LETTER TO THE EDITOR. Statins alone are ineffective in cerebral malaria but potentiate artesunate ACCEPTED

Transcription

1 AAC Accepts, published online ahead of print on 8 September 2008 Antimicrob. Agents Chemother. doi: /aac Copyright 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved. LETTER TO THE EDITOR Statins alone are ineffective in cerebral malaria but potentiate artesunate Statins are a family of lipid-lowering drugs widely used to control cholesterol level and to prevent stroke and cardiac failure in patients at high risk of coronary artery disease. Recently, statins demonstrated pleiotropic cholesterol-independent effects (1). Used after stroke, statins proved to be neuroprotective in the setting of cerebral ischemia with improved functional outcome in patients (2). Used after septic insult, statins demonstrated increased survival time due to restoration of cardiac function and haemodynamic status (3). These effects occur before cholesterol lowering and without pre-treatment. According to these benefits, we postulate that statins could be considered as new potential drugs during acute cerebral infectious diseases. Among these, cerebral malaria due to Plasmodium falciparum is still one of the worst killers in tropical countries. Considering the role of inflammatory and ischemic injuries during cerebral malaria, we addressed the place of statins as emergency treatment in a clinically relevant murine model. Statins differ in terms of their chemical structures, pharmacokinetic profiles and lipid modifying efficacy (4). As differences could be expected in HMG-coA reductase inhibition, several statins were tested for neuroprotective potential. Pravastatin, fluvastatin, simvastatin and atorvastatin were compared to the neuroprotective effect of erythropoietin, known to provide 60% survival in an experimental model of cerebral malaria (5). Pravastatin and fluvastatin were administrated at high doses (40 to 200 mg/kg), simvastatin at 40 mg/kg and atorvastatin at 20 mg/kg, once per day for three to five days at the onset of the disease. Surprisingly, all statins used alone failed to prevent death from cerebral malaria (table I), and it raises questions for the scientific community during a recent meeting (6). Despite the in vitro antimalarial effect of atorvastatin described by Pradines et al (7), none of these statins showed an effect on parasitemia in mice when used at the same range of doses than in vitro ( µm). There is a growing body of literature suggesting that the 1

2 pleiotropic effects of statins may be useful in a wide range of indications, including post-stroke reperfusion, septic insult, anticancer drug resistance and inflammatory rheumatoid diseases. While statins failed to prevent death, it could be speculated that it could act as adjuvant therapy. Mice were treated with a drug combination of artesunate and atorvastatin in the same conditions than described, and we observed a significant improvement in survival at day 13 post-infection, compared to atorvastatin alone (p<0.02, log-rank test, cumulative survival analysis, figure1). Considering sepsis, authors speculated that statins could be a panacea (8). In the light of our observations during cerebral malaria, this new paradigm should rather be reconsidered as an adjuvant effect. As pleiotropic effects may largely depend on the pathophysiology of the respective disease and on the patient status, convincing clinical trials are needed to explore the scope of these drugs. The safety of statins when administrated after the insult also needs to be addressed since these molecules were not originally designed for these therapeutic approaches. 2

3 Control 1 Pravastatin Control 2 Fluvastatin Control 3 Simvastatin** Control 4 Atorvastatin Atorvastatin Artesunate Treatment (intraperitoneal) mg/kg Days postinfection Mean ± SD (%) Parasitemia (Day 6) Student t-test (drug vs saline) Number of surviving mice Survival (Day 7) saline 9.9 ± saline Kaplan Meier 11.5 ± p > ± P = ± ± p > ± p = 0.013* saline 3 to ± to ± p = 0.19 saline 4 to ± to ± p > to ± 0.9 < p<0.02 Table I: Treatment of mice presenting cerebral malaria with statins used with different regimen. Parasitemia (Student t-test) and survival data (Kaplan Meier log. rank, SPSS 11.5) are compared between treated groups and infected non-treated control groups. All treated and non-treated mice have comparable weight and parasitemia before treatment. n: number of mice per experiment. * Fluvastatin had a toxic effect as demonstrated by the p-value and the premature death of mice compared to control ** Simvastatin was chemically activated by alkaline hydrolysis prior to injection. 3

4 Figure 1: Univariate analysis of survival (SPSS 11.5) Benefit of the drug combination artesunate atorvastatin on survival compared to atorvastatin treatment alone. The log rank test revealed that artesunate atorvastatin given from day 4 to day 6 post-infection had an effect on survival (p<0.02). Anne-Lise Bienvenu Stéphane Picot University Lyon 1, EA 4170 Malaria Research Unit, Faculty of Medicine, 8 avenue Rockefeller, Lyon cedex 08, France Phone: Fax: Corresponding author: Anne-Lise.Bienvenu@recherche.univ-lyon1.fr We declare that we have no conflict of interest. Acknowledgements Authors are particularly grateful to Novartis Pharma AG Stein and Merck Research Laboratory for kindly provided fluvastatin and simvastatin, respectively. Special thanks to Dr. B. Pradines and Dr. T. Fusai (IMTSSA, Marseilles, France) for their gift of atorvastatin and for helpful discussions. 4

5 REFERENCES 1 Corsini, A., N. Ferri, and M. Cortellaro Are pleiotropic effects of statins real? Vasc. Health Risk Manag. 3: Moonis, M., K. Kane, U. Schwiderski, B.W. Sandage, and M. Fisher HMG-CoA reductase inhibitors improve acute ischemic stroke outcome. Stroke. 36: Merx, M.W., E.A. Liehn, J. Graf, A. van de Sandt, M. Schaltenbrand, J. Schrader, P. Hanrath, and C. Weber Statin treatment after onset of sepsis in a murine model improves survival. Circulation. 112: Schachter, M Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam. Clin. Pharmacol. 19: Kaiser, K., A. Texier, J. Ferrandiz, A. Buguet, A. Meiller, C. Latour, F. Peyron, R. Cespuglio, and S. Picot Recombinant human erythropoietin prevents the death of mice during cerebral malaria. J. Infect. Dis. 193: Bienvenu, A.L., J. Ferrandiz, D. Autheman, and S. Picot Statins failed to protect mice from cerebral malaria, abstr Abstr. 56th Annual Meeting. American Society of Tropical Medicine and Hygiene, Philadelphia, PA. 7 Pradines, B., M. Torrentino-Madamet, A. Fontaine, M. Henry, E. Baret, J. Mosnier, S. Briolant, T. Fusai, and C. Rogier Atorvastatin is 10-fold more active in vitro than other statins against Plasmodium falciparum. Antimicrob. Agents Chemother. 51: Terblanche, M., Y. Almog, R.S. Rosenson, T.S. Smith, and D.G. Hackam Statins and sepsis: multiple modifications at multiple levels. Lancet Infect. Dis. 7: