scholarly journals Safety Evaluation of Nano-Liposomal Formulation of Amphotericin B (SinaAmpholeish) in Animal Model as a Candidate for Treatment of Cutaneous Leishmaniasis

2018 ◽  
Author(s):  
Seyed Ebrahim Eskandari ◽  
Alireza Firooz ◽  
Mansour Nassiri-Kashani ◽  
Mahmoud Reza Jaafari ◽  
Amir Javadi ◽  
...  
Keyword(s):  
Animal Model ◽  
Cutaneous Leishmaniasis ◽  
Amphotericin B ◽  
Leishmania Major ◽  
Skin Diseases ◽  
Average Score ◽  
Topical Formulation ◽  
Liposomal Form

Background: Development of a topical treatment for cutaneous leishmaniasis (CL) is an important step in the im­provement of lesion management. Amphotericin B (AmB) is effective against Leishmania species but it is toxic, a Nano-liposomal form of AmB with a size of about 100nm (Lip-AmB) was developed and showed to be effective against Leishmania major, and Leishmania tropica in vitro and against L. major in vivo in animal model. This study was designed to check the irritancy Draize test in rabbits and was completed in the Center for Research and Training in Skin Diseases and Leprosy, TUMS, in 2012. Methods: Twenty rabbits in 3 steps were housed individually with artificial lighting (12/12h light/dark). SinaAm­pholeish cream or empty liposomes (prepared under GMP condition at Minoo Company, Tehran, Iran), was applied on a gauze patch and the patches were placed on the designated sites of the skin in the back of the rabbits. At 48 and 72h later, the erythema and oedema were checked, scored and recorded. Results: The erythema score in rabbits was 0.83+0.41 for the SinaAmpholeish and 0.5+0.55 for empty liposomes (P= 0.16). The average score for oedema was 0.67+0.52 for SinaAmpholeish and 0.33+0.52 for empty liposomes (P= 0.16). Conclusion: Based on skin irritancy reactions the topical formulation of SinaAmpholeish is safe and could be further checked in human trials.

scholarly journals Gallic and Ellagic Acids Are Promising Adjuvants to Conventional Amphotericin B for the Treatment of Cutaneous Leishmaniasis

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Michel Muálem de Moraes Alves ◽  
Daniel Dias Rufino Arcanjo ◽  
Kayo Alves Figueiredo ◽  
Jéssica Sara de Sousa Macêdo Oliveira ◽  
Felipe José Costa Viana ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Amphotericin B ◽  
Leishmania Major ◽  
Negative Control ◽  
Control Group ◽  
Histopathological Analysis ◽  
Activated Macrophages ◽  
Content Type

ABSTRACT In this study, we demonstrated the potential associative effect of combining conventional amphotericin B (Amph B) with gallic acid (GA) and with ellagic acid (EA) in topical formulations for the treatment of cutaneous leishmaniasis in BALB/c mice. Preliminary stability tests of the formulations and in vitro drug release studies with Amph B, GA, Amph B plus GA, EA, and Amph B plus EA were carried out, as well as assessment of the in vivo treatment of BALB/c mice infected with Leishmania major. After 40 days of infection, the animals were divided into 6 groups and treated twice a day for 21 days with a gel containing Amph B, GA, Amph B plus GA, EA, or Amph B plus EA, and the negative-control group was treated with the vehicle. In the animals that received treatment, there was reduction of the lesion size and reduction of the parasitic load. Histopathological analysis of the treatments with GA, EA, and combinations with Amph B showed circumscribed lesions with the presence of fibroblasts, granulation tissue, and collagen deposition, as well as the presence of activated macrophages. The formulations containing GA and EA activated macrophages in all evaluated parameters, resulting in the activation of cells of the innate immune response, which can generate healing and protection. GA and EA produced an associative effect with Amph B, which makes them promising for use with conventional Amph B in the treatment of cutaneous leishmaniasis.

scholarly journals Zinc(II)-Dipicolylamine Coordination Complexes as Targeting and Chemotherapeutic Agents for Leishmania major

2016 ◽  
Vol 60 (5) ◽  
pp. 2932-2940 ◽  
Author(s):  
Douglas R. Rice ◽  
Paola Vacchina ◽  
Brianna Norris-Mullins ◽  
Miguel A. Morales ◽  
Bradley D. Smith
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Mammalian Cells ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Coordination Complexes ◽  
Chemotherapeutic Agents ◽  
Selective Toxicity ◽  
Content Type

