kutkin and Disease-Models--Animal

Combination therapy for the treatment of visceral leishmaniasis has increasingly been advocated as a way to increase treatment efficacy and tolerance, to reduce treatment duration and cost, and to limit the emergence of drug resistance. In the present work, we have adopted a rational approach, which can modulate the immune response to overcome the negative control systems and to boost the positive killing responses. This study was designed to investigate the immunomodulatory effect of picroliv (standardized fraction from the alcoholic extract of root and rhizome of Picrorhiza kurroa) on a combination of paromomycin and miltefosine using Leishmania donovani/hamster model. Picroliv has significantly enhanced antileishmanial efficacy and lymphocyte proliferation when given in combination with paromomycin and miltefosine. Increased toxic oxygen metabolite generation and phagocytosis were also witnessed. Present study thus establishes the possible use of picroliv as adjunct to antileishmanial chemotherapy.

Topics: Animals; Antiprotozoal Agents; Cell Proliferation; Cinnamates; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glycosides; Leishmania donovani; Leishmaniasis, Visceral; Lymphocytes; Male; Mesocricetus; Paromomycin; Phagocytosis; Phosphorylcholine; Random Allocation; Reactive Nitrogen Species; Reactive Oxygen Species; Vanillic Acid

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.

Topics: Animals; Antiprotozoal Agents; Cinnamates; Cricetinae; Disease Models, Animal; Drug Therapy, Combination; Female; Glycosides; Hydrogen Peroxide; Immunologic Factors; Ketoconazole; Leishmania donovani; Leishmaniasis, Visceral; Male; Phagocytosis; Phosphorylcholine; Reactive Nitrogen Species; Reactive Oxygen Species; Rodent Diseases; Treatment Outcome; Vanillic Acid

The protective effect of picroliv (PIC) obtained from Picrorhiza kurroa (family: Scrophulariaceae) against hydrazine (Hz)-induced hyperlipidemia was evaluated in rats. Hz administration (50 mg/kg, i.p.) caused an increase in triglyceride (TG), cholesterol (CHO), free fatty acids (FFA), and total lipids (TL) in both the plasma and liver tissue of rats accompanied by a fall in phospholipids (PL) in the liver tissue 24 h after its administration, indicating its hyperlipidemic property. The above abnormality was prevented by simultaneous treatment of PIC (50 mg/kg, p.o.) with Hz. Hz treatment also caused an increase in the mobility of TG and TL from adipose tissue, and these results indicate that Hz administration could cause hepatic steatosis by nonhepatocellular factors (such as mobilization of depot fats). This effect was also prevented by simultaneous treatment of PIC with Hz. PIC-alone treatment, however, did not produce any change in the status of all the lipid parameters evaluated in plasma, liver, and adipose tissues. These results indicate that increased mobilization of depot fats from adipose tissue may contribute to the development of hepatic steatosis in addition to decreased lipoprotein secretion, increased hepatic TG biosynthesis, and increased hepatic uptake of FFA. These have been reported as the mechanism responsible for the development of Hz-induced hepatic steatosis. PIC prevents Hz-induced hyperlipidemia, hepatic steatosis, and mobilization of lipids from depot fats, but the mechanism behind the protective effect of PIC remains to be elucidated.

Topics: Adipose Tissue; Animals; Cholesterol; Cinnamates; Disease Models, Animal; Fatty Acids, Nonesterified; Fatty Liver; Glycosides; Hydrazines; Hyperlipidemias; Hypolipidemic Agents; Lipid Metabolism; Liver; Male; Phospholipids; Rats; Rats, Wistar; Triglycerides; Vanillic Acid