Rosiglitazone

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Rosiglitazone
260px
Systematic (IUPAC) name
(RS)-5-[4-(2-[methyl(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability 99%
Protein binding 99.8%
Metabolism Hepatic (CYP2C8-mediated)
Biological half-life 3-4 hours
Excretion Renal (64%) and fecal (23%)
Identifiers
CAS Number 122320-73-4
ATC code A10BG02 (WHO)
PubChem CID 77999
IUPHAR/BPS 1056
DrugBank APRD00403
ChemSpider 70383
Chemical data
Formula C18H19N3O3S
Molar mass 357.428 g/mol[[Script error: No such module "String".]]
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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 (GSK) 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 is currently the subject of many lawsuits against GSK. Over 13,000 have been brought against the company due to the drug. [3] As of July 2010, GSK has agreed to settlements on more that 11,500 of these suits.

The drug is 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., subject to significant restrictions.[4]

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 PPARα, PPARβ/δ, and PPARγ. Thiazolidinediones bind to PPARγ.

PPARs are expressed in fat cells, cells of the liver, muscle, heart, and inner wall (endothelium) and smooth muscle of blood vessels. PPARγ 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.[5] Rosiglitazone is a selective ligand of PPARγ and has no PPARα-binding action. Other drugs bind to PPARα.

Rosiglitazone also appears to have an anti-inflammatory effect in addition to its effect on insulin resistance. Nuclear factor kappa-B (NF-κB) is a signaling molecule which stimulates the inflammatory pathways. NF-κB inhibitor (IκB) is an inhibitor which downregulates the inflammatory pathways. When patients take rosiglitazone, NF-κB levels fall and IκB levels increase.[6]

Rosiglitazone may also benefit patients with Alzheimer's disease who do not express the ApoE4 allele.[7] This is the subject of a clinical trial currently underway.[8]

Rosiglitazone may also treat mild to moderate Ulcerative Colitis, due to its antiinflammatory properties as a PPAR ligand.[9]

A clinical trial has suggested that these agents may be of use in treating malaria.[10]

Side-effects and contraindications

Heart disease

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

A study in 2007, found that Avandia may increase the risk of heart attack by as much as 43%.[11][12] 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).[13] The U.S. Food and Drug Administration (FDA) issued an alert on May 21, 2007.[14] 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.[15]

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.[16][17]

In June 2010, David Graham et al. published a retrospective study of 227,571 elderly American patients, comparing roziglitazone to pioglitazone, the other thiazolidinedione marketed in the United States. The authors concluded that rosiglitazone was associated with "an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of AMI, stroke, heart failure, or all-cause mortality in patients 65 years or older" [18]. The number needed to treat with roziglitazone to cause harm in one was sixty.

Stroke

Avandia has been linked to stroke. In some studies, it was found that the drug increases the risk of stroke by over 27%.[19][20]

A study found that Avandia increases risk of stroke more than alternative drug Actos in elderly patients.[21]

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.[22] The information was based on data from the ADOPT trial.[23] The same increase has been found with pioglitazone (Actos), another TZD.

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[24] documented several occurrences and recommended discontinuation at the first sign of vision problems.

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.[25]

Sales

US sales of $2.2 billion in 2006.[26] Sales in 2Q 2007 down 22% compared to 2006.[27] 4Q 2007 sales down to $252 million.[28]

Though sales have gone down since 2007 due to safety concerns, Avandia sales for 2009 totalled $1.2 billion worldwide.[17]

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.[29] 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".[30] In May 2010, GlaxoSmithKline (GSK) reached settlement agreements for some of the cases against the company, agreeing to pay $60 million to resolve 700 suits.[31] In July 2010, GSK reached settlement agreements to close another 10,000 of the lawsuits against it, agreeing to pay about $460 million to settle these suits.[32][33] In a statement, Michael Miller, the attorney representing 1,500 patients in the suit, said about the settlement "It's a compromise that allows both sides to put this behind them and move on."[34]

Government investigations

The drug is currently being investigated in the US and in Europe. The decisions by the European Medicines Agency (EMEA) and by the US FDA are both expected to come in September 2010. [35][36] The EMEA and the FDA may vote to take the drug off the market, revise the warning labels and/or prescribing information, or leave it on the market with no changes.

United States Investigations

The FDA began investigating the drug in 2007 after it was reported that it likely caused an increased risk in heart attacks, but following a 2007 study, an FDA advisory panel agreed that Avandia did not cause a statistically significant increase in heart attacks. The FDA voted to keep the drug on the market, however a few months later the agency added a black-box warning about potential heart risks of Avandia.[37] In 2007, a panel of independent researchers reported that Avandia could, in fact, increase patients' risk of heart attack. However they recommended that it remain on the market. An FDA oversight committee voted, in 2007, 8 to 7 to accept that advice and keep it on the market.[38]

GlaxoSmithKline is currently being investigated by the FDA and the US Congress regarding Avandia.

