Trovafloxacin

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Trovafloxacin
Trovafloxacin.svg
Systematic (IUPAC) name
7-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-[1,8] naphthyridine-3-carboxylic acid
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
MedlinePlus a605016
Legal status Withdrawn from market
Routes Oral, intravenous
Identifiers
CAS number 147059-72-1 YesY
ATC code J01MA13
PubChem CID 62959
DrugBank DB00685
ChemSpider 16736478 YesY
UNII 9F388J00UK YesY
KEGG D08654 YesY
ChEBI CHEBI:9763 N
ChEMBL CHEMBL428 YesY
Chemical data
Formula C20H15F3N4O3 
Mol. mass 416.353 g/mol
 N (what is this?)  (verify)

Trovafloxacin (sold as Trovan by Pfizer and Turvel by Laboratorios Almirall) was a broad spectrum antibiotic that inhibits the uncoiling of supercoiled DNA in various bacteria by blocking the activity of DNA gyrase and topoisomerase IV.[1] It was withdrawn from the market due to the risk of hepatotoxicity.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.

Adverse reactions[edit]

Trovafloxacin use is significantly restricted due to its high potential for inducing serious, sometimes fatal liver damage.[2]

Controversy[edit]

Nigerian clinical trial[edit]

In 1996, during a meningitis epidemic in Kano, Nigeria, the then-untested drug was administered to approximately 200 [3] infected children. Eleven children died in the trial: five after taking Trovan and six after taking an older antibiotic used for comparison in the clinical trial. Others suffered blindness, deafness and brain damage, the cause of which is difficult to determine because these disabilities are relatively common outcomes of the disease itself. 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.[4] 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.

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. [5] 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.[5] According to Wikileaked US embassy cables, Pfizer's country manager admitted that "Pfizer had hired investigators to uncover corruption links to federal attorney general Michael Aondoakaa to expose him and put pressure on him to drop the federal cases."[6]

Post approval link to hepatotoxicity[edit]

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.[7] 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.[8]

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.[8][9]

See also[edit]

References[edit]

  1. ^ Gootz, TD; Zaniewski R, Haskell S, Schmieder B, Tankovic J, Girard D, Courvalin P, Polzer RJ (December 2006). "Activity of the new fluoroquinolone trovafloxacin (CP-99,219) against DNA gyrase and topoisomerase IV mutants of Streptococcus pneumoniae selected in vitro". Antimicrob Agents Chemother 40 (12): 2691–7. PMC 163605. PMID 9124824. 
  2. ^ "Acute liver failure due to trovafloxacin: CT findings". doi:10.1007/PL00011876. 
  3. ^ Nigeria. Federal Ministry of Health. Investigation Committee. Report of the Investigation Committee on the Clinical Trial of Trovafloxacin (Trovan) by Pfizer, Kano, 1996. N.p.: n.p., n.d. Print.
  4. ^ Stephens, Joe (May 7, 2006). "Panel Faults Pfizer in '96 Clinical Trial In Nigeria". The Washington Post. p. A01. Retrieved 2006-08-28. 
  5. ^ a b Stephens, Joe (July 31, 2009). "Pfizer to Pay $75 Million to Settle Nigerian Trovan Drug-Testing Suit". The Washington Post. Retrieved May 26, 2010. 
  6. ^ Boseley, Sarah (9 December 2010). "WikiLeaks cables: Pfizer 'used dirty tricks to avoid clinical trial payout'". The Guardian (London). http://www.guardian.co.uk/business/2010/dec/09/wikileaks-cables-pfizer-nigeria
  7. ^ Bloomberg News (April 15, 1998). "2 Drug Companies Report Big Quarterly Profit Gains". The New York Times. p. D.5. ISSN 03624331.  (via ProQuest, Document ID 28630468)
  8. ^ a b Petersen, Melody (August 27, 2000). "Unforeseen Side Effects Ruined One Blockbuster". The New York Times. p. 3.11.  (via ProQuest, Document ID 58860021)
  9. ^ Reuters (June 12, 1999). "Suspension of Trovan Drug in Europe Is Urged". The New York Times. p. C.3.  (via ProQuest, Document ID 42327418)

External links[edit]