Potentiation of antimalarial drug action by chlorpheniramine against multidrug-resistant Plasmodium falciparum in vitro

ArticleinParasitology International 55(3):195-9 · October 2006with27 Reads
DOI: 10.1016/j.parint.2005.11.058 · Source: PubMed
Abstract
Chlorpheniramine, a histamine H1 receptor antagonist, was assayed for in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum K1 strain and chloroquine-resistant P. falciparum T9/94 clone, by measuring the 3H-hypoxanthine incorporation. Chlorphenirame inhibited P. falciparum K1 and T9/94 growth with IC50 values of 136.0+/-40.2 microM and 102.0+/-22.6 microM respectively. A combination of antimalarial drug and chlorpheniramine was tested against resistant P. falciparum in vitro. Isobologram analysis showed that chlorpheniramine exerts marked synergistic action on chloroquine against P. falciparum K1 and T9/94. Chlorpheniramine also potentiated antimalarial action of mefloquine, quinine or pyronaridine against both of the resistant strains of P. falciparum. However, chlorpheniramine antagonism with artesunate was obtained in both P. falciparum K1 and T9/94. The results in this study indicate that antihistaminic drugs may be promising candidates for potentiating antimalarial drug action against drug resistant malarial parasites.
    • "The synthesis and release of histamine, which is also a neurotransmitter, is negatively controlled by the H3R receptor [71]. We recently found that this receptor has a protective effect against CM since H3R −/− mice were less resistant to CM as compared to wild-type mice [71]. which, once activated by parasite antigens, release histamine and other inflammatory mediators (Fig. 2). "
    [Show abstract] [Hide abstract] ABSTRACT: Plasmodium falciparum, the aetiological agent of human lethal malaria, is responsible for over 2 million deaths per year and malaria episodes may vary considerably in their severity and clinical manifestations. Dysregulated balance of the inflammatory response and a defect in the anti-Plasmodium parasite immune response represent the hallmarks of malaria disease. Among the many possible mechanisms, it is now widely recognized that the production of pro-inflammatory mediators and cytokines and upregulation of endothelial cell adhesion molecules play important roles in malaria pathogenesis. We and others provided evidence that some components of allergic inflammatory response to malaria parasites or elicited by by-products of parasite infection may contribute to malaria pathogenesis. This review provides some clue regarding these mechanisms where mast cells and histamine, an inflammatory mediator generated following IgE-independent or IgE-mediated immune response, were found to play a major role in parasite transmission and malaria pathogenesis, respectively. This article is part of a Special Issue entitled: Mast cells in inflammation.
    Article · Feb 2011
    • "Recently, it was shown that anti-histamine treatment of PbAinfected susceptible mice prolonged survival [31]. Moreover, anti-histamines potentiate the anti-Plasmodium effect of quinolinecontaining antimalarials against multidrug resistant malaria in vitro [63] . With low manufacturing and production costs, as well as considerable ease of distribution, storage and delivery, anti-histamines represent attractive candidates as immunomodulatory agents in a combinatorial CM treatment strategy. "
    [Show abstract] [Hide abstract] ABSTRACT: Severe forms of malaria infection claim over 1 million lives annually. One aspect of severe malaria pathogenesis is an excessive or dysregulated inflammatory response to infection. With the characterization of Toll-like receptors (TLRs), which initiate inflammation upon detection of microbial products, involvement of TLRs in the host response to malaria has undergone intense investigation. While TLRs appear to mediate inflammation in malaria infection and may contribute to development of severe malaria, it is unlikely that they operate in isolation from other components of innate immunity. Here, we highlight recent findings implicating other innate immune mechanisms in the host inflammatory response to malaria, propose how they may integrate and synergize with TLR pathways, and discuss opportunities and challenges associated with anti-inflammatory adjunctive therapy for the treatment of severe malaria.
    Full-text · Article · Sep 2008
    • "Nevertheless, our results with antihistamines and genetic knockouts strongly suggest that antihistamine could have a therapeutic value in the treatment of malaria infection, particularly by reducing the likelihood of adverse complications. This is supported by the fact that antihistaminic drugs such as chlorpheniramine potentiate the anti-Plasmodium effect of mefloquine, quinine, or pyronaridine (55). It should be pointed out that the antihistamine drugs do not very likely exert their effect directly on the parasite. "
    [Show abstract] [Hide abstract] ABSTRACT: From the inoculation of Plasmodium sporozoites via Anopheles mosquito bites to the development of blood-stage parasites, a hallmark of the host response is an inflammatory reaction characterized by elevated histamine levels in the serum and tissues. Given the proinflammatory and immunosuppressive activities associated with histamine, we postulated that this vasoactive amine participates in malaria pathogenesis. Combined genetic and pharmacologic approaches demonstrated that histamine binding to H1R and H2R but not H3R and H4R increases the susceptibility of mice to infection with Plasmodium. To further understand the role of histamine in malaria pathogenesis, we used histidine decarboxylase-deficient (HDC(-/-)) mice, which are free of histamine. HDC(-/-) mice were highly resistant to severe malaria whether infected by mosquito bites or via injection of infected erythrocytes. HDC(-/-) mice displayed resistance to two lethal strains: Plasmodium berghei (Pb) ANKA, which triggers cerebral malaria (CM), and Pb NK65, which causes death without neurological symptoms. The resistance of HDC(-/-) mice to CM was associated with preserved blood-brain barrier integrity, the absence of infected erythrocyte aggregation in the brain vessels, and a lack of sequestration of CD4 and CD8 T cells. We demonstrate that histamine-mediated signaling contributes to malaria pathogenesis. Understanding the basis for these biological effects of histamine during infection may lead to novel therapeutic strategies to alleviate the severity of malaria.
    Full-text · Article · Mar 2008
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