Senators Democrat Max Baucus and Republican Charles Grassley filed a report urging GSK to withdraw Avandia in 2008 due to the side effects. The report cited that the drug caused 500 avoidable heart attacks a month and that Glaxo officials sought to intimidate doctors who criticized the drug. It also said that GSK continued to sell and promote the drug despite knowing the increased risk of heart attacks and stroke.[39]

The Senate Finance Committee, in a panel investigation, revealed emails from GSK company officials that suggest the company downplayed scientific findings about safety risks dating back to 2000. It was also alledged by the Senate committee that the company initiated a "ghostwriting campaign", whereby GSK sought outside companies to write positive articles about Avandia to submit to medical journals.[40] GSK defended itself by presenting data that its own tests found Avandia to be safe. Although an FDA staff report showed that the conclusions were flawed.[41] Many studies have found the drug to have serious safety concerns.[42]

On July 14, 2010, after two days of extensive deliberations, the FDA panel investigating Avandia came to a mixed vote. 12 members of the panel voted to take the drug off the market, 17 recommended to leave it on but with a more revised warning label, and 3 voted to keep it on the market with the current warning label.[43][44] The panel has come to some controversy, however, on July 20, 2010, it was discovered that one of the panelists was a paid speaker for GlaxoSmithKline. This arouse questions of a conflict of interest. This panel member was one of the three who voted to keep Avandia on the market with no additional warning labels.[45][46][47] The FDA is expected to vote soon on what to do next in regards to Avandia, though the FDA almost always agrees with its panel votes.

European investigations

According to a probe by the British Medical Journal in September 2010, the United Kingdom's Commission on Human Medicines recommended to the Medicines and Healthcare products Regulatory Agency (MHRA) back in July of 2010, to withdraw Avandia sale because its "risks outweigh its benefits". Additionally, the probe revealed that in 2000, members of the European panel in charge of reviewing Avandia prior to its approval had concerns about the long-term risks of the drug.[48][49]

Controversy and response

Following the reports in 2007, that Avandia can significantly increase the risk of heart attacks, the drug has been controversial. A 2010 article in Time uses the Avandia case as evidence of a broken FDA regulatory system that 'may prove criminal as well as fatal'. It details the disclosure failures, adding that 'Congressional reports revealed that GSK sat on early evidence of the heart risks of its drug, and that the FDA knew of the dangers months before it informed the public.' It reports that 'the FDA is investigating whether GSK broke the law by failing to fully inform the agency of Avandia's heart risks', according to deputy FDA commissioner Dr. Joshua Sharfstein. GSK threatened academics who reported adverse research results, and received multiple warning letters from the FDA for deceptive marketing and failure to report clinical data [50]


The maker of the drug, GlaxoSmithKline, has dealt with serious backlash against the company for the drug's controversy.[51] Sales on the drug dropped significantly after the story first broke in 2007, dropping from $2.5 billion in 2006 to less than $408 million in 2009 in the US.[52]

In response to the raise in risk of heart attacks, the Indian government ordered GSK to suspend its research study, called TIDE in 2010.[53][54] Takeda Pharmaceuticals responded to the controversy by running a large advertising campaign for its rival diabetes drug Actos, first in 2007 and again in 2010.[55] The FDA also halted the TIDE study in the United States.[56][57]

Three doctors' groups, the Endocrine Society, the American Diabetes Association and the American Association of Clinical Endocrinologists, urged patients to continue to take the drug as it would be much worse to stop all treatment, despite any associated risk, but that patients could consult their doctors and begin a switch to a different drug if they or their doctor find concern.[58][59] [60] The American Heart Association said in a statement in June 2010: " ...the reports deserves serious consideration, and patients with diabetes who are 65 years of age or older and being treated with rosiglitazone should discuss the findings with their prescribing physician. . . "For patients with diabetes, the most serious consequences are heart disease and stroke, and the risk of suffering from them is significantly increased when diabetes is present. As in most situations, patients should not change or stop medications without consulting their healthcare provider."[61][62]

It has also been reported that some doctors have begun to stop prescribing Avandia.[63][64][65]

PCRM Lawsuit

On July 19, 2010 the non-profit doctors' group Physicians Committee for Responsible Medicine (PCRM) announced that they were suing the FDA for failing to notify patients of dietary substitutes for diabetes drugs. The lawsuit, filed in the U.S. District Court for the District of Columbia, is currently underway.[66][67]

