Troglitazone

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Troglitazone
Clinical data
Trade namesRezulin, Resulin, Romozin, Noscal
Routes of
administration		By mouth (tablets)
ATC code
Legal status
Legal status
  • Production and promotion ceased
Pharmacokinetic data
Elimination half-life16–34 hours
Identifiers
  • (RS)-5-(4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl)thiazolidine-2,4-dione
JSmol)
Melting point184 to 186 °C (363 to 367 °F)
  • O=C1NC(=O)SC1Cc4ccc(OCC3(Oc2c(c(c(O)c(c2CC3)C)C)C)C)cc4
  • InChI=1S/C24H27NO5S/c1-13-14(2)21-18(15(3)20(13)26)9-10-24(4,30-21)12-29-17-7-5-16(6-8-17)11-19-22(27)25-23(28)31-19/h5-8,19,26H,9-12H2,1-4H3,(H,25,27,28) checkY
  • Key:GXPHKUHSUJUWKP-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Troglitazone is an

diabetes mellitus type 2.[1]

It was patented in 1983 and approved for medical use in 1997.[2] It was subsequently withdrawn.

Mechanism of action

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 an α-Tocopherol moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown to reduce inflammation.[3] 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.

History

A 30-tablet pharmacy stock bottle of Rezulin (troglitazone) (400 mg) from Parke-Davis. Manufactured 1997. Shown also is one broken tablet. Tablet branding is PD353.

Troglitazone was developed by

liver toxicity; Parke-Davis complained to the FDA, and Gueriguian was subsequently removed from his post.[4] A panel of experts approved it in January 1997.[5] Once the prevalence of adverse liver effects became known, troglitazone was withdrawn from the British market in December 1997, from the United States market in 2000, and from the Japanese
market soon afterwards. It did not get approval in the rest of Europe.

Troglitazone was developed as the first anti-diabetic drug having a mechanism of action involving the enhancement of insulin resistance. At the time, it was widely believed that such drugs, by addressing the primary metabolic defect associated with Type 2 diabetes, would have numerous benefits including avoiding the risk of hypoglycemia associated with insulin and earlier oral antidiabetic drugs. It was further believed that reducing insulin resistance would potentially reduce the very high rate of cardiovascular disease that is associated with diabetes.[6][7]

Peter Gøtzsche, when the company provided these additional data one week after approval, they showed a substantially greater risk for liver toxicity.[12]

The FDA approved the drug on January 29, 1997, and it appeared in pharmacies in late March. At the time, Dr. Solomon Sobel, a director at the FDA overseeing diabetes drugs, said in a

New York Times interview that adverse effects of troglitazone appeared to be rare and relatively mild.[13]

Glaxo Wellcome received approval from the British Medicines Control Agency (MCA) to market troglitazone, as Romozin, in July 1997.[14] After reports of sudden liver failure in patients receiving the drug, Parke-Davis and the FDA added warnings to the drug label requiring monthly monitoring of liver enzyme levels.[15] Glaxo Wellcome removed troglitazone from the market in Britain on December 1, 1997.[8] Glaxo Wellcome had licensed the drug from Sankyo Company of Japan and had sold it in Britain from October 1, 1997.[16][17]

On May 17, 1998, a 55-year-old patient named Audrey LaRue Jones died of

Edward M. Kennedy (D-Mass.): "I believe that the company... deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by patients in their clinical studies."[22]

On March 21, 2000, the FDA withdrew the drug from the market.[23] Dr. Robert I. Misbin, an FDA medical officer, wrote in a March 3, 2000 letter to Senator John Ashcroft of strong evidence that Rezulin could not be used safely. He was later threatened by the FDA with dismissal. [8][24] By that time, the drug had been linked to 63 liver-failure deaths and had generated sales of more than $2.1 billion for Warner-Lambert.[21] The drug cost $1,400 a year per patient in 1998.[17] Pfizer, which had acquired Warner-Lambert in February 2000, reported the withdrawal of Rezulin cost $136 million.[25]

Mechanisms of hepatotoxicity

Since the withdrawal in 2000, mechanisms of troglitazone

cell lines.[30]

Lawsuits

In 2009, Pfizer resolved all but three of 35,000 claims over its withdrawn diabetes drug Rezulin for a total of about $750 million. Pfizer, which acquired rival Wyeth for almost $64 billion, paid about $500 million to settle Rezulin cases consolidated in federal court in New York, according to court filings. The company also paid as much as $250 million to resolve state-court suits. In 2004, it set aside $955 million to end Rezulin cases.[31]

References

  1. ^ Fisher L (4 November 1997). "Adverse Diabetes Drug News Sends Warner-Lambert Down". The New York Times. Retrieved 12 December 2012.
  2. ISBN 9783527607495
    .
  3. PMID 11443197
    .
  4. ^ Hintertheur A (November 2008). "Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights". wired.com.
  5. PMID 16601971
    .
  6. S2CID 34080394
    .
  7. PMID 7935664
    .
  8. ^ a b c Willman D (20 December 2000). "NEW FDA: Rezulin Fast-Track Approval and a Slow Withdrawal". The Los Angeles Times. Retrieved 12 December 2012.
  9. ^ a b c Willman D (4 June 2000). "The Rise and Fall of the Killer Drug Rezulin". The Los Angeles Times. Retrieved 12 December 2012.
  10. ^ "Report: FDA Removes Medical Officer". Associated Press.
  11. ^ Avorn J (2005). Powerful medicines. New York: Vintage books.
  12. ISBN 9781846198847
    .
  13. ^ Leary W (31 January 1997). "New Class of Diabetes Drug Is Approved". The New York Times. Retrieved 12 December 2012.
  14. ^ Sinclair N (31 July 1997). "Glaxo Wellcome gets approval for Romozin". ICIS News. Retrieved 12 December 2012.
  15. ^ "Approval package for Rezulin (troglitazone)" (PDF). Center for Drug Evaluation and Research. U.S. Food and Drug Administration. 4 April 1997. Archived from the original (PDF) on 5 November 2014.
  16. ^ "Diabetes drug withdrawn from sale". BBC. British Broadcasting Corporation. 1 December 1997. Retrieved 12 December 2012.
  17. ^ a b Fisher L (17 January 1998). "Drug Makers at Threshold of a New Therapy; With a Dose of Biotechnology, Big Change Is Ahead in the Treatment of Diabetes". The New York Times. Retrieved 12 December 2012.
  18. PMID 10189543
    .
  19. PMID 11832527
    .
  20. PMID 16362281
    .
  21. ^ a b Willman D (16 August 2000). "FDA's Approval and Delay in Withdrawing Rezulin Probed". The Los Angeles Times. Retrieved 12 December 2012.
  22. ^ Willman D (10 March 2000). "Fears Grow Over Delay in Removing Rezulin". The Los Angeles Times. Retrieved 12 December 2012.
  23. ^ "2000 Safety Alerts for Human Medical Products". U.S. Food and Drug Administration. Retrieved 12 December 2012.
  24. ^ Willman D (March 17, 2000). "Physician Who Opposes Rezulin Is Threatened by FDA With Dismissal". Los Angeles Times.
  25. ^ "Pfizer Annual Report 2001" (PDF). Pfizer. Retrieved 12 December 2012.
  26. ^
    PMID 11170509
    .
  27. PMID 11179459
    .
  28. ^
    PMID 21657230
    .
  29. PMID 17072088
    .
  30. PMID 22409968
    .
  31. ^ Feeley J (March 31, 2009). "Pfizer Ends Rezulin Cases With $205 Million to Spare". Bloomberg. Retrieved 6 April 2014.

External links

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