Browsing by Author "Krishna Das Manandhar"

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Antileishmanial activity of nano-amphotericin B deoxycholate
(2008) Krishna Das Manandhar; Thakur Prasad Yadav; Vijay Kumar Prajapati; Subodh Kumar; Madhukar Rai; Anuradha Dube; Onkar Nath Srivastava; Shyam Sundar
Objectives: The aim of the present study was to compare the efficacy of a nano form of amphotericin B deoxycholate with that of conventional amphotericin B deoxycholate for the treatment of visceral leishmaniasis. Methods We have formulated nanoparticles (10-20 μM) from amphotericin B deoxycholate (1-2 nM) by applying high-pressure (150 argon) milling homogenization and have tested their efficacy in a J774A cell line and in hamsters. Parasite survival and tissue burden in spleen were evaluated for nano-amphotericin B and conventional amphotericin B. Both nano-amphotericin B and conventional amphotericin B were injected intraperitoneally at 5 mg/kg per day for 5 days. Results: The inhibition of amastigotes in the splenic tissue with nano-amphotericin B was significantly more than with conventional amphotericin B (92.18% versus 74.57%, P = 0.005). Similarly, the suppression of parasite replication in the spleen was also found to be significant (99.18% versus 97.17%, P = 0.05). In a cytotoxicity test, nano-amphotericin B against the J774A cell line had a CC50 of 12.67 mg/L in comparison with 10.61 mg/L for amphotericin B, far higher than the doses used for ED50. Conclusions: Nanoparticles of amphotericin B had significantly greater efficacy than conventional amphotericin B. This formulation may have a favourable safety profile, and if production costs are low, it may prove to be a feasible alternative to conventional amphotericin B. © The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
Nanonization increases the antileishmanial efficacy of amphotericin B: An ex vivo approach
(Springer New York LLC, 2014) Krishna Das Manandhar; Thakur Prasad Yadav; Vijay Kumar Prajapati; Om Basukala; Ram Prasad Aganja; Anuradha Dude; Onkar Nath Shrivastav; Shyam Sundar
With widespread resistance to pentavalent antimonial in the endemic eastern terai belt of Nepal and Bihar, India, Amphotericin B deoxycholate is now the first-line antileishmanial drug for the treatment of visceral leishmaniasis (VL). However, universal occurrence of infusion-related fever and rigors with amphotericin B (AmB), occasional serious life-threatening toxicities like cardiotoxicity, anaphylaxis, hypokalemia, and nephrotoxicity are major barriers to its use in areas with limited medical facilities. Liposomal amphotericins, however, are devoid of adverse effects, high cost makes it unaffordable. We had formulated nanoparticles (10–20 nm) from amphotericin B deoxycholate (1–2 µm) applying high pressure (150 atm) milling homogenization in argon atmosphere and tested its ex vivo efficacy in Leishmania infected J774A cell line and peritoneal macrophage. The ex vivo ED50 for intracellular amastigotes in peritoneal macrophage by nanoamphotericin was 0.0027 ± 0.001 lg/mL which was significantly less (p = 0.0029) than the required dose of amphotericin B (0.0426 ± 0.003 µg/mL). Similarly, in J774A cell line, 50 % of intracellular amastigotes were cleared by 0.0038 ± 0.001 µg/mL of nano-amphotericin while the dose was a bit more for AmB (0.0196 ± 0.001 µg/mL) illustrating the significant difference (p value, 0.0122). The nanoformulation has also shown high efficacy (ED50, 0.0028–0.0035 µg/mL) in inhibition of infected macrophage count. The new formulation accumulated to spleen, the targeted organ, 7 days after inoculation of drug to the infected hamster as traced in vivo by TEM convincing it as potential drug. Given a favorable safety profile and very low cost of production contemplated, it may prove to be a feasible alternative for conventional amphotericin B. © Springer India 2014.
Preface
(Springer Science and Business Media B.V., 2024) Vibhav Gautam; Rajiv Kumar; Krishna Das Manandhar; Swapnil C. Kamble
[No abstract available]
Splenic accumulation of IL-10 mRNA in T cells distinct from CD4 +CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis
(2007) Susanne Nylén; Radheshyam Maurya; Liv Eidsmo; Krishna Das Manandhar; Shyam Sundar; David Sacks
Visceral leishmaniasis (VL) is a life-threatening disease characterized by uncontrolled parasitization of the spleen, liver, and bone marrow. Interleukin (IL)-10 has been implicated in the suppression of host immunity in human VL based on the elevated levels of IL-10 observed in plasma and lesional tissue, and its role in preventing clearance of Leishmania donovani in murine models of VL. The aim of this study was to identify the cellular source of IL-10 in human VL and determine if CD4+CD25+ (Foxp3high) regulatory T (T reg) cells are associated with active disease. We analyzed surface marker and gene expression in peripheral blood mononuclear cells and splenic aspirates from Indian VL patients before and 3-4 wk after treatment with Amphotericin B. The results did not point to an important role for natural CD4+CD25+ (Foxp3high) T reg cells in human VL. They did not accumulate in and were not a major source of IL-10 in the spleen, and their removal did not rescue antigen-specific interferon γ responses. In contrast, splenic T cells depleted of CD25+ cells expressed the highest levels of IL-10 mRNA and were the predominant lymphocyte population in the VL spleen. The elevated levels of IL-10 in VL plasma significantly enhanced the growth of L. donovani amastigotes in human macrophages. The data implicate IL-10-producing CD25-Foxp3- T cells in the pathogenesis of human VL.
The matrilineal ancestry of Nepali populations
(Springer Science and Business Media Deutschland GmbH, 2023) Rajdip Basnet; Niraj Rai; Rakesh Tamang; Nagendra Prasad Awasthi; Isha Pradhan; Pawan Parajuli; Deepak Kashyap; Alla Govardhan Reddy; Gyaneshwer Chaubey; Krishna Das Manandhar; Tilak Ram Shrestha; Kumarasamy Thangaraj
The Tibetan plateau and high mountain ranges of Nepal are one of the challenging geographical regions inhabited by modern humans. While much of the ethnographic and population-based genetic studies were carried out to investigate the Tibetan and Sherpa highlanders, little is known about the demographic processes that enabled the colonization of the hilly areas of Nepal. Thus, the present study aimed to investigate the past demographic events that shaped the extant Nepalese genetic diversity using mitochondrial DNA (mtDNA) variations from ethnic Nepalese groups. We have analyzed mtDNA sequences of 999 Nepalese and compared data with 38,622 published mtDNA sequences from rest of the world. Our analysis revealed that the genomic landscapes of prehistoric Himalayan settlers of Nepal were similar to that of the low-altitude extant Nepalese (LAN), especially Newar and Magar population groups, but differ from contemporary high-altitude Sherpas. LAN might have derived their East Eurasian ancestry mainly from low-altitude Tibeto-Burmans, who likely have migrated from East Asia and assimilated across the Eastern Himalayas extended from the Eastern Nepal to the North-East of India, Bhutan, Tibet and Northern Myanmar. We also identified a clear genetic sub-structure across different ethnic groups of Nepal based on mtDNA haplogroups and ectodysplasin-A receptor (EDAR) gene polymorphism. Our comprehensive high-resolution mtDNA-based genetic study of Tibeto-Burman communities reconstructs the maternal origins of prehistoric Himalayan populations and sheds light on migration events that have brought most of the East Eurasian ancestry to the present-day Nepalese population. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.