192 Recent Patents on Anti-Infective Drug Discovery, 2008, 3, 192-198 1574-891X/08 $100.00+.00 © 2008 Bentham Science Publishers Ltd. Visceral Leishmaniasis: Advances in Treatment Helen C. Maltezou* Department for Interventions in Health-Care Facilities, Hellenic Center for Disease Control and Prevention, Athens, Greece Received: August 13, 2008; Accepted: September 8, 2008; Revised: September 11, 2008 Abstract: Visceral leishmaniasis continues to be an important public health problem worldwide. This vector-borne infection affects approximately 500,000 people annually with more than 50,000 associated deaths, a number that among parasite diseases is surpassed by malaria only. Leishmaniasis was recently selected by the World Health Organization for elimination by 2015. Major obstacles for achieving this goal include lack of an antileishmanial vaccine, wide-spread resistance to pentavalent antimonials in the State of Bihar, India where half of cases globally occur, and drawbacks of alternative antileishmanial drugs, including prolonged administration, serious adverse effects, and high costs in poor endemic areas. During the past decade, significant progress has been made towards the development of new and less toxic antileishmanial agents, including the oral agent miltefosine. Currently, there are several agents with antileishmanial activity under investigation as well as patents that may deserve further testing within combination regimens. In order to preserve the activity of available antileishmanial agents, monitoring of their delivery, response, and resistance should be implemented globally. Combination regimens should be further investigated in large trials. The costs of antileishmanial agents should be minimized in poor endemic areas where there are needed most. Keywords: Visceral leishmaniasis, treatment, antileishmanial agents, resistance, antimonials, amphotericin-B, miltefosine. INTRODUCTION Leishmaniasis remains an important public health problem worldwide. This illness is endemic in several tropical and subtropical regions and countries bordering the Mediterranean Sea, affecting approximately 12 million people and threatening a total of 350 million people in 88 countries. Leishmaniasis is caused by protozoa of the genus Leishmania and transmitted to humans by sandflies. Leishmanial infection has a wide spectrum of manifestations, including asymptomatic infection, cutaneous leishmaniasis, mucous leishmaniasis, and visceral leishmaniasis (VL; also known as “kala-azar”) [1, 2]. VL is the most severe form of leishmaniasis. VL typically manifests 2-8 months after infec- tion with intermittent fever, pallor, massive hepatospleno- megaly, weight loss, and progressive deterioration of the host [2-7]. Epistaxis, gingival hemorrhage, abdominal distension, edema, and ascites may develop at late stages. Untreated VL is almost allways lethal [5,8]. Given the global burden of leishmaniasis, the World Health Organization recently included this illness in the list of 14 neglected tropical diseases targeted for elimination by 2015 [9]. During the last decade, our comprehension of the patho- genesis and immunity of leishmaniasis expanded. Several drugs with antileishmanial activity became available including the oral agent miltefosine, while at the same time resistance to pentavalent antimonials is noted in more than 60% of newly diagnosed VL cases in India [1,2, 10]. Given the unavailability of an antileishmanial vaccine in clinical use, treatment remains a major tool for leishmaniasis control, along with intensive surveillance, prompt diagnosis, and *Address correspondence to this author at the Department for Interventions in Health-Care Facilities, Hellenic Center for Disease Control and Prevention, 42 3 rd Septemvriou Street, Athens, 10433, Greece; Tel: 30-210- 8899-000; Fax: 30-210-8899-330; E-mail: helen-maltezou@ath.forthnet.gr vector control. Strategies to preserve the efficacy of the currently available antileishmanial drugs, including the investigation of treatment combinations are needed. This article will review current literature on antileishmanial treatment as well as patents published from 2006 and on. The epidemiology, pathogenesis, and immunity of visceral leishmaniasis are also presented. PATHOGENESIS AND IMMUNITY Leishmanias are obligatory intracellular protozoal para- sites of the genus Leishmania, family Trypanosomatidae. There are more than 17 Leishmania species known to cause infection in humans. VL is caused by the Leishmania donovani complex, which includes L. donovani in the Indian subcontinent, Asia, and Africa, L. infantum in the Medi- terranean basin, and L. chagasi in South America [1,4, 10,11]. Leishmanias remain within sandflies with the extra- cellular promastigote flagellate form. Following a sandfly bite and inoculation into the skin of the host, leishmanias are phagocytized by dermal macrophages where they transform into the intracellular amastigote form [1-3]. Leishmanias replicate and disseminate to additional local or distal macrophages in the reticuloendothelial system of the host, resulting in infiltration of bone marrow, liver, spleen, and lymph nodes [1-3,12]. Immunity against leishmanial infection is mainly T- helper cell-type 1 (Th1)-depended [1,2,13-15]. Following phagocytosis by macrophages, immune responses are trig- gered. The maintenance of macrophages in a deactivation stage mainly determines progression of intracellular leishmanial infection and further dissemination. Non-specific and antigen-specific (cell-mediated) immune responses mediate clinical expression of leishmanial infection and prevention of reactivation, and also determine responses to