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Journal ArticleDOI

Leishmania treatment and prevention: Natural and synthesized drugs.

TL;DR: This review focuses on recent findings in drugs used for the treatment of leishmaniasis including; chemical and natural antileishmanial moieties, different potential targets, as well as various trials of vaccination development.
About: This article is published in European Journal of Medicinal Chemistry.The article was published on 2018-12-05 and is currently open access. It has received 55 citations till now.

Summary (1 min read)

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Summary

  • Leishmaniasis affects over 150 million people all over the world, especially in subtropical regions.
  • Currently used antileishmanial synthesized drugs are associated with some drawbacks such as resistance and cytotoxicity, which hamper the chances of treatment.
  • Furthermore, effective leishmanial vaccines are not well developed.
  • Promising chemotherapy, either from natural or synthetic compounds, was or still is the most promising treatment.
  • This review focuses on recent findings in drugs used for the treatment of leishmaniasis including; chemical and natural antileishmanial moieties, different potential targets, as well as various trials of vaccination development.
  • Special emphasis has been paid to the mechanisms of the drugs, their safety and where possible, the structure-activity relationship to enable guided future drug discovery.

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Citations
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Journal ArticleDOI
TL;DR: The design and synthesis of selective antifolates targeting DHFR from L. major and donovani promastigotes based on 3,4-dihydropyrimidine-2-one and 5-(3,5-dimethoxybenzyl)pyrimidine -2, 4-diamine motif are focused on.

21 citations

Journal ArticleDOI
TL;DR: The mechanisms involved in neutrophil recruitment to the skin following Leishmania infection focusing on the role of keratinocytes in this process are reviewed and the distinct involvement of neutrophils in the outcome of leishmaniasis is discussed.
Abstract: Leishmania (L.) are obligate intracellular protozoan parasites that cause the leishmaniases, a spectrum of neglected infectious vector-borne diseases with a broad range of clinical manifestations ranging from local cutaneous, to visceral forms of the diseases. The parasites are deposited in the mammalian skin during the blood meal of an infected female phlebotomine sand fly. The skin is a complex organ acting as the first line of physical and immune defense against pathogens. Insults to skin integrity, such as that occurring during insect feeding, induces the local secretion of pro-inflammatory molecules generating the rapid recruitment of neutrophils. At the site of infection, skin keratinocytes play a first role in host defense contributing to the recruitment of inflammatory cells to the infected dermis, of which neutrophils are the first recruited cells. Although neutrophils efficiently kill various pathogens including Leishmania, several Leishmania species have developed mechanisms to survive in these cells. In addition, through their rapid release of cytokines, neutrophils modulate the skin microenvironment at the site of infection, a process shaping the subsequent development of the adaptive immune response. Neutrophils may also be recruited later on in unhealing forms of cutaneous leishmaniasis and to the spleen and liver in visceral forms of the disease. Here, we will review the mechanisms involved in neutrophil recruitment to the skin following Leishmania infection focusing on the role of keratinocytes in this process. We will also discuss the distinct involvement of neutrophils in the outcome of leishmaniasis.

19 citations

Journal ArticleDOI
TL;DR: Evaluating the effect of the substitution pattern on leishmanicidal and trypanocidal activity in chalcones suggested that 11 could be a useful lead compound for further SAR studies.

19 citations

Journal ArticleDOI
TL;DR: Biological evaluation of these scaffolds demonstrates that 2-vinylquinolines 3x - 3z possess excellent antimalarial activities against chloroquine-resistant Dd2 strain of Plasmodium falciparum.

15 citations

Journal ArticleDOI
TL;DR: The in vitro cytotoxicity test of the most active compounds displayed higher selectivity indices than that of miltefosine emphasizing their safety on mammalian cells, and the docking experiments on Lm-PTR1 as a putative target rationalized the in Vitro anti-leishmanial activity.

