TROGLITAZONE

US Previously Marketed

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12475986 | http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20719S12_Prelay_prntlbl.pdf

Troglitazone (TGZ, brand name: Rezulin and Prelay) is a peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand, which was developed by Daiichi Sankyo and approved for the US market for the treatment of Type II diabetes mellitus. The drug is used alone or in combination with a sulfonylurea, metformin, or insulin as an adjunct to diet and exercise, and was not indicated as initial therapy in patients with type 2 diabetes. This drug was withdrawn from the UK market due to liver toxicity. It was removed from the US market in 2000, only 3 years after its introduction and from Japan, shortly afterward. In addition, was conducted a clinical trial for the treatment of patients with advanced liposarcoma by using troglitazone, but the positive result wasn’t obtained. It was shown, that in case of cancer cells troglitazone acted independently of PPAR gamma, by up-regulation of early growth response-1 (Egr-1). Egr-1 transcription factor has been linked to apoptosis and shown to be activated by extracellular signal-regulated kinase (ERK).

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Peroxisome proliferator-activated receptor gamma 109 Target ID: CHEMBL235 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10691680	Agonist 2662		780.0 nM [EC50]
Early growth response protein 1 1 Target ID: P18146 Gene ID: 1958.0 Gene Symbol: EGR1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/12475986	Activator 1410

