Trovafloxacin
Encyclopedia
Trovafloxacin is a broad spectrum antibiotic
that inhibits the uncoiling of supercoiled DNA
in various bacteria
by blocking the activity of DNA gyrase
and topoisomerase
IV. It was withdrawn from the market due to the risk of hepatotoxicity
. It had better gram-positive
bacterial coverage and less gram-negative
coverage than the previous fluoroquinolones.
epidemic
in Kano
, Nigeria
, the then-untested drug was administered to approximately 100 infected children. 11 of the children died and the rest suffered various long term effects. A panel of medical experts later implicated Pfizer
in the incident, concluding the drug had been administered as part of an illegal clinical trial
without authorization from the Nigerian government or consent
from the children's parents. The case came to light in December 2000 as the result of an investigation by The Washington Post
, and sparked significant public outcry. The Nigerian federal government has subsequently sued the drug giant for $8.5bn and Pfizer will face criminal and civil charges brought by the state and federal governments of Nigeria. The most serious error was the falsification and backdating of an ethics approval leader by the lead investigator of the trial, Dr. Abdulhamid Isa Dutse. Dr. Dutse is now the chief medical officer of Aminu Kano Teaching Hospital. The result of the trial was that children treated with oral trovafloxacin had a 5% (5/100) mortality rate compared to a 6% (6/100) mortality rate with intravenous ceftriaxone. This was a non-significant difference.
When it went on the market in 1998 Trovan became one of Pfizer's top-selling drugs. When first-quarter earnings were announced in April of that year, the company's earnings had increased by 15% over the previous year, with analysts attributing much of that increase to the sales of the "new antibiotic" Trovan. Pfizer had spent hundreds of millions of dollars developing Trovan. In the first year it brought over US$160 million and investors expected it to eventually bring in US$1 billion per year.
In June 1999 the U.S. Food and Drug Administration
advised doctors to limit the prescription of Trovan after it had been found "strongly associated" with 14 cases of acute liver failure and six deaths. The FDA had received over 100 reports of liver problems in people taking Trovan, which was at that time being prescribed at a rate of 300,000 patients per month in the United States. Two days later the Committee for Proprietary Medicinal Products recommended to the European Commission
that marketing approval of Trovan be suspended for a year. Between 2002 and 2005 the victims of the Trovan tests in Nigeria filed a series of unsuccessful lawsuits
in the United States. However, in January 2009, the United States Court of Appeals for the Second Circuit ruled that the Nigerian victims and their families were entitled to bring suit against Pfizer
in the United States under the Alien Tort Statute
. A US$75 million settlement with the State of Kano was reached July 30, 2009.
The charges filed against Pfizer by Nigeria's federal government, which is still seeking about $6 billion in damages, were not affected by this settlement. Additionally two lawsuits also remain pending in New York, United States.
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
that inhibits the uncoiling of supercoiled DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
in various bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
by blocking the activity of DNA gyrase
DNA gyrase
DNA gyrase, often referred to simply as gyrase, is an enzyme that relieves strain while double-stranded DNA is being unwound by helicase. This causes negative supercoiling of the DNA...
and topoisomerase
Topoisomerase
Topoisomerases are enzymes that regulate the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double helical structure. For example, during DNA replication, DNA becomes overwound ahead of a replication fork...
IV. It was withdrawn from the market due to the risk of hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
. It had better gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacterial coverage and less gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
coverage than the previous fluoroquinolones.
Adverse reactions
Trovafloxacin is seriously restricted in its use due to its serious potential for inducing serious sometimes fatal liver damage.Controversy
In 1996, during a meningitisMeningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
epidemic
Epidemic
In epidemiology, an epidemic , occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience...
in Kano
Kano
Kano is a city in Nigeria and the capital of Kano State in Northern Nigeria. Its metropolitan population is the second largest in Nigeria after Lagos. The Kano Urban area covers 137 sq.km and comprises six Local Government Area - Kano Municipal, Fagge, Dala, Gwale, Tarauni and Nassarawa - with a...
