ISSN   0974-3618  (Print)                    www.rjptonline.org

            0974-360X (Online)

 

 

REVIEW ARTICLE

 

A Review on Drug Disaster in the History of Medicine

 

Dr. Suja C, Navaneeth Krishna Manoj, Shuhaib. B, Rishana K.V, Nidina P,

Mohammed Ashfaque

Crescent College of Pharmaceutical Sciences, Madayipara, Payangadi R.S.(Post),  Kannur, Kerala.

*Corresponding Author E-mail:

 

ABSTRACT:

A drug is, in the broadest of terms, a chemical substance that has known biological effects on humans or other animals. In pharmacology, a drug is "a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being." Drugs may be used for a limited duration, or on a regular basis for chronic disorders. Drug disaster may be defined as the ill effect/hazards it causes or it may cause after it reaches the market for the patients. This article presents a broad review of drug disaster in the history of medicine. This becomes a major problem since it is observed after the routine and detailed research and clinical studies .In this review ,eight drug disaster cases  was studied and the criteria for the study being  drug category , use, disaster, manufacture and  incidents .The drugs involved in this disaster studies are Sulfanilamide, Diethyl stilbesterol, Rofecoxib, Thalidomide, Fenfluramine/ Phenteramine, Cerivastatin, Troglitazone and Nimesulide. From the different cases we reviewed, all were either due to the incomplete and thorough clinical studies of the active pharmaceutical ingredient and the excipients as a whole or due to the inadequate post marketing surveillance of the specified product.

 

KEYWORDS: Drug, drug disaster, drug category, incident, excipient.

 


 

INTRODUCTION:

A drug is, in the broadest of terms, a chemical substance that has known biological effects on humans or other animals.1 Foods are generally excluded from this definition, in spite of their physiological effects on animal species. In pharmacology, a drug is "a chemical substance used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being."2.  A drug disaster may be defined as the ill effect/hazards it causes or it may cause after it reaches the market for the patients. This becomes a major problem since it is observed after the routine and detailed research and clinical studies (Phase 0 to 4). 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Received on 04.02.2015       Modified on 21.02.2015

Accepted on 25.02.2015      © RJPT All right reserved

Research J. Pharm. and Tech. 8(4): April, 2015; Page 481-485

DOI: 10.5958/0974-360X.2015.00080.3

 

Drug disaster may arise due to various reasons. This can be caused during the administration  of  elevated doses  of certain drug or arises during manufacturing time  either by  use of toxic chemicals, solvents or other excipients.; The perceived inability of the Food and Drug Administration (FDA) and the pharmaceutical industry to evaluate drugs impartially and to respond adequately to signals indicating potential drug-safety problem3. The most severe drug disaster that is reported is that of phocomelia with thalidomide. Thalidomide is an immuno modulatory drug, and is used as sedative or hypnotic, it was used for nausea and to alleviate morning sickness in pregnant women.  But the drugs produce serious side effect to the society.  Throughout the world, about 10,000 cases were reported of infants with phocomelia due to thalidomide. It also caused   deformed eyes and hearts, deformed alimentary and urinary tracts, blindness and deafness in new born. Canada was the last country to end sales of the drug. In the United Kingdom, the drug was licensed in 1958 and withdrawn in 1961. Of the approximately 2,000 babies born with defects, around half died within a few months and 466 survived to at least 2010.

Recent withdrawals from the market of high-profile drugs have led to a re-examination of the process of drug regulation and have stimulated concern that the current process is inadequate for protection of the public health.

 

LITERATURE REVIEW:

Drug disasters:

1. Sulfanilamide:

Category: - Antibacterial

M.O.A:-   As a sulfonamide antibiotic, it functions by competitively inhibiting (i.e., by acting as a substrate analogue) enzymatic reactions involving para-aminobenzoic acid (PABA). PABA is needed in enzymatic reactions that produce folic acid which acts as a coenzyme in the synthesis of purine, pyrimidine and other amino acids.

Manufacturer: - S.E. Massengill Company

USE: as a first-aid treatment to reduce infection rates use for treatment of vaginal yeast infections.

