Scientific Publications - VL

2012
 
Translational pharmacokinetics modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine by Dorlo TPC, Balasegaram M, Lima MA, de Vries PJ, Beijnen JH, Huitema ADR. Journal of antimicrobial Chemotherapy, doi: 10.1093/jac/dks164, May 10, 2012
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2011

Visceral leishmaniasis treatment: What do we have, what do we need and how to deliver it? By Freitas-Junior LH, Chatelain E, Kim HA, Siqueira-Neto JL. International Journal for Parasitology: Drugs and Drug Resistance, Volume 2, December 2011
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Kinetoplastid Parasites by Tomas von Geldern, Michael Oscar Harhay, Ivan Scandale and Robert Don
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Who Is a Typical Patient with Visceral Leishmaniasis? Characterizing the Demographic and Nutritional Profile of Patients in Brazil, East Africa, and South Asia by Harhay M.o, Olliaro P.L, Vaillant M, Chappuis F, Lima M.A, Ritmeijer K, Costa C.H, Costa D.L, Rijal S, Sundar S, Balasegaram M. Am. J. Trop. Med. Hyg. 84(4), 2011, pp. 543–550, doi:10.4269/ajtmh.2011.10-0321
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Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial by Sundar S, Sinha P.K, Rai M, Verma D.K, Nawin K, Alam S, Chakravarty J, Vaillant M, Verma N, Pandey K, Kumari P, Lal C.S, Arora R, Sharma B, Ellis S, Strub-Wourgaft N, Balasegaram M, Olliaro P, Das P, Modabber F. Lancet, 2011 January, DOI:10.1016/S0140-6736(10)62050-8.
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2010

