Leishmaniasis, visceral

In 1912, however, (201) it was discovered that espundia (American mucocutaneous leishmaniasis) can be cured by tartar emetic. It was soon learned that kala-a2ar (visceral leishmaniasis) and oriental sore (a cutaneous form of the disease occurring in the Middle East) also respond to antimonial therapy, especially when compounds of pentavalent antimony are employed. Treatment of leishmaniasis with the latter type of antimonials is safe and effective in over 90% of the cases (202). In 1918, it was demonstrated that tartar emetic is of value in the treatment of schistosomiasis (203). Pentavalent antimonials proved to be less effective. The introduction of antimony compounds for the treatment of parasitic diseases is undoubtedly one of the important milestones in the history of therapeutics (see Antiparasitic agents). 

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. 

Miltefosine, an alkylphosphocholine derivative, is a new antileishmanial drug and the first effective oral treatment of visceral leishmaniasis. However, there are concerns regarding teratogenicity, rapid emergence of resistance, and variable cure rates, possibly due to species differences in drug sensitivity. The mechanism of action of miltefosine is not known. 

Liposomal Amphotericin B This is a highly effective drug against visceral leishmaniasis with remarkably few side effects. There is, however, only one producer and the price per treatment (US 1,500) is beyond the reaches for most communities affected by the disease. 

Patomomycin This oral aminoglycoside was first shown to be effective as a topical treatment for cutaneous leishmaniasis, and later as a parenteral drug against visceral leishmaniasis. Phase III clinical trials were completed in 2005 in India, 15 years after the potential of this component for treating viscer al leishmaniasis was discovered. It is currently not registered for this use. 

Diseases which will probably be subject to control by insecticides but have not yet been adequately tested include sandfly fever, dengue, urban yellow fever, bartonellosis, cutaneous leishmaniasis, Chagas disease, filariasis, trench fever, and louse-born relapsing fever. Some of the virus encephalitides. sleeping sickness, and visceral leishmaniasis may also be susceptible of control. 

Niosomes (prepared using surfactant I and surfactant I, II, or III and 30% cholesterol) containing stibogluconate have been as effective as the corresponding liposomal drugs in the visceral leishmaniasis model. Free drug showed reduced efficacy [169],... 

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. 

P. Chakraborty, A. N. Bhaduri, and P. K. Das, Neoglycoproteins as carriers for receptor-mediated drug targeting in the treatment of experimental visceral leishmaniasis, J. Protozool., 37 (1990) 358-364. 

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. 

Mullen AB, Carter KC, Baillie AJ. Comparison of the efficacy of various formulations of amphotericin B against murine visceral leishmaniasis. Antimicrob Agents Chemother 1997 41 2089. 

Guerin PJ, et al. Visceral leishmaniasis current status of control, diagnosis and treatment, and a proposed research and development agenda. Lancet Infect Dis 2002 2 494. 

Leishmaniasis For treatment of visceral leishmaniasis (liposomal only) treatment of American mucocutaneous leishmaniasis but not as primary therapy (deoxycholate). Unlabeled uses Prophylaxis for fungal infection in patients with bone marrow transplantation (0.1 mg/kg/day). 

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. 

Amphotericin B, a polyene, is discussed more fully in Chapter 52. It has produced healing of the mucocutaneous lesions of American leishmaniasis, but its potential for nephrotoxicity makes it a drug of second choice. On the other hand, liposomal amphotericin B, approved by the U. S. Food and Drug Administration (FDA) for treatment of visceral leishmaniasis, is considered the drug of choice for that indication and is much less toxic than pentavalent antimonials or amphotericin B. 

Pentamidine is an alternative drug for visceral leishmaniasis, especially when sodium stibogluconate has failed or is contraindicated. Pentamidine is also a reserve agent for the treatment of trypanosomiasis before the CNS is invaded. This characteristic largely restricts its use to Gambian trypanosomiasis. 

