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Troglitazone (Rezulin, Resulin, Romozin, Noscal) is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones. It was prescribed for patients with diabetes mellitus type 2.^[1] It was developed by Daiichi Sankyo Co.(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. One F.D.A. medical officer evaluating troglitazone, John Gueriguian, did not recommend its approval due to potential high liver toxicity,^[2] but a full panel of experts approved it in January 1997.^[3] Once the prevalence of adverse liver effects became known, troglitazone was withdrawn from the British market in December 1997, from the United States market in 2000, and from the Japanese market soon afterwards.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 didn't get approval in the rest of Europe.

Approval history

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.^[4]^[5] 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.^[6] When the company provided these additional data one week after approval, they showed a substantial greater risk for liver toxicity.^[7]

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.^[8]

Glaxo Wellcome P.L.C. received approval from the British Medicines Control Agency (MCA) to market troglitazone, as Romozin, in July 1997.^[9] After reports of sudden liver failure in patients receiving the drug, Glaxo removed troglitazone from the market in Britain on December 1, 1997.^[4] Glaxo had licensed the drug from Sankyo Company of Japan and had sold it in Britain from October 1, 1997.^[10]^[11]

The F.D.A. and Warner-Lambert responded to the U.K. withdrawal of troglitazone by recommending that patient liver-function be monitored on a monthly basis. 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 as a participant in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) diabetes prevention study.^[12]^[13] This called into question the efficacy of the monitoring strategy. The N.I.H. responded on June 4 by dropping troglitazone from the study.^[5]^[14] Dr. David J. Graham, an F.D.A. 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.^[5]^[15] 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."^[16]

On March 21, 2000, the F.D.A. withdrew the drug from the market.^[17] Dr. Robert I. Misbin, an F.D.A. medical officer, wrote in a July 3, 2000 letter to the House Energy and Commerce Committee of strong evidence that Rezulin could not be used safely, after having been threatened by the FDA with dismissal in March 2000.^[4]^[18] 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.^[15] The drug cost $1,400 a year per patient in 1998.^[11] Pfizer, which had acquired Warner-Lambert in February 2000, reported the withdrawal of Rezulin cost $136 million.^[19]

Lawsuits

In 2009 Pfizer Inc. 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.^[20]

Mode 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-tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown to reduce inflammation:^[21] 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.

References

^ Fisher, Lawrence (4 November 1997). "Adverse Diabetes Drug News Sends Warner-Lambert Down". The New York Times. Retrieved 12 December 2012.
^ Retired Drugs: Failed Blockbusters, Homicidal Tampering, Fatal Oversights, wired.com
^ Cohen, J. S. (2006). "Risks of troglitazone apparent before approval in USA". Diabetologia 49 (6): 1454–5. doi:10.1007/s00125-006-0245-0. PMID 16601971.
^ ^a ^b ^c Willman, David (20 December 2000). "NEW FDA: Rezulin Fast-Track Approval and a Slow Withdrawal". The Los Angeles Times. Retrieved 12 December 2012.
^ ^a ^b ^c Willman, David (4 June 2000). "The Rise and Fall of the Killer Drug Rezulin". The Los Angeles Times. Retrieved 12 December 2012.
^ Avorn, J (2005). Powerful medicines. New York: Vintage books.
^ Gøtzsche, Peter; Rennie, Drummond (2013). Deadly medicines and organised crime : how big pharma has corrupted healthcare. London [u.a.]: Radcliffe Publ. p. 185. ISBN 9781846198847. Cite uses deprecated parameters (help)
^ Leary, Warren (31 January 1997). "New Class of Diabetes Drug Is Approved". The New York Times. Retrieved 12 December 2012.
^ Sinclair, Neil (31 July 1997). "Glaxo Wellcome gets approval for Romozin". ICIS News. Retrieved 12 December 2012.
^ British Broadcasting Corporation (1 December 1997). "Diabetes drug withdrawn from sale". BBC. Retrieved 12 December 2012.
^ ^a ^b Fisher, Lawrence (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.
^ Diabetes Prevention Research Group (April 1999). "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. Retrieved 12 December 2012.
^ Diabetes Prevention Program Research Group (7 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. PMC 1370926. PMID 11832527. Retrieved 12 December 2012.
^ Gale, Edwin (January 2006). "Troglitazone: the lesson that nobody learned?". Diabetologia 49 (1): 1–6. |accessdate= requires |url= (help)
^ ^a ^b Willman, David (16 August 2000). "FDA's Approval and Delay in Withdrawing Rezulin Probed". The Los Angeles Times. Retrieved 12 December 2012.
^ Willman, David (10 March 2000). "Fears Grow Over Delay in Removing Rezulin". The Los Angeles Times. Retrieved 12 December 2012.
^ U.S. Food and Drug Administration. "2000 Safety Alerts for Human Medical Products". U.S. Food and Drug Administration. Retrieved 12 December 2012.
^ Willman, David (March 17, 2000). "Physician Who Opposes Rezulin Is Threatened by FDA With Dismissal". Los Angeles Times.
^ Pfizer. "Pfizer Annual Report 2001". Pfizer. Retrieved 12 December 2012.
^ Feeley, Jef (March 31, 2009). "Pfizer Ends Rezulin Cases With $205 Million to Spare". Bloomberg. Retrieved 6 April 2014.
^ Aljada A, Garg R, Ghanim H, et al. (2001). "Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action?". J. Clin. Endocrinol. Metab. 86 (7): 3250–6. doi:10.1210/jc.86.7.3250. PMID 11443197.

