Treatment of Experimental Visceral Leishmaniasis with Amphotericin B in Stable Albumin Microspheres

ABSTRACT Hydrophilic albumin microspheres are proposed as a new delivery system for amphotericin B (AMB; AMB microspheres). The acute toxicity of AMB microspheres was lower than that of the AMB-deoxycholate (AMB-Doc) reference formulation in hamsters. Lethal doses in healthy and infected animals were improved at least eight times. Intravenous bolus administration of doses of AMB microspheres up to 40 mg/kg of body weight did not produce acute symptoms of toxicity. The efficacy of this new formulation was tested against Leishmania infantum-infected hamsters at doses of 2, 10, 20, and 40 mg/kg. With the 2-mg/kg dose, the activity of AMB, as assessed through the parasite load reductions in the liver and spleen and the evolution of antibody levels, was also improved (P < 0.05) by use of the AMB microsphere system. At the higher doses of 10, 20, and 40 mg/kg, reductions in parasite levels of more than 99% were achieved in the liver and spleen after the administration of AMB microspheres. A pharmacokinetic study was performed to study the serum, liver, and spleen AMB concentrations after administration of AMB microspheres and the reference formulation. Interestingly, a significant accumulation of AMB in the spleen and liver was observed after AMB microsphere administration. Our results suggest that this new formulation is a promising alternative to the conventional AMB-Doc formulation for the treatment of visceral leishmaniasis.

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The Effect of Iodium 30c on Experimental Visceral Leishmaniasis

Homeopathy ◽

10.1055/s-0040-1713361 ◽

2020 ◽

Vol 109 (04) ◽

pp. 213-223

Author(s):

Jyoti Joshi ◽

Chetna Bandral ◽

Raj Kumar Manchanda ◽

Anil Khurana ◽

Debadatta Nayak ◽

...

Keyword(s):

T Cells ◽

Visceral Leishmaniasis ◽

Amphotericin B ◽

Cd8 T Cells ◽

Therapeutic Efficacy ◽

Leishmania Donovani ◽

Neglected Tropical Diseases ◽

Parasite Load ◽

Poor People

Abstract Background Leishmaniasis is one of several neglected tropical diseases that warrant serious attention. A disease of socio-economically poor people, it demands safer and cheaper drugs that help to overcome the limitations faced by the existing anti-leishmanials. Complementary or traditional medicines might be a good option, with an added advantage that resistance may not develop against these drugs. Thus, the present investigation was performed to evaluate the anti-leishmanial efficacy of an ultra-diluted homeopathic medicine (Iodium 30c) in experimental visceral leishmaniasis (VL). Methods Compliant with strict ethical standards in animal experimentation, the study was performed in-vivo in inbred BALB/c mice which were injected intravenously with 1 × 107 promastigotes of Leishmania donovani before (therapeutic) or after (prophylactic) treatment with Iodium 30c for 30 days. In other groups of mice (n = 6 per group), amphotericin B served as positive control, infected animals as the disease control, while the naïve controls included normal animals; animals receiving only Iodium 30c or Alcohol 30c served as sham controls. The anti-leishmanial efficacy was assessed by determining the hepatic parasite load and analysing percentages of CD4+ and CD8+ T cells. Biochemical analysis and histological studies were performed to check any toxicities. Results Iodium-treated animals showed a significantly reduced parasite load (to 1503 ± 39 Leishman Donovan Units, LDU) as compared with the infected controls (4489 ± 256 LDU) (p < 0.05): thus, the mean therapeutic efficacy of Iodium 30c was 66.5%. In addition, the population of CD4+ and CD8+ T cells was significantly increased (p < 0.05) after treatment. No toxicity was observed, as evidenced from biochemical and histopathological studies of the liver and kidneys. Efficacy of Iodium 30c prophylaxis was 58.3%, while the therapeutic efficacy of amphotericin B was 85.9%. Conclusion This original study has shown that Iodium 30c had significant impact in controlling parasite replication in experimental VL, though the effect was less than that using standard pharmaceutical treatment.

