Abstract
Leishmaniasis is a vector-borne parasitic disease caused by Leishmania species. The disease affects humans and animals, particularly dogs, provoking cutaneous, mucocutaneous, or visceral processes depending on the Leishmania sp. and the host immune response. No vaccine for humans is available, and the control relies mainly on chemotherapy. However, currently used drugs are old, some are toxic, and the safer presentations are largely unaffordable by the most severely affected human populations. Moreover, its efficacy has shortcomings, and it has been challenged by the growing reports of resistance and therapeutic failure. This manuscript presents an overview of the currently used drugs, the prevailing model to develop new antileishmanial drugs and its low efficiency, and the impact of deconstruction of the drug pipeline on the high failure rate of potential drugs. To improve the predictive value of preclinical research in the chemotherapy of leishmaniasis, several proposals are presented to circumvent critical hurdles—namely, lack of common goals of collaborative research, particularly in public–private partnership; fragmented efforts; use of inadequate surrogate models, especially for in vivo trials; shortcomings of target product profile (TPP) guides.
Highlights
Drug discovery and development (DDD) of antileishmanial drugs follow the same pattern as any other drug: identification of hits, leads, and candidates from natural sources, chemical libraries from pharmaceutical companies or those for public access, or small chemical collections from academia
Our goal is to pinpoint several factors that could have a higher-than-accepted impact on the efficiency of antileishmanial drugs R&D. They refer to the aim and type of research carried out in academia, and how it could act as bottlenecks of DDD and, have a direct effect on its attrition rate
For those scientists involved in the search for potential antileishmanial agents, drug delivery systems, or drug combinations, crossing from in vitro screening to an exploratory in vivo test in a surrogate model is not an easy task and should not be considered a straightforward step [174]
Summary
Leishmaniasis is a group of vectorial parasitic diseases widely distributed in the world. More refined analysis of these numbers shows that, in many cases, the actual relationship of the contributions to the chemotherapy of the disease is low This occurs in both human and dog leishmaniasis [21]. Around 25 drugs or combinations have been used for humans in leishmaniasis [22,23,24] This high number suggests that there are limitations in the currently available chemotherapy. The WHO-OMS (2004) concluded that the most promising drugs for the treatment of leishmanial infections were amphotericin B in its liposomal presentation, miltefosine, and paromomycin Current antileishmanial chemotherapy still relies on pentavalent antimonials, amphotericin B, pentamidine isethionate, miltefosine, and paromomycin [42] These drugs are far from being novelties or providing an ideal chemotherapeutic control of the disease. Less toxic drug delivery systems (DDSs), such as PLGA nanoparticles or liposomes [41], and presentations (e.g., polyaggregated forms of AmB) [45] or amphiphilic antimony [46]
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