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Posted by plosmedicine on 30 Mar 2009 at 23:44 GMT

Author: Roberto Scatena
Position: Associate Professor
Institution: Istituto di Biochimica e Biochimica Clinica - Universita' Cattolica
Additional Authors: Patrizia Bottoni, Giuseppe E. Martorana, Bruno Giardina
Submitted Date: July 13, 2005
Published Date: July 14, 2005
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

Recent international events on drug surveillance, together with the publication of some statistical corrections for bias in important preclinical works, seem to indicate that the problems of so-called 'side-effects' is often underestimated. In our opinion this has great relevance form both the bioethical and economic points of view.

In recent years we have read too often about abrupt episodes of drug toxicity, especially for new molecules recently introduced in the market and/or related to new clinical indications. In the meantime, these molecules have been the subject of numerous biochemical, pharmacological and pre-clinical studies published in prestigious biomedical journals. For some of these molecules, however, it seems that toxicological data have been overlooked.

As example, we may cite the case of cerivastatin which, alone or in combination with fibrates, has caused numerous episodes of rhabdomyolysis and consequent acute renal insufficiency [1]; cardiocirculatory collapses due to the neglected nitric oxide scavenger effect of some oxygen carriers [2]; dramatic episodes of acute liver failure induced by troglitazone, later ascribed to hypersensibility to this particular drug, while similar episodes of acute liver insufficiency and even of heart failure have been reported as a consequence of the treatment with newer thiazolidinediones [3,4]. Most important, the inappropriate indication for erythropoietin (EPO) as therapy for some forms of anemia associated with cancer This has exponentially enlarged the market for such an expensive drug but may compromise prognosis for some neoplastic patients, due to the not-considered possibility that some cancers in their typical multistep progression may express on their cell membrane functional receptors for this and/or other growth factors and that EPO can stimulate angiogenesis and metalloproteinase synthesis [5]. Lastly, the case of COX-2 inhibitors, intensively studied for a lot of promising therapeutic indications but which, after a few months of marketing, displayed a series of dangerous side-effects, which should have not be unexpected considering the known pathophysiology of eicosanoid metabolism [6].

For completeness, we also wish to underline the new evidence of a serious bias occurred in some important recent studies on the discovery of accurate and sensitive new diagnostic and prognostic markers of some neoplastic diseases with the adoption a proteomic approach [7].

Overlooking such 'side-effects?' can have (directly and/or indirectly) serious consequences for morbility and mortality of patients, with an incidence that often is impossible to quantify (i.e. the so-called iceberg effect).

1. Omar, M.A. and Wilson, J.P. (2002). FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother 36, 288-95
2. Scatena R, Giardina B. (2001) O-raffinose-polymerized hemoglobin. A biochemical and pharmacological profile of an oxygen carrier. Exp Opin Biol Ther 1: 121-127.
3. Farley-Hills E, Sivasankar R, Martin M. (2004) Fatal liver failure associated with pioglitazone. BMJ. 329: 429.
4. Nesto RW, Bell D, Bonow RO, Fonseca V, et al (2004). Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 27: 256-63.
5. Brower W. (2003) Erythropoietin may impair, not improve, cancer survival. Nat Med 9, 1439.
6. Solomon DS, McMurray JJV, Pfeffer MA, et al (2005). Cardiovascular risk associated wit celecobix in a clinical trial for colorectal adenoma prevention. N Engl J Med 352, 1-10.
7. Ransohoff DF (2005) Bias a threat to the validity of cancer molecular-marker research. Nat Rev Cancer 5, 142-149.

No competing interests declared.