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Subclinical tumor lysis-like syndrome during treatment of visceral leishmaniasis with low-dose intermittent liposomal amphotericin B

Open Medicine ◽

10.2478/s11536-011-0147-5 ◽

2012 ◽

Vol 7 (3) ◽

pp. 305-309

Author(s):

Sarah Georgiadou ◽

Dimitrios Kontoyiannis ◽

Nikolaos Sipsas

Keyword(s):

Renal Function ◽

Visceral Leishmaniasis ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Low Dose ◽

Parasite Load ◽

Liposomal Amphotericin B ◽

Tumor Lysis ◽

Electrolyte Disturbances ◽

High Parasite

AbstractWe retrospectively evaluated the rate of renal dysfunction during treatment with liposomal amphotericin B (L-AmB) (3–4 mg/kg, for 7–10 days) in nine consecutive patients with visceral leishmaniasis (VL). During the first week of treatment, 5 patients (56%) experienced transient deterioration of renal function, with a rise in serum creatinine to 1.27–2.44 times the baseline level, and a parallel elevation of uric acid levels without other metabolic or electrolyte disturbances. Serum renal function parameters were restored to normal levels after the completion of therapy, on day 21. These 5 patients had presented with prolonged fever and/or significant spleen enlargement, reflecting high parasite load. This observation suggests that treatment of VL with intermittent L-AmB causes a subclinical tumor lysis-like syndrome, especially in patients with high parasite load.

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A clioquinol-containing Pluronic® F127 polymeric micelle system is effective in the treatment of visceral leishmaniasis in a murine model

Parasite ◽

10.1051/parasite/2020027 ◽

2020 ◽

Vol 27 ◽

pp. 29 ◽

Cited By ~ 4

Author(s):

Grasiele S.V. Tavares ◽

Débora V.C. Mendonça ◽

Isabela A.G. Pereira ◽

João A. Oliveira-da-Silva ◽

Fernanda F. Ramos ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Murine Model ◽

Parasite Load ◽

Polymeric Micelle ◽

Oral Route ◽

Immunological Parameters ◽

Gm Csf ◽

Ifn Γ ◽

Antibody Levels ◽

Micelle System

A clioquinol (ICHQ)-containing Pluronic® F127 polymeric micelle system (ICHQ/Mic) was recently shown to be effective against Leishmania amazonensis infection in a murine model. In the present study, ICHQ/Mic was tested against L. infantum infection. BALB/c mice (n = 12 per group) were infected with L. infantum stationary promastigotes through subcutaneous injection and, 45 days after challenge, received saline or were treated via the subcutaneous route with empty micelles, ICHQ or ICHQ/Mic. In addition, animals were treated with miltefosine by the oral route, as a drug control. Half of the animals were euthanized 1 and 15 days after treatment, aiming to evaluate two endpoints after therapy, when parasitological and immunological parameters were investigated. Results showed that the treatment using miltefosine, ICHQ or ICHQ/Mic induced significantly higher anti-parasite IFN-γ, IL-12, GM-CSF, nitrite and IgG2a isotype antibody levels, which were associated with low IL-4 and IL-10 production. In addition, a higher frequency of IFN-γ and TNF-α-producing CD4+ and CD8+ T-cells was found in these animals. The parasite load was evaluated in distinct organs, and results showed that the treatment using miltefosine, ICHQ or ICHQ/Mic induced significant reductions in organic parasitism in the treated and infected mice. A comparison between the treatments suggested that ICHQ/Mic was the most effective in inducing a highly polarized Th1-type response, as well as reducing the parasite load in significant levels in the treated and infected animals. Data obtained 15 days after treatment suggested maintenance of the immunological and parasitological responses. In conclusion, ICHQ/Mic could be considered in future studies for the treatment of visceral leishmaniasis.

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Antigenicity, immunogenicity and protective efficacy of a conserved Leishmania hypothetical protein against visceral leishmaniasis

Parasitology ◽

10.1017/s0031182017001731 ◽

2017 ◽

Vol 145 (6) ◽

pp. 740-751 ◽

Cited By ~ 8

Author(s):

Daniel S. Dias ◽

Vívian T. Martins ◽

Patrícia A. F. Ribeiro ◽

Fernanda F. Ramos ◽

Daniela P. Lage ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Mononuclear Cells ◽

