Rosiglitazone
From Wikipedia, the free encyclopedia
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| Systematic (IUPAC) name | |
|---|---|
| (RS)-5-[4-(2-[methyl(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione | |
| Identifiers | |
| CAS number | 122320-73-4 |
| ATC code | A10BG02 |
| PubChem | 77999 |
| DrugBank | APRD00403 |
| ChemSpider | 70383 |
| Chemical data | |
| Formula | C18H19N3O3S |
| Mol. mass | 357.428 g/mol |
| SMILES | eMolecules & PubChem |
| Pharmacokinetic data | |
| Bioavailability | 99% |
| Protein binding | 99.8% |
| Metabolism | Hepatic (CYP2C8-mediated) |
| Half life | 3-4 hours |
| Excretion | Renal (64%) and fecal (23%) |
| Therapeutic considerations | |
| Licence data | |
| Pregnancy cat. | |
| Legal status | |
| Routes | Oral |
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Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is marketed by the pharmaceutical company GlaxoSmithKline as a stand-alone drug (Avandia) and in combination with metformin (Avandamet) or with glimepiride (Avandaryl). Annual sales peaked at approx $2.5bn in 2006. The drug's patent expires in 2012.[1]
Some reports have suggested that rosiglitazone is associated with a statistically significant risk of heart attacks, but other reports have disagreed, and the controversy has not been resolved. Concern about adverse effects has reduced the use of rosiglitazone despite its important and sustained effects on glycemic control.[2]
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[edit] Pharmacology
Like other thiazolidinediones (TZDs), the mechanism of action of rosiglitazone is through activation of the intracellular receptor class of the peroxisome proliferator-activated receptors (PPARs), specifically PPARγ. Rosiglitazone is a selective ligand of PPARγ and has no PPARα-binding action.
Apart from its effect on insulin resistance, it appears to have an anti-inflammatory effect: nuclear factor kappa-B (NFκB) levels fall and inhibitor (IκB) levels increase in patients on rosiglitazone.[3]
Recent research has suggested that rosiglitazone may also be of benefit to a subset of patients with Alzheimer's disease not expressing the ApoE4 allele.[4] This is the subject of a clinical trial currently underway.[5]
The medication might also be effective in the treatment of mild to moderate Ulcerative Colitis, due to its antiinflammatory properties as a PPAR ligand.[6]
A clinical trial has suggested that these agents may be of use in treating malaria.[7]
[edit] Side-effects and contraindications
A press release by GlaxoSmithKline in February 2007 noted that there is a greater incidence of fractures of the upper arms, hands and feet in female diabetics given rosiglitazone compared with those given metformin or glyburide.[8] The information was based on data from the ADOPT trial.[9] The same increase has been found with pioglitazone (Actos), another TZD.
A meta-analysis reported in May 2007 that the use of rosiglitazone was associated with a significantly increased risk of heart attack (odds ratio=1.43, (95% confidence interval, 1.03 to 1.98; P=0.03)), and an even higher risk of death from all cardiovascular diseases (odds ratio=1.64).[10] The U.S. Food and Drug Administration (FDA) issued an alert on May 21, 2007.[11] On July 30, 2007 an Advisory Committee of the Food and Drug Administration concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of myocardial ischemic events (including heart attacks) than a placebo, but data from several long term, prospective clinical trials showed that when rosiglitazone was compared to metformin, or sulfonylurea, there was no difference in the risk of heart attack. This data, coupled with the meta-analysis, prompted the FDA to state that the data on the association between rosiglitazone and myocardial ischemia were inconclusive. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate this, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has dramatically reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control.[2]
In 2009 the RECORD study, an open label trial published in the Lancet, found that there was no increase in cardiovascular hospitalisation or death with rosiglitazone compared to metformin plus sulfonylurea, but the rate of heart failure causing admission to hospital or death was significantly increased.[12]
As early as September 2005, both Rosiglitazone and Pioglitazone have been suspected of causing Macular Edema, which causes partial blindness in various spots of the angle of vision. While blindness is also a possible effect of diabetes, which Rosiglitazone is intended to treat, an article in Canadian journal CMAJ has documented several occurrences and recommends discontinuation at the first sign of vision problems. Both TZD's are contraindicated in patients with NYHA Class III and IV heart failure.
[edit] Sales
US sales of $2.2 billion in 2006.[13] Sales in 2Q 2007 down 22% compared to 2006.[14] 4Q 2007 sales down to $252 million.[15]
[edit] References
- ^ Details for patent 5,002,953
- ^ a b Ajjan RA, Grant PJ (2008). "The cardiovascular safety of rosiglitazone". Expert Opin Drug Saf 7 (4): 367–76. doi:. PMID 18613801.
- ^ Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P (2004). "Evidence for a potent antiinflammatory effect of rosiglitazone". J Clin Endocrinol Metab 89 (6): 2728–35. doi:. PMID 15181049.
- ^ Risner ME et al. (2006). "Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease". The Pharmacogenomics Journal 6: 246–254.
- ^ http://www.alzforum.org/drg/drc/detail.asp?id=116
- ^ Lewis JD, Lichtenstein GR, Deren JJ, et al. (2008). "Rosiglitazone for Active Ulcerative Colitis: A Randomized Placebo Controlled Trials". Gastroenterology 134: 688–695. doi:.
- ^ Boggild AK, Krudsood S, Patel SN, Serghides L, Tangpukdee N, Katz K, Wilairatana P, Liles WC, Looareesuwan S, Kain KC (2009). "Use of Peroxisome proliferator-activated receptor gamma agonists as adjunctive treatment for Plasmodium falciparum malaria: A randomized, double-blind, placebo-controlled trial.". Clin. Infect. Dis..
- ^ Cobitz, Alexander R (February 2007). Clinical Trial Observation of an Increased Incidence of Fractures in Female Patients Who Received Long-Term Treatment with Avandia (rosiglitazone maleate) Tablets for Type 2 Diabetes MellitusPDF (49.9 KiB). GlaxoSmithKline. Retrieved on 10 April 2007.
- ^ Kahn S, Haffner S, Heise M, Herman W, Holman R, Jones N, Kravitz B, Lachin J, O'Neill M, Zinman B, Viberti G (2006). "Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy". N Engl J Med 355 (23): 2427–43. doi:. PMID 17145742.
- ^ Nissen SE, Wolski K (2007). "Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes". N Engl J Med 356 (24): 2457–71. doi:. PMID 17517853. http://content.nejm.org/cgi/content/full/356/24/2457. Lay summary – Associated Press (2007-05-21).
- ^ U.S. Food and Drug Administration (May 21, 2007). "FDA Issues Safety Alert on Avandia". http://www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html.
- ^ Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. The Lancet. In Press, Corrected Proof. Available at: http://www.sciencedirect.com/science/article/B6T1B-4WGD87Y-1/2/0efabb7eba7ca1f4f7c556bd636e19ab.
- ^ http://www.mmm-online.com/FDA-toughens-Avandia-warnings/article/96354/
- ^ http://www.usatoday.com/news/health/2007-07-25-avandia-fda_N.htm
- ^ http://www.bloomberg.com/apps/news?pid=20601087&sid=aHobgoX8jyfg&refer=home
[edit] External links
- Official website
- MedlinePlus article
- Medscape
- ClinicalTrials.gov NCT00265148 Brain Imaging Study of Rosiglitazone Efficacy and Safety in Alzheimer's Disease
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