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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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