Troglitazone

Overview

Troglitazone is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones. It was prescribed for people with diabetes mellitus type 2.[1] WP

It was patented in 1983 and approved for medical use in 1997. It was subsequently withdrawn.[2][3] WP

Pharmacology

Mechanism of action

Troglitazone, like the other thiazolidinediones (pioglitazone and rosiglitazone), works by activating peroxisome proliferator-activated receptors (PPARs). WP

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. 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.[4][5] WP

History

History

Troglitazone was developed by Daiichi Sankyo (Japan). In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s but turned out to be associated with an idiosyncratic reaction leading to drug-induced hepatitis. The Food and Drug Administration (FDA) medical officer assigned to evaluate troglitazone, John Gueriguian, did not recommend its approval due to potentially high liver toxicity; Parke-Davis complained to the FDA, and Gueriguian was subsequently removed from his post. A panel of experts approved it in January 1997. Once the prevalence of adverse liver effects became known, troglitazone was withdrawn from the British market in December 1997, from the United States market in 2000, and from the Japanese market soon afterwards.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.[6][7] WP

Troglitazone was developed as the first anti-diabetic drug having a mechanism of action involving a decrease in 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.[8][9] WP

Parke-Davis/Warner Lambert submitted the diabetes drug Rezulin for FDA review on July 31, 1996. The medical officer assigned to the review, Dr. John L. Gueriguian, cited Rezulin's potential to harm the liver and the heart, and he questioned its viability in lowering blood sugar for patients with adult-onset diabetes, recommending against the drug's approval. After complaints from the drugmaker, Gueriguian was removed on November 4, 1996, and his review was purged by the FDA. Gueriguian and the company had a single meeting at which Gueriguian used "intemperate" language; the company said its objections were based on inappropriate remarks made by Gueriguian. Parke-Davis said at the advisory committee that the risk of liver toxicity was comparable to placebo and that additional data of other studies confirmed this. According to Peter Gøtzsche, when the company provided these additional data one week after approval, they showed a substantially greater risk for liver toxicity.[10–14] WP

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.[15] WP

Glaxo Wellcome received approval from the British Medicines Control Agency (MCA) to market troglitazone, as Romozin, in July 1997. 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. Glaxo Wellcome removed troglitazone from the market in Britain on December 1, 1997. Glaxo Wellcome had licensed the drug from Sankyo Company of Japan and had sold it in Britain from October 1, 1997.[10][16–19] WP

On May 17, 1998, a 55-year-old patient named Audrey LaRue Jones died of acute liver failure after taking troglitazone. Importantly, she had been monitored closely by physicians at the National Institutes of Health (NIH) as a participant in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) diabetes prevention study. This called into question the efficacy of the monitoring strategy. The NIH responded on June 4 by dropping troglitazone from the study. Dr. David J. Graham, an FDA epidemiologist charged with evaluating the drug, warned on March 26, 1999, of the dangers of using it and concluded that patient monitoring was not effective in protecting against liver failure. He estimated that the drug could be linked to over 430 liver failures and that patients incurred 1,200 times greater risk of liver failure when taking Rezulin. Dr. Janet B. McGill, an endocrinologist who had assisted in the Warner–Lambert's early clinical testing of Rezulin, wrote in a March 1, 2000, letter to Sen. 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."[11][20–24] WP

On March 21, 2000, the FDA withdrew the drug from the market. 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. 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. The drug cost $1,400 a year per patient in 1998. Pfizer, which had acquired Warner-Lambert in February 2000, reported the withdrawal of Rezulin cost $136 million.[10][19][23][25][26][27] WP

Chemistry

Formula

C24H27NO5S PC

CAS number

97322-87-7 PC

Molar mass (g/mol)

441.5 PC

IUPAC name (computed by PubChem)

5-[[4-[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromen-2-yl)methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione PC

SMILES

CC1=C(C2=C(CCC(O2)(C)COC3=CC=C(C=C3)CC4C(=O)NC(=O)S4)C(=C1O)C)C PC

InChIKey

GXPHKUHSUJUWKP-UHFFFAOYSA-N PC

PubChem CID

5591

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Other Fisher L. Adverse Diabetes Drug News Sends Warner-Lambert Down. November 4, 1997
2. Other Fischer J, Ganellin CR. Analogue-based Drug Discovery. 2006
3. Journal / agency Troglitazone
4. Other Троглитазон | 97322-87-7
5. Journal / agency Aljada A, Garg R, Ghanim H, Mohanty P, Hamouda W, Assian E, Dandona P. Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action?. The Journal of Clinical Endocrinology and Metabolism. July 2001. doi:10.1210/jcem.86.7.7564 · PMID 11443197
6. Other Hintertheur A. Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights. November 2008
7. Journal / agency Cohen JS. Risks of troglitazone apparent before approval in USA. Diabetologia. June 2006. doi:10.1007/s00125-006-0245-0 · PMID 16601971
8. Journal / agency Henry RR. Effects of troglitazone on insulin sensitivity. Diabetic Medicine. September 1996. doi:10.1002/dme.1996.13.s6.148 · PMID 8894499
9. Journal / agency Keen H. Insulin resistance and the prevention of diabetes mellitus. The New England Journal of Medicine. November 1994. doi:10.1056/NEJM199411033311812 · PMID 7935664
10. Other Willman D. NEW FDA: Rezulin Fast-Track Approval and a Slow Withdrawal. December 20, 2000
11. Other Willman D. The Rise and Fall of the Killer Drug Rezulin. June 4, 2000
12. Other Report: FDA Removes Medical Officer
13. Other Avorn J. Powerful medicines. 2005
14. Other Gøtzsche P. Deadly medicines and organised crime: how big pharma has corrupted healthcare. 2013
15. Other Leary W. New Class of Diabetes Drug Is Approved. January 31, 1997
16. Other Sinclair N. Glaxo Wellcome gets approval for Romozin. July 31, 1997
17. Journal / agency Approval package for Rezulin (troglitazone). April 4, 1997
18. Other Diabetes drug withdrawn from sale. December 1, 1997
19. Other Fisher L. Drug Makers at Threshold of a New Therapy; With a Dose of Biotechnology, Big Change Is Ahead in the Treatment of Diabetes. January 17, 1998
20. Journal / agency The Diabetes Prevention Program Research Group. The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care. April 1999. doi:10.2337/diacare.22.4.623 · PMID 10189543 · PMC1351026
21. Journal / agency Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England Journal of Medicine. February 2002. doi:10.1056/NEJMoa012512 · PMID 11832527 · PMC1370926
22. Journal / agency Gale EA. Troglitazone: the lesson that nobody learned?. Diabetologia. January 2006. doi:10.1007/s00125-005-0074-6 · PMID 16362281
23. Other Willman D. FDA's Approval and Delay in Withdrawing Rezulin Probed. August 16, 2000
24. Other Willman D. Fears Grow Over Delay in Removing Rezulin. March 10, 2000
25. Journal / agency 2000 Safety Alerts for Human Medical Products
26. Other Willman D. Physician Who Opposes Rezulin Is Threatened by FDA With Dismissal. March 17, 2000
27. Other Pfizer Annual Report 2001

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