and surely require lot of vigilance.


Drugs Once Withdrawn But Re-Introduced
These are drugs which were banned initially due to their adverse effects but have been reintroduced into the market subsequently either for a totally different indication or for similar indication to be used with strict restriction(34),(35)(Table/Fig 4).


Here Are A Few Examples Of Drugs Of Doubtful Efficacy But Routinely And Commonly Prescribed(36) .

1. Digestive Enzymes
Digestive enzymes are prescribed to promote digestion in patients who lack one or more of the specific substances that are required for digestion. Although a large number of products are marketed, only the preparations of pancreatic enzymes are considered efficacious.

The pancreatic enzymes are destroyed by the acid and peptic activity in the stomach; hence enteric coated capsules are used. However, the enteric coating sometimes may prevent the delivery of enzymes in the duodenum. In addition, at recommended doses, the enteric coated preparations have a lipase activity that is less than half the lipase activity of conventional preparations.

2. Cerebral vasodilators
The vasodilatation induced by cerebral vasodilators is thought to be of questionable value. Some researchers advise cautious use of these drugs in patients with severe coronary artery disease or cerebral vascular disease since the disease areas may be compromised because of the vasodilatory action of these drugs elsewhere.
Examples-nimodipine, pentoxiphylline, isoxsuprine, cyclandelate, xanthinol nicotinate, nylidrin, piracetam, ginkgo biloba, codergocrine, piribedil, L-Glutamic acid and pyritinol.

3. Clofibrate In Cardiology
The lithogenecity of bile is increased by all fibric acid derivatives. Clofibrate use was associated with increased myocardial infarction and increased mortality in addition to increased risk of gallstone formation in the Coronary Drug Project and the WHO trial.

4. Appetite Stimulants(Cyproheptadine And Buclizine) in Children
These should not be used in infants and children because overdosage has serious adverse effects on the central nervous system and may even cause death.

Conclusion

Banned and Bannable drugs are an ever increasing problem. More and more drugs are being synthesized and marketed with better efficacy and improved safety. Availability of better alternatives raise doubts about earlier drugs of doubtful efficacy or harmful safety profile and need to be replaced. Drug authorities should be prompt enough to withdraw the sale of drugs which are harmful, useless or of little benefit to mankind.

There is a clear need for pharmacovigilance studies in our country as it is still in infancy(37). With the unhindered availability of bannable drugs over the counter in India(38) it’s time that the Drug Controller General of India (DCGI) should seriously attempt to implement the pharmacovigilance program for the interest of common man. It should take strict measures towards pharmaceutical companies which seem to be uninterested in voluntary recall of already banned drugs or drugs with documented adverse effect profile. This will ensure marketing of safe medicines and aid better patient care. Measures should be taken to pick up adverse effects of drugs at the earliest. It’s the need of hour that suggestions given by Biswas et al in her article(8) should be followed, where she fantastically describes and discusses the various strategies and proposals to build, maintain and implement a robust pharmacovigilance system for various stakeholders and eventually trying to make it happen in India.

Drugs banned elsewhere need to be seriously looked at and banned from use or in certain cases restricted to be used only for severe illness, in absence of other available drugs for the same indication. Awareness programs should be conducted in Government hospitals as well as for private medical practitioners to make them aware of the current status of drugs in market. Medical students should be taught about drugs banned from use and drugs surrounded by various controversies, so that they can refrain from using the same for patient care. Physicians should begin reporting ADRs to the nearest pharmacovigilance centre to help generate ADR database(39). As suggested by Parmar et al(40) the current status of marketed drugs, particularly hazardous ones, should be clearly mentioned in interest of public as citation of such information will help to increase the awareness about hazardous drugs and will serve the purpose of pharmacovigilance in a true sense.

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