External links

Diabetes Monitor article on troglitazone
RxList article on troglitazone

UpToDate Contents

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1. 糖尿病の治療におけるチアゾリジン thiazolidinediones in the treatment of diabetes mellitus
2. 2型糖尿病の予防 prevention of type 2 diabetes mellitus
3. 転移性軟部組織肉腫の全身治療 systemic treatment of metastatic soft tissue sarcoma
4. 薬と肝臓：代謝および肝障害の機序 drugs and the liver metabolism and mechanisms of injury
5. デキサメタゾン抑制試験 dexamethasone suppression tests

English Journal

Novel method to differentiate 3T3 L1 cells in vitro to produce highly sensitive adipocytes for a GLUT4 mediated glucose uptake using fluorescent glucose analog.

Vishwanath D, Srinivasan H, Patil MS, Seetarama S, Agrawal SK, Dixit MN, Dhar K.SourceBioanalytical Laboratory for Large Molecules, Clinigene International Limited, Third floor, Tower 1, Electronics City, Bangalore, 560 100, India, Divya.Vishwanath@clinigeneintl.com.
Journal of cell communication and signaling.J Cell Commun Signal.2013 Jun;7(2):129-40. doi: 10.1007/s12079-012-0188-9. Epub 2013 Jan 6.
Adipocytes play a vital role in glucose metabolism. 3T3 L1 pre adipocytes after differentiation to adipocytes serve as excellent in vitro models and are useful tools in understanding the glucose metabolism. The traditional approaches adopted in pre adipocyte differentiation are lengthy exercises inv
PMID 23292944

Adapalene suppresses sebum accumulation via the inhibition of triacylglycerol biosynthesis and perilipin expression in differentiated hamster sebocytes in vitro.

Sato T, Akimoto N, Kitamura K, Kurihara H, Hayashi N, Ito A.SourceDepartment of Biochemistry and Molecular Biology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. Electronic address: satotak@toyaku.ac.jp.
Journal of dermatological science.J Dermatol Sci.2013 Jun;70(3):204-10. doi: 10.1016/j.jdermsci.2013.02.003. Epub 2013 Feb 14.
BACKGROUND: Acne is a chronic inflammatory disease in sebaceous glands and pilosebaceous units where excess sebum production and follicular hyperkeratinization are observed. Adapalene, which exerts comedolytic and anti-inflammatory effects, is used for the topical treatment of mild to moderate acne.
PMID 23473858

Japanese Journal

Development of a Novel PPARγ Ligand Screening System Using Pinpoint Fluorescence-Probed Protein

NAGAI Hiroyuki,EBISU Shogo,ABE Ryoji,GOTO Tsuyoshi,TAKAHASHI Nobuyuki,HOSAKA Takahiro,KAWADA Teruo
Bioscience, biotechnology, and biochemistry 75(2), 337-341, 2011-02-23
… The disassociation constants (Kd) of the PPARγ synthesized ligands, pioglitazone (221 nM), troglitazone (83.0 nM), and 15-deoxy-Δ12,14-prostaglandin J2 (15d-ΔPGJ2) (156 nM), were determined by this method. …
NAID 10027897986

In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth

HAMAGUCHI Naohiko,HAMADA Hironobu,MIYOSHI Seigo,IRIFUNE Kazunori,ITO Ryoji,MIYAZAKI Tatsuhiko,HIGAKI Jitsuo
Cancer science 101(9), 1955-1964, 2010-09-10
NAID 10027831273

Inhibitory Effects of Coumarins from the Stem Barks of Fraxinus rhynchophylla on Adipocyte Differentiation in 3T3-L1 Cells

Shin Eunjin,Choi Kyeong-Mi,Yoo Hwan-Soo,Lee Chong-Kil,Hwang Bang Yeon,Lee Mi Kyeong
Biological & Pharmaceutical Bulletin 33(9), 1610-1614, 2010
… Esculetin (1) significantly blocked the induction of PPARγ protein expression and inhibited adipocyte differentiation induced by troglitazone, a PPARγ agonist. …
NAID 130000322365