References

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External links

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fr:Rosiglitazone he:רוזיגליטזון pl:Rozyglitazon ru:Росиглитазон tr:Rosiglitazon

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  1. ↑ Details for patent 5,002,953
  2. ↑ 2.0 2.1 Ajjan RA, Grant PJ (2008). "The cardiovascular safety of rosiglitazone". Expert Opin Drug Saf. 7 (4): 367–76. doi:10.1517/14740338.7.4.367. PMID 18613801. 
  3. ↑ http://www.businessweek.com/news/2010-07-10/ex-regulator-said-to-testify-glaxosmithkline-withheld-study.html
  4. ↑ Controversial Diabetes Drug Harms Heart, U.S. Concludes By GARDINER HARRIS, New York Times, February 19, 2010
  5. ↑ Thiazolidinediones, Hannele Yki-Järvinen, New Engl J Med 351:1106-1118 (September 9, 2004)
  6. ↑ 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. 
  7. ↑ Risner ME; et al. (2006). "Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease". The Pharmacogenomics Journal. 6 (4): 246–254. doi:10.1038/sj.tpj.6500369. PMID 16446752. 
  8. ↑ http://www.alzforum.org/drg/drc/detail.asp?id=116
  9. ↑ Lewis JD, Lichtenstein GR, Deren JJ; et al. (2008). "Rosiglitazone for Active Ulcerative Colitis: A Randomized Placebo Controlled Trials". Gastroenterology. 134 (5): 688–695. doi:10.1053/j.gastro.2008.03.030. PMID 18471502. 
  10. ↑ 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. 
  11. ↑ http://articles.latimes.com/2010/jul/01/business/la-fi-lazarus-20100702 LA Times Avandia: When does a drug's harm outweigh its benefit? by David Lazarus. 1 July 2010. Access date = July 24, 2010
  12. ↑ http://news.bostonherald.com/news/opinion/editorials/view.bg?articleid=1268462&srvc=home&position=emailed
  13. ↑ 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:10.1056/NEJMoa072761. PMID 17517853. Lay summary – Associated Press (2007-05-21). 
  14. ↑ U.S. Food and Drug Administration (May 21, 2007). "FDA Issues Safety Alert on Avandia". 
  15. ↑ 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.
  16. ↑ "Diabetes Drug Avandia Targeted By Reviewers on Safety". ABC News. 2010-02-23. 
  17. ↑ 17.0 17.1 Ranii, David (2010-02-23). "Avandia fallout could hit Triangle". News & Observer. Retrieved 2010-03-05. 
  18. ↑ Graham, D.J. et al.: Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone. JAMA. 2010;304(4):(doi:10.1001/jama.2010.920) Full text
  19. ↑ Freeman, David W (2010-06-29). "Diabetes Drug and Risk: Avandia Linked to Stroke, Heart Trouble, Deaths". CBS News. 
  20. ↑ http://www.aarp.org/health/drugs-supplements/info-06-2010/diabetes_drug_found_to_increase_risk_of_stroke_heart_failure_and_death.html
  21. ↑ http://diabetes.webmd.com/news/20100628/new-study-avandia-riskier-than-actos
  22. ↑ 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.
  23. ↑ 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:10.1056/NEJMoa066224. PMID 17145742. 
  24. ↑ CMAJ
  25. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1399-1400.
  26. ↑ http://www.mmm-online.com/FDA-toughens-Avandia-warnings/article/96354/
  27. ↑ Rubin, Rita (2007-07-26). "FDA panels to weigh Avandia heart risks". USA Today. Retrieved 2010-05-22. 
  28. ↑ http://www.bloomberg.com/apps/news?pid=20601087&sid=aHobgoX8jyfg&refer=home
  29. ↑ Ranii, David (2010-03-05). "Avandia could cost GSK billions". News & Observer. Retrieved 2010-03-05. 
  30. ↑ Ranii, David (2010-03-01). "California county sues Glaxo over diabetes drug". News & Observer. Retrieved 2010-03-05. 
  31. ↑ http://www.bloomberg.com/news/2010-05-10/glaxo-said-to-pay-about-60-million-in-first-settlement-of-avandia-drug.html
  32. ↑ http://noir.bloomberg.com/apps/news?pid=newsarchive&sid=aP.inHBfGVcU
  33. ↑ Dawber, Alistair (2010-07-14). "GSK 'settles Avandia claims' on first day of safety hearing". The Independent. London. 
