Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis.
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ABSTRACT:
SUBMITTER: Caridha D
PROVIDER: S-EPMC6904839 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis.
Caridha Diana D Vesely Brian B van Bocxlaer Katrien K Arana Byron B Mowbray Charles E CE Rafati Sima S Uliana Silvia S Reguera Rosa R Kreishman-Deitrick Mara M Sciotti Richard R Buffet Pierre P Croft Simon L SL
International journal for parasitology. Drugs and drug resistance 20190620
Although there have been significant advances in the treatment of visceral leishmaniasis (VL) and several novel compounds are currently in pre-clinical and clinical development for this manifestation of leishmaniasis, there have been limited advances in drug research and development (R & D) for cutaneous leishmaniasis (CL). Here we review the need for new treatments for CL, describe in vitro and in vivo assays, models and approaches taken over the past decade to establish a pathway for the disco ...[more]
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Project description:The current in vivo models for the utility and discovery of new potential anti-leishmanial drugs targeting Cutaneous Leishmaniasis (CL) differ vastly in their immunological responses to the disease and clinical presentation of symptoms. Animal models that show similarities to the human form of CL after infection with Leishmania should be more representative as to the effect of the parasite within a human. Thus, these models are used to evaluate the efficacy of new anti-leishmanial compounds before human clinical trials. Current animal models aim to investigate (i) host-parasite interactions, (ii) pathogenesis, (iii) biochemical changes/pathways, (iv) in vivo maintenance of parasites, and (v) clinical evaluation of drug candidates. This review focuses on the trends of infection observed between Leishmania parasites, the predictability of different strains, and the determination of parasite load. These factors were used to investigate the overall effectiveness of the current animal models. The main aim was to assess the efficacy and limitations of the various CL models and their potential for drug discovery and evaluation. In conclusion, we found that the following models are the most suitable for the assessment of anti-leishmanial drugs: L. major-C57BL/6 mice (or-vervet monkey, or-rhesus monkeys), L. tropica-CsS-16 mice, L. amazonensis-CBA mice, L. braziliensis-golden hamster (or-rhesus monkey). We also provide in-depth guidance for which models are not suitable for these investigations.
| S-EPMC4559374 | biostudies-other
Project description:BackgroundParomomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis.MethodsWe conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse.ResultsThe clinical cure of the index lesion for paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus.ConclusionsSuperiority of paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials.
| S-EPMC6497224 | biostudies-literature
Project description:Cutaneous leishmaniasis (CL) was discovered in the farms of the Karamay suburb, Xinjiang Uygur Autonomous Region in the 1990s. Between 1992 and 1994, a house-to-house survey revealed a prevalence of 1.0-1.6% in the residents. The clinical types of skin lesions included papule, plaque, ulcer and nodular prurigo. Observations verified that, in some cases, the skin lesions healed spontaneously in 10-14 months, whilst in other cases, they persisted for several years. Sporadic cases of CL have continued to appear at the dermatology clinic of the local hospital since 2000. Phlebotomus wui (Ph. wui), subgenus Larroussius was confirmed as the transmitting vector. The causative agent is Leishmania infantum sensu lato.
| S-EPMC3856449 | biostudies-literature
Project description:Leishmaniasis is a debilitating disease caused by protozoan parasites of the genus Leishmania, which affects an estimated 12 million people worldwide. The discovery of new lead compounds for leishmaniasis is therefore a pressing concern for global health programs. The organic extract of a Panamanian collection of the marine cyanobacterium Lyngbya majuscula showed strong in vitro activity in two complementary screens against the tropical parasite Leishmania donovani, the causative agent of visceral leishmaniasis. Chromatographic separation of this complex mixture led to the isolation of the highly N-methylated linear lipopeptides, almiramides A-C (1-3). Comparison with the biological activities of a number of related metabolites and semisynthetic derivatives revealed key features required for activity and afforded one new compound (11) with superior in vitro activity. Subsequent synthesis of a library of simplified analogues led to the discovery of several compounds with improved therapeutic indices to the natural products.