, Nigeria
Nigeria
Nigeria , officially the Federal Republic of Nigeria, is a federal constitutional republic comprising 36 states and its Federal Capital Territory, Abuja. The country is located in West Africa and shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in...
, the then-untested drug was administered to approximately 100 infected children. 11 of the children died and the rest suffered various long term effects. A panel of medical experts later implicated Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
in the incident, concluding the drug had been administered as part of an illegal clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
without authorization from the Nigerian government or consent
Consent
Consent refers to the provision of approval or agreement, particularly and especially after thoughtful consideration.- Types of consent :*Implied consent is a controversial form of consent which is not expressly granted by a person, but rather inferred from a person's actions and the facts and...
from the children's parents. The case came to light in December 2000 as the result of an investigation by The Washington Post
The Washington Post
The Washington Post is Washington, D.C.'s largest newspaper and its oldest still-existing paper, founded in 1877. Located in the capital of the United States, The Post has a particular emphasis on national politics. D.C., Maryland, and Virginia editions are printed for daily circulation...
, and sparked significant public outcry. The Nigerian federal government has subsequently sued the drug giant for $8.5bn and Pfizer will face criminal and civil charges brought by the state and federal governments of Nigeria. The most serious error was the falsification and backdating of an ethics approval leader by the lead investigator of the trial, Dr. Abdulhamid Isa Dutse. Dr. Dutse is now the chief medical officer of Aminu Kano Teaching Hospital. The result of the trial was that children treated with oral trovafloxacin had a 5% (5/100) mortality rate compared to a 6% (6/100) mortality rate with intravenous ceftriaxone. This was a non-significant difference.
When it went on the market in 1998 Trovan became one of Pfizer's top-selling drugs. When first-quarter earnings were announced in April of that year, the company's earnings had increased by 15% over the previous year, with analysts attributing much of that increase to the sales of the "new antibiotic" Trovan. Pfizer had spent hundreds of millions of dollars developing Trovan. In the first year it brought over US$160 million and investors expected it to eventually bring in US$1 billion per year.
In June 1999 the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
advised doctors to limit the prescription of Trovan after it had been found "strongly associated" with 14 cases of acute liver failure and six deaths. The FDA had received over 100 reports of liver problems in people taking Trovan, which was at that time being prescribed at a rate of 300,000 patients per month in the United States. Two days later the Committee for Proprietary Medicinal Products recommended to the European Commission
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....
that marketing approval of Trovan be suspended for a year. Between 2002 and 2005 the victims of the Trovan tests in Nigeria filed a series of unsuccessful lawsuits
Kano Trovafloxacin trial litigation
The Kano trovafloxacin trial litigation relates to a 1996 incident when the pharmaceutical company Pfizer conducted tests of trovafloxacin in Nigeria on 100 children, five of whom died, with many others suffering life-altering injuries. All of the children treated with the drug were already...
in the United States. However, in January 2009, the United States Court of Appeals for the Second Circuit ruled that the Nigerian victims and their families were entitled to bring suit against Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
in the United States under the Alien Tort Statute
Alien Tort Statute
The Alien Tort Statute ) is a section of the United States Code that reads: "The district courts shall have original jurisdiction of any civil action by an alien for a tort only, committed in violation of the law of nations or a treaty of the United States." This statute is notable for allowing...
. A US$75 million settlement with the State of Kano was reached July 30, 2009.
The charges filed against Pfizer by Nigeria's federal government, which is still seeking about $6 billion in damages, were not affected by this settlement. Additionally two lawsuits also remain pending in New York, United States.
See also
- AlatrofloxacinAlatrofloxacinAlatrofloxacin is a fluoroquinolone antibiotic developed by Pfizer, delivered as a mesylate salt. It is the parental prodrug of trovafloxacin meant for intravenous administration...
, a prodrugProdrugA prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
of trovafloxacin for intravenous administration - Fluoroquinolone toxicity
- Fluoroquinolone