Year of Occurrence: - 1937

Place: United States of America

 

Disaster:

Elixir sulfanilamide was an improperly prepared sulphanilamide medicine that caused mass poisoning in the United States in 1937. It caused the deaths of more than 100 people. 

 

In 1937, S. E. Massengill Company, a pharmaceutical manufacturer, created a preparation of sulfanilamide using diethylene glycol (DEG) as a solvent and raspberry flavour, and called the preparation "Elixir Sulfanilamide". The company started selling and distributing the medication in September 1937. By October 11, the American Medical Association received a report of several deaths caused by the medication. The Food and Drug Administration was notified, and an extensive search was conducted to recover the distributed medicine. DEG was responsible for the fatal adverse effects since it is poisonous to humans and other mammals. At least 100 deaths were blamed on the medication.

 

2.Diethylstilbesterol (DES):

Category: - Synthetic estrogen

USE:-    DES (in tablets up to 5 mg) was approved by the United States Food and Drug Administration on September 19, 1941 for four indications: gonorrheal vaginitis,  atrophicvaginitis, menopausal symptoms, and postpartum lactation suppression to prevent breast engorgement

Year of Occurrence:-1940-1971

Place: United States of America

Incident: DES (diethyl stilbestrol), a toxic and carcinogenic synthetic estrogen, is considered the world’s first drug disaster. It was prescribed to millions of pregnant women for decades: from 1938 until 1971 (and in a small number of cases for several years thereafter) in the United States; and until the mid-1980s in parts of Latin America, Europe, Australia, and the Third World. The currently proven effects of exposure include a rare vaginal cancer in DES Daughters; greater risk for breast cancer in DES Mothers; possible risk for testicular cancer in DES Sons; abnormal reproductive organs; infertility; high-risk pregnancies; and an increased risk for breast cancer in DES Daughters after age 40.

 

DES gained notoriety when it was shown to cause a rare vaginal tumor in girls and young women who had been exposed to this drug in uterus. In 1971, the New England Journal of Medicine published a report showing that seven of eight girls and young women (ages 14 to 22) who had been diagnosed with vaginal clear cell adenocarcinoma had been exposed prenatally to DES. Subsequent studies have shown an approximate 40-fold increased risk of vaginal/cervical clear cell adenocarcinoma in women exposed in uterus to DES. As a consequence of this evidence, DES is considered an established human carcinogen5.

 

3. Rofecoxib (Vioxx):

Category: - NSAID:

M.O.A:- (COX) has two well-studied iso forms, called COX-1 and COX-2. COX-1 mediates the synthesis of prostaglandins responsible for protection of the stomach lining, while COX-2 mediates the synthesis of prostaglandins responsible for pain and inflammation. By creating "selective" NSAIDs that inhibit COX-2, but not COX-1, the same pain relief as traditional NSAIDs offered, but with greatly reduced risk of fatal or debilitating peptic ulcers. Rofecoxib is a selective COX-2 inhibitor, or "coxib".

Use:-  to treat osteoarthritis, acute pain conditions, and dysmenorrhoea.

Manufacturer:-Merck & Co.

Year of Withdrawal:-2004

Place:- U.S.A

Incident: On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease.6 Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market.

 

4. Thalidomide:

Category: - Immunomodulatory drug

M.O.A: The precise mechanism of action for thalidomide is unknown but possible mechanisms include anti-angiogenic and oxidative stress-inducing effects.7 It also inhibits TNF-α, IL-6, IL-10 and IL-12 production,8 modulates the production of IFN-γ and enhances the production of IL-2, IL-4 and IL-5 by immune cells. It increases lymphocyte count, costimulates T cells and modulates natural killer cell cytotoxicity It also inhibits NF-κB and COX-2 activity.

Use:-prescribed as a sedative or hypnotic, thalidomide also claimed to cure “anxiety, insomnia, gastritis, and tension"9. Afterwards it was used against nausea and to alleviate morning sickness in pregnant women.

