686 JAPI • VOL. 51 • JULY 2003 Update Article Orally Effective Drugs for Kala-azar (Visceral Leishmaniasis) : Focus on Miltefosine and Sitamaquine H Sangraula*, KK Sharma**, S Rijal+, S Dwivedi++, S Koirala++ Abstract Currently there are no effective orally administered drugs or visceral leishmaniasis or kala-azar, a parasitic disease affecting about 0.5 million people a year, majority of whom are in India and adjacent areas of Nepal. Symptoms of affected patients are fever, cachexia, hepatosplenomegaly and pancytopenia. The disease is usually fatal, if left untreated. Traditionally kala-azar is treated with four weeks of injections of sodium stibogluconate, a pentavalent antimonial. However, this treatment has not only shown resistance in 37-64% patients of the current Indian epidemic in Bihar (the epicentrre) but also life-threatening cardiotoxicity in 7-10% and treatment- related deaths in 5-10% cases, besides being unsuccessful at times. Parenteral amphotericin B is used as a secondary agent that shows 95% effectiveness but its toxicity and high cost of even the well tolerated liposomal complex precludes its wide use in the developing countries, where the disease is present in epidemic proportions. Recently, miltefosine (hexadecylphosphocholine), a compound originally developed as an antitumour agent has been shown to be an orally effective drugs against kala-azar. All clinical trials with this drug are conducted in India in patients of visceral leishmaniasis. A regimen of 100 mg per day or 50 mg twice daily for 3-4 weeks was observed to produce a cure rate of 100%. Gastrointestinal side effects were frequent (62%) but no patient discontinued the therapy. A phase III trial involving 300 HIV-negative adults and adolescents is underway in India and the drug is hoped to be licensed in the next 2-3 years. Few studies of phase II clinical trials mainly conducted in Kenya with another drug, sitamaquine or kalazaquine (WR 6026), an 8-aminoquinoline has also shown promise as an orally effective agent (in a dose of 1 mg/kg/day for two weeks) for visceral leishmaniasis. These studies with two orally effective compounds, it appears, will open new vistas for orally effective, affordable and acceptable drugs in the armamentarium for the treatment of kala-azar. It is expected that in future we would have effective ways to prevent and treat all forms of leishmaniasis without discomforting the patient. world), whereas visceral leishmaniasis is caused by L. donovani. Visceral leishmaniasis, although has been reported in 66 countries to affect 500,000 persons worldwide per year, 90% of these patients are in India, Nepal, Bangladesh, Brazil and Sudan. 1,2 In the Indian subcontinent, the disease is called “kala-azar” a Hindi word for black fever or black sickness and has been endemic for many decades. However, it has re- emerged in the last three decades from near eradication and is a major health problem in Bihar, West Bengal, Eastern Uttar Pradesh and neighbouring areas of Nepal. The latest in the series of epidemics of kala-azar, centered in north-eastern India, flared up in 1970s, probably because of the discontinuation of insecticide spraying for malaria which also affects the ‘Phlebotomus’ sandfly that transmits the disease *Assistant Professor, **Professor, Department of Pharmacology; +Associate Professor, ++Professor, Department of Medicine; BP Koirala Institute of Health Sciences, Dharan, Nepal. Received : 16.8.2001; Revised : 13.3.2002; Accepted : 13.2.2003 I NTRODUCTION O ut of the three clinical manifestations of leishmaniasis- cutaneous, mucocutaneous and visceral, the latter is a potentially fatal form of the disease and has more severe public health consequences in several parts of the world. Cutaneous and mucocutaneous leishmaniases are caused respectively by Leishmania braziliensis and L. tropica (and also by over a dozen other species in different parts of the