Efficacy of histamine H1 receptor antagonists azelastine and fexofenadine against cutaneous Leishmania major infection
| Autor: | E. Yaneth Osorio, Alex G. Peniche, Bruno L. Travi, Peter C. Melby |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine RC955-962 Pharmacology Biochemistry Tissue Culture Techniques Mice White Blood Cells chemistry.chemical_compound Medical Conditions 0302 clinical medicine Animal Cells Arctic medicine. Tropical medicine Medicine and Health Sciences Medicine Leishmania major Protozoans Leishmania Mice Inbred BALB C Fexofenadine Molecular Structure biology Pharmaceutics Organic Compounds Eukaryota Neurochemistry Animal Models Neurotransmitters Histamine H1 Antagonists Chemistry Infectious Diseases Experimental Organism Systems Physical Sciences Terfenadine Anatomy Cellular Types Public aspects of medicine RA1-1270 Histamine Research Article medicine.drug Histamine H1 Antagonists Non-Sedating Biogenic Amines Immune Cells Immunology 030231 tropical medicine Leishmaniasis Cutaneous Mouse Models Research and Analysis Methods Lymphatic System 03 medical and health sciences Model Organisms Therapeutic index Drug Therapy Cutaneous leishmaniasis Parasitic Diseases Animals Blood Cells business.industry Macrophages Organic Chemistry Organisms Chemical Compounds Public Health Environmental and Occupational Health Biology and Life Sciences Cell Biology medicine.disease biology.organism_classification Azelastine Parasitic Protozoans 030104 developmental biology chemistry Animal Studies Phthalazines Lymph Nodes business Receptor Antagonist Therapy Ex vivo Neuroscience |
| Zdroj: | PLoS Neglected Tropical Diseases, Vol 14, Iss 8, p e0008482 (2020) PLoS Neglected Tropical Diseases |
| ISSN: | 1935-2735 |
| DOI: | 10.1371/journal.pntd.0008482 |
| Popis: | 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. Author summary Cutaneous leishmaniasis (CL) is a parasitic disease present in more than 90 countries. Different species of Leishmania produce 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 anti-leishmanial efficacy of antihistamine drugs. Using cell cultures of lymph nodes obtained from Leishmania major infected mice, we evaluated the parasiticidal activity of the antihistamine drugs azelastine and fexofenadine. Both drugs showed high efficacy against L. major and 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 anti-leishmanial drugs. |
| Databáze: | OpenAIRE |
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