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      Strategies to Overcome Antileishmanial Drugs Unresponsiveness

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      Journal of Tropical Medicine
      Hindawi Publishing Corporation

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          Abstract

          In the absence of effective vector control measures and vaccines against leishmaniasis, effective chemotherapy remains the mainstay of treatment. As the armoury of antileishmanial drugs is limited, strategies should be made to target the emergence of drug resistance. The loss of efficacy of antimonials such as sodium stibogluconate in the Indian subcontinent which has been the mainstay of treatment for more than six decades has raised concern to save the other drugs. In the current review, we highlight various steps which could be implemented to halt the increasing unresponsiveness of drugs such as monitoring of therapy in the form of rational dosing and duration of treatment, understanding the mechanism of action of the drugs and drug resistance, identification of markers of resistance, distribution of drugs free of cost, evolution of effective combination therapy and immunotherapy, and proper management of HIV/VL coinfection and post-kala-azar dermal leishmaniasis (PKDL). Strong support from governmental agencies and local communities in the form of education and orientation programmes for feasibility of implementing these strategies and affordability within the context of their health systems is needed in controlling and preventing leishmaniasis.

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          Most cited references62

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          CPIC: Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network.

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            The relationship between leishmaniasis and AIDS: the second 10 years.

            To date, most Leishmania and human immunodeficiency virus (HIV) coinfection cases reported to WHO come from Southern Europe. Up to the year 2001, nearly 2,000 cases of coinfection were identified, of which 90% were from Spain, Italy, France, and Portugal. However, these figures are misleading because they do not account for the large proportion of cases in many African and Asian countries that are missed due to a lack of diagnostic facilities and poor reporting systems. Most cases of coinfection in the Americas are reported in Brazil, where the incidence of leishmaniasis has spread in recent years due to overlap with major areas of HIV transmission. In some areas of Africa, the number of coinfection cases has increased dramatically due to social phenomena such as mass migration and wars. In northwest Ethiopia, up to 30% of all visceral leishmaniasis patients are also infected with HIV. In Asia, coinfections are increasingly being reported in India, which also has the highest global burden of leishmaniasis and a high rate of resistance to antimonial drugs. Based on the previous experience of 20 years of coinfection in Europe, this review focuses on the management of Leishmania-HIV-coinfected patients in low-income countries where leishmaniasis is endemic.
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              Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis.

              Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells as well as some pathogenic bacteria and fungi. For 10 years it has been licensed in India for the treatment of visceral leishmaniasis (VL), a fatal neglected parasitic disease. It is the first and still the only oral drug that can be used to treat VL and cutaneous leishmaniasis (CL). The standard 28 day miltefosine monotherapy regimen is well tolerated, except for mild gastrointestinal side effects, although its teratogenic potential severely hampers its general use in the clinic and roll-out in national elimination programmes. The pharmacokinetics of miltefosine are mainly characterized by its long residence time in the body, resulting in extensive drug accumulation during treatment and long elimination half-lives. At the moment, different combination therapy strategies encompassing miltefosine are being tested in multiple controlled clinical trials in various geographical areas of endemicity, both in South Asia and East Africa. We here review the most salient pre-clinical and clinical pharmacological aspects of miltefosine, its mechanism of action against Leishmania parasites and other pathogens, and provide a systematic overview of the efficacy and safety data from all clinical trials of miltefosine, either alone or in combination, in the treatment of VL and CL.
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                Author and article information

                Journal
                J Trop Med
                J Trop Med
                JTM
                Journal of Tropical Medicine
                Hindawi Publishing Corporation
                1687-9686
                1687-9694
                2014
                30 April 2014
                : 2014
                : 646932
                Affiliations
                Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
                Author notes

                Academic Editor: Marcel Tanner

                Author information
                http://orcid.org/0000-0001-9988-582X
                Article
                10.1155/2014/646932
                4021741
                24876851
                fc0f7e9e-1894-49ca-b091-07c39e4f24a4
                Copyright © 2014 Shyam Sundar et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 February 2014
                : 30 March 2014
                : 13 April 2014
                Funding
                Funded by: http://dx.doi.org/10.13039/100000060 National Institute of Allergy and Infectious Diseases
                Award ID: P50AI074321
                Categories
                Review Article

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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