ABSTRACTCutaneous leishmaniasis is a neglected tropical disease that causes painful lesions and severe disfigurement. Modern treatment relies on a few chemotherapeutics with serious limitations, and there is a need for more effective alternatives. This study describes the selective targeting of zinc(II)-dipicolylamine (ZnDPA) coordination complexes towardLeishmania major, one of the species responsible for cutaneous leishmaniasis. Fluorescence microscopy ofL. majorpromastigotes treated with a fluorescently labeled ZnDPA probe indicated rapid accumulation of the probe within the axenic promastigote cytosol. The antileishmanial activities of eight ZnDPA complexes were measured using anin vitroassay. All tested complexes exhibited selective toxicity againstL. majoraxenic promastigotes, with 50% effective concentration values in the range of 12.7 to 0.3 μM. Similar toxicity was observed against intracellular amastigotes, but there was almost no effect on the viability of mammalian cells, including mouse peritoneal macrophages.In vivotreatment efficacy studies used fluorescence imaging to noninvasively monitor changes in the red fluorescence produced by an infection of mCherry-L. majorin a mouse model. A ZnDPA treatment regimen reduced the parasite burden nearly as well as the reference care agent, potassium antimony(III) tartrate, and with less necrosis in the local host tissue. The results demonstrate that ZnDPA coordination complexes are a promising new class of antileishmanial agents with potential for clinical translation.

scholarly journals Efficacious Treatment of Experimental Leishmaniasis with Amphotericin B-Arabinogalactan Water-Soluble Derivatives

1999 ◽  
Vol 43 (9) ◽  
pp. 2209-2214 ◽  
Author(s):  
Jacob Golenser ◽  
Shoshana Frankenburg ◽  
Tirtsa Ehrenfreund ◽  
Abraham J. Domb
Keyword(s):  
Amphotericin B ◽  
Leishmania Major ◽  
Water Soluble ◽  
In Vivo Experiments ◽  
Drug Concentrations ◽  
Efficacious Treatment ◽  
Lipid Formulations ◽  
Established Infection

ABSTRACT In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalactan (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED50s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 μg/ml, respectively, forLeishmania major promastigotes and 0.17 and 0.31 μg/ml, respectively, for amastigotes. The effect on Leishmania infantum-infected macrophages was more marked, with ED50s of 0.035 μg/ml for rAmB-AG and 0.027 μg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with L. major were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of body weight) and Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than Fungizone. Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (compared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections.

scholarly journals Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies

2015 ◽  
Vol 59 (9) ◽  
pp. 5804-5813 ◽  
Author(s):  
Andrés Montoya ◽  
Alejandro Daza ◽  
Diana Muñoz ◽  
Karina Ríos ◽  
Viviana Taylor ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Cutaneous Leishmaniasis ◽  
Hypericum Perforatum ◽  
Topical Formulation ◽  
Hamster Model ◽  
Content Type ◽  
Intracellular Amastigotes ◽  
Infected Cells

ABSTRACTAn evaluation of the leishmanicidal activityin vitroandin vivoof hypericin, an expanded-spectrum photosensitizer found inHypericum perforatum, is presented. Hypericin was evaluated against intracellular amastigotesin vitroofLeishmania(Viannia)panamensis. A topical formulation containing 0.5% hypericin was developed and assayedin vivoin a hamster model of cutaneous leishmaniasis. Results demonstrate that hypericin induces a significant antiamastigote effectin vitroagainstL. panamensisby decreasing the number of parasites inside infected cells. The topical formulation of 0.5% hypericin allows healing ofL. panamensis-induced lesions upon a topical application of 40 mg/day plus visible-light irradiation (5 J/cm2, 15 min), twice a week for 3 weeks.

scholarly journals Biodistribution and In Vivo Antileishmanial Activity of 1,2-Distigmasterylhemisuccinoyl-sn-Glycero-3-Phosphocholine Liposome-Intercalated Amphotericin B

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Maryam Iman ◽  
Zhaohua Huang ◽  
Seyedeh Hoda Alavizadeh ◽  
Francis C. Szoka ◽  
Mahmoud R. Jaafari
Keyword(s):  
Amphotericin B ◽  
Leishmania Major ◽  
Parasite Load ◽  
Tissue Concentrations ◽  
Content Type ◽  
Colloidal Properties ◽  
Covalently Linked ◽  
Antileishmanial Activities

