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| Trade names | Rezulin, Resulin, Romozin, Noscal |
| Routes of administration | By mouth (tablets) |
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| Eliminationhalf-life | 16–34 hours |
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| Chemical and physical data | |
| Formula | C24H27NO5S |
| Molar mass | 441.54 g·mol−1 |
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| Melting point | 184 to 186 °C (363 to 367 °F) |
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Troglitazone is anantidiabetic andanti-inflammatory drug, and a member of thedrug class of thethiazolidinediones. It was prescribed for people withdiabetes mellitus type 2.[1]
It was patented in 1983 and approved for medical use in 1997.[2] It was subsequently withdrawn.
Troglitazone, like the otherthiazolidinediones (pioglitazone androsiglitazone), works by activatingperoxisome proliferator-activated receptors (PPARs).
Troglitazone is aligand to both PPARα and – more strongly – PPARγ. Troglitazone also contains anα-Tocopherolmoiety, potentially giving itvitamin E-like activity in addition to its PPAR activation. It has been shown to reduceinflammation.[3] Troglitazone use was associated with a decrease ofnuclear factor kappa-B (NF-κB) and a concomitant increase in its inhibitor (IκB). NFκB is an important cellulartranscription regulator for the immune response.
Troglitazone was developed byDaiichi Sankyo (Japan). In the United States, it was introduced and manufactured byParke-Davis in the late 1990s but turned out to be associated with anidiosyncratic reaction leading to drug-inducedhepatitis. TheFood and Drug Administration (FDA) medical officer assigned to evaluate troglitazone, John Gueriguian, did not recommend its approval due to potentially highliver 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of experts approved it in January 1997.[5] Once the prevalence of adverseliver effects became known, troglitazone was withdrawn from theBritish market in December 1997, from theUnited States market in 2000, and from theJapanese market soon afterwards.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 ofinsulin 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 ofhypoglycemia associated withinsulin and earlier oral antidiabetic drugs. It was further believed that reducing insulin resistance would potentially reduce the very high rate ofcardiovascular disease that is associated with diabetes.[6][7]
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.[8][9] 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.[10] 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.[11] According toPeter 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 aNew York Times interview that adverse effects of troglitazone appeared to be rare and relatively mild.[13]
Glaxo Wellcome received approval from theBritish 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 fromSankyo 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 ofacute liver failure after taking troglitazone. Importantly, she had been monitored closely by physicians at theNational Institutes of Health (NIH) as a participant in theNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) diabetes prevention study.[18][19] This called into question the efficacy of the monitoring strategy. The NIH responded on June 4 by dropping troglitazone from the study.[9][20] Dr. David J. Graham, an FDAepidemiologist 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.[9][21] Dr. Janet B. McGill, anendocrinologist 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."[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 SenatorJohn 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]
Since the withdrawal in 2000, mechanisms of troglitazonehepatotoxicity have been extensively studied using a variety ofin vivo,[26]in vitro,[27] and computational methods.[28] These studies have suggested that hepatotoxicity of troglitazone results from a combination ofmetabolic and nonmetabolic factors.[29] The nonmetabolic toxicity is a complex function of drug-protein interactions in theliver andbiliary system. Initially, the metabolic toxicity was largely associated with reactive metabolite formation from thethiazolidinedione andchromane rings of troglitazone. Moreover, the formation ofquinone ando-quinonemethide reactive metabolites were proposed to be formed by metabolic oxidation of thehydroxy group (OH group) of the chromane ring.[26] Detailed quantum chemical analysis of the metabolic pathways for troglitazone has shown that quinone reactive metabolite is generated by oxidation of the OH group, but o-quinone methide reactive metabolite is formed by the oxidation of themethyl groups (CH3 groups) ortho to the OH group of the chromane ring.[28] This understanding has been recently used in the design of novel troglitazone derivatives withantiproliferative activity inbreast cancercell lines.[30]
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 rivalWyeth 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]
