Thiazolidinedione

# Overview
The medication class of thiazolidinedione was introduced in the late 1990s as an adjunctive therapy for diabetes mellitus (type 2) and related diseases.

# Mode of action
Thiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPAR (gamma). The normal ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes.
Genes upregulated by PPAR can be found in the main article on peroxisome proliferator-activated receptors.
By activating PPAR:
- Insulin resistance is decreased
- Adipocyte differentiation is modified
- VEGF-induced angiogenesis is inhibited
- Leptin levels decrease (leading to an increased appetite)
- Levels of certain interleukins (e.g. IL-6) fall
- Adiponectin levels rise

# Members of the class
Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:
- Rosiglitazone (Avandia)
- Pioglitazone (Actos)
- Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis.
Experimental agents include MCC-555, a powerful antidiabetic agent and the early non-marketed thiazolidinedione ciglitazone.

# Uses
The only approved use of the thiazolidinediones is in diabetes mellitus type 2.
It is being investigated experimentally in polycystic ovary syndrome (PCOS), non-alcoholic steatohepatitis (NASH), psoriasis, and other conditions.
Several forms of lipodystrophy cause insulin resistance, which has responded favorably to thiazolidinediones. There are some indications that thiazolidinediones provide some degree of the protection against initial stages of the breast carcinoma development.

# Side effects and contraindications
The withdrawal of troglitazone has led to concerns of other thiazolidinediones increasing the risk of hepatitis. Guidelines now mention that for the first year of thiazolidinedione therapy, a two- or three-monthly check of liver enzymes is conducted to ascertain that no liver damage is occurring.
The main side effect of all thiazolidinediones is fluid retention, leading to edema, weight gain, and potentially aggravating heart failure. Therefore, thiazolidinediones should not be prescribed in patients with decreased ventricular function (NYHA grade III or IV heart failure).
Recent studies have shown there may be an increase risk of CHD with Rosiglitazone.  However, the PROactive study has shown that pioglitazone dose not have this same risk.

# Footnotes
-  Panigrahy D, Singer S, Shen LQ;  et al. (2002). "PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis". J. Clin. Invest. 110 (7): 92332. PMID 12370270.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
-  Belfort R et. al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355(22): 2297-307. PMID 17135584 Clinical trial info
-  Krentz AJ, Friedmann PS. Type 2 diabetes, psoriasis and thiazolidinediones. Int J Clin Pract 2006;60:362-3. PMID 16494655.
-  Clinical Trials for Rosiglitazone - from ClinicalTrials.gov, a service of the U.S. National Institutes of Health
-  "Avandia to Carry Stronger Heart Failure Warning - Forbes.com". Retrieved 2007-08-15.
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