ABSTRACT 1,2-Distigmasterylhemisuccinoyl-sn-glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Our previous study revealed that liposome (Lip)-intercalated amphotericin B (AMB) prepared from DSHemsPC (DSHemsPC-AMB-Lip) possesses excellent colloidal properties and in vitro antifungal and antileishmanial activities similar to those of the liposomal AMB preparation AmBisome. The aim of this study was to determine the biodistribution and evaluate the antileishmanial effects of DSHemsPC-AMB-Lip in Leishmania major-infected BALB/c mice. The serum profile and tissue concentrations of AMB were similar in DSHemsPC-AMB-Lip- and AmBisome-treated mice after intravenous (i.v.) injection. Multiple i.v. doses of the micellar formulation of AMB (Fungizone; 1 mg/kg of body weight), DSHemsPC-AMB-Lip (5 mg/kg), and AmBisome (5 mg/kg) were used in L. major-infected BALB/c mouse models of early and established lesions. In a model of the early lesions of cutaneous leishmaniasis (CL), the results indicated that the level of footpad inflammation was significantly (P < 0.001) lower in mice treated with DSHemsPC-AMB-Lip and AmBisome than mice treated with empty liposomes or 5% dextrose. The splenic and footpad parasite load was also significantly (P < 0.001) lower in these groups of mice than in control mice that received 5% DW or free liposome. The in vivo activity of DSHemsPC-AMB-Lip was comparable to that of AmBisome, and both provided improved results compared to those achieved with Fungizone at the designated doses. The results suggest that systemic DSHemsPC-AMB-Lip administration may be useful for the treatment of leishmaniasis, and because it costs less to produce DSHemsPC-AMB-Lip than AmBisome, DSHemsPC-AMB-Lip merits further investigation.

scholarly journals Combination of topical liposomal amphotericin B and Glucantime in comparison with glucantime alone for the treatment of anthroponotic cutaneous leishmaniasis (ACL) caused by Leishmania tropica: study protocol for a randomized, controlled trial

2021 ◽  
Author(s):  
Seyed Ebrahim Eskandari ◽  
Ali Khamesipour ◽  
Mahmoud Reza Jaafari ◽  
Amir Javadi ◽  
Akram Miramin Mohammadi ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Controlled Trial ◽  
Liposomal Amphotericin B ◽  
Topical Formulation ◽  
Liposomal Form ◽  
Double Blind ◽  
Well Design ◽  
Intralesional Injections

Background and Objectives: Cutaneous leishmaniasis (CL) treatment is a challenging issue, although numerous modalities have been introduced as candidate treatment for CL yet only antimonial agents are commonly used to treat CL, a different form of amphotericin B is used to treat visceral form of leishmaniasis but the efficacy against CL is not high. There are a few reliable clinical trials on CL, the main reason is the nature of the disease which required a well design protocol to evaluate the efficacy of any candidate treatment against CL. In this study, a protocol was developed and used to evaluate a topical formulation of a nano-liposomal form of amphotericin B in addition to glucantime  to treat CL caused by L. tropica. Materials and Methods: This study is a phase 3, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of topical nano-liposomal amphotericin B (SinaAmpholeish 0.4%) in combination with intralesional injections of meglumine antimoniate in the treatment of ACL caused by L. tropica. Overall, 130 patients, aged 12-60 years, with a diag- nosis of ACL caused by L. tropica are recruited and treated according to the protocol. Results: A total of 130 patients with CL lesion will be recruited and double- blind randomly treated with received intralesional injections of Glucantime weekly or Glucantime plus SinaAmpholeish for 4 weeks. Conclusion: The results of this study showed that the protocol works well and the treatment was tolerated by both groups of patients.

scholarly journals Microtubule inhibitors: structure-activity analyses suggest rational models to identify potentially active compounds.

1996 ◽  
Vol 40 (4) ◽  
pp. 947-952 ◽  
Author(s):  
H L Callahan ◽  
C Kelley ◽  
T Pereira ◽  
M Grogl
Keyword(s):  
Leishmania Major ◽  
Leishmania Species ◽  
Significant Activity ◽  
Topical Formulation ◽  
Microtubule Inhibitor ◽  
Microtubule Inhibitors ◽  
Structure Activity ◽  
Putative Mechanism