| S-EPMC4418807 | biostudies-literature
Project description:BACKGROUND:The impact of cutaneous leishmaniasis (CL) on the quality of life of patients has been neglected in research studies worldwide. The few reported studies have used non-specific questionnaires for the disease, which represents a limitation since generic instruments may not address specific aspects of the disease, compromising the evaluation of its real impact. The aim of this paper is to describe the development and the initial validation of an instrument for evaluating the impact of CL, named the Cutaneous Leishmaniasis Impact Questionnaire. METHODOLOGY:The formulation and validation of the instrument consisted of the following steps: (1) literature review; (2) conceptual framework construction and initial item generation; (3) tool analysis by health professionals (experts); (4) tool evaluation performed by the patients; and (5) a pilot study with 100 patients with localized CL, evaluated at a reference ambulatory facility in Belo Horizonte, in the state of Minas Gerais, Brazil. The structure of the proposed instrument was analyzed using hierarchical cluster analysis (ICLUST). RESULTS:Twenty-seven items were initially proposed by the researchers to compose the questionnaire. Content validity (evaluates if the instrument fully assesses the construct of interest) was evaluated by the panel of experts, while face validity (evaluates how potential participants interpret the items) was evaluated by the target population. In this step, some items were excluded, reformulated and/or included. After evaluating a factorial structure of the items in accordance with the cluster analysis, we assembled a questionnaire with 25 items (alpha = 0.86), with high reliability and homogeneity, which address the following: 1) the general impact of the disease (alpha = 0.91, beta = 0.67) and 2) the evaluation of the perception about the treatment and health services (alpha = 0.72, beta = 0.51). CONCLUSIONS:The Cutaneous Leishmaniasis Impact Questionnaire, developed with contributions from patients and experts, was confirmed, in this first validation, as a useful and reliable instrument.
| S-EPMC6117079 | biostudies-literature
Project description:The survival, growth, and virulence of Leishmania spp., a group of protozoan parasites, depends on the proper access and regulation of iron. Macrophages, Leishmania's host cell, may divert iron traffic by reducing uptake or by increasing the efflux of iron via the exporter ferroportin. This parasite has adapted by inhibiting the synthesis and inducing the degradation of ferroportin. To study the role of iron in leishmaniasis, we employed Hjv-/- mice, a model of hemochromatosis. The disruption of hemojuvelin (Hjv) abrogates the expression of the iron hormone hepcidin. This allows unrestricted iron entry into the plasma from ferroportin-expressing intestinal epithelial cells and tissue macrophages, resulting in systemic iron overload. Mice were injected with Leishmania major in hind footpads or intraperitoneally. Compared with wild-type controls, Hjv-/- mice displayed transient delayed growth of L. major in hind footpads, with a significant difference in parasite burden 4 weeks post-infection. Following acute intraperitoneal exposure to L. major, Hjv-/- peritoneal cells manifested increased expression of inflammatory cytokines and chemokines (Il1b, Tnfa, Cxcl2, and Ccl2). In response to infection with L. infantum, the causative agent of visceral leishmaniasis, Hjv-/- and control mice developed similar liver and splenic parasite burden despite vastly different tissue iron content and ferroportin expression. Thus, genetic iron overload due to hemojuvelin deficiency appears to mitigate the early development of only cutaneous leishmaniasis.
| S-EPMC9864902 | biostudies-literature
Project description:New hypoglycemic drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose cotransporter 2 inhibitors (SGLT-2i), which brings more options for the treatment of type 2 diabetes (T2DM). They are generally well tolerated, although caution is required in rare cases. Clinical trials have show good glycemic control with combination therapy with new hypoglycemic drugs in prediabetes and T2DM (mostly traditional stepwise therapy), but early combination therapy appears to have faster, more, and longer-lasting benefits. With the widespread clinical application of oral semaglutide, it is time to develop combinations drugs containing new hypoglycemic drugs, especially SGLT-2i and/or GLP-1RA, to control the risk of prediabetes and newly diagnosed T2DM and its cardiovascular complications, while improving patient compliance. Clinical and preclinical studies support that SGLT-2i exerts its protective effect on heart failure through indirect and direct effects. How this comprehensive protective effect regulates the dynamic changes of heart genes needs further study. We provide ideas for the development of heart failure drugs from the perspective of "clinical drug-mechanism-intensive disease treatment." This will help to accelerate the development of heart failure drugs, and to some extent guide the use of heart failure drugs.