14 citations

References
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Journal ArticleDOI
31 May 2012-PLOS ONE
TL;DR: Visceral and cutaneous leishmaniasis incidence ranges were estimated by country and epidemiological region based on reported incidence, underreporting rates if available, and the judgment of national and international experts.
Abstract: As part of a World Health Organization-led effort to update the empirical evidence base for the leishmaniases, national experts provided leishmaniasis case data for the last 5 years and information regarding treatment and control in their respective countries and a comprehensive literature review was conducted covering publications on leishmaniasis in 98 regional level between 2007 and 2011. Two questionnaires regarding epidemiology and drug access were completed by experts and national program managers. Visceral and cutaneous leishmaniasis incidence ranges were estimated by country and epidemiological region based on reported incidence, underreporting rates if available, and the judgment of national and international experts. Based on these estimates, approximately 0.2 to 0.4 cases and 0.7 to 1.2 million VL and CL cases, respectively, occur each year. More than 90% of global VL cases occur in six countries: India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil. Cutaneous leishmaniasis is more widely distributed, with about one-third of cases occurring in each of three epidemiological regions, the Americas, the Mediterranean basin, and western Asia from the Middle East to Central Asia. The ten countries with the highest estimated case counts, Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia, North Sudan, Costa Rica and Peru, together account for 70 to 75% of global estimated CL incidence. Mortality data were extremely sparse and generally represent hospital-based deaths only. Using an overall case-fatality rate of 10%, we reach a tentative estimate of 20,000 to 40,000 leishmaniasis deaths per year. Although the information is very poor in a number of countries, this is the first in-depth exercise to better estimate the real impact of leishmaniasis. These data should help to define control strategies and reinforce leishmaniasis advocacy. Funding: The Spanish Agency for International Cooperation for Development (AECID) has provided generous support to the WHO Leishmaniasis program since 2005. This support permitted among many other activities regional meetings with the AFRO, EURO, PAHO and SEARO countries, and provided for short term contracts for IDV, MdB, MH and JS related to the preparation of the country profiles. Sanofi provided a grant for a regional meeting with the EMRO countries and various activities related to the control of cutaneous Leishmaniasis in the EMRO region. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: alvarj@who.int . These authors contributed equally to this work " For a full list of the members of the WHO Leishmaniasis Control Team please see the Acknowledgments section.

4,242 citations

Journal ArticleDOI
TL;DR: Millefosine, paromomycin and liposomal amphotericin B are gradually replacing pentavalent antimonials and conventional amphoteric in B as the preferred treatments in some regions, but in other areas these drugs are still being evaluated in both mono- and combination therapies.
Abstract: Visceral leishmaniasis (VL) is a systemic protozoan disease that is transmitted by phlebotomine sandflies. Poor and neglected populations in East Africa and the Indian sub-continent are particularly affected. Early and accurate diagnosis and treatment remain key components of VL control. In addition to improved diagnostic tests, accurate and simple tests are needed to identify treatment failures. Miltefosine, paromomycin and liposomal amphotericin B are gradually replacing pentavalent antimonials and conventional amphotericin B as the preferred treatments in some regions, but in other areas these drugs are still being evaluated in both mono- and combination therapies. New diagnostic tools and new treatment strategies will only have an impact if they are made widely available to patients.

1,463 citations

Journal ArticleDOI
TL;DR: The quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.
Abstract: CD4+ T cells have a crucial role in mediating protection against a variety of pathogens through production of specific cytokines. However, substantial heterogeneity in CD4+ T-cell cytokine responses has limited the ability to define an immune correlate of protection after vaccination. Here, using multiparameter flow cytometry to assess the immune responses after immunization, we show that the degree of protection against Leishmania major infection in mice is predicted by the frequency of CD4+ T cells simultaneously producing interferon-gamma, interleukin-2 and tumor necrosis factor. Notably, multifunctional effector cells generated by all vaccines tested are unique in their capacity to produce high amounts of interferon-gamma. These data show that the quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.

1,308 citations

Journal ArticleDOI
TL;DR: Established models of T-helper-2-cell dominance in BALB/c mice infected with Leishmania major — involving the early production of interleukin-4 by a small subset of LeishMania-specific CD4+ T cells — have been refined by accumulating evidence that this response is not sufficient and, under some circumstances, not required to promote susceptibility.
Abstract: Established models of T-helper-2-cell dominance in BALB/c mice infected with Leishmania major -- involving the early production of interleukin-4 by a small subset of Leishmania-specific CD4+ T cells -- have been refined by accumulating evidence that this response is not sufficient and, under some circumstances, not required to promote susceptibility. In addition, more recent studies in L. major-resistant mice have revealed complexities in the mechanisms responsible for acquired immunity, which necessitate the redesign of vaccines against Leishmania and other pathogens that require sustained cell-mediated immune responses.

1,136 citations

Journal ArticleDOI
TL;DR: The immunomodulator imiquimod has proved to be an adjunct for CL therapy and the search for new drugs continues, with bisphosphonates, for example, risedronate and pamidronate, and plant derivatives being reported to have activity against experimental animal infections.

851 citations

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This review focuses on recent findings in drugs used for the treatment of leishmaniasis including ; chemical and natural antileishmanial moieties, different potential targets, as well as various trials of vaccination development.