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A New Antileishmanial Preparation of Combined Solamargine and Solasonine Heals Cutaneous Leishmaniasis through Different Immunochemical Pathways.

ABSTRACT: Little has been done during the past 100 years to develop new antileishmanial drugs. Most infected individuals live in poor countries and have a low cash income to be attractive targets to pharmaceutical corporations. Two heterosidic steroids, solamargine and solasonine, initially identified as major components of the Brazilian plant Solanum lycocarpum, were tested for leishmanicidal activity. Both alkaloids killed intracellular and extracellular Leishmania mexicana parasites more efficiently than the reference drug sodium stibogluconate. A total of 10 ?M each individual alkaloid significantly reduced parasite counts in infected macrophages and dendritic cells. In vivo treatment of C57BL/6 mice with a standardized topical preparation containing solamargine (45.1%) and solasonine (44.4%) gave significant reductions in lesion sizes and parasite counts recovered from lesions. Alkaloids present different immunochemical pathways in macrophages and dendritic cells. We conclude that this topical preparation is effective and a potential new and inexpensive treatment for cutaneous leishmaniasis.

SUBMITTER: Lezama-Davila CM

PROVIDER: S-EPMC4862480 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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A New Antileishmanial Preparation of Combined Solamargine and Solasonine Heals Cutaneous Leishmaniasis through Different Immunochemical Pathways.

Lezama-Dávila C M CM McChesney J D JD Bastos J K JK Miranda M A MA Tiossi R F RF da Costa J de C Jde C Bentley M V MV Gaitan-Puch S E SE Isaac-Márquez A P AP

Antimicrobial agents and chemotherapy 20160422 5

Little has been done during the past 100 years to develop new antileishmanial drugs. Most infected individuals live in poor countries and have a low cash income to be attractive targets to pharmaceutical corporations. Two heterosidic steroids, solamargine and solasonine, initially identified as major components of the Brazilian plant Solanum lycocarpum, were tested for leishmanicidal activity. Both alkaloids killed intracellular and extracellular Leishmania mexicana parasites more efficiently th ...[more]

PMID: 26883711

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Project description:IntroductionTo sustain the achievement of kala-azar elimination program (KEP), early detection and treatment of the visceral leishmaniasis (VL) cases and associated modalities such as treatment failure (TF), relapse VL (RVL), and Post-kala-azar dermal leishmaniasis (PKDL) is the cornerstone. A predictive biomarker for VL development and related complications could also play a crucial role in curtailing disease incidence and transmission. Investigations to find a biomarker with prospective capabilities are, however, scarce. Using samples and known clinical outcomes generated within two previous longitudinal cohort studies, we aimed to determine if fluctuations in serum anti-rK39 antibody levels could provide such predictive value.Materials and methodsSerum samples collected at four different time points (Baseline, 12, 18, and 24 months) from 16 patients who had developed VL within the monitoring period and 15 of their asymptomatic healthy controls counterparts were investigated. To investigate potential prediction of VL related complications, serum samples of 32 PKDL, 10 RVL, 07 TF, and 38 cured VL from a single dose AmBisome trial were analyzed. Of this second panel, all patients were monitored for 5 years and sera were collected at four time points (Baseline then 1, 6, and 12 months after treatment). The level of anti-rK39 antibodies in archived samples was measured by a semi-quantitative ELISA.ResultsThe mean antibody level was significantly higher in VL patients compared to their asymptomatic healthy counterparts at each time point. Likewise, we observed a trend toward elevations in antibody levels for PKDL, RVL, TF relative to the reducing levels observed in cured VL. Receiver operating characteristic (ROC) analysis found a promising predictive power of rK39 antibody levels to reveal progression from asymptomatic Leishmania donovani infection stage to VL, defined as 87.5% sensitive and 95% specific. Following treatment, rk39 antibody notably showed 100% sensitivity and 95% specificity in predicting TF.ConclusionOur data indicate that the relative quantity of serum anti-rK39 antibody has promise within either a predictive or prognostic algorithm for VL and VL-related modalities. These could enable VL control programs to implement more effective measures to eliminate the disease. Further research is, however, imperative to standardize the rK39 antibody ELISA between sites prior to broader use.