Conditions

Condition	Modality	Highest Phase	Product
Polycystic ovary syndrome 2 Sources: https://adisinsight.springer.com/drugs/800000013 https://www.ncbi.nlm.nih.gov/pubmed/21105563 https://www.ncbi.nlm.nih.gov/pubmed/15767238	Primary	Phase III 663	Unknown Approved Use Unknown
Type 2 diabetes mellitus 256 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20719S12_Prelay_prntlbl.pdf	Palliative	Withdrawn	PRELAY Approved Use Prelay is indicated to improve glycemic control in patients with type 2 diabetes mellitus as an adjunct to diet and exercise in combination with (not substituted for): · A sulfonylurea drug for patients who are not adequately controlled with a sulfonylurea alone or, · A sulfonylurea drug together with metformin for patients who are not adequately controlled with the combination of a sulfonylurea and metformin or, · Insulin in patients who are not adequately controlled with insulin alone. Prelay is not indicated as initial therapy in patients with type 2 diabetes Launch Date 8.5449599E11
Liposarcoma 6 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10097144	Primary	Phase II 1144	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone.	2000 Apr	10871190
Leptin production in adipocytes from morbidly obese subjects: stimulation by dexamethasone, inhibition with troglitazone, and influence of gender.	2000 Aug	10946865
Dehydroepiandrosterone suppresses elevated hepatic glucose-6-phosphatase mRNA level in C57BL/KsJ-db/db mice: comparison with troglitazone.	2000 Dec	11228057
Enhancing effect of troglitazone on porcine adipocyte differentiation in primary culture: a comparison with dexamethasone.	2000 Dec	11225715
Vitamin K(2) inhibits adipogenesis, osteoclastogenesis, and ODF/RANK ligand expression in murine bone marrow cell cultures.	2000 Dec	11113387
UCP3 gene expression does not correlate with muscle oxidation rates in troglitazone-treated Zucker fatty rats.	2000 Dec 15	11118623
Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene.	2000 Jul	10909982
Down-regulation by troglitazone of hepatic tumor necrosis factor-alpha and interleukin-6 mRNA expression in a murine model of non-insulin-dependent diabetes.	2000 Jul 1	10807946
Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets.	2000 Jul 18	10900012
Inhibitory effect of troglitazone on TNF-alpha-induced expression of monocyte chemoattractant protein-1 (MCP-1) in human endothelial cells.	2000 Jun	10802155
Troglitazone improves psoriasis and normalizes models of proliferative skin disease: ligands for peroxisome proliferator-activated receptor-gamma inhibit keratinocyte proliferation.	2000 May	10815854
Troglitazone inhibits mitogenic signaling by insulin in vascular smooth muscle cells.	2000 May	10813377
Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells.	2000 May 19	10814527
Troglitazone-induced fulminant hepatitis: report of a case with autopsy findings.	2000 May-Jun	10989325
Activation of peroxisome proliferator-activated receptor gamma by troglitazone inhibits cell growth through the increase of p27KiP1 in human. Pancreatic carcinoma cells.	2000 Oct 1	11034103
Down-regulation of uncoupling protein-3 and -2 by thiazolidinediones in C2C12 myotubes.	2000 Oct 27	11056218
Two opposing effects of non-steroidal anti-inflammatory drugs on the expression of the inducible cyclooxygenase. Mediation through different signaling pathways.	2000 Sep 8	10866999
Effects of type-2 diabetes and troglitazone on the expression patterns of small intestinal sugar transporters and PPAR-gamma in the Zucker diabetic fatty rat.	2001	11244250
Effect of obesity and troglitazone on expression of two glutathione peroxidases: cellular and extracellular types in serum, kidney and adipose tissue.	2001 Apr	11328671
Peroxisome proliferator-activated receptor gamma ligands suppress the transcriptional activation of cyclooxygenase-2. Evidence for involvement of activator protein-1 and CREB-binding protein/p300.	2001 Apr 13	11278336
Dual function of troglitazone in ICAM-1 gene expression in human vascular endothelium.	2001 Apr 6	11401521
Myositis, microvesicular hepatitis, and progression to cirrhosis from troglitazone added to simvastatin.	2001 Feb	11281188
Troglitazone and rosiglitazone induce apoptosis of vascular smooth muscle cells through an extracellular signal-regulated kinase-independent pathway.	2001 Feb	11218074
Failure to develop hepatic injury from rosiglitazone in a patient with a history of troglitazone-induced hepatitis.	2001 Jan	11194222
The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+,Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells.	2001 Jan	11172467
Effects of troglitazone on cellular differentiation, insulin signaling, and glucose metabolism in cultured human skeletal muscle cells.	2001 Jan 26	11162573
Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action?	2001 Jul	11443197
Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL.	2001 Mar	11231916
Enzymatic characterization and interspecies difference of phenol sulfotransferases, ST1A forms.	2001 Mar	11181495
Bezafibrate attenuates the overexpression of plasminogen activator inhibitor-1 messenger RNA by a combination of mono-unsaturated fatty acid and insulin in hepG2 cells.	2001 Mar 9	11292061
Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes.	2001 May	11334422
Troglitazone induces GLUT4 translocation in L6 myotubes.	2001 May	11334413
Peroxisome proliferator-activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats.	2001 May	11318962
Troglitazone improves endothelial function and augments renal klotho mRNA expression in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with multiple atherogenic risk factors.	2001 Nov	11768731
Regulation of the glyoxalase pathway in human brain microvascular endothelium: effects of troglitazone and tertiary butylhydroperoxide.	2002	12572858
Thiazolidinedione derivatives ameliorate albuminuria in streptozotocin-induced diabetic spontaneous hypertensive rat.	2002 Apr	11912544
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets.	2002 Dec	12468449
Receptor-dependent regulation of the CYP3A4 gene.	2002 Dec 27	12505310
Troglitazone suppresses cell growth of KU812 cells independently of PPARgamma.	2002 Feb 1	11834241
Unique ability of troglitazone to up-regulate peroxisome proliferator-activated receptor-gamma expression in hepatocytes.	2002 Jan	11752099
Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB.	2002 Jan 11	11779144
Nonsteroidal anti-inflammatory drugs induce apoptosis in association with activation of peroxisome proliferator-activated receptor gamma in rheumatoid synovial cells.	2002 Jul	12065695
Effects of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane (p,p'-DDT) on 3T3-L1 and 3T3-F442A adipocyte differentiation.	2002 Mar 1	11911853
Troglitazone activates p21Cip/WAF1 through the ERK pathway in HCT15 human colorectal cancer cells.	2002 May 28	11888673
Effects of leptin, troglitazone, and dietary fat on stearoyl CoA desaturase.	2002 Oct 11	12372423
Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition.	2003 Apr	12642470
The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: a placebo-controlled randomized clinical trial.	2003 Feb	12601628
Troglitazone, a peroxisome proliferator-activated receptor gamma (PPAR gamma ) ligand, selectively induces the early growth response-1 gene independently of PPAR gamma. A novel mechanism for its anti-tumorigenic activity.	2003 Feb 21	12475986
Troglitazone but not rosiglitazone induces G1 cell cycle arrest and apoptosis in human and rat hepatoma cell lines.	2003 Mar 20	12595159
A cohort study of the incidence of serious acute liver injury in diabetic patients treated with hypoglycemic agents.	2003 Mar 24	12639207

