Abstract
Current drug therapies for cutaneous leishmaniasis are often difficult to administer and treatment failure is an increasingly common occurrence. The efficacy of anti-leishmanial therapy relies on a combination of anti-parasite activity of drugs and the patient’s immune response. Previous studies have reported in vitro antimicrobial activity of histamine 1-receptor antagonists (H1RAs) against different pathogens. We used an ex vivo explant culture of lymph nodes from mice infected with Leishmania major to screen H1RAs compounds. Azelastine (AZ) and Fexofenadine (FX) showed remarkable ex vivo efficacy (EC50 = 0.05 and 1.50 μM respectively) and low in vitro cytotoxicity yielding a high therapeutic index. AZ significantly decreased the expression of H1R and the proinflammatory cytokine IL-1ẞ in the ex vivo system, 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. major infected 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.
Highlights
The leishmaniases are a group of diseases reported in >95 countries across five continents [1]
There are several drugs used to treat Cutaneous leishmaniasis (CL) but most of them are toxic or difficult to administer and there is increasing drug resistance leading to treatment failure
The objective of this study was to determine the anti-leishmanial efficacy of antihistamine drugs
Summary
The leishmaniases are a group of diseases reported in >95 countries across five continents [1]. Cutaneous leishmaniasis is endemic in many countries of the Old and New World affecting between 600,000 and 1 million people worldwide (https://www.who.int/leishmaniasis/en/). Current systemic treatments (sodium stibogluconate, pentamidine, miltefosine, amphotericin B) are difficult to administer, have high toxicity and the frequent appearance of drug-resistant parasites have resulted in increasing numbers of unresponsive individuals [3,4,5,6,7,8,9]. The identification of new, less toxic anti-leishmanial drugs that have a direct effect on Leishmania or promote efficient parasite killing through immunological enhancement is an urgent need
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