Name:	Rosiglitazone
Other Names:	5-[[4-[2-(methyl-pyridin-2-yl-amino)ethoxy]phenyl]methyl]thiazolidine-2,4-dione , AVANDIA®, Rosiglitazone maleate
Therapeutic Applications:	Approved for type 2 diabetes mellitus. In clinical testing for mild to moderate Alzheimer disease.
Therapy Types:	Small molecule, orally administered.
Mechanisms:	Rosiglitazone maleate is an oral anti-diabetic agent which acts primarily by increasing insulin sensitivity.
Development Status:	investigational in U.S.
FDA Phase:	Discontinued
Primary Medical Role:	Rosiglitazone is an agonist of the nuclear hormone receptor peroxisome proliferators-activated receptor gamma (PPARγ). PPAR receptors are involved in insulin sensitization in adipose tissue, skeletal muscle, and liver. Peripheral insulin resistance characterizes type 2 diabetes, as evidenced by hyperglycemia and/or impaired glucose tolerance. Rosiglitazone reduces blood glucose levels and reduces hyperinsulinemia (reducing circulating insulin levels).
Role in Alzheimer's Disease:	Type 2 diabetes, insulin metabolism, and Alzheimer disease are linked in a variety of ways. Numerous epidemiological studies have shown that there is an increased risk of developing AD among type 2 diabetic patients (Arvanitakis et al., 2004; Leibson et al., 1997). Diet-induced peripheral insulin resistance in Tg2576 mice has been shown to increase γ-secretase activity and decrease insulin-degrading enzyme activity. These combined changes result in increased Aβ40 and Aβ42 levels and amyloid plaque burden in the brain, and impaired performance in a water maze test of learning and memory (Ho et al., 2004). ApoE4 allele-positive individuals account for 40-50 percent of sporadic late-onset AD (Risner et al., 2006). Glucose is the brain’s primary fuel, and it is metabolized by the tricarboxylic acid (TCA) cycle. ApoE4 carriers have declines in brain mitochondrial TCA enzyme activities (Gibson et al., 2000; Bubber et al., 2005). Rosiglitazone therapy has been shown to improve cognitive function in both a subset of human AD patients (Watson et al., 2005; Risner et al., 2006) as well as in preclinical AD model mice (Pedersen et al., 2006). In two small clinical trials, rosiglitazone treatment for 24 weeks resulted in a modest but significant improvement in cognition in non-ApoE4 subjects, but no improvement and rather a decline in cognition in ApoE4 allele carriers (Risner et al., 2006). Preliminary results from Phase III clinical study NCT00428090 were reported at ICAD 2009 (Rabiner et al 2009). This study failed to demonstrate significant efficacy at any dose, in any test group (by ApoE genotype) assessed by either ADAS-cog or CIBIC-Plus (Clinician Interview Based Impression of Change) tests.
Pharmacological Role:	Rosiglitazone is an agonist of the nuclear hormone receptor peroxisome proliferators-activated receptor gamma (PPARγ). In humans, PPAR receptors are expressed in key tissues for insulin action. Activation of PPARγ nuclear receptors regulates the transcription of insulin- responsive genes involved in the control of glucose production, transport, and utilization. PPARγ is thought to be a lipid sensor, as its natural ligands are long-chain fatty acids, eicosanoids, oxidized lipoproteins, and lipids. The activation of PPARγ in macrophages results in suppression of inflammatory gene expression, as well as a marked reduction of cholesterol esterification, promoting cholesterol efflux from macrophages to HDL.
Side Effects:	Rosiglitazone was well tolerated in clinical trial testing of Alzheimer disease patients (Risner et al., 2006). The frequency of adverse effects in treatment groups was not different than that of placebo group. Edema is the most common side effect associated with rosiglitazone treatment. In the previous clinical trial of rosiglitazone in AD, one fatality occurred in the highest dose group (8 mg), due to atrial fibrillation and cardiac failure (Risner et al., 2006).
Companies:	GlaxoSmithKline
Notes:	The negative reported preliminary results from the completed clinical trial NCT00428090 has resulted in the recent termination of three other clinical trials to test Avandia XR in AD (See Phase III trials NCT00550420 and NCT00490568) and Phase II trial NCT00334568. This entry was last updated Oct 7, 2010.

References

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Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD; Rosiglitazone in Alzheimer's Disease Study Group. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 2006 Jul-Aug;6(4):246-54. Abstract

Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol. 2006 Jun;199(2):265-73. Abstract

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