Rosiglitazone

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Chemical structure of Rosiglitazone
Rosiglitazone
Systematic (IUPAC) name
5-((4-(2-(methyl-2-pyridinylamino) ethoxy)phenyl)methyl)- 2,4-thiazolidinedione
Identifiers
CAS number 122320-73-4
ATC code A10BG02
PubChem 77999
DrugBank APRD00403
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

EU, US
Pregnancy cat.

B3(AU) C(US)
Legal status

POM(UK) ℞-only(US)
Routes 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.[1][2]

Contents

[edit] 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.[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.

The medication might also be effective in the treatment of mild to moderate Ulcerative Colitis, due to its antiinflammatory properties as a PPAR ligand.[5]

[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.[6] The information was based on data from the ADOPT trial.[7] 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 slightly increased risk of heart attack (20% more likely, odds ratio=1.43).[1][8] The FDA issued an alert on May 21, 2007.[9]

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, an article in Canadian journal CMAJ has documented several occurences and recommends discontinuation at the first sign of vision problems. Both TZD's are contraindicated in patients with NYHA Class III & IV heart failure.


[edit] References

  1. ^ a b Nissen SE, Wolski K (2007). "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes". N Engl J Med: 2457. doi:10.1056/NEJMoa072761.  Free full text with registration
  2. ^ Lipscombe LL, Gomes T, Lévesque LE, Hux JE, Juurlink DN, Alter DA (2007). "Thiazolidinediones and cardiovascular outcomes in older patients with diabetes". JAMA 298 (22): 2634–43. doi:10.1001/jama.298.22.2634. PMID 18073359. 
  3. ^ 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:10.1210/jc.2003-032103. PMID 15181049. 
  4. ^ Risner ME et al (2006). "Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease". The Pharmacogenomics Jounal 6: 246-254. 
  5. ^ Lewis JD, Lichtenstein GR, Deren JJ, et al. (2008). "Rosiglitazone for Active Ulcerative Colitis: A Randomized Placebo Controlled Trials". Gastroenterology 134: 688-695. 
  6. ^ 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 2007-04-10.
  7. ^ 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. PMID 17145742. 
  8. ^ Associated Press. "Diabetes drug linked to heart attacks, death", MSNBC, May 21, 2007. Retrieved on 2007-05-21. 
  9. ^ FDA. "FDA Issues Safety Alert on Avandia", May 21, 2007. 

[edit] External links

v • d • e
Oral antidiabetic drugs and Insulin analogs (A10)
Biguanides
Sulfonylureas
Alpha-glucosidase inhibitors
Thiazolidinediones (TZD)
Pioglitazone, Rivoglitazone†, Rosiglitazone, Troglitazone‡
Meglitinides
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Glucagon-like peptide-1 analog
Exenatide, Liraglutide†, Albiglutide†
Amylin analog
Insulin analogs
Dual PPAR agonists
SGLT2 inhibitor
Dapagliflozin†, Remogliflozin†
†Undergoing clinical trials. ‡ Withdrawn from market. §Development halted.