Troglitazone

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. 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. It was patented in 1983 and approved for medical use in 1997. It was subsequently withdrawn. 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-tocopheroyl 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. It 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 F.D.A. medical officer assigned to evaluate troglitazone, John Gueriguian, did not recommend its approval due to potential 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 Once the prevalence of adverse liver effects became known, troglitazone was withdrawn from the British market in December 1997, from the United States market in 2000, and from the Japanese market soon afterwards.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. Troglitazone was developed as the first anti-diabetic drug having a mechanism of action involving the enhancement of insulin sensitivity. 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. Parke-Davis/Warner Lambert submitted the diabetes drug Rezulin for U.S. Food and Drug Administration (F.D.A.) 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 F.D.A. 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. The F.D.A. 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 F.D.A., overseeing diabetes drugs, said in a New York Times interview that adverse effects of troglitazone appeared to be rare and relatively mild. Glaxo Wellcome P.L.C. 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, the Parke-Davis and the FDA added warnings to the drug label requiring monthly monitoring of liver enzyme levels. Glaxo removed troglitazone from the market in Britain on December 1, 1997. Glaxo had licensed the drug from Sankyo Company of Japan and had sold it in Britain from October 1, 1997.