1 : 1 mixture (racemate)

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	EU EMEA:link, US FDA:link
Pregnancy cat.	B3(AU) C(US)
Legal status	POM (UK) ?-only (US)
Routes	Oral
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Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It works as an insulin sensitizer, by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. 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, but declined after reports of adverse effects. 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 sustained effects on glycemic control.^[2]

The drug was controversial in the U.S. Food and Drug Administration. Some reviewers concluded that rosiglitazone caused more deaths than pioglitazone (Actos) and recommended that rosiglitazone be taken off the market, but an F.D.A. panel disagreed and it remains on the market in the U.S.^[3]

[edit] Pharmacology

Rosiglitazone is a member of the thiazolidinedione class of drugs. Thiazolidinediones act as insulin sensitizers. They reduce glucose, fatty acid, and insulin blood concentrations. They work by binding to the peroxisome proliferator-activated receptors (PPARs). PPARs are receptors on the membrane of the cell nucleus. Thiazolidinediones enter the cell, bind to the nuclear receptors, and affect the expression of DNA. There are several PPARs, including PPARa, PPARß/d, and PPAR?. Thiazolidinediones bind to PPAR?.

PPARs are expressed in fat cells, cells of the liver, muscle, heart, and inner wall (endothelium) and smooth muscle of blood vessels. PPAR? is expressed mainly in fat tissue, where it regulates genes involved in fat cell (adipocyte) differentiation, fatty acid uptake and storage, and glucose uptake. It is also found in pancreatic beta cells, vascular endothelium, and macrophages.^[4] Rosiglitazone is a selective ligand of PPAR? and has no PPARa-binding action. Other drugs bind to PPARa.

Rosiglitazone also appears to have an anti-inflammatory effect in addition to its effect on insulin resistance. Nuclear factor kappa-B (NF?B) is a signaling molecule which stimulates the inflammatory pathways. NF?B inhibitor (I?B) is an inhibitor which downregulates the inflammatory pathways. When patients take rosiglitazone, NF?B levels fall and I?B levels increase.^[5]

Rosiglitazone may also benefit patients with Alzheimer's disease who do not express the ApoE4 allele.^[6] This is the subject of a clinical trial currently underway.^[7]

Rosiglitazone may also treat mild to moderate Ulcerative Colitis, due to its antiinflammatory properties as a PPAR ligand.^[8]

A clinical trial has suggested that these agents may be of use in treating malaria.^[9]

[edit] Side-effects and contraindications

[edit] Heart disease

Some studies conclude that rosiglitazone increases fatalities from heart disease, but other studies do not.

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]

Both TZD's are contraindicated in patients with NYHA Class III and IV heart failure.

In February 2010, David Graham, the FDA's associate director of drug safety, recommended that rosiglitazone be taken off the market. Graham argued that rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor. At the same time, a report by the Senate Finance Committee accused GlaxoSmithKline of knowing about the drug's risks well before they became public. The report also criticized the FDA for letting clinical trials continue despite 83,000 heart attacks from 1999 to 2007 that the FDA linked to rosiglitazone. GlaxoSmithKline maintains that the drug is safe and that the Senate report did not consider scientific evidence or the company's efforts to make known its concerns to the parties involved. However, the FDA still recommends that patients continue taking it unless their doctor tells them otherwise.^[13][14]

[edit] Bone fractures

GlaxoSmithKline reported a greater incidence of fractures of the upper arms, hands and feet in female diabetics given rosiglitazone compared with those given metformin or glyburide.^[15] The information was based on data from the ADOPT trial.^[16] The same increase has been found with pioglitazone (Actos), another TZD.

[edit] Eye damage

Both rosiglitazone and pioglitazone have been suspected of causing macular edema, which damages the retina of the eye and causes partial blindness. Blindness is also a possible effect of diabetes, which rosiglitazone is intended to treat. One report^[17] documented several occurrences and recommended discontinuation at the first sign of vision problems.

[edit] Hepatotoxicity

Moderate to severe acute hepatitis has occurred in several adults who had been taking the drug at the recommended dose for 2-4 weeks. Plasma rosiglitazone concentrations may be significantly increased in patients with pre-existing hepatic impairment.^[18]

[edit] Sales

US sales of $2.2 billion in 2006.^[19] Sales in 2Q 2007 down 22% compared to 2006.^[20] 4Q 2007 sales down to $252 million.^[21]

Though sales have gone down since 2007 due to safety concerns, Avandia sales for 2009 totalled $1.2 billion worldwide.^[14]

[edit] Lawsuits

The Guardian reports lawsuits over the drug could total anywhere from $1 billion to $6 billion. This is based on research by analysts for UBS, who say 13,000 suits have been filed.^[22] Included among those suing: Santa Clara County, California, which claims to have spent $2 million on rosiglitazone between 1999 and 2007 at its public hospital and is asking for "triple damages".^[23]

[edit] References

[edit] External links

• Official website
• MedlinePlus article
• Medscape
• ClinicalTrials.gov NCT00265148 Brain Imaging Study of Rosiglitazone Efficacy and Safety in Alzheimer's Disease

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Rosiglitazone".