| S-EPMC9295075 | biostudies-literature
Project description:Research in visceral leishmaniasis in the last decade has been focused on how better to use the existing medicines as monotherapy or in combination. Systematic research by geographical regions has shown that a universal treatment is far from today's reality. Substantial progress has been made in the elimination of kala-azar in South Asia, with a clear strategy on first- and second-line therapy options of single-dose liposomal amphotericin B and a combination of paromomycin and miltefosine, respectively, among other interventions. In Eastern Africa, sodium stibogluconate (SSG) and paromomycin in combination offer an advantage compared to the previous SSG monotherapy, although not exempted of limitations, as this therapy requires 17 days of painful double injections and bears the risk of SSG-related cardiotoxicity. In this region, attempts to improve the combination therapy have been unsuccessful. However, pharmacokinetic studies have led to a better understanding of underlying mechanisms, like the underexposure of children to miltefosine treatment, and an improved regimen using an allometric dosage. Given this global scenario of progress and pitfalls, we here review what steps need to be taken with existing medicines and highlight the urgent need for oral drugs. Furthermore, it should be noted that six candidates belonging to five new chemical classes are reaching phase I, ensuring an optimistic near future.
| S-EPMC6148188 | biostudies-literature
Project description:We evaluated the trancriptome of primary cutaneous leisions caused by infection with Leishmania braziliensis. mRNA-seq technique was used to study the trancriptome of both host and parasite. A total of 10 samples was obtained from primary skin ulcers of two extreme clinical forms of American tegumentary leishmaniasis: (i) individuals that after antimonial treatment cured completely (localized cutaneous leishmaniasis - LCL, n=5) and (ii) individuals that developed mucosal lesions in naso and oropharynx areas long after initial healing of the cutaneous lesion (mucosal leishmaniasis - ML, n=5). The sequencing generated an average of 13+ 5 million reads per samples. The reads were aligned to Homo sapiens (USCS - hg19) and to Leishmania braziliensis (Wellcome Trust Sanger Institute - V2_29072008) genomes. Approximately, 15,000 human genes could be detected in the samples. Low amount of L. braziliensis reads did not allow the evaluation of parasite gene expression. LCL and ML samples showed different patterns of gene expression, indicating a more robust immune response in LCL individuals. In summary, this study demonstrated that next-generation sequencing can be used for identification of potentially important biological pathways and drug targets in the host-response to L. braziliensis infection and for characterization of a gene expression signature that could be used to predict the disease outcome. Moreover, we also showed the ability of this technique in, simultaneously, sequence host and pathogen mRNA. Examination of 10 fragments of cutaneous lesions: 5 from localized cutaneous leishmaniasis patients and 5 from mucosal leishmaniasis patients.
2012-10-24 | E-GEOD-33601 | biostudies-arrayexpress
Project description:BACKGROUND AND OBJECTIVES:Cutaneous leishmaniasis is responsible for chronic and disfiguring skin lesions resulting in morbidity and social stigma. The gold standard to diagnose cutaneous leishmaniasis is microscopy but has a variable sensitivity and requires trained personnel. Using four scenarios, the objective of this study is to compare the cost effectiveness of microscopy with two new tools: Loopamp™ Leishmania Detection Kit (LAMP) and CL Detect™ Rapid Test (RDT). METHODS:Data related to the cost and accuracy of these tools were collected at the clinic of the National Malaria and Leishmaniasis Control Program in Kabul, Afghanistan. The effectiveness estimates were measured based on the tools' performance but also indirectly, using the disability-adjusted life years. A decision tree was designed in TreeAge Healthcare Pro 2016, combined with a Markov model representing the natural history of cutaneous leishmaniasis. In addition to a deterministic analysis, univariate sensitivity and probabilistic analyses were performed to test the robustness of the results. RESULTS:If the tools are compared at the National Malaria and Leishmaniasis Control Program level in a period of low incidence, microscopy remains the preferred option. LAMP becomes more appropriate during cutaneous leishmaniasis seasons or outbreaks when its capacity to process several tests (e.g. up to 48) at a time can be maximised. RDT has a cost similar to microscopy when used at the reference clinic but as it is relatively easy to use, it could be implemented at the peripheral level, which would become cheaper than employing microscopy at the reference clinic. Moreover, combining RDT with microscopy or LAMP at the reference clinic for the negative suspects is economically more interesting than directly performing LAMP or microscopy respectively on all cutaneous leishmaniasis suspects at the reference clinic. CONCLUSIONS:When taking advantage of their respective strengths, LAMP and RDT can prove to be cost-effective alternatives to using microscopy alone at the reference clinic.
| S-EPMC6439180 | biostudies-literature