Trifluralin, a dinitroaniline microtubule inhibitor currently in use as an herbicide, has been shown to inhibit the proliferation of Plasmodium falciparum, Trypanosoma brucei, and several species of Leishmania, in vitro. As a topical formulation, trifluralin is also effective in vivo (in BALB/c mice) against Leishmania major and Leishmania mexicana. Although trifluralin and other dinitroaniline herbicides show significant activity as antiparasitic compounds, disputed indications of potential carcinogenicity will probably limit advanced development of these substances. However, researchers have suggested that the activity of trifluralin is due to an impurity or contaminant, not to trifluralin itself. We have pursued this lead and identified the structure of the active impurity. This compound, chloralin, is 100 times more active than trifluralin. On the basis of its structure, we developed a rational structure-activity model for chloralin. Using this model, we have successfully predicted and tested active analogs in a Leishmania promastigote assay; thus, we have identified the putative mechanism of action of this class of drugs in Leishmania species. Potentially, this will allow the design of noncarcinogenic, active drugs.

scholarly journals Appraisal of a Leishmania major Strain Stably Expressing mCherry Fluorescent Protein for Both In Vitro and In Vivo Studies of Potential Drugs and Vaccine against Cutaneous Leishmaniasis

2012 ◽  
Vol 6 (11) ◽  
pp. e1927 ◽  
Author(s):  
Estefania Calvo-Álvarez ◽  
Nestor Adrian Guerrero ◽  
Raquel Álvarez-Velilla ◽  
Christopher Fernández Prada ◽  
Jose María Requena ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Fluorescent Protein ◽  
In Vivo Studies ◽  
Major Strain

scholarly journals Efficacy of Paromomycin-Chloroquine Combination Therapy in Experimental Cutaneous Leishmaniasis

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Gert-Jan Wijnant ◽  
Katrien Van Bocxlaer ◽  
Vanessa Yardley ◽  
Sudaxshina Murdan ◽  
Simon L. Croft
Keyword(s):  
Combination Therapy ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Q Fever ◽  
Parasite Load ◽  
Potential Candidate ◽  
Preclinical Development ◽  
Content Type

ABSTRACT The 4-aminoquinoline chloroquine (CQ) is clinically used in combination with doxycycline to cure chronic Q fever, as it enhances the activity of the antibiotic against the causative bacterium Coxiella burnetii residing within macrophage phagolysosomes. As there is a similar cellular host-pathogen biology for Leishmania parasites, this study aimed to determine whether such an approach could also be the basis for a new, improved treatment for cutaneous leishmaniasis (CL). We have evaluated the in vitro and in vivo activities of combinations of CQ with the standard drugs paromomycin (PM), miltefosine, and amphotericin B against Leishmania major and Leishmania mexicana. In 72-h intracellular antileishmanial assays, outcomes were variable for different drugs. Significantly, the addition of 10 μM CQ to PM reduced 50% effective concentrations (EC50s) by over 5-fold against L. major and against normally insensitive L. mexicana parasites. In murine models of L. major and L. mexicana CL, daily coadministration of 50 mg/kg of body weight PM and 25 mg/kg CQ for 10 days resulted in a significant reduction in lesion size but not in parasite load compared to those for mice given the same doses of PM alone. Overall, our data indicate that PM-CQ combination therapy is unlikely to be a potential candidate for further preclinical development.

scholarly journals Evaluation of Skin Permeation and Retention of Topical Dapsone in Murine Cutaneous Leishmaniasis Lesions

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 607
Author(s):  
Moreno ◽  
Calvo ◽  
Schwartz ◽  
Navarro-Blasco ◽  
González-Peñas ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Ex Vivo ◽  
Skin Permeation ◽  
Topical Therapy ◽  
Parasite Burden ◽  
Skin Penetration ◽  
High Plasma

The oral administration of dapsone (DAP) for the treatment of cutaneous leishmaniasis (CL) is effective, although serious hematological side effects limit its use. In this study, we evaluated this drug for the topical treatment of CL. As efficacy depends on potency and skin penetration, we first determined its antileishmanial activity (IC50 = 100 μM) and selectivity index in vitro against Leishmania major-infected macrophages. In order to evaluate the skin penetration ex vivo, we compared an O/W cream containing DAP that had been micronized with a pluronic lecithin emulgel, in which the drug was solubilized with diethylene glycol monoethyl ether. For both formulations we obtained similar low flux values that increased when the stratum corneum and the epidermis were removed. In vivo efficacy studies performed on L. major-infected BALB/c mice revealed that treatment not only failed to cure the lesions but made their evolution and appearance worse. High plasma drug levels were detected and were concomitant with anemia and iron accumulation in the spleen. This side effect was correlated with a reduction of parasite burden in this organ. Our results evidenced that DAP in these formulations does not have an adequate safety index for use in the topical therapy of CL.

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