Project description:BackgroundPhotodynamic therapy (PDT) using chloroaluminium phthalocyanine (ClAlPc) and paromomycin sulfate (PM) can be effective against New World Leishmania species involved in cutaneous leishmaniasis (CL). The aim of this study is to assay the skin permeation and the antileishmanial effects of a nanoemulsion (NE) containing both ClAlPc and PM in experimental CL by Leishmania (Viannia) braziliensis.Material and methodsCremophor ELP/castor oil-based NEs were prepared by a low-energy method and characterized for their physicochemical parameters. The NEs were used to deliver both ClAlPc and PM to leishmania cells. The in vitro toxicity of NEs were tested in vitro against L. (V.) braziliensis and THP-1 cells. The in vivo toxicity was assessed in non-infected BALB/c mice. Ex-vivo permeation and retention studies using healthy mice skin were also conducted. Finally, the in vivo activity of NE-PM+ClAlPc after PDT was tested in BALB/c mice infected with parasites.ResultsNEs are colloidally stable with average droplet diameter of 30 nm, polydispersity index (PDI) below 0.2, and zeta potential near zero. Both promastigotes and intracellular amastigotes treated with NE-PM, NE-ClAlPc and NE-PM+ClAlPc were inhibited at >50%, >95%, >88%, respectively, after PDT with a phototoxic index (PI) >1.2. No skin ClAlPc permeation was observed. In contrast, PM skin permeation was 80-fold higher using PM-loaded NE formulation in comparison to aqueous PM solution. Topical treatment with NE formulations showed no signs of local toxicity or genotoxicity. In addition, concentrations of PM between 27.3 - 292.5 μM/25 mg of tissue were detected in different organs. In vivo, the NE-PM+ClAlPc treatment did not reduce skin lesions.ConclusionThe Cremophor ELP/castor oil NE formulation increases the permeation of PM through the skin and can be used to co-deliver PM plus ClAlPc for combined PDT protocols. However, the lack of efficacy in the in vivo model evidences that the therapeutical scheme has to be improved.

Project description:BackgroundCaseating granulomas are often associated with a mycobacterial infection (TB) and are thought to be exceedingly rare in cutaneous leishmaniasis (CL). However, no large series has accurately documented the incidence of caseating granulomas in CL.MethodsA multiregional cohort consisting of 317 patients with CL [Syria (157), Pakistan (66), Lebanon (47), Saudi Arabia (43), Ethiopia (2) and Iran (2)] was reviewed. Clinical [age, sex, disease duration, lesion type and geographic and anatomic location] and microscopic data [presence of and type of granuloma, Ridley's parasitic index (PI) and pattern (RP)] were documented. Presence of microorganisms was evaluated using special stains (GMS, PAS, AFB and Gram) and polymerase chain reaction (PCR) for TB and CL. All cases included in this study were confirmed as CL by PCR followed by restriction fragment length polymorphism analysis for molecular speciation and were negative for other organisms by all other studies performed. Categorical and continuous factors were compared for granuloma types using Chi-square, t-test or Mann-Whitney test as appropriate.ResultsGranulomas were identified in 195 (61.5%) cases of CL and these were divided to 49 caseating (25.2%), 9 suppurative (4.6%) and 137 tuberculoid without necrosis (70.2%). Caseating and tuberculoid granuloma groups were significantly different in terms of the geographical source, with more cases harboring caseating granulomas in Saudi Arabia (p<0.0001). Histologically, both groups were also different in the distribution of their RP (p<0.0001) with a doubling RP3 in caseating granulomas (31% vs. 15%) as opposed to doubling of RP5 in tuberculoid granuloma group (38% vs. 19%). Time needed to achieve healing (RP5) was notably shorter in tuberculoid vs. caseating group (4.0 vs. 6.2 months). Parasitic Index, CL species and other considered variables did not differ for the granuloma type groups.ConclusionIn our multiregional large cohort, a notable 18.2% of all CL cases harbored caseating granulomas therefore; CL should be considered part of the differential diagnosis for cases with caseating granulomas in endemic regions, especially considering that the regions included in our cohort are also endemic for TB. Of note, cases of CL with caseating granulomas also showed a slower healing process, with no association with specific species, which may be due to worse host immune response in such cases or to a more aggressive leishmania strains.

Dataset Information

A New Antileishmanial Preparation of Combined Solamargine and Solasonine Heals Cutaneous Leishmaniasis through Different Immunochemical Pathways.

Publications

A New Antileishmanial Preparation of Combined Solamargine and Solasonine Heals Cutaneous Leishmaniasis through Different Immunochemical Pathways.

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