THIAZOLIDINEDIONE

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

Contents

Mode of action

Members of the class

Uses

Side effects and contraindications

Footnotes

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 ''PPARγ'' (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 PPARγ can be found in the ''main article'' on ''peroxisome proliferator-activated receptors''.
By activating PPARγ:

★ Insulin resistance is decreased

★ Adipocyte differentiation is modified

★ VEGF-induced angiogenesis is inhibited^[1]

★ 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★ Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis.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),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 psoriasis,^[2] and other conditions.Clinical Trials for Rosiglitazone - from ClinicalTrials.gov, a service of the U.S. National Institutes of Health
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.^[3] However, the PROactive study has shown that pioglitazone dose not have this same risk.

Footnotes

1. PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis, Panigrahy D, Singer S, Shen LQ, ''et al'', , , J. Clin. Invest., 2002
2. Krentz AJ, Friedmann PS. Type 2 diabetes, psoriasis and thiazolidinediones. ''Int J Clin Pract'' 2006;60:362-3. PMID 16494655.
3. Avandia to Carry Stronger Heart Failure Warning - Forbes.com