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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
Pharmacokineticdata
Eliminationhalf-life16–34 hours
Identifiers
  • (RS)-5-(4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl)thiazolidine-2,4-dione
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
Chemical and physical data
FormulaC24H27NO5S
Molar mass441.54g·mol−1
3D model (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-NcheckY
☒NcheckY(what is this?)(verify)

Troglitazoneis anantidiabeticandanti-inflammatorydrug, and a member of thedrugclass 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It was patented in 1983 and approved for medical use in 1997.[2]It was subsequently withdrawn.

Mechanism of action

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Troglitazone, like the otherthiazolidinediones(pioglitazoneandrosiglitazone), works by activatingperoxisome proliferator-activated receptors(PPARs).

Troglitazone is aligandto 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 regulatorfor the immune response.

History

[edit]
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 byDaiichi Sankyo(Japan). In the United States, it was introduced and manufactured byParke-Davisin the late 1990s but turned out to be associated with anidiosyncratic reactionleading 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 adverselivereffects became known, troglitazone was withdrawn from theBritishmarket in December 1997, from theUnited Statesmarket in 2000, and from theJapanesemarket 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 ofhypoglycemiaassociated withinsulinand earlier oral antidiabetic drugs. It was further believed that reducing insulin resistance would potentially reduce the very high rate ofcardiovascular diseasethat is associated with diabetes.[6][7]

Parke-Davis/Warner Lambertsubmitted 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 Timesinterview that adverse effects of troglitazone appeared to be rare and relatively mild.[13]

Glaxo Wellcomereceived 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 Companyof 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 failureafter 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 FDAepidemiologistcharged 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, anendocrinologistwho 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 Ashcroftof 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

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Since the withdrawal in 2000, mechanisms of troglitazonehepatotoxicityhave 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 ofmetabolicand nonmetabolic factors.[29]The nonmetabolic toxicity is a complex function of drug-protein interactions in theliverandbiliary system.Initially, the metabolic toxicity was largely associated with reactive metabolite formation from thethiazolidinedioneandchromanerings of troglitazone. Moreover, the formation ofquinoneando-quinonemethidereactive 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(CH3groups) ortho to the OH group of the chromane ring.[28]This understanding has been recently used in the design of novel troglitazone derivatives withantiproliferativeactivity inbreast cancercell lines.[30]

Lawsuits

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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 rivalWyethfor 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

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  1. ^Fisher L (4 November 1997)."Adverse Diabetes Drug News Sends Warner-Lambert Down".The New York Times.Retrieved12 December2012.
  2. ^Fischer J, Ganellin CR (2006).Analogue-based Drug Discovery.John Wiley & Sons. p. 450.ISBN9783527607495.
  3. ^Aljada A, Garg R, Ghanim H, Mohanty P, Hamouda W, Assian E, Dandona P (July 2001)."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.86(7): 3250–3256.doi:10.1210/jcem.86.7.7564.PMID11443197.
  4. ^Hintertheur A (November 2008)."Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights".wired.com.
  5. ^Cohen JS (June 2006)."Risks of troglitazone apparent before approval in USA".Diabetologia.49(6): 1454–1455.doi:10.1007/s00125-006-0245-0.PMID16601971.
  6. ^Henry RR (September 1996). "Effects of troglitazone on insulin sensitivity".Diabetic Medicine.13(9 Suppl 6): S148–S150.doi:10.1002/dme.1996.13.s6.148.PMID8894499.S2CID34080394.
  7. ^Keen H (November 1994). "Insulin resistance and the prevention of diabetes mellitus".The New England Journal of Medicine.331(18): 1226–1227.doi:10.1056/NEJM199411033311812.PMID7935664.
  8. ^abcWillman D (20 December 2000)."NEW FDA: Rezulin Fast-Track Approval and a Slow Withdrawal".The Los Angeles Times.Retrieved12 December2012.
  9. ^abcWillman D (4 June 2000)."The Rise and Fall of the Killer Drug Rezulin".The Los Angeles Times.Retrieved12 December2012.
  10. ^"Report: FDA Removes Medical Officer".Associated Press.
  11. ^Avorn J (2005).Powerful medicines.New York: Vintage books.
  12. ^Gøtzsche P (2013).Deadly medicines and organised crime: how big pharma has corrupted healthcare.London [u.a.]: Radcliffe Publ. p. 185.ISBN9781846198847.
  13. ^Leary W (31 January 1997)."New Class of Diabetes Drug Is Approved".The New York Times.Retrieved12 December2012.
  14. ^Sinclair N (31 July 1997)."Glaxo Wellcome gets approval for Romozin".ICIS News.Retrieved12 December2012.
  15. ^"Approval package for Rezulin (troglitazone)"(PDF).Center for Drug Evaluation and Research.U.S. Food and Drug Administration. 4 April 1997. Archived fromthe original(PDF)on 5 November 2014.
  16. ^"Diabetes drug withdrawn from sale".BBC.British Broadcasting Corporation. 1 December 1997.Retrieved12 December2012.
  17. ^abFisher 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.Retrieved12 December2012.
  18. ^The Diabetes Prevention Program Research Group (April 1999)."The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes".Diabetes Care.22(4): 623–634.doi:10.2337/diacare.22.4.623.PMC1351026.PMID10189543.
  19. ^Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM (February 2002)."Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin".The New England Journal of Medicine.346(6): 393–403.doi:10.1056/NEJMoa012512.PMC1370926.PMID11832527.
  20. ^Gale EA (January 2006)."Troglitazone: the lesson that nobody learned?".Diabetologia.49(1): 1–6.doi:10.1007/s00125-005-0074-6.PMID16362281.
  21. ^abWillman D (16 August 2000)."FDA's Approval and Delay in Withdrawing Rezulin Probed".The Los Angeles Times.Retrieved12 December2012.
  22. ^Willman D (10 March 2000)."Fears Grow Over Delay in Removing Rezulin".The Los Angeles Times.Retrieved12 December2012.
  23. ^"2000 Safety Alerts for Human Medical Products".U.S. Food and Drug Administration.Retrieved12 December2012.
  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.Retrieved12 December2012.
  26. ^abKassahun K, Pearson PG, Tang W, McIntosh I, Leung K, Elmore C, et al. (January 2001). "Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission".Chemical Research in Toxicology.14(1): 62–70.doi:10.1021/tx000180q.PMID11170509.
  27. ^Funk C, Ponelle C, Scheuermann G, Pantze M (March 2001). "Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat".Molecular Pharmacology.59(3): 627–635.doi:10.1124/mol.59.3.627.PMID11179459.
  28. ^abDixit VA, Bharatam PV (July 2011). "Toxic metabolite formation from Troglitazone (TGZ): new insights from a DFT study".Chemical Research in Toxicology.24(7): 1113–1122.doi:10.1021/tx200110h.PMID21657230.
  29. ^Masubuchi Y (October 2006). "Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review".Drug Metabolism and Pharmacokinetics.21(5): 347–356.doi:10.2133/dmpk.21.347.PMID17072088.
  30. ^Salamone S, Colin C, Grillier-Vuissoz I, Kuntz S, Mazerbourg S, Flament S, et al. (May 2012). "Synthesis of new troglitazone derivatives: anti-proliferative activity in breast cancer cell lines and preliminary toxicological study".European Journal of Medicinal Chemistry.51:206–215.doi:10.1016/j.ejmech.2012.02.044.PMID22409968.
  31. ^Feeley J (March 31, 2009)."Pfizer Ends Rezulin Cases With $205 Million to Spare".Bloomberg.Retrieved6 April2014.
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