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      Sitamaquine as a putative antileishmanial drug candidate: from the mechanism of action to the risk of drug resistance Translated title: La sitamaquine comme candidat-médicament antileishmanien : du mécanisme d’action au risque de chimiorésistance

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          Abstract

          Sitamaquine is a 8-aminoquinoline in development for the treatment of visceral leishmaniasis by oral route, no activity being observed on the experimental cutaneous leishmaniasis experimental models. Recent data explain how sitamaquine accumulate in Leishmania parasites, however its molecular targets remain to be identified. An advantage of sitamaquine is its short elimination half-life, preventing a rapid resistance emergence. The antileishmanial action of its metabolites is not known. The selection of a sitamaquine-resistant clone of L. donovani in laboratory and the phase II clinical trials pointing out some adverse effects such as methemoglobinemia and nephrotoxicity are considered for a further development decision.

          Translated abstract

          La sitamaquine est une 8-aminoquinoléine en développement pour le traitement exclusif de la leishmaniose viscérale par voie orale, aucune activité n’ayant été observée sur les modèles expérimentaux de leishmaniose cutanée. Les données récentes de la littérature expliquent comment la sitamaquine s’accumule chez les leishmanies ; cependant, les cibles moléculaires de cette molécule restent à être identifiées. Un avantage de la sitamaquine réside dans sa demi-vie d’élimination courte, limitant l’émergence rapide de chimiorésistance. De même, l’action antileishmanienne de ses métabolites n’est pas encore connue. La selection d’un clone de Leishmania donovani résistant à la sitamaquine en laboratoire et les essais cliniques de phase II mettant en évidence des effets secondaires, tels que la methémoglobinémie et la néphrotoxicité, sont pris en considération pour une décision quant au développement de cette molécule.

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          Most cited references 24

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          Oral miltefosine for Indian visceral leishmaniasis.

          There are 500,000 cases per year of visceral leishmaniasis, which occurs primarily in the Indian subcontinent. Almost all untreated patients die, and all the effective agents have been parenteral. Miltefosine is an oral agent that has been shown in small numbers of patients to have a favorable therapeutic index for Indian visceral leishmaniasis. We performed a clinical trial in India comparing miltefosine with the most effective standard treatment, amphotericin B. The study was a randomized, open-label comparison, in which 299 patients 12 years of age or older received orally administered miltefosine (50 or 100 mg [approximately 2.5 mg per kilogram of body weight] daily for 28 days) and 99 patients received intravenously administered amphotericin B (1 mg per kilogram every other day for a total of 15 injections). The groups were well matched in terms of age, weight, proportion with previous failure of treatment for leishmaniasis, parasitologic grade of splenic aspirate, and splenomegaly. At the end of treatment, splenic aspirates were obtained from 293 patients in the miltefosine group and 98 patients in the amphotericin B group. No parasites were identified, for an initial cure rate of 100 percent. By six months after the completion of treatment, 282 of the 299 patients in the miltefosine group (94 percent [95 percent confidence interval, 91 to 97]) and 96 of the 99 patients in the amphotericin B group (97 percent) had not had a relapse; these patients were classified as cured. Vomiting and diarrhea, generally lasting one to two days, occurred in 38 percent and 20 percent of the patients in the miltefosine group, respectively. Oral miltefosine is an effective and safe treatment for Indian visceral leishmaniasis. Miltefosine may be particularly advantageous because it can be administered orally. It may also be helpful in regions where parasites are resistant to current agents. Copyright 2002 Massachusetts Medical Society
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            Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis.

            There is no effective orally administered medication for any leishmania infection. We investigated miltefosine, which can be taken orally, for the treatment of Indian visceral leishmaniasis. Miltefosine is a phosphocholine analogue that affects cell-signaling pathways and membrane synthesis. The study was an open-label, multicenter, phase 2 trial in which four 30-person cohorts received 50, 100, or 150 mg of miltefosine per day for four or six weeks. The 120 patients, who ranged in age from 12 to 50 years, had anorexia, fever, and splenomegaly with at least moderate (2+) leishmania in a splenic aspirate. A parasitologic cure was defined by the absence of parasites in a splenic aspirate obtained two weeks after completion of treatment. The clinical response was assessed at six months. In all 120 patients there was an initial parasitologic cure. Six patients had clinical and parasitologic relapses; the remaining 114 patients had not relapsed by six months after treatment, for a cure rate of 95 percent (95 percent confidence interval, 89 to 98 percent). With the regimen of 100 mg of miltefosine per day (approximately 2.5 mg per kilogram of body weight per day) for four weeks, 29 of 30 patients (97 percent) were cured. Gastrointestinal side effects were frequent (occurring in 62 percent of patients) but mild to moderate in severity, and no patient discontinued therapy because of gastrointestinal side effects. In two patients, treatment was discontinued because of elevated levels of aspartate aminotransferase or creatinine; in both patients the levels rapidly returned to normal. In 12 other patients, the level of aspartate aminotransferase increased to 100 to 150 U per liter during treatment. Orally administered miltefosine appears to be an effective treatment for Indian visceral leishmaniasis.
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              Miltefosine for new world cutaneous leishmaniasis.

              The oral agent miltefosine has demonstrated a >95% cure rate in Indian visceral leishmaniasis. We performed a large, placebo-controlled study of miltefosine therapy (2.5 mg/kg per day orally for 28 days) against cutaneous leishmaniasis in Colombia and Guatemala. In regions in Colombia where Leishmania vianna panamensis is common, the per-protocol cure rates for miltefosine and placebo were 91% (40 of 44 patients) and 38% (9 of 24). These values are similar to historic values for the antimony standard of care and placebo. In regions in Guatemala where L. v. braziliensis and L. mexicana mexicana are common, the per-protocol cure rates were 53% (20 of 38) for miltefosine and 21% (4 of 19) for placebo. The miltefosine rate was lower than historic antimony cure rates of >90%. Miltefosine was well tolerated. Miltefosine is a useful oral agent against cutaneous leishmaniasis due to L. v. panamensis in Colombia but not against leishmaniasis due to L. v. braziliensis in Guatemala.
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                Author and article information

                Journal
                Parasite
                Parasite
                parasite
                Parasite : journal de la Société Française de Parasitologie
                EDP Sciences
                1252-607X
                1776-1042
                May 2011
                15 May 2011
                : 18
                : 2 ( publisher-idID: parasite/2011/02 )
                : 115-119
                Affiliations
                [1 ] Groupe Chimiothérapie Antiparasitaire, UMR 8076 CNRS, Faculté de Pharmacie, Université Paris-Sud 11 92290 Châtenay-Malabry France
                [2 ] Muséum National d’Histoire Naturelle, Département RDDM, UMR 7245 CNRS CP 52 61, rue Buffon 75231 Paris Cedex 05 France
                Author notes
                [* ]Correspondence: Philippe Loiseau. E-mail: philippe.loiseau@ 123456u-psud.fr
                Article
                parasite2011182p115 10.1051/parasite/2011182115
                10.1051/parasite/2011182115
                3671420
                21678786
                © PRINCEPS Editions, Paris, 2011

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 1, Tables: 1, Equations: 1, References: 29, Pages: 5
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