Related Pictures

INVOLVEMENT OF ORGANIC ANION TRANSPORTING POLYPEPTIDES IN THE TRANSPORT OF Introduction to Adverse Drug Reactions Formation of a Novel Quinone Epoxide Metabolite of Troglitazone with Cytotoxic to Troglitazone (Romglizone) an antidiabetic Revisted « New Drug Approvals Phenol Sulfotransferase, ST1A3, as the Main Enzyme Catalyzing Sulfation of Troglitazone|STEMCELL Technologies Troglitazone - Wikipedia Oncotarget | PPARγ activation by troglitazone enhances human lung cancer cells to

★リンクテーブル★

リンク元	「チアゾリジン薬」「インスリン抵抗解除薬」「トログリタゾン」

「チアゾリジン薬」

Troglitazone
Systematic (IUPAC) name
	(RS)-5-(4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl)thiazolidine-2,4-dione
Clinical data
Legal status	?
Pharmacokinetic data
Half-life	16-34 hours
Identifiers
CAS number	97322-87-7
ATC code	A10BG01
PubChem	CID 5591
IUPHAR ligand	2693
DrugBank	DB00197
ChemSpider	5389
UNII	I66ZZ0ZN0E
KEGG	D00395
ChEBI	CHEBI:9753
ChEMBL	CHEMBL408
Chemical data
Formula	C24H27NO5S
Mol. mass	441.541 g/mol
	SMILES O=C1NC(=O)SC1Cc4ccc(OCC3(Oc2c(c(c(O)c(c2CC3)C)C)C)C)cc4;
	InChI 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) ; Key:GXPHKUHSUJUWKP-UHFFFAOYSA-N ;
(what is this?) (verify)

　　[★]

関: インスリン抵抗解除薬

[show details]

チアゾリジン薬 : 約 4,380 件
チアゾリジン系薬 : 約 4,970 件
チアゾリジン誘導体 : 約 12,500 件
チアゾリジンジオン薬 : 32 件
チアゾリジンジオン系薬 : 約 15 件
チアゾリジンジオン誘導体 : 約 20,000 件

分類

糖尿病治療薬

インスリン抵抗解除薬

チアゾリジン薬

ピオグリタゾン pioglitazone
トログリタゾン troglitazone　←販売中止

特徴

チアゾリジンジオン環を有する
肥満者やインスリン抵抗性が疑われる糖尿病において有効性が高い

作用機序

thiazolidinedioneはPPARγ(nuclear peroxisome proliferator-activated receptor-γ)の選択的アゴニスト。 (GOO.1639)

炭化水素や脂質代謝を制御するインスリン応答遺伝子insulin-responsive genesを活性化する

薬理作用を示すにはインスリンの存在が必要

筋肉にはPPARγは欠いており、脂肪組織で発現している (GOO.1639)

脂肪組織でのPPARγの活性化は筋肉への遊離脂肪酸への流れを止める (GOO.1639)
脂肪組織が放出するadipocyte hormoneやadipokineの活性化、おそらくアディポネクチンによる (GOO.1639)

アディポネクチンはインスリンへの感受性を上げる。(AMP kinaseが関与？) (GOO.1639)

薬理作用

末梢でのインスリン抵抗性を改善する、すなわちインスリンの感受性を上げる。 (GOO.1639)
肝臓ではグルコースの産生を抑制する(かもしれない)。 (GOO.1639)
肝臓や筋肉でグルコース輸送体の合成と膜上への発現を促す。末梢で脂質代謝を調節する遺伝子の発現を促進する (GOO.1639)
前脂肪細胞は小型脂肪細胞なり、大型脂肪細胞はネクローシスを起こす。

DMR.112

脂肪組織：炎症性サイトカインの発現低下、アディポネクチンの発現増強
骨格筋：インスリン依存的なブドウ糖取り込み増強。
肝臓：ブドウ糖産生抑制。　肝臓内脂肪酸量減少　→　インスリン抵抗性解除
末梢血：血糖↓、血中インスリン↓

適応

2型糖尿病

禁忌

心不全患者、心不全の既往がある患者　←　循環血漿量を増加させるため

副作用

循環血漿量の増加
浮腫：循環血漿量の増加に伴う。ピオグリタゾン服用者の7-8%で報告されており、特に女性で発症頻度が高い。
体重増加：循環血漿量の増加とは独立した要因
肝機能障害：
低血糖：稀

「インスリン抵抗解除薬」

　　[★]

英: insulin-resistant release agent
同: インスリン抵抗性解除薬
関: 糖尿病治療薬、薬理学、インスリン抵抗性