Efficacy of histamine H1 receptor antagonists azelastine and fexofenadine against cutaneous Leishmania major infection.

Author summary Cutaneous leishmaniasis (CL) is a parasitic disease present in more than 90 countries. Different species ofLeishmaniaproduce skin ulcers upon infection through the bite of infected sand fly vectors. There are several drugs used to treat CL but most of them are toxic or difficult to administer and there is increasing drug resistance leading to treatment failure. Therefore, new drugs are needed for treating CL. The objective of this study was to determine the antileishmanial efficacy of antihistamine drugs. Using cell cultures of lymph nodes obtained fromLeishmania majorinfected mice, we evaluated the parasiticidal activity of the antihistamine drugs azelastine and fexofenadine. Both drug showed high efficacy againstL.majorand low toxicity for a human cell line. Treatment of mice infected in the skin with L. major indicated that both azelastine and fexofenadine significantly reduced the size of the lesions and suppressed parasite multiplication. Consequently, these two drugs are good candidates to further evaluate their efficacy as monotherapies or in combination with other antileishmanial drugs. Current drug therapies for cutaneous leishmaniasis are often difficult to administer and treatment failure is an increasingly common occurrence. The efficacy of antileishmanial therapy relies on a combination of anti-parasite activity of drugs and the patient's immune response. Previous studies have reportedin vitroantimicrobial activity of histamine 1-receptor antagonists (H1RAs) against different pathogens. We used anex vivoexplant culture of lymph nodes from mice infected withLeishmania majorto screen H1RAs compounds. Azelastine (AZ) and Fexofenadine (FX) showed remarkableex vivoefficacy (EC50= 0.05 and 1.50 mu M respectively) and lowin vitrocytotoxicity yielding a high therapeutic index. AZ significantly decreased the expression of H1R and the proinflammatory cytokineIL-1 & x1e9e;in theex vivosystem, which were shown to be augmented by histamine addition. The anti-leishmanial efficacy of AZ was enhanced in the presence of T cells from infected mice suggesting an immune-modulatory mechanism of parasite suppression.L.majorinfected BALB/c mice treated per os with FX or intralesionally with AZ showed a significant reduction of lesion size (FX = 69%; AZ = 52%). Furthermore, there was significant parasite suppression in the lesion (FX = 82%; AZ = 87%) and lymph nodes (FX = 81%; AZ = 36%) with no observable side effects. AZ and FX and potentially other H1RAs are good candidates for assessing efficacy in larger studies as monotherapies or in combination with current anti-leishmanial drugs to treat cutaneous leishmaniasis.