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[SANET-MG] aprotinin a pharm crop derailed



February 9, 2006

Prof. Joe Cummins

The aprotinin drug: A pharm crop derailed

Genetically modified (GM) crops bearing human or other genes for pharmaceutical proteins (pharm crops) are being promoted as an outstanding aspect of crop genetic modification. However, there have been serious concerns expressed about the use of food crops to produce pharmaceutical proteins. The ultimate hazard is pollution of major food crops with genes specifying pharmaceuticals that expose the public to pathological side effects (1,2,3). That nightmare scenario was realized in 2001 when maize bearing a gene for a pharmaceutical product was allowed to produce “volunteers” from carry over of seeds from the pharm crop which polluted a food crop (4). The company, Prodigene, involved in the pharmaceutical gene pollution incident is still active and features , as a main product currently for sale, a pharmaceutical AproliZean a recombinant bovine aprotinin expressed in maize. The product is produced in quantities for research and manufacturing (5). Aprotinin is used extensively in surgery because it inhibits enzymes that enhance bleeding The drug is recommended to be used only once with a patient because repeated use may lead to fatal anaphylaxis (2)The pharm crop product does not appear to have been approved for use as a drug for humans. However, should its gene pollute crops grown for food its impact may be severe.

On February 8,2006 the US FDA issued a public health advisory for the drug Trasylol (aprotinin injection) used in surgery to prevent blood loss has been linked , in two scientific publications, to risks of side effects including kidney problems, heart attacks and stroke . Questions and Answers on Aprotinin (marketed as Trasylol)

1. What is Trasylol and what is it used to treat? Trasylol, or aprotinin, a product derived from bovine lung tissue, inhibits certain enzymes that increase the risk for bleeding. Trasylol administration aids the body's ability to prevent bleeding. Patients undergoing coronary artery bypass grafting (CABG) using cardiopulmonary bypass may be at risk for bleeding complications due to prior use of anticoagulants or clinical conditions that predispose to bleeding. Trasylol is used to decrease this bleeding risk.

2. What is the concern regarding Trasylol? A January 26, 2006 report in The New England Journal of Medicine suggests that Trasylol administration may increase the risk for serious side-effects among some patients undergoing CABG. This report describes the occurrence of serious kidney damage, heart attack (myocardial infarction) and stroke among CABG patients receiving Trasylol. More patients receiving Trasylol experienced these events than patients receiving either no medications intended to decrease blood loss or other medications intended to decrease blood loss.

Another recently published study has suggested that patients receiving Trasylol may be at higher risk for kidney damage. This report (published January 20, 2006 in the on-line edition of Transfusion) used methods similar to those used in The New England Journal of Medicine study but included a smaller number (6).

An abstract from the New England Journal of Medicine report: Volume 354:353-365 January 26, 2006

The Risk Associated with Aprotinin in Cardiac Surgery

Dennis T. Mangano, Ph.D., M.D., Iulia C. Tudor, Ph.D., Cynthia Dietzel, M.D.

ABSTRACT Background The majority of patients undergoing surgical treatment for ST-elevation myocardial infarction receive antifibrinolytic therapy to limit blood loss. This approach appears counterintuitive to the accepted medical treatment of the same condition — namely, fibrinolysis to limit thrombosis. Despite this concern, no independent, large-scale safety assessment has been undertaken.

Methods In this observational study involving 4374 patients undergoing revascularization, we prospectively assessed three agents (aprotinin [1295 patients], aminocaproic acid [883], and tranexamic acid [822]) as compared with no agent (1374 patients) with regard to serious outcomes by propensity and multivariable methods. (Although aprotinin is a serine protease inhibitor, here we use the term antifibrinolytic therapy to include all three agents.)

Results In propensity-adjusted, multivariable logistic regression (C-index, 0.72), use of aprotinin was associated with a doubling in the risk of renal failure requiring dialysis among patients undergoing complex coronary-artery surgery (odds ratio, 2.59; 95 percent confidence interval, 1.36 to 4.95) or primary surgery (odds ratio, 2.34; 95 percent confidence interval, 1.27 to 4.31). Similarly, use of aprotinin in the latter group was associated with a 55 percent increase in the risk of myocardial infarction or heart failure (P<0.001) and a 181 percent increase in the risk of stroke or encephalopathy (P=0.001). Neither aminocaproic acid nor tranexamic acid was associated with an increased risk of renal, cardiac, or cerebral events. Adjustment according to propensity score for the use of any one of the three agents as compared with no agent yielded nearly identical findings. All the agents reduced blood loss.

Conclusions The association between aprotinin and serious end-organ damage indicates that continued use is not prudent. In contrast, the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives.

The two studies showing that aprotinin treatment adversely effects patients adds to the evidence previously reviewed showing numerous adverse impacts of the drug (2). It seems likely that the therapeutic use of the drug will be discontinued in the near future. However, the drug has been produced in maize and there must have been field test releases of the GM maize to the environment , but drugs tested in such field tests are frequently designated confidential business information. Bystanders exposed to pollen, seed or dust from debris from the maize plants or seed should be informed of the locations of such tests and any ill effects of the exposure should be reported and treated. The GM pharm crops modified with aprotinin ,which has been show to be a hazardous drug , is a paradigm for the pharm crops being proposed for field testing and production. All too often adverse effects of the drugs being produced in food crops are ignored or groundlessly minimized. Field testing and production are undertaken with such secrecy that those adversely effected by the tests or production have no way of knowing what it was that hurt them. Environmental field test releases of pharm crops must be curtailed.

References

1.Ho,MW Pharmageddon Science in Society 2003,17,23

2.Cummins,J Pharm Crop Products in US Market Science in Society 2004,23,28

3. Cummins,J and Ho MW Ban Plant-Based Transgenic Pharmaceuticals 2004,23, 29

4.Fox,J Puzzling industry response to ProdiGene fiasco Nature Biotechnology 2003,21,3-4

5.ProdiGene AproliZean TM Recombinant Bovine Aprotinin Expressed in Maize 2004 http://www.prodigene.com <http://www.prodigene.com/>

6 US Food and Drug Administration Questions and Answers on Aprotinin (marketed as Trasylol).2006 http://www.fda.gov/cder/drug/infopage/aprotinin/aprotininQA.htm

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