The potential of secondary metabolites from plants as drugs or leads against protozoan neglected diseases - part I

Infections with protozoan parasites are a major cause of disease and mortality in many tropical countries of the world. Diseases caused by species of the genera Trypanosoma (Human African Trypanosomiasis and Chagas Disease) and Leishmania (various forms of Leishmaniasis) are among the seventeen "Neglected Tropical Diseases" (NTDs) defined as such by WHO due to the neglect of financial investment into research and development of new drugs by a large part of pharmaceutical industry and neglect of public awareness in high income countries. Another major tropical protozoan disease is malaria (caused by various Plasmodium species), which -although not mentioned currently by the WHO as a neglected disease- still represents a major problem, especially to people living under poor circumstances in tropical countries. Malaria causes by far the highest number of deaths of all protozoan infections and is often (as in this review) included in the NTDs. The mentioned diseases threaten many millions of lives world-wide and they are mostly associated with poor socioeconomic and hygienic environment. Existing therapies suffer from various shortcomings, namely, a high degree of toxicity and unwanted effects, lack of availability and/or problematic application under the life conditions of affected populations. Development of new, safe and affordable drugs is therefore an urgent need. Nature has provided an innumerable number of drugs for the treatment of many serious diseases. Among the natural sources for new bioactive chemicals, plants are still predominant. Their secondary metabolism yields an immeasurable wealth of chemical structures which has been and will continue to be a source of new drugs, directly in their native form and after optimization by synthetic medicinal chemistry. The current review, published in two parts, attempts to give an overview on the potential of such plant-derived natural products as antiprotozoal leads and/or drugs in the fight against NTDs.

Differential effect of amphotericin B on the three evolutive stages of Trypanosoma cruzi and on the host cell-parasite interaction

1. Amphotericin B (Am.B) was shown to have a direct effect on T. cruzi, with the three forms of the parasite presenting different susceptibilities to the drug in the following order: amastigotes > trypomastigotes > epimastigotes. These differences highlight the importance of using the vertebrate forms of the parasite in tests of new drugs. 2. The treated parasites showed alterations of the plasma membrane, suggesting that, as in fungi, the primary effect of Am.B was probably via formation of complexes with membrane components. 3. When exposed to filipin, another polyene antibiotic, the three parasite forms were observed to present a similar order of susceptibility, with comparable ultrastructural modifications. 4. Higher concentrations of Am.B were required to damage the intracellular parasites in vitro, 2.3 micrograms/ml for parasites inside peritoneal macrophages and 7 micrograms/ml for parasites inside heart muscle cells. 5. Am.B is effective against the parasite, but is also toxic to mammalian cells. Testing of Am.B for the control of Chagas' disease by blood transfusion may be useful, since bloodstream forms are lysed by lower concentrations of the drug than those required to affect intracellular parasites