DESCRIPTION
Troglitazone (Rezulin®, Resulin® or Romozin®) is an anti-diabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones.
It was introduced in the late 1990s but turned out to be associated with an idiosyncratic reaction leading to drug-induced hepatitis. It was withdrawn from the USA market on 21 March 2000, and from other markets soon afterwards.
CLASSIFICATION
It is a member of the Thiazolidinediones ( TZDs ), oral hypoglycemic agents:
- Troglitazone: Rezulin®, withdrawn from the market due to hepatitis and liver damage risk
- Rosiglitazone: Avandia®
- Pioglitazone: Actos®, Glustin®
INDICATIONS
Anti-diabetic : an adjunctive therapy for diabetes mellitus, type 2
- reduces insulin resistance
- improves glucose uptake by the skeletal muscle
- reduces neoglucogenesis
- decrease hepatic glucose production and hepatic triglyceride synthesis
It is investigated experimentally in: polycystic ovary syndrome (PCOS), non-alcoholic steatohepatitis (NASH), psoriasis, initial stages of the breast carcinoma development and other conditions
MOLECULAR MECHANISM
Troglitazone, works by activating PPARs ( peroxisome proliferator-activated receptors ). Troglitazone is a ligand to both PPARα and - more strongly - PPARγ .
PPARs is a group of receptor molecules inside the cell nucleus. The normal ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, PPARγ binds its heterodimeric patner RXRα (retinoid X receptor alpha) and migrates to the DNA, activating transcription of a number of specific genes.
By activating PPARγ :
- 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
Troglitazone also contains an α-tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. It has been shown (Aljada et al) to reduce inflammation: troglitazone use was associated with a decrease of nuclear factor kappa-B ( NFκB ) and a concomitant increase in its inhibitor (IκB). NFκB is an important cellular transcription regulator for the immune response
SIDE EFFECTS
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).
TOXICITY
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.