 

Manufacturer:-Chemie Grünenthal 

Year of Withdrawal:- 1957

Place: - West Germany

Incident: - Thalidomide became an over the counter drug in Germany on October 1, 1957. Shortly after the drug was sold, in Germany, between 5,000 and 7,000 infants were born with phocomelia (malformation of the limbs). Only 40% of these children survived. Throughout the world, about 10,000 cases were reported of infants with phocomelia due to thalidomide; only 50% of the 10,000 survived. Those subjected to thalidomide while in the womb experienced limb deficiencies in a way that the long limbs either were not developed or presented themselves as stumps. Other effects included deformed eyes and hearts, deformed alimentary and urinary tracts, blindness and deafness.10 The negative effects of thalidomide led to the development of more structured drug regulations and control over drug use and development.  In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities such as phocomelia as a consequence of thalidomide use.11 Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962; Canada was the last country to end sales of the drug.

 

5. Fenfluramine/Phentermine:

Use: - anti-obesity drug

M.O.A:- It is the racemic mixture of two enantiomers, dextrofenfluramine and levofenfluramine. It increases the level of the neurotransmitter serotonin, a chemical that regulates mood, appetite and other functions. Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter, and reversing serotonin transporter function.12 .The result is a feeling of fullness and loss of appetite.

 

Manufacturer: - Wyeth

Year of withdrawal:-1997

Place: - U.S.A

Incident:-The drug was withdrawn from the U.S. market in 1997 after reports of heart valve disease,13,17 and pulmonary hypertension, including a condition known as cardiac fibrosis. After the US withdrawal of fenfluramine, it was also withdrawn from other markets around the world. It was banned in India in 1998.14

 

The distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet and chordae tendineae. One mechanism used to explain this phenomenon involves heart valve serotonin receptors, which are thought to help regulate growth. Since fenfluramine and its active metabolite norfenfluramine stimulate serotonin receptors, this may have led to the valvular abnormalities found in patients using fenfluramine. In particular norfenfluramine is a potent agonist of 5-HT2B receptors, which are plentiful in human cardiac valves. The suggested mechanism by which fenfluramine causes damage is through over or inappropriate stimulation of these receptors leading to inappropriate valve cell division. Supporting this idea is the fact that this valve abnormality has also occurred in patients using other drugs that act on 5-HT2B receptors.15

 

According to a study of 5743 former users conducted by a plaintiff's expert cardiologist, damage to the heart valve continued long after stopping the medication.16 Of the users tested, 20 percent of women, and 12 percent of men were affected. For all ex-users, there was a sevenfold increase of chances of needing surgery for faulty heart valves caused by the drug.

 

6. Cerivastatin (Baycol):

Category: - Statin

Use: - anti-hyperlipidemic agent to reduce cholesterol and cardiovascular diseases

M.O.A:- HMG-COA reductase inhibitor

Manufacturer: - Bayer

Year of withdrawal:-2001

Place: USA

Incident:-During post marketing surveillance, 52 deaths were reported in patients using cerivastatin, mainly from rhabdomyolysis and its resultant renal failure. According to press reports, the use of cerivastatin was linked to rhabdomyolysis, which lead to kidney failure, and was responsible for 31 fatalities in the United States and a further 21 deaths worldwide. In addition, there were 385 nonfatal cases reported among the estimated 700,000 users in the United States, most of whom required hospitalization. In many of the fatal cases, patients had received the full dose of cerivastatin (0.8 mg/day) or were using gemfibrozil (Lopid®) concomitantly. This drug—drug interaction was implicated in 12 of the 31 fatalities in the United States.

 

Rhabdomyolysis17 is a condition in which damaged skeletal muscle tissue (Greek: ραβδω rhabdo- striped μυς myo-muscle) breaks down (Greek: λύσις –lysis) rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure. The severity of the symptoms, which may include muscle pains, vomiting and confusion, depends on the extent of muscle damage and whether kidney failure develops.

 

7. Troglitazone (Rezulin):

Category: - Thiazolidinediones

Use: - anti-diabetic and anti-inflammatory

M.O.A:-Troglitazone, like the other thiazolidinediones (pioglitazone and rosiglitazone), works by activating  peroxisome  proliferator-activated receptors (PPARs). Troglitazone is a ligand to both PPARα and – more strongly –PPARγ. Troglitazone also contains a               α-tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown to reduce inflammation18. Troglitazone use was associated with a decrease of nuclear factor kappa-B (NF-κB) and a concomitant increase in its inhibitor (IκB). NFκB is an important cellular transcription regulator for the immune response.