Patents

Sample Use Guides

In Vivo Use Guide

Prelay (TROGLITAZONE tablet) should be taken with a meal. Combination Therapy: Sulfonylureas: Prelay in combination with a sulfonylurea should be initiated at 200 mg once daily. The current sulfonylurea dose should be continued upon initiation of Prelay therapy. For patients not responding adequately, the Rezulin dose should be increased at 2 to 4 weeks. The maximum recommended dose is 600 mg once daily. The dose of sulfonylurea may require lowering to optimize therapy. Metformin: For patients not responding adequately to metformin and sulfonylurea therapy, 400 mg daily of Prelay may be added. Insulin: The current insulin dose should be continued upon initiation of Prelay therapy. Prelay therapy should be initiated at 200 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of Prelay should be increased after approximately 2 to 4 weeks. The usual dose of Prelay is 400 mg once daily. The maximum recommended daily dose is 600 mg. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and Prelay. Further adjustments should be individualized based on glucose-lowering response. Patients With Renal Insufficiency: Dose adjustment in patients with renal insufficiency is not required

Route of Administration: Oral

In Vitro Use Guide

Human HCC cell lines Huh7 and Hep3B were cultured in the presence or absence of troglitazone. Cell growth was determined via WST-1 assay, proliferation by cell cycle analysis and proliferating cell nuclear antigen (PCNA) Western blotting, and apoptosis by flow cytometry and TUNEL. In cultures of Hep3B and Huh7 cells, basal expression of PPARgamma was relatively low, but troglitazone caused dose-dependent induction of PPARgamma expression.

Substance Class	Mixture Created by `admin` on `Thu Jul 06 00:03:57 UTC 2023` Edited by `admin` on `Thu Jul 06 00:03:57 UTC 2023`
Record UNII	I66ZZ0ZN0E
Record Status	`Validated (UNII)`
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Name

Type

Language

TROGLITAZONE

Official Name

English

TROGLITAZONE [USAN]

Common Name

English

TROGLITAZONE [JAN]

Common Name

English

TROGLITAZONE [MI]

Common Name

English

CS-045

Code

English

TROGLITAZONE [MART.]

Common Name

English

Troglitazone [WHO-DD]

Common Name

English

REZULIN

Brand Name

English

TROGLITAZONE [VANDF]

Common Name

English

PRELAY

Brand Name

English

CI-991

Code

English

2,4-THIAZOLIDINEDIONE, 5-((4-((3,4-DIHYDRO-6-HYDROXY-2,5,7,8-TETRAMETHYL-2H-1-BENZOPYRAN-2-YL)METHOXY)PHENYL)METHYL)-

Common Name

English

troglitazone [INN]

Common Name

English

GR92132X

Code

English

GR-92132X

Code

English

TROGLITAZONE [ORANGE BOOK]

Common Name

English

(±)-ALL-RAC-5-(P-((6-HYDROXY-2,5,7,8-TETRAMETHYL-2-CHROMANYL)METHOXY)BENZYL)-2,4-THIAZOLIDINEDIONE

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1934