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      Pharmacological Approaches to Antitrypanosomal Chemotherapy

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          Abstract

          There is an urgent need for new drugs for the chemotherapy of human African trypanosomiasis, Chagas disease and leishmaniasis. Progress has been made in the identification and characterization of novel drug targets for rational chemotherapy and inhibitors of trypanosomatid glycosomal enzymes, trypanothione reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, cysteine proteases and of the purine and sterol biosynthetic pathways. However, less attention has been paid to the pharmacological aspects of drug design or to the use of drug delivery systems in the chemotherapy of African trypanosomiasis and Chagas disease. A review of research on pharmacology and drug delivery systems shows that there are new opportunities for improving the chemotherapy of these diseases.

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          The treatment of human African trypanosomiasis.

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            Amphotericin B: new life for an old drug.

            Interest in amphotericin B has undergone a renaissance of sorts over the past few years despite the advent of the newer less-toxic azole antifungal drugs. This is, in part, owing to the unfortunate increase in fungal diseases worldwide. It is also, however, owing to the reduction of toxicity via innovative liposomal delivery systems, better understanding of drug mechanism and distribution and a surprising expansion of the antibiotic spectrum of amphotericin B to include select virus, parasite and possibly prion infections. In this article, Scott Hartsel and Jacques Bolard summarize the recent leaps in pharmaceutics, spectrum and molecular mechanistic knowledge of this surprising molecule.
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              Lipid biosynthesis pathways as chemotherapeutic targets in kinetoplastid parasites.

              Inhibitors of sterol and phospholipid biosynthesis in kinetoplastid parasites such as Trypanosoma cruzi, the causative agent of Chagas' disease, and different species of Leishmania have potent and selective activity as chemotherapeutic agents in vitro and in vivo. Recent work with the sterol C14 alpha-demethylase inhibitor D0870, a bis triazole derivative, showed that this compound is capable of inducing radical parasitological cure in murine models of both acute and chronic Chagas' disease. Other inhibitors of this type, such as SCH 56592, have also shown curative, rather than suppressive, activity against T. cruzi in these models. Leishmania species have different susceptibilities to sterol biosynthesis inhibitors, both in vitro and in vivo. Leishmania braziliensis promastigotes, naturally resistant to C14 alpha-demethylase inhibitors such as ketoconazole and D0870, were susceptible to these drugs when used in combination with the squalene epoxidase inhibitor terbinafine. Inhibitors of delta 24(25) sterol methyl transferase have been shown to act as potent antiproliferative agents against Trypanosoma cruzi, both in vitro and in vivo. New inhibitors of this type which show enhanced activity and novel mechanisms of action have been synthesized. Recent work has also demonstrated that this type of enzyme inhibitors can block sterol biosynthesis and cell proliferation in Pneumocystis carinii, a fungal pathogen which had previously been found resistant to other sterol biosynthesis inhibitors. Ajoene, an antiplatelet compound derived from garlic, was shown to have potent antiproliferative activity against epimastigotes and amastigotes of Trypanosoma cruzi in vitro; this activity was associated with a significant alteration of the phospholipid composition of the cells with no significant effects on the sterol content. In addition, alkyllsophospholipids such as ilmofosine, miltefosine and edelfosine have been shown to block the proliferation of T. cruzi and Leishmania and alter both the phospholipid and sterol composition. These results indicate the potential of lipid biosynthesis inhibitors as useful therapeutic agents in the treatment of leishmaniasis and Chagas' disease.
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                Author and article information

                Contributors
                Role: ND
                Journal
                mioc
                Memórias do Instituto Oswaldo Cruz
                Mem. Inst. Oswaldo Cruz
                Instituto Oswaldo Cruz, Ministério da Saúde (Rio de Janeiro )
                1678-8060
                March 1999
                : 94
                : 2
                : 215-220
                Affiliations
                [1 ] London School of Hygiene and Tropical Medicine United Kingdom
                Article
                S0074-02761999000200017
                10.1590/S0074-02761999000200017
                ab7a2c21-ebb5-4755-961a-c02bde56e32a

                http://creativecommons.org/licenses/by/4.0/

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                Product

                SciELO Brazil

                Self URI (journal page): http://www.scielo.br/scielo.php?script=sci_serial&pid=0074-0276&lng=en
                Categories
                PARASITOLOGY
                TROPICAL MEDICINE

                Parasitology,Infectious disease & Microbiology
                Trypanosoma brucei,Trypanosoma cruzi,drug delivery systems,liposomes,blood brain barrier

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