Visceral Leishmaniasis - Treatments

Treatments

As with many diseases in developing nations, (including trypanosomiasis and malaria) effective and affordable chemotherapy is sorely lacking and parasites or insect vectors are becoming increasingly resistant to existing anti-parasite drugs. Presumably due to the lack of financial return, new drugs are slow to emerge and much of the basic research into potential drug targets takes place in universities, funded by charitable organisations. This may change as a result of infection of members of the armed forces from the developed nations that currently occupy nations such as Afghanistan and Iraq, where Leishmania is commonplace.

The traditional treatment is with pentavalent antimonials such as sodium stibogluconate and meglumine antimoniate. Resistance is now common in India, and rates of resistance have been shown to be as high as 60% in parts of Bihar, India.

The Indian medical practitioner, Upendra Nath Brahmachari, was nominated for the Nobel Prize in Physiology or Medicine in 1929 for his discovery of ureastibamine (an antimonial compound for the treatment of kala-azar) and a new disease, post kala-azar dermal leishmaniasis. Brahmachari's cure for visceral leishmaniasis was the urea salt of para-amino-phenyl stibnic acid which he called Urea Stibamine.

The treatment of choice for visceral leishmaniasis acquired in India is now Amphotericin B in its various liposomal preparations (AmBisome, Abelcet, Amphocil)

• AmBisome dose: total dose 21 mg/kg (Mediterranean/Brazilian VL); total dose 7.5 mg/kg over 6 days (Indian VL)
• Amphocil dose: total dose 7.5 mg/kg over 6 days (Indian VL)

A low dose (0.5–1 mg/kg) is given on the first day, increasing to 1–2 mg/kg on the second day, followed by 1.5–3 mg/kg on the third and subsequent days.

Miltefosine Impavido is the first oral treatment for this disease. The cure rate of miltefosine in Phase III clinical trials is 95%; Studies in Ethiopia show that is also effective in Africa. In HIV immunosuppressed people which are coinfected with leishmaniasis it has shown that even in resistant cases 2/3 of the people responded to this new treatment. Miltefosine has received approval by the Indian regulatory authorities in 2002 and in Germany in 2004.It is now registered in many countries.

The drug is generally better tolerated than other drugs. Main side effects are gastrointetinal disturbance in the first or second day of treatment (a course of treatment is 28 days) which does not affect the efficiency. Because it is available as an oral formulation, the expense and inconvenience of hospitalization is avoided, and outpatient distribution of the drug becomes an option, making Miltefosine a drug of choice.

The nonprofit Institute for OneWorld Health has adopted the broad spectrum antibiotic paromomycin for use in treating VL; its antileishmanial properties were first identified in the 1980s. A treatment with paromomycin costs about $15 USD. The drug had originally been identified in the 1960s. The Indian government approved paromomycin for sale and use in August 2006.

In 2009, the Hebrew University of Jerusalem Kuvin Center for the Study of Infectious and Tropical Diseases, in a collaborative effort with Addis Ababa University, was awarded a grant by the Bill & Melinda Gates Foundation for research into visceral leishmaniasis in Ethiopia. The project will gather data to be analyzed to identify the weak links in the transmission cycle and devise methods for control of the disease.

Combination drug therapies are currently under investigation, particularly by the Drugs for Neglected Diseases initiative (DNDi). Combination therapies allow for the use of existing drugs in combination, each in lower doses, which helps to decrease the incidence of severe side effects and drug toxicity, as well as the risk for development of resistance against the drugs; they have been shown to be cost-effective strategies strategies. Comparative homology modelling of the enzyme Hypoxanthine-guanine phosphoribosyl transferase (HGPRT; EC 2.4.2.8) in L. donovani suggest that among all of the computationally screened compounds, pentamidine, 1,3-dinitroadamantane, acyclovir and analogs of acyclovir had higher binding affinities than the real substrate (guanosine monophosphate).

The drug development pipeline is lacking significantly, and no novel drug targets are expected for approval in the next 5 years. In the meantime, new combination therapies, and well as improvements to existing drugs targets, are under development. Single-dosage administrations of liposomal amphotericin B have been shown to be effective, and oral formulations are currently under development to increase access and facilitate distribution of the efficacious drug in the field.