Rosiglitazone
From Proteopedia
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| - | < | + | <StructureSection load='' size='340' side='right' caption='Rosiglitazone, also known as Avandia' scene='Rosiglitazone/Rosiglitazon/1'> |
===Better Known as: Avandia=== | ===Better Known as: Avandia=== | ||
* Marketed By: GlaxoSmithKline (No Longer Marketed)<br /> | * Marketed By: GlaxoSmithKline (No Longer Marketed)<br /> | ||
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===Mechanism of Action=== | ===Mechanism of Action=== | ||
Rosiglitazone is a selective agonist for <scene name='Rosiglitazone/Ppar/1'>Peroxisome Proliferator-Activated Receptor Gamma </scene> ([[PPAR]]). Unliganded PPAR forms a complex with various co-repressors which possess histone deacetylation activity, maintaining tight chromatin structure and preventing gene transcription. This complex is released upon ligand binding (typical ligands are lipids), allowing various co-activators and co-activator-associated proteins to be recruited. Rosiglitazone functions by by binding to the active site of PPARγ, causing the release of co-repressors and activation of the receptor. Activation of PPAR results in transcription of [[Molecular Playground/Insulin|insulin]] responsive genes involved in the control of glucose production, transport and utilization. This explains why the glitazones are referred to as "insulin sensitizers." Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group <scene name='Rosiglitazone/Rosiglitazone_binding/3'>forming a number of interactions </scene>that stabilize the agonist. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its TZD group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282, Leu330, Ile326 and Leu469, and the central benzene ring occupies a pocket formed by Cys285 and Met364 <ref>PMID:9744270</ref> | Rosiglitazone is a selective agonist for <scene name='Rosiglitazone/Ppar/1'>Peroxisome Proliferator-Activated Receptor Gamma </scene> ([[PPAR]]). Unliganded PPAR forms a complex with various co-repressors which possess histone deacetylation activity, maintaining tight chromatin structure and preventing gene transcription. This complex is released upon ligand binding (typical ligands are lipids), allowing various co-activators and co-activator-associated proteins to be recruited. Rosiglitazone functions by by binding to the active site of PPARγ, causing the release of co-repressors and activation of the receptor. Activation of PPAR results in transcription of [[Molecular Playground/Insulin|insulin]] responsive genes involved in the control of glucose production, transport and utilization. This explains why the glitazones are referred to as "insulin sensitizers." Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group <scene name='Rosiglitazone/Rosiglitazone_binding/3'>forming a number of interactions </scene>that stabilize the agonist. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its TZD group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282, Leu330, Ile326 and Leu469, and the central benzene ring occupies a pocket formed by Cys285 and Met364 <ref>PMID:9744270</ref> | ||
| - | + | </StructureSection> | |
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
<table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%"> | <table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%"> | ||
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===Effectiveness=== | ===Effectiveness=== | ||
Current revision
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Pharmacokinetics
For Pharmacokinetic Data References, See: References |
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Effectiveness
Effectiveness
A number of clinical trials were conducted and validated that Rosiglitazone dramatically reduces Fasting plasma glucose (FPG), a measure of the concentration of glucose in the blood, as well as Glycalated Hemoglobin (HbA1c), a measure of average glucose concentration over a long period of time. At two 4mg doses per day, Rosiglitazone reduced FPG by 40.8 mg/dl compared to 30mg/dl with Glyburide (the state of the art medication at the time). Further, the rate of hypoglycemia among glyburide treated patients was 12.1% while only 1.6% among Rosiglitazone treated patients. When combined with Metformin (another hypoglycemia medication), 45% of patients had a greater than 30mg/dl FPG decrease from baseline while 46% had a greater than .7% decrease in HbA1c, compared to 20% and 11%, respectively, for Metformin alone. Similar results were observed when Rosiglitazone was combined with Sulfonylurea (a third hypoglycemia medication). Efficacy comparisons between Rosiglitazone and Pioglitazone revealed minimal differences at equivalent dosage levels. [3] [4]
References
- ↑ http://drugpatentwatch.com/ultimate/preview/tradename/index.php?query=AVANDIA
- ↑ Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature. 1998 Sep 10;395(6698):137-43. PMID:9744270 doi:10.1038/25931
- ↑ Norris SL, Carson S, Roberts C. Comparative effectiveness of pioglitazone and rosiglitazone in type 2 diabetes, prediabetes, and the metabolic syndrome: a meta-analysis. Curr Diabetes Rev. 2007 May;3(2):127-40. PMID:18220664
- ↑ Park JY, Kim KA, Kang MH, Kim SL, Shin JG. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol Ther. 2004 Mar;75(3):157-62. PMID:15001966 doi:10.1016/j.clpt.2003.10.003
