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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