title: Improved treatment of visceral leishmaniasis (kala-azar) by using combination of ketoconazole, miltefosine with an immunomodulator-Picroliv.
abstract: Visceral leishmaniasis (VL) caused by the parasite Leishmania donovani, is a potentially fatal disease. It is characterized by prolonged fever, enlarged spleen and liver, substantial weight loss and progressive anemia. Available drugs are toxic, costly and require prolonged treatment duration viz; 28 days of oral treatment with miltefosine, 30 days infusion with Amphotericin B and 21 days intramascular with paromomycin sulfate. Drug combination for VL clinically proved to shorten the duration of treatment. The efficacy of drugs is also compromised due to suppression of immune function during the course of infection. To combat this situation leishmanicidal efficacy of already marketed standard antifungal drug, ketoconazole under the approach of 'therapeutic switching' in combination with standard antileishmanial drug, miltefosine and a potent immunomodulator agent, picroliv were evaluated in L. donovani/hamsters model. Animals treated with combination of ketoconazole (50 mg/kg, 5 days, po)+miltefosine (5 mg/kg, 5 days, po) showed augmentation in efficacy against leishmania parasite (72%) in comparison to those treated with ketoconazole (54.67%) and miltefosine (54.77%) separately. Co-administration of picroliv (10 mg/kg, 12 days, po) has further enhanced antileishmanial efficacy from 72% to 82%. Significant generation of ROS, RNS and H(2)O(2) and increased phagocytosis was observed in animals treated with ketoconazole+miltefosine; however, addition of picroliv to this combination did not alter the level of metabolites and phagocytosis due to its antioxidative and nonleishmanicidal characteristics, respectively. Significant rise in cell mediated immunity witnessed in this group reveals the role played by the immunomodulator, picroliv and justifies the significance of enhanced cell mediated immunity in the therapy. These findings suggest a new strategy for leishmanial chemotherapy at reduced cost and toxicity.
authors.affiliation: Division of Parasitology, Central Drug Research Institute, Lucknow, UP, India.
authors.forename: Nishi
authors.initials: N
authors.lastname: Shakya
authors.forename: Shraddha A
authors.initials: SA
authors.lastname: Sane
authors.forename: Preeti
authors.initials: P
authors.lastname: Vishwakarma
authors.forename: Preeti
authors.initials: P
authors.lastname: Bajpai
authors.forename: Suman
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage*; D002934:Cinnamates / Q000008:administration & dosage*; D006224:Cricetinae; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006027:Glycosides / Q000008:administration & dosage*; D006861:Hydrogen Peroxide / Q000276:immunology / Q000378:metabolism; D007155:Immunologic Factors / Q000008:administration & dosage*; D007654:Ketoconazole / Q000008:administration & dosage*; D007893:Leishmania donovani / Q000187:drug effects; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D008297:Male; D010587:Phagocytosis / Q000276:immunology; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D026361:Reactive Nitrogen Species / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D012376:Rodent Diseases / Q000188:drug therapy / Q000276:immunology / Q000469:parasitology; D016896:Treatment Outcome; D014641:Vanillic Acid / Q000008:administration & dosage*
chemical_list: D000981:Antiprotozoal Agents; D002934:Cinnamates; D006027:Glycosides; D007155:Immunologic Factors; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D010767:Phosphorylcholine; C057463:kutkin; C039128:miltefosine; D006861:Hydrogen Peroxide; D014641:Vanillic Acid; D007654:Ketoconazole