  34. ↑ http://www.fiercepharma.com/story/gsk-settles-bulk-avandia-suits-460m/2010-07-14?utm_medium=nl&utm_source=internal
  35. ↑ http://www.newsinferno.com/archives/22316
  36. ↑ Rubin, Rita (2010-07-09). "FDA to consider fate of diabetes drug Avandia". USA Today. 
  37. ↑ http://www.aarp.org/health/drugs-supplements/info-06-2010/diabetes_drug_found_to_increase_risk_of_stroke_heart_failure_and_death.2.html
  38. ↑ Lazarus, David (2010-07-01). "Avandia: When does a drug's harm outweigh its benefit?". The Los Angeles Times. 
  39. ↑ http://www.businessweek.com/news/2010-07-10/ex-regulator-said-to-testify-glaxosmithkline-withheld-study.html
  40. ↑ http://www.portfolio.com/views/blogs/heavy-doses/2010/07/14/medical-experts-vote-on-whether-to-pull-avandia-from-market#ixzz0tgGHXXRG
  41. ↑ http://www.portfolio.com/views/blogs/heavy-doses/2010/07/09/avandia-safety-questioned-again-before-a-government-panel-review
  42. ↑ http://www.portfolio.com/views/blogs/heavy-doses/2010/06/28/avandia-heart-risks-found-in-two-studies
  43. ↑ http://www.fiercepharma.com/story/breaking-news-12-panel-members-recommend-avandia-withdrawal/2010-07-14
  44. ↑ http://www.fiercepharma.com/story/what-does-avandia-vote-mean/2010-07-14?utm_medium=nl&utm_source=internal
  45. ↑ http://www.pharmalot.com/2010/07/an-undisclosed-conflict-on-the-fda-avandia-panel/
  46. ↑ Mundy, Alicia (2010-07-20). "Panelist Who Backed Avandia Gets Fees From Glaxo". The Wall Street Journal. 
  47. ↑ http://triangle.bizjournals.com/triangle/stories/2010/07/19/daily18.html
  48. ↑ http://online.wsj.com/article/SB10001424052748703713504575475884140520538.html?mod=googlenews_wsj
  49. ↑ http://www.fiercepharma.com/story/u-k-watchdogs-vote-avandia-withdrawal/2010-09-07?utm_medium=nl&utm_source=internal
  50. ↑ After Avandia: Does the FDA Have a Drug Problem? Time, Thursday, Aug. 12, 2010, http://www.time.com/time/health/article/0,8599,2010028,00.html
  51. ↑ http://health.usnews.com/health-news/managing-your-healthcare/diabetes/articles/2010/07/09/will-avandia-be-yanked-off-the-market.html
  52. ↑ http://www.mmm-online.com/exclusive-takeda-launches-actos-dtc-campaign-today/article/174652/
  53. ↑ http://wwj.cbslocal.com/2010/07/14/avandia-drug-trials-shut-down-in-india/
  54. ↑ http://www.pharmalot.com/2010/07/india-suspends-avandia-clinical-trials-over-risks/
  55. ↑ http://www.fiercepharma.com/story/india-suspends-tide-takeda-touts-actos/2010-07-16?utm_medium=nl&utm_source=internal
  56. ↑ http://www.foodconsumer.org/newsite/Non-food/Drug/fda_orders_glaxo_to_stop_an_avandia_trial_2307100700.html
  57. ↑ http://www.foodconsumer.org/newsite/Non-food/Drug/fda_orders_glaxo_to_stop_an_avandia_trial_2307100700.html
  58. ↑ "Don't dump Avandia, diabetes groups urge patients". Reuters. 2010-07-15. 
  59. ↑ Maugh II, Thomas H. (2010-07-15). "Patients taking Avandia should keep on doing so, doctor groups say". The Los Angeles Times. 
  60. ↑ Katz, Neil (2010-07-16). "Avandia News: What You Need to Know". CBS News. 
  61. ↑ "Booster Shots". The Los Angeles Times. 2010-06-29. 
  62. ↑ http://www.redorbit.com/news/health/1892007/american_heart_association_comment_advisory_committee_recommends_that_us_food/index.html?source=r_health
  63. ↑ Rubin, Rita (2010-07-19). "Doctors say it's already over for diabetes drug Avandia". USA Today. 
  64. ↑ http://www.californiahealthline.org/articles/2010/7/19/physicians-weighing-benefits-risks-of-prescribing-avandia.aspx
  65. ↑ http://www.medscape.com/viewarticle/725422
  66. ↑ http://www.justicenewsflash.com/2010/07/23/fda-sued-for-failure-to-alert-diabetics_201007235075.html
  67. ↑ http://www.pcrm.org/news/avandia_pcrm_lawsuit_1007.html
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