medicationclass of thiazolidinedione (also called glitazones) 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 "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 resistanceis decreased
Adipocytedifferentiation is modified
VEGF-induced angiogenesisis inhibited [cite journal |author=Panigrahy D, Singer S, Shen LQ, "et al" |title=PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis |journal=J. Clin. Invest. |volume=110 |issue=7 |pages=923–32 |year=2002 |pmid=12370270 |doi=10.1172/JCI15634 ]
Leptinlevels decrease (leading to an increased appetite)
* Levels of certain
interleukins (e.g. IL-6) fall
Members of the class
Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:
Troglitazone(Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis.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,
rivoglitazone, and the early non-marketed thiazolidinedione "ciglitazone".
The only approved use of the thiazolidinediones is in
diabetes mellitustype 2.
It is being investigated experimentally in
polycystic ovary syndrome(PCOS), non-alcoholic steatohepatitis(NASH),cite journal |author=Belfort R, Harrison SA, Brown K, "et al" |title=A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis |journal=N. Engl. J. Med. |volume=355 |issue=22 |pages=2297–307 |year=2006 |month=Nov |pmid=17135584 |doi=10.1056/NEJMoa060326 |url= [http://clinicaltrials.gov/show/NCT00227110 Clinical trial info] ] psoriasis, [cite journal |author=Krentz AJ, Friedmann PS |title=Type 2 diabetes, psoriasis and thiazolidinediones |journal=Int. J. Clin. Pract. |volume=60 |issue=3 |pages=362–3 |year=2006 |month=Mar |pmid=16494655 |doi=10.1111/j.1368-5031.2005.00765.x |url=] autism, [Boris et al. Effect of pioglitazone treatment on behavioral symptoms in autistic children, Journal of Neuroinflammation 2007,4:3 [http://www.jneuroinflammation.com/content/4/1/3] and other conditions. [http://clinicaltrials.gov/ct/search?term=rosiglitazone&submit=Search Clinical Trials for Rosiglitazone] - from ClinicalTrials.gov, a service of the U.S. National Institutes of Health]
Several forms of
lipodystrophycause 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 carcinomadevelopment.
Side effects and contraindications
The withdrawal of
troglitazonehas led to concerns of the other thiazolidinediones also increasing the incidence of hepatitisand potential liver failure, an approximately 1 in 20,000 individual occurrence with troglitazone. Because of this, the FDA recommends two to three month checks of liver enzymes for the first year of thiazolidinedione therapy to check for this rare but potentially catastrophic complication. To date, 2008, the newer thiazolidinediones, rosiglitazoneand pioglitazonehave been free of this problem.
The main side effect of all thiazolidinediones is water retention, leading to
edema, generally a problem in less than 5% of individuals, but a big problem for some and potentially, with significant water retention, leading to a decompensation of potentially previously unrecognized heart failure. Therefore, thiazolidinediones should be prescribed with both caution and patient warnings about the potential for water retention/weight gain, especially in patients with decreased ventricular function (NYHA grade III or IV heart failure).
Though recent studies have shown there may be an increased risk of
coronary heart diseaseand heart attacks with rosiglitazone [cite web |url=http://www.forbes.com/forbeslife/health/feeds/hscout/2007/08/14/hscout607350.html |title=Avandia to Carry Stronger Heart Failure Warning - Forbes.com |accessdate=2007-08-15 |format= |work=] pioglitazonetreatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and plaque progressioncite journal |author=Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A |title=The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients |journal=Diabetes Care |volume=27 |issue=7 |pages=1647–53 |year=2004 |month=Jul |pmid=15220241 |doi= |url=http://care.diabetesjournals.org/cgi/content/abstract/27/7/1647 ] cite journal |author=Mannucci E, Monami M, Lamanna C, Gensini GF, Marchionni N |title=Pioglitazone and cardiovascular risk. A comprehensive meta-analysis of randomized clinical trials |journal=Diabetes Obes Metab |volume= |issue= |pages= |year=2008 |month=May |pmid=18505403 |doi=10.1111/j.1463-1326.2008.00892.x |url=] cite journal |author=Nissen SE, Nicholls SJ, Wolski K, "et al" |title=Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial |journal=JAMA |volume=299 |issue=13 |pages=1561–73 |year=2008 |month=Apr |pmid=18378631 |doi=10.1001/jama.299.13.1561 |url=http://jama.ama-assn.org/cgi/content/full/299/13/1561 ] .
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