Analysis of immune response patterns in naïve and Plasmodium berghei-infected young rats following a ferroquine treatment

ArticleinInternational Journal for Parasitology 35(14):1601-10 · January 2006with4 Reads
Impact Factor: 3.87 · DOI: 10.1016/j.ijpara.2005.07.007 · Source: PubMed
Abstract

The direct antimalarial activity of ferroquine (FQ, SSR97193), a chloroquine (CQ) derivative, is well established. To determine whether the FQ anti-parasite activity affects the host immune properties, we have investigated its effect on several immunological parameters in young rats infected with Plasmodium berghei and compared it with that of CQ. In uninfected young rats, treatment with either drug did not show any impairment in the cellular distribution of spleen cells in their response to mitogens and did not induce the production of IL-10 in vivo. After infection, rats treated with CQ or FQ showed no parasitemia and survived with no recrudescence, in comparison with placebo. Nevertheless, FQ cured young rats more rapidly than its parent drug. Analysis of cellular distribution including CD4+TCR+, CD8+TCR+, NK and NKT cells in blood and spleen and the production of specific antibodies did not reveal any alteration of these parameters in infected young rats treated either with CQ or FQ. However, we observed a persistence of CD4+CD25+T-cells in infected CQ-treated rats when compared with infected FQ-treated rats, very likely related to the delay of blood parasite clearance by CQ-treatment. Another significant difference is that the CQ treatment dramatically inhibited the lymphoproliferative response of young infected rats when compared with FQ. Collectively, the absence of any observable immunotoxic effects due to FQ in naïve and infected young rats, together with previous results indicating the susceptibility to FQ of all Plasmodium falciparum field isolates and CQ-resistant strains make it a promising drug for malarial treatment.

    • "Thus, a decrease in the number of these cells would be very helpful for the expression of protective immunity. The second advantage was the potential to maintain the proliferation ability of spleen cells in reply to different mitogens [12] . Thus, on account of the absence of any noticeable immunotoxicity in rats along with in vitro efficacy against CQ-resistant strains, FQ was suggested as an effective alternative treatment for P. falciparum. "
    [Show abstract] [Hide abstract] ABSTRACT: Malaria has been teasing human populations from a long time. Presently, several classes of antimalarial drugs are available in market, but the issues of toxicity, lower efficacy and the resistance by malarial parasites have decreased their overall therapeutic indices. Thus, the search for new promising antimalarials continues, however, the battle against malaria is far from over. Ferroquine is a derivative of chloroquine with antimalarial properties. It is the most successful of the chloroquine derivatives. Not only ferroquine, but also its derivatives have shown promising potential as antimalarials of clinical interest. Presently, much research is dedicated to the development of ferroquine derivatives as safe alternatives to antimalarial chemotherapy. The present article describes the structural, chemical and biological features of ferroquine. Several classes of ferroquine derivatives including hydroxyferroquines, trioxaferroquines, chloroquine-bridged ferrocenophanes, thiosemicarbazone derivatives, ferrocene dual conjugates, 4-N-substituted derivatives, and others have been discussed. Besides, the mechanism of action of ferroquine has been discussed. A careful observation has been made into pharmacologically significant ferroquine derivatives with better or equal therapeutic effects to that of chloroquine and ferroquine. A brief discussion of the toxicities of ferroquine derivatives has been made. Finally, efforts have been made to discuss the current challenges and future perspectives of ferroquine-based antimalarial drug development. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Full-text · Article · Jul 2015 · European Journal of Medicinal Chemistry
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    • "Hence, any decrease of these cells would be very beneficial for the expression of protective immunity. Second, its ability to maintain the capacity of spleen cells to proliferate in response to different mitogens [26].Taking into account the absence of any observable immuno-toxicity in rats, together with its efficacy against CQ-resistant strains in vitro, FQ could provide an effective alternative treatment for P. falciparum in the future. Results of both in vitro tests on field isolates and in vivo experiments on rodent models indicated that a potential resistance to FQ does not depend on a gene polymorphism already involved in CQ resistance. "
    [Show abstract] [Hide abstract] ABSTRACT: Ferroquine (FQ or SR97193) is a novel antimalarial drug candidate, currently in development at Sanofi-Aventis. In contrast to conventional drugs, FQ is the first organometallic drug: a ferrocenyl group covalently flanked by a 4-aminoquinoline and a basic alkylamine. FQ is able to overcome the CQ resistance problem, an important limit to the control of Plasmodium falciparum, the principal causative agent of malaria. After fifteen years of effort, it is now possible to propose a multifactorial mechanism of action of FQ by its capacity to target lipids, to inhibit the formation of hemozoin and to generate reactive oxygen species.
    Full-text · Article · Feb 2008 · Molecules
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  • [Show abstract] [Hide abstract] ABSTRACT: Three ferroquine (FQ) derivatives, closely mimicking the antimalarial drug hydroxychloroquine (HCQ), have been prepared. Whereas these organometallic compounds provide the expected reduced cytotoxic effects compared to FQ, they inhibit in vitro growth of Plasmodium falciparum far better than chloroquine (CQ). Moreover, this new class of bioorganometallic compounds exert antiviral effects with some selectivity toward SARS-CoV infection. These new drugs may offer an interesting alternative for Asia where SARS originated and malaria has remained endemic.
    Full-text · Article · Jun 2006 · Journal of Medicinal Chemistry
    0Comments 47Citations