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Polyamines are important regulators of growth and differentiation in a variety of cells, including parasitic protozoa. Promastigotes of Leishmania species have high levels of putrescine and spermidine and their growth can be inhibited by polyamine biosynthesis antagonists. The putrescine analogue 1,4-diamino-2-butanone (DAB) is microbicidal against Tritrichomonas foetus and Trypanosoma cruzi, so we tested its effects on Leishmania amazonensis proliferation, viability, organization, putrescine transport and synthesis as well as in vitro infectivity. DAB impaired promastigote proliferation dose-dependently (I[C.sub.50] 144 [micro]M) and the parasite putrescine concentration was reduced by nearly 50%. This analogue markedly inhibited both ornithine decarboxylase activity and [[H.sup.3]]putrescine uptake by promastigotes. Pre-treatment with DAB for 24 h led to compensatory enhancement of putrescine uptake, indicating an adaptive mechanism in DAB-treated parasites. Remarkably, DAB caused mitochondrial damage, assessed by transmission electron microscopy, and 3 h treatment with 1 mM DAB enhanced lipid peroxidation, whereas incubation with 10 mM DAB or for 24 h resulted in decreased peroxidation levels in the parasites. This effect was probably due to the loss of mitochondrial function, demonstrated by the diminished reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), not observed in macrophages. Murine macrophages infected with L. amazonensis amastigotes treated with DAB had parasite loads significantly (P

The ethanolic extracts of a number of Turkish freshwater macrophytes (Potamogeton perfoliatus, Ranunculus tricophyllus and Cladophora glomerata) and marine macroalgae (Dictyota dichotoma, Halopteris scoparia, Posidonia oceanica, Scinaia furcellata, Sargassum natans [...]

Resistance to murine leishmaniasis correlates with development of a [CD4.sup.+] T helper 1 (Th1)-predominant immune response. To determine whether immunostimulatory CpG-containing oligodeoxynucleotides (CpG-ODN), known to promote a Th1 immune response, could provide protection from Leishmania infection, CpG-ODN and freeze-thawed (F/T) Leishmania major were coinjected intradermally into susceptible BALB/c mice. A Leishmania-specific Th1-predominant immune response was induced, and 40% of animals were protected from subsequent challenge with infectious organisms, with 0% protection of animals injected with F/T Leishmania organisms and PBS, F/T organisms and control ODN, or F/T organisms alone. More striking protection (65-95%) was seen in mice first infected with intact Leishmania organisms and then injected with CpG-ODN, either at the site of infection or at a remote site. To determine whether the therapeutic protection provided by CpG-ODN depended on IL-12 and IFN-[Gamma] production, both IFN-[Gamma]-deficient BALB/c mice and BALB/c mice treated with neutralizing anti-IL-12 mAb were first inoculated with Leishmania and then treated with either CpG-ODN, ODN, or PBS. None of these IFN-[Gamma]-deficient mice survived (0/20, 0/20, and 0/20 respectively). Furthermore, neutralization of IL-12 completely abolished the therapeutic protection provided by CpG-ODN (0/20 mice surviving). We conclude that immunostimulatory DNA sequences likely exert systemic effects via IL-12 and IFN-[Gamma]-dependent mechanisms and hold considerable promise as both vaccine adjuvants and potential therapeutic agents in the prevention and treatment of leishmaniasis.

Author(s): Carolina M. C. Catta-Preta, Jeremy C. MottramAuthor Affiliations:Drug candidate and target for leishmaniasis It is more than 100 years[sup.3] since drugs based on the chemical element antimony[sup.4] were first [...], Better treatments are needed for the neglected tropical disease leishmaniasis. The development of a compound that tackles the disease in mice, and the identification of the protein it targets, offer a way forward.Better treatments are needed for the neglected tropical disease leishmaniasis. The development of a compound that tackles the disease in mice, and the identification of the protein it targets, offer a way forward.

IgE-IC helps in intracellular killing of L. major in human monocyte-derived macrophages by the induction of the L-arginine: NO pathway, which is revealed by increased generation of nitrite (NO2 negative), the stable oxidation product of NO, and by the ability of N (super G)-monomethyl-L-arginine to block NO generation and as well as parasite killing. Similarly NO-dependent effect is seen with interferon gamma-treated cells due to tumour necrosis factor alpha as both the induction of NO synthase and the killing of parasites.

A combination of interleukin 12 (IL-12) and the antimony-based leishmanicidal drug Pentostam is used to treat Leishmania major infected mice. This treatment is connected to a switch from a type 2 to a type 1 T helper (Th2 and Th1) cell response. When the levels of antigen are diminished the IL-12 appears to restrain a Th2 response and activate a Th1 response.

Objective To compare the use of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis (kala-azar). Methods A total of 102 patients with confirmed kala-azar were treated in [...]