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A Review: The Current In Vivo Models for the Discovery and Utility of New Anti-leishmanial Drugs Targeting Cutaneous Leishmaniasis.

ABSTRACT: 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.

SUBMITTER: Mears ER

PROVIDER: S-EPMC4559374 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description:BackgroundCutaneous leishmaniasis (CL), endemic in Guatemala, mostly affects poor people living in the northern region. A national control program that includes surveillance, diagnose, and treatment offered free of cost by the Ministry of Health (MoH) has been in place since 2003. However, the incidence is increasing and treatment rates are not optimal, suggesting that current efforts are not being effective. This study aimed to understand barriers and facilitators of CL control in Guatemala as experienced and perceived by key stakeholders in order to comprehend what works well and does not and suggest evidence-informed interventions.MethodsThe study was conducted in the Cobán municipality, the most endemic of Guatemala, situated in the Department of Alta Verapaz. Data were collected during May and June 2019 via focus groups and semi-structured interviews with key stakeholders, including local and national health personnel and residents of four communities of the endemic region. Thematic and content analysis of the collected data was conducted using NVIVO.ResultsThree overarching issues hamper the effectiveness of current CL efforts: resource scarcity, treatment challenges, and knowledge-action gaps. Scarce economic resources from the MoH and community residents negatively impact incidence, detection of cases and treatment rates in that preventive action is insufficient and healthcare access is low. In addition, local health workers often lack specialized CL training and access to the national CL control guidelines. With regards to the population living in the study area, misunderstanding of disease causation, shame associated with CL lesions, treatment pain fear, and long (often uncertain) waiting times for diagnose and treatment negatively affect people's willingness to seek help, treatment adherence, and their trust on the healthcare provided.ConclusionsCulturally sensitive CL preventive action must be developed. Given the scarce economic resources available for CL control in the country, the involvement of trained community health workers and the inclusion of thermotherapy as a treatment option is also advised. Other cost-effective actions include: ensuring all health workers receive CL training and have access to national CL control guidelines, improving national procurement system to avoid treatment shortages, and provision of motorized vehicles to increase active surveillance and treatment rates.

Project description:Cutaneous leishmaniasis (CL) remains a globally spreading public health problem. Among Latin America countries, Brazil has the greatest number of recorded CL cases with several Leishmania species being associated with human cases. Laboratory diagnosis is one of the major challenges to disease control due to the low accuracy of parasitological techniques, the restricted use of molecular techniques, and the importance of differential diagnosis with regard to several dermatological and systemic diseases. In response, we have developed and validated an immunohistochemistry (IHC) technique for CL diagnosis using anti-mTXNPx monoclonal antibody (mAb). Recombinant Leishmania-mTXNPx was produced and used as an immunogen for mAb production through the somatic hybridization technique. The viability of mAb labeling of Leishmania amastigotes was tested by IHC performed with skin biopsies from hamsters experimentally infected with Leishmania amazonensis, Leishmania braziliensis, and Leishmania guyanensis. The enzymes horseradish peroxidase (IHC-HRP) and alkaline phosphatase (IHC-AP), both biotin-free polymer detection systems, were used in the standardization step. The IHC was further validated with skin biopsies from 49 CL patients diagnosed by clinical examination and quantitative real-time polymerase chain reaction and from 37 patients presenting other dermatological infectious diseases. Other parasitological techniques, such as direct examination and culture, were also performed for confirmed CL patients. Histopathology and IHC were performed for all included patients. Overall, the highest sensitivity was observed for IHC-AP (85.7%), followed by IHC-HRP (79.6%), direct examination (77.6%), histopathological examination (HE; 65.3%), and in vitro culture (49%). Only IHC and HE presented specificity over 90% and were able to detect CL patients regardless of parasite burden (odds ratio > 1.94; 95%CI: 0.34-11.23). A significant increase in positivity rates was observed when IHC-AP was combined with direct examination (95.9%) and HE (93.9%). The IHC techniques evaluated in here detected the main Leishmania species causing CL in Brazil and can support diagnostic strategies for controlling this neglected disease, especially if used in combination with other approaches for an integrative laboratorial diagnosis.

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A Review: The Current In Vivo Models for the Discovery and Utility of New Anti-leishmanial Drugs Targeting Cutaneous Leishmaniasis.

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