Rosiglitazone

drugbox
IUPAC_name = 5-((4-(2-(methyl-2-pyridinylamino) ethoxy)phenyl)methyl)- 2,4-thiazolidinedione


width = 95
CAS_number = 122320-73-4
ATC_prefix = A10
ATC_suffix = BG02
PubChem = 77999
DrugBank = APRD00403
C = 18 | H = 19 | N = 3 | O = 3 | S = 1
molecular_weight = 357.428 g/mol
smiles = OC(=O)C(Cc1ccc(OCCc2nc(oc2C)c2ccccc2)cc1)Nc1ccccc1C(=O)c1ccccc1
bioavailability = 99%
protein_bound = 99.8%
metabolism = Hepatic (CYP2C8-mediated)
elimination_half-life = 3-4 hours
excretion = Renal (64%) and fecal (23%)
licence_EU = Avandia
licence_US = Rosiglitazone
pregnancy_AU = B3
pregnancy_US = C
legal_UK = POM
legal_US = Rx-only
routes_of_administration = Oral

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). Recent findings suggest that Rosiglitazone is associated with a statistically significant risk of myocardial ischemic events.cite journal |author=Lipscombe LL, Gomes T, Lévesque LE, Hux JE, Juurlink DN, Alter DA |title=Thiazolidinediones and cardiovascular outcomes in older patients with diabetes |journal=JAMA |volume=298 |issue=22 |pages=2634–43 |year=2007 |pmid=18073359 |doi=10.1001/jama.298.22.2634]

Pharmacology

Like other thiazolidinediones, the mechanism of action of rosiglitazone is by 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. [cite journal |author=Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P |title=Evidence for a potent antiinflammatory effect of rosiglitazone |journal=J Clin Endocrinol Metab |volume=89 |issue=6 |pages=2728–35 |year=2004 |pmid=15181049 |doi=10.1210/jc.2003-032103]

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. [cite journal |author=Risner ME et al |title=Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease |journal=The Pharmacogenomics Jounal |volume=6 |pages=246–254 |year=2006] This is the subject of a clinical trial currently underway.

The medication might also be effective in the treatment of mild to moderate Ulcerative Colitis, due to its antiinflammatory properties as a PPAR ligand. [cite journal |author=Lewis JD, Lichtenstein GR, Deren JJ, et al.|title=Rosiglitazone for Active Ulcerative Colitis: A Randomized Placebo Controlled Trials|journal=Gastroenterology |volume=134|pages=688–695|year=2008 |doi=10.1053/j.gastro.2008.03.030]

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. [Cobitz, Alexander R (February 2007). PDFlink| [http://www.fda.gov/medwatch/safety/2007/Avandia_GSK_Ltr.pdf 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 Mellitus] |49.9 KiB . GlaxoSmithKline. Retrieved on 2007-04-10.] The information was based on data from the ADOPT trial. [cite journal |author=Kahn S, Haffner S, Heise M, Herman W, Holman R, Jones N, Kravitz B, Lachin J, O'Neill M, Zinman B, Viberti G |title=Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy |journal=N Engl J Med |volume=355 |issue=23 |pages=2427–43 |year=2006 |pmid=17145742 |doi=10.1056/NEJMoa066224] The same increase has been found with pioglitazone (Actos).

An article by Dr. Steven Nissen and his colleague Kathy Wolski in the June 14, 2007 issue of "The New England Journal of Medicine" reported that the use of rosiglitazone was associated with a significantly increased risk of heart attack (43% more likely, odds ratio=1.43). and an even higher risk of death from all cardiovascular diseases, (64% more likely, odds ratio=1.64).cite journal | author = Nissen SE, Wolski K | title = Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes | journal = N Engl J Med | volume = 356| issue = | year = 2007 | pmid = 17517853| doi = 10.1056/NEJMoa072761 | pages = 2457 [http://content.nejm.org/cgi/content/full/NEJMoa072761 Free full text with registration] ] [cite news | url = http://www.msnbc.msn.com/id/18783816 | title = Diabetes drug linked to heart attacks, death | author = Associated Press | date = May 21 2007 | publisher = MSNBC | accessdate = 2007-05-21] The FDA issued an alert on May 21 2007. [ cite news| url = http://www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html | title = FDA Issues Safety Alert on Avandia | date = May 21 2007 | author = FDA ]

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 than 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. As early as September, 2005, both Rosiglitazone and Pioglitazone have been suspected of causing Macular Edema, which causes partial blindless in various spots of the angle of vision. While blindness is also a possible effect of diabetes, which Rosiglitazone is intended to treat, [http://www.cmaj.ca/cgi/content/full/174/5/623?ijkey=c62043c5958397dd3d7487e5f9e6b845bab8fae5&keytype2=tf_ipsecsha#R3-17 an article] in Canadian journal [http://www.cmaj.ca/ 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 & IV heart failure.

References

External links

* [http://www.avandia.com Official website]
* [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a699023.html MedlinePlus] article
* [http://www.medscape.com/viewarticle/483837 Medscape]
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