Protective Efficacy ◽

High Sensitivity ◽

Parasite Load ◽

Hypothetical Protein ◽

Enzyme Linked Immunosorbent Assay ◽

Peripheral Blood Mononuclear ◽

Macrophage Colony ◽

Antibody Levels

AbstractIn this study, a Leishmania hypothetical protein, LiHyS, was evaluated regarding its antigenicity, immunogenicity and protective efficacy against visceral leishmaniasis (VL). Regarding antigenicity, immunoblottings and an enzyme-linked immunosorbent assay using human and canine sera showed high sensitivity and specificity values for the recombinant protein (rLiHyS) in the diagnosis of VL. When evaluating the immunogenicity of LiHyS, which is possibly located in the parasite's flagellar pocket, proliferative assays using peripheral blood mononuclear cells from healthy subjects or VL patients showed a high proliferative index in both individuals, when compared to the results obtained using rA2 or unstimulated cultures. Later, rLiHyS/saponin was inoculated in BALB/c mice, which were then challenged with Leishmania infantum promastigotes. The vaccine induced an interferon-γ, interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor production, which was maintained after infection and which was associated with high nitrite and IgG2a antibody levels, as well as low IL-4 and IL-10 production. Significant reductions in the parasite load in liver, spleen, bone marrow and draining lymph nodes were found in these animals. In this context, the present study shows that the rLiHyS has the capacity to be evaluated as a diagnostic marker or vaccine candidate against VL.

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Liposomal amphotericin B is more effective in polymorphic lesions of post kala-azar dermal leishmaniasis

Indian Journal of Dermatology Venereology and Leprology ◽

10.25259/ijdvl_338_20 ◽

2021 ◽

Vol 0 ◽

pp. 1-6

Author(s):

Srija Moulik ◽

Ritika Sengupta ◽

Manab Kumar Ghosh ◽

Nilay Kanti Das ◽

Bibhuti Saha ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Amphotericin B ◽

Liposomal Amphotericin ◽

Parasite Burden ◽

Parasite Load ◽

Liposomal Amphotericin B ◽

Macular Disease ◽

Tissue Sections ◽

Kala Azar ◽

Skin Biopsies

Background: Post kala-azar dermal leishmaniasis (PKDL) is thought to be the reservoir of infection for visceral leishmaniasis in South Asia. The development of strategies for the diagnosis and treatment of PKDL are important for the implementation of the visceral leishmaniasis elimination program. Aims: Liposomal amphotericin B (L-AMB) has been an overwhelming success in the treatment of visceral leishmaniasis. However, the empirical three-week regimen of L-AMB proposed for PKDL was shown to be inadequate, especially in the macular variant. This study aimed to delineate response of the different variants of PKDL to L-AMB. Methods: Skin biopsies were collected from PKDL cases at disease presentation and upon completion of treatment with L-AMB. Parasite DNA was detected by Internal Transcribed Spacer-1 PCR (ITS-1 PCR) and quantified by amplification of parasite kDNA. CD68 + macrophages were estimated in tissue sections by immunohistochemistry. Results: Treatment with L-AMB decreased the parasite load by 97% in polymorphic cases but only by 45% in macular cases. The median parasite load (89965 vs 5445 parasites/μg of genomic DNA) as well as infiltration by CD68+ cells before treatment was much greater in the polymorphic cases. Limitations: Although monitoring of the parasite load for 12 months post-treatment would have been ideal, this was not possible owing to logistical issues as well as the invasive nature of biopsy collection procedure. Conclusion: A dramatic decrease in the parasite burden was noted in patients with polymorphic lesions. Although patients with macular disease also had a decrease in parasite burden, this was not as marked as in the polymorphic cases. There was also a significantly greater infiltration of CD68 + macrophages in polymorphic PKDL before therapy.

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Experimental Evaluation of Second-Line Oral Treatments of Visceral Leishmaniasis Caused by Leishmania infantum

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.1.172 ◽

1999 ◽

Vol 43 (1) ◽

pp. 172-174 ◽

Cited By ~ 34

Author(s):

Jean-Pierre Gangneux ◽

Michael Dullin ◽

Annie Sulahian ◽

Yves Jean-Francois Garin ◽

Francis Derouin

Keyword(s):

Visceral Leishmaniasis ◽

Murine Model ◽

Experimental Evaluation ◽

Leishmania Infantum ◽

Parasite Load ◽

Second Line ◽

Meglumine Antimoniate ◽

Marked Activity

ABSTRACT In a murine model of Leishmania infantum visceral leishmaniasis, metronidazole, ketoconazole, fluconazole, itraconazole, and terbinafine were less effective than antimonial agents in reducing hepatic parasite load. Ketoconazole potentiated the effect of meglumine antimoniate reference therapy through its marked activity against spleen infection.

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