A. Liposomal amphotericin B was approved by the US. Food and Drug Administration to treat visceral leishmaniasis. Pentavalent antimony compounds, pentamidine, amphotericin B, and aminosi-dine (paromomycin) have all been demonstrated efficacious here. The liposomal amphotericin appears to be better taken up by the reticuloendothelial system, where the parasite resides, and partitions less in the kidney, where amphotericin B traditionally manifests its toxicity. In addition to being better tolerated by patients, it has proved to be very effective in India, where resistance to antimony drugs is widespread. This patient appears to have acquired his infection there, where many infected patients develop darkening of the skin, hence the name kala-azar, or black sickness. Albendazole, an anthelmintic, has no role here. Atovaquone, a naphthoquinone, is used to treat malaria, babesiosis, and pneumocystosis. Pyrimethamine-sulfadoxine is used to treat malaria and toxoplasmosis. Proguanil inhibits the dihydrofolate reductase of malaria parasites and is used in combination with atovaquone. 

Berman JD. Editorial response U. S. Food and Drug Administration approval of AmBisome (Liposomal Amphotericin B) for treatment of visceral leishmaniasis. Clin Infect Dis 1999 28 49-51. 

It is pentavalent antimonial. It inhibits -SH dependent enzymes and block glycolytic fatty acid oxidation pathways. It is rapidly absorbed after IM injection and excreted unchanged in urine. Used in cutaneous and visceral leishmaniasis. It is given parenterally (20 mg/kg/day IM/IV) for three weeks in cutaneous leishmaniasis and for four weeks in visceral and mucocutaneous disease. 

Neomycin and kanamycin are now limited to topical and oral use. Neomycin is too toxic for parenteral use. With the advent of more potent and less toxic aminoglycosides, parenteral administration of kanamycin has also been largely abandoned. Paromomycin has recently been shown to be effective against visceral leishmaniasis when given parenterally (see Chapter 52), and this serious infection may represent an important new use for this drug. 

Pentamidine is an alternative to sodium stibogluconate in the treatment of visceral leishmaniasis, with similar efficacy, although resistance has been reported. The drug has been successful in some cases that have failed therapy with antimonials. The dosage is 2-4 mg/kg intramuscularly daily or every other day for up to 15 doses, and a second course may be necessary. Pentamidine has also shown success against cutaneous leishmaniasis, but it is not routinely used for this purpose. 

Available therapies for all forms of trypanosomiasis are seriously deficient in efficacy, safety, or both. Availability of these therapies is also a concern, since they are supplied mainly through donation or nonprofit production by pharmaceutical companies. For visceral leishmaniasis, three new promising therapies are liposomal amphotericin, miltefosine, and paromomycin. 

This important antifungal drug (see Chapter 48) is an alternative therapy for visceral leishmaniasis, especially in parts of India with high-level resistance to sodium stibogluconate. Liposomal amphotericin has shown excellent efficacy at a dosage of 3 mg/kg/d intravenously on days 1-5, 14, and 21. Nonliposomal amphotericin (1 mg/kg intravenously every other day for 30 days) is much less expensive, also efficacious, and widely used in India. Amphotericin is also used for cutaneous leishmaniasis in some areas. The use of amphotericin, and especially liposomal preparations, is limited in developing countries by difficulty of administration, cost, and toxicity. 

Paromomycin sulfate is an aminoglycoside antibiotic that until recently was used in parasitology only for oral therapy of intestinal parasitic infections (see previous text). It has recently been developed for the treatment of visceral leishmaniasis. A phase 3 trial in India showed excellent efficacy for this disease, with a daily intramuscular dosage of 11 mg/kg for 21 days yielding a 95% cure rate, and noninferiority compared with amphotericin. The drug was registered for the treatment of visceral leishmaniasis in India in 2006. In initial studies, paromomycin was well tolerated, with common mild injection pain, uncommon ototoxicity and reversible liver enzyme elevations, and no nephrotoxicity. Paromomycin is much less expensive than liposomal amphotericin or miltefosine, the other promising new therapies for visceral leishmaniasis. 

Bhattacharya SK et al Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis. J Infect Dis 2007 196 591. 

Chappuis F et al Visceral leishmaniasis What are the needs for diagnosis, treatment and control Nat Rev Microbiol 2007 5 873. [PMID 17938629]... 

Sundar S et al Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 2002 347 1739. [PMID 12456849]... 

---