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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 [...]

The drug miltefosine appears to be as effective as amphotericin B for treating visceral leishmaniasis, according to a study of 299 patients. This is important because miltefosine can be given orally, whereas amphotericin B must be given intravenously. Cure rates of over 90% were achieved using either drug. Leishmaniasis is a parasitic disease.

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.

Visceral leishmaniasis is an infectious parasitic disease transmitted by the bite of the female sandfly. The disease, which involves fever, anemia, enlarged liver and spleen and low white blood cell count, occurs all over the world. For over 40 years the standard therapy has been pentavalent antimonial drugs. These drugs are not always effective and can also be toxic. Alternative therapies can be toxic as well. A new treatment was evaluated, recombinant human interferon gamma in combination with conventional pentavalent antimonial drugs. The eight patients had had visceral leishmaniasis for an average of 17 months and had not responded to repeated pentavalent antimony therapy. Six of the eight were helped by the combination of interferon gamma and pentavalent antimony given for 10 to 40 days. Two patients showed initial improvement but then required other therapy. Another nine patients with the disease had not been treated previously; eight of them responded well to interferon gamma and pentavalent antimony. This combination regimen appears effective for treating patients with severe visceral leishmaniasis who have not yet been treated or do not respond to pentavalent antimony alone. (Consumer Summary produced by Reliance Medical Information, Inc.)