Leishmania visceral

Leishmania is a disease complex caused by different species of Leishmania. The parasite, which is transmitted to humans by the bite of phlebotomine sandflies, multiplies within human macrophages. There are an estimated 1.5 million cases in approximately 88 countries each year, with 0.5 million patients suffering from the visceral leishmaniasis. 

Scheme 45 summarizes Mori s synthesis of the male-produced sex pheromone [(l ,3 ,7S)-3-methyl-a-himachalene (31)] of the sandfly (Lutzomyia longipalpis) in Jacobina, Brazil [70]. This sandfly is the vector of Leishmania chagasU the causative protozoan parasite of visceral leishmaniasis in South America. The key-steps of the synthesis of 31 were the asymmetric methylation of A to give C via B and the intramolecular Diels-Alder reaction of D to give E. 

Murray, H.W. and Nathan, C.F., Macrophage microbial mechanisms in vivo Reactive nitrogen versus oxygen intermediates in the killing of intracellular visceral Leishmania donovani, J. Exp. Med., 189, 741, 1999. 

Al-Abdely HM, et al. Efficacies of KY62 against Leishmania amazonensis and Leishmania donovani in experimental murine cutaneous leishmaniasis and visceral leishmaniasis. Antimicrob Agents Chemother 1998 42 2542. 

The flagellate leishmania is transmitted to humans by the bite of the female sandfly of the genus Phlebotomus. Three principal diseases result from infection with Leishmania spp. L. donovani causes visceral leishmaniasis (kala-azar) L. tropica and L. major produce cutaneous leishmaniasis, and L. braziliensis causes South American mucocutaneous leishmaniasis. In visceral leishmaniasis, the protozoan parasitizes the reticuloendothelial cells, and this results in an enlargement of the lymph nodes, liver, and spleen the spleen can become massive. Cutaneous leishmaniasis remains localized to the site of inoculation, where it forms a raised disfiguring ulcerative lesion. South American leishmaniasis is variable in its presentation. It is characterized by ulceration of the mucous membranes of the nose, mouth, and pharynx some disfiguring skin involvement also is possible. 

Iwli et al [97] have reports based on the evaluation of plant-extract of D. multiradiata for antileishmanial activity using a mechanism-based radiorespirometric micro-technique. Extracts were found to be active at concentrations of 50 pg/ml or less against a visceral leishmania isolate. A number of Dorstenia species used traditionally as anti-snake venom were subjected to a pharmacological screening process and were found to possess analgesic and anti-inflammatory activities [98]. Many of the flavonoids isolated from African Dorstenia show moderate to good antioxidant activities [Croft, unpublished results]. The cytotoxic properties of... 

Dietze R, Carvalho SF, Valli LC, Berman J, Brewer T, Milhous W, Sanchez J, Schuster B, Grogl M. Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral leishmaniasis caused by Leishmania chagasi. Am J Trop Med Hyg 2001 65(6) 685-9. 

The potential therapeutic effect of berbamine (10, 25, and 50 pg/ml)(and thirteen other bisbenzylisoquinoline alkaloids) against the protozoan disease leishmaniasis was studied by biological assays on in vitro culture forms of three strains of Leishmania L. brasiliensis brasiliensis (cutaneous and mucocutaneous leishmaniasis), L. mexicana amazonensis (cutaneous), and L. donovani (visceral leishmaniasis). Berbamine was found to inhibit the growth of all three types to differing degrees, but was not as active as daphnandrine, gyrocarpine, or obaberine [194]. 

In the adult, both the cutaneous and mucocutaneous forms of leishmaniasis [Leishmania braziliensis and L. mexicana) are treated with stibogluconate. An alternative drug for the visceral form is amphotericin B. 

Pearson RD, De Queiroz Souza A, Jeronimo SMB. Leishmania species Visceral (kala-azar), cutaneous, and mucosal leishmaniasis. In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. New York, Churchill-Livingstone, 2000 2831-2845. 

The sandfly Lutzomyia longipalpis is the vector of the protozoan parasite Leishmania chagasi, the causative agent of visceral leishmaniasis in South and Central America. Population control of L. longipalpis is therefore of urgent importance to prevent the disease. In 1994, Hamilton and coworkers isolated the male-produced pheromone of L. longipalpis from Jacobina, Brazil, and proposed its structure as 3-methyl-a-himachalene (96, Figure 4.47) with unknown stereochemistry. We first synthesized ( R, 3R, 1 S )-( )-96.81 Enantiomer separation (optical resolution) of a synthetic intermediate enabled us to prepare both the enantiomers of 96, and their bioassay and GC comparisons with the natural pheromone showed the latter to be (lS,3S,lR)-96. 

Hofman V, Brousset P, Mougneau E, et al. Immunostaining of visceral leishmaniasis caused by Leishmania infantum using monoclonal antibody (19-11) to the Leishmania homo-logue of receptors for activated C-kinase. Am J Clin Pathol. 2003 120 567-574. 

ANTIPROTOZOAL EFFECTS Miltefosine is the first orally available therapy for leishmaniasis. It is safe and effective treatment for visceral leishmaniasis and has also shown >95% efficacy against cutaneous leishmaniasis. In Leishmania, the drug may alter ether-lipid metabohsm, ceU signaling, or glycosylphosphatidylinosital anchor biosynthesis. Mutations in a P-type ATPase of the aminophospholipid translocase subfamily apparently decrease drug uptake and thereby confer resistance. 

Leishmania, parasitic protozoa transmitted by flesh-eating flies, cause various diseases ranging from cutaneous or mucocutaneous lesions to splenic and hepatic enlargement with fever. Soilium stibogluconate (pentavalent antimony), the primary drug in all forms of the disease, appears to kill the parasite by inhibition of glycolysis or effects on nucleic acid metabolism. Alternative agents include pentamidine (for visceral leishmaniasis), metronidazole (for cutaneous lesions), and amphotericin B (for mucocutaneous leishmaniasis). 

Leishmaniasis is a disease caused by a number of protozoa in the genus Leishmania. The protozoa may be harbored in diseased rodents, canines, and various other mammals and transmitted from the infected mammal to man by bites from female sandflies of the genus Phlehotomus and then appears in one of four major clinical syndromes visceral leishmaniasis, cutaneous leishmaniasis, mucocutaneous leishmaniasis, or diffuse cutaneous leishmaniasis. 

The visceral leishmaniasis, also known as kala azar (black fever), is caused by Leishmania donovani. This form of the disease is systemic and is characterized in patients by fever, typically nocturnal, diarrhea, cough, and enlarged liver and spleen. The skin of the patient may become darkened. Without treatment, death may occur in 20 months and is commonly associated with diarrhea, superinfections, or Gl hemorrhage. Visceral leishmaniasis is most commonly found in India and Sudan. 

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