piperine and Leishmaniasis--Visceral

Amphotericin B (AmB) exhibits potential antileishmanial activity, with only a little rate of recurrence. However, low bioavailability and severe nephrotoxicity are among the major shortcomings of AmB-based therapy. Various AmB nanoformulations have been developed, which to an extent, have reduced its toxicity and increased the drug efficacy. To further reduce the nonspecific tissue distribution and the cost of the treatment, the current AmB-based formulations require additional improvements. Combination of natural bioenhancers with AmB is expected to further increase its bioavailability. Therefore, we developed a nanoformulation of AmB and piperine (Pip), a plant alkaloid, known to enhance the bioavailability of various drugs, by entrapping them in guar gum, a macrophage targeting polymer. Owing to the ease of oral delivery, these nanoparticles (NPs) were coated with eudragit to make them suitable for oral administration. The formulated eudragit-coated AmB and Pip-loaded NPs (Eu-HDGG-AmB-Pip-NPs) exhibited controlled release of the loaded therapeutic agents and protected the drug from acidic pH. These NPs exhibited effective suppression of growth of both promastigotes and amastigotes of Leishmania donovani parasite under in vitro. In vivo evaluation of these NPs for therapeutic efficacy in golden hamster-L. donovani model demonstrated enhanced drug bioavailability, non-nephrotoxic nature, and potential antileishmanial activity with up to 96% inhibition of the parasite. Graphical abstract.

Topics: Alkaloids; Amphotericin B; Animals; Benzodioxoles; Cricetinae; Drug Carriers; Galactans; Leishmaniasis, Visceral; Mannans; Nanoparticles; Piperidines; Plant Gums; Polyunsaturated Alkamides

Topics: Alkaloids; Antiprotozoal Agents; Benzodioxoles; Capsaicin; Chromatography, High Pressure Liquid; Drug Synergism; Inhibitory Concentration 50; Leishmania infantum; Leishmaniasis, Visceral; Magnetic Resonance Spectroscopy; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Piperidines; Polyunsaturated Alkamides; Spectrophotometry, Ultraviolet

Present studies are aimed to find out the utility of oil-in-water emulsions also known as lipid nanospheres (LN) or fat emulsions for delivering piperine for the treatment of visceral leishmaniasis. Lipid nanosphere formulations of piperine were prepared using soybean oil, egg lecithin, cholesterol, stearylamine and phosphatidylethanolamine distearylmethoxypolyethyleneglycol (DSPE-PEG) by homogenization followed by ultrasonication of oil and aqueous phases. Antileishmanial activity of all the formulations was assessed in BALB/c mice infected with Leishmania donovani AG83 for 60 days. A single dose (5 mg/kg) of piperine, or lipid nanospheres of piperine (LN-P), or lipid nanosphere of piperine with stearylamine (LN-P-SA) or pegylated lipid nanospheres of piperine (LN-P-PEG) was injected intravenously. Mice were sacrificed after 15 days of treatment with piperine or formulations and Leishman Donovan Unit (LDU) is counted. Toxicity of formulations and pure piperine was assessed in normal mice. The size distribution of formulations ranged from 200 to 885 nm. Piperine reduced the parasite burden in liver and spleen by 38% and 31% after 15 days post infection respectively. LN-P reduced the parasite burden in liver and spleen by 63% and 52% after 15 days post infection, respectively. LN-P-PEG reduced the parasite burden in liver and spleen by 78% and 75% after 15 days post infection, respectively. LN-P-SA reduced the parasite burden in liver and spleen by 90% and 85% after 15 days post infection, respectively. LN-P, LN-P-PEG, LN-P-SA treated mice did not show any significant changes in the serum levels of SGOT, ALP, creatinine and urea compared to normal mice. Stable and sterile formulations of lipid nanospheres of piperine were developed. A single dose of 5 mg/kg of lipid nanospheres of piperine could significantly reduce the liver and splenic parasite burden.

Topics: Algorithms; Alkaloids; Animals; Antiprotozoal Agents; Benzodioxoles; Chemical Phenomena; Chemistry, Pharmaceutical; Chemistry, Physical; Emulsions; Leishmania donovani; Leishmaniasis, Visceral; Liposomes; Liver; Mice; Mice, Inbred BALB C; Microspheres; Oils; Particle Size; Piperidines; Polyunsaturated Alkamides; Solutions; Spleen; Sterilization; Water

The leishmanicidal property of piperine intercalated in liposomes and in mannose-coated liposomes was tested in experimental visceral leishmaniasis in hamsters. Mannose-coated liposomal piperine eliminated intracellular amastigotes of Leishmania donovani in splenic macrophages much more efficiently than did the liposomal piperine or free piperine. At a dose equivalent to 6 mg/kg body wt every 4th day for a total of 4 doses in 12 days, the mannose-coated liposomal piperine was found to reduce spleen parasite load to the extent of 90% in comparison to that achieved by liposomal piperine (77%) or free piperine (29%). Histological examination of spleen and liver function tests showed that the toxicity of piperine was reduced when mannosylated liposomal piperine was administered.

Topics: Alkaloids; Animals; Antiprotozoal Agents; Benzodioxoles; Cricetinae; Drug Carriers; Leishmaniasis, Visceral; Liposomes; Liver Function Tests; Macrophages; Mannose; Mesocricetus; Piperidines; Polyunsaturated Alkamides; Spleen