 

Manufacturer: - Daichi Sankyo and Parke-Davis

Year of withdrawal:-2000

Place: - Great Britain

Incident:-Troglitazone was the first thiazolidinedione approved for use in the United States and was licensed for use in type 2 diabetes in 1997, but withdrawn 3 years later because of the frequency of liver injury including acute liver failure associated with its use. Troglitazone was approved for use to be used alone or in combination with other antidiabetic medications.  However, reports of severe liver injury and death from acute liver failure began to arise soon after its general availability, and it was withdrawn from use in 2000.  Troglitazone was sold under the brand name Rezulin and was available in 400 mg tablets.  The recommended dosage was 400 to 800 mg once daily. Large prospective studies showed that significant elevations in serum aminotransferase levels (equal to or greater than 3 times the upper limit of the normal range [ULN]) occurred in 1.9% of patients with diabetes treated with troglitazone for 24 to 48 weeks, compared to only 0.6% in placebo recipients.  These enzyme elevations were usually asymptomatic and often resolved despite continuation of therapy. Nevertheless, elevations greater than 10 times ULN occurred in 0.5% of patients (but in no placebo recipient) and a proportion of these developed symptoms of liver injury and jaundice.

 

Liver biopsies showed acute inflammatory changes and variable degrees of necrosis, ranging from rare spotty necrosis to bridging hepatic necrosis and submassive or massive necrosis.  At least two dozen cases of acute liver failure and death or need for liver transplantation were reported to the FDA before troglitazone was withdrawn from use in 2000.

 

 

 

8 Nimesulide:

Category: - NSAID (selective cox-2 inhibitor)

Manufacturer:-Helsinn Healthcare SA

Use:- Treatment of acute pain, the symptomatic treatment of osteoarthritis and primary dysmenorrhoea in adolescents and adults above 12 years old. It has a multifactorial mode of action and is characterized by a fast onset of action.

 

The Irish Medicines Board (IMB) has decided to suspend Nimesulide from the Irish market and refer it to the EU Committee for Human Medicinal Products (CHMP) for a review of its benefit/ risk profile. The decision is due to the reporting of six (6) cases of potentially related liver failures to the IMB by the National Liver Transplant Unit, St Vincent Hospital. These cases occurred in the period from 1999 to 2006.19

Several reports have been made of adverse drug reactions in India 20-22, On Feb 12, 2011, Express India that the Union Ministry of Health and Family Welfare had finally decided to ban the pediatric use of the analgesic, Nimesulide suspension. From 10 March 2011 onwards Nimesulide formulations for human use in children below 12 years of age has been banned23 On 23 June 2011, the European Medicines Agency concluded the review of systemic nimesulide-containing medicine. They concluded that the benefits of systemic nimesulide continue to outweigh their risks in the treatment of patients with acute pain and primary dysmenorrhea.  Alembic Ltd. issued a circular asking wholesalers and retailers to withdraw all stocks of Nimegesic Drops (a pediatric dosage form of nimesulide) in 2003, consistent with the fact that nimesulide is, like most NSAIDs, not indicated in children.

 

CONCLUSION:

Management of Drug Disasters all among the human population remains a major therapeutic challenge throughout the world. We performed a critical review of evidence of past drug disasters that had affected the patients round the globe. The results of this review show that there is limited evidence on the highest level to justify a change in routine clinical practice. From the different cases we reviewed, all were either due to the incomplete thorough clinical studies of the active pharmaceutical ingredient and the excipients as a whole or due to the inadequate post marketing surveillance of the specified product. A well planned procedure has to be in place for reporting and evaluating adverse drug reactions and thereby recalling the product swiftly. By this considerable amount of health problems can be avoided.

 

In conclusion, when the results of this updated review are taken together with those of the earlier reports, proper and prolonged research becomes the need of the hour. For this reason, there is an urgent need to increase the quality of clinical studies. Detailed clinical studies with 24x7 post marketing surveillance becomes the topmost criteria for the future to put an end the disasters that has happened in the field of medicine that have become a dark spot for the health industry.

 

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