Leishmaniasis vaccines: past, present and future by F. Moddaber. International Journal of antimicrobial agents, 2010 Nov;36 Suppl 1:S58-61.
No vaccine exists against any form of leishmaniasis. Because recovery from infection is usually accompanied by a strong immunity and because it is possible to protect experimental animals against live challenge, hope for the development of a vaccine for humans has been high. However, leishmaniasis is a disease of the poor and the market for a vaccine is very limited. Until a few years ago, with minimal resources, only a pragmatic approach was possible for testing the first-generation vaccines (i.e. killed whole parasites). Recently, funding has become available for developing defined second-generation vaccines, including recombinant proteins and DNA constructs. With new adjuvants also being developed there is new hope, and several new vaccines are in development against leishmaniasis.
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Paromomycin for the Treatment of Visceral Leishmaniasis in Sudan: A Randomized, Open-Label, Dose-Finding Study by Musa A, Younis B, Fadlalla A, Royce C, Balasegaram M, wasunna M, Hailu A, Edwards T, Omollo R, Mudawi M, Kokwaro G, El-Hassan A, Khalil E. PLoS NTD, 2010 October, 4(10):e855
A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days.
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Geographical Variation in the Response of Visceral Leishmaniasis to Paromomycin in East Africa: A Multicentre, Open-Label, Randomized Trial by Hailu A, Musa A, Wasunna M, Balasegaram M, Yifru S, Mengistu G, Hurissa Z, Hailu W, Weldegebreal T, Tesfaye S, Makonnen E, Khalil E, Ahmed O, Fadlalla A, El-Hassan A, Raheem M, Muellerm, Koummuki Y, Rashid J, Mbui J, Mucee G, Njoroge S, Manduku V, Musibi A, Mutuma G, Kirui F, Lodenyo H, Mutea D, Kirigi G, Edwards T, Smith P, Muthami L, Royce C, Ellis S, Alobo M, Omollo R, Kesusu J, Owiti R, Kinuthia J, for the Leishmaniasis East Africa Platform (LEAP) group. PLoS NTD, 2010 October, 4(10):e709
Visceral leishmaniasis (VL) is a major health problem in developing countries. The untreated disease is fatal, available treatment is expensive and often toxic, and drug resistance is increasing. Improved treatment options are needed. Paromomycin was shown to be an efficacious first-line treatment with low toxicity in India.
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Cost-Effectiveness Analysis of Combination Therapies for Visceral Leishmaniasis in the Indian Subcontinent by Meheus F, Balasegaram M, Olliaro P, Sundar S, Rijal S, Faiz Md. Al, Boelaert M. PLoS NTD, 2010 September, 4(9):e818
Visceral leishmaniasis is a systemic parasitic disease that is fatal unless treated. The article assesses the cost and costeffectiveness of alternative strategies for the treatment of visceral leishmaniasis in the Indian subcontinent. In particular it examines whether combination therapies are a cost-effective alternative compared to monotherapies.
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Antileishmanial High-Throughput Drug Screening Reveals Drug Candidates with New Scaffolds by Siqueira-Neto J L, Song O-R., Oh H, Sohn J-H, Yang G, Nam J, Jang J, Cechetto J, Lee C B, Moon S, Genovesio A, Chatelain E, Christophe T, Freitas-Junior L H. PLoS Neglected Tropical Diseases, 2010 May, Volume 4, Issue 5.
Drugs currently available for leishmaniasis treatment often show parasite resistance, highly toxic side effects and prohibitive costs commonly incompatible with patients from the tropical endemic countries. In this sense, there is an urgent need for new drugs as a treatment solution for this neglected disease. Here we show the development and implementation of an automated high-throughput viability screening assay for the discovery of new drugs against Leishmania. Assay validation was done with Leishmania promastigote forms, including the screening of 4,000 compounds with known pharmacological properties. In an attempt to find new compounds with leishmanicidal properties, 26,500 structurally diverse chemical compounds were screened. A cut-off of 70% growth inhibition in the primary screening led to the identification of 567 active compounds. Cellular toxicity and selectivity were responsible for the exclusion of 78% of the pre-selected compounds. The activity of the remaining 124 compounds was confirmed against the intramacrophagic amastigote form of the parasite. In vitro microsomal stability and cytochrome P450 (CYP) inhibition of the two most active compounds from this screening effort were assessed to obtain preliminary information on their metabolism in the host. The HTS approach employed here resulted in the discovery of two new antileishmanial compounds, bringing promising candidates to the leishmaniasis drug discovery pipeline.
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Combination therapy for visceral leishmaniasis by van Griensven J, Balasegaram M, Meheus F, Alvar J, Lynen L, Boelaert M. In Lancet Infect Dis 2010; 10: 184–94
Combination therapy for the treatment of visceral leishmaniasis has increasingly been advocated as a way to increase treatment efficacy and tolerance, reduce treatment duration and cost, and limit the emergence of drug resistance. The authors reviewed the evidence and potential for combination therapy, and the criteria for the choice of drugs in such regimens.
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2009

Developments in the treatment of visceral leishmaniasis by den Boer M. L, Alvar J, Davidson‌ R. N, Ritmeijer‌ K, Balasegaram M. In Expert Opinion on Emerging Drugs, 2009 Sept, 14; 3, 395-410.
Visceral leishmaniasis (VL) is one of the most neglected parasitic diseases causing large scale mortality and morbidity among the poorest of the poor in the Indian subcontinent and Africa. Objective: This review aims to describe the potential and the (lack of) current impact of newly developed treatments on the control of VL. It describes how the problem of an empty research pipeline is addressed, and discusses the emerging threat of incurable HIV/VL coinfection. Methods: The literature was searched for drugs used in VL. Conclusion: Research and development of VL drugs has received a financial boost but no new drugs are expected in the next 5 years. Only three new and highly effective treatments have been licensed in the past 10 years. These remain, however, largely inaccessible as VL control programs in the developing world are lacking. This is deserving of immediate and urgent attention, especially in the context of the rapidly expanding HIV/VL coinfection.
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Drug discovery for neglected diseases: View of a public-private partnership by Chatelain E, Don R. In Antiparasitic Antibacterial Drug Discovery by Paul M. Selzer (Ed); 2009 Apr: Wiley-Blackwell.
In answer to the lack of modern and effective drugs for diseases such as human African trypanosomiasis (HAT; sleeping sickness) and Chagas disease which present no financial viability for the pharmaceutical industry, new models of drug discovery have been developed.
The Drugs for Neglected Diseases initiative (DNDi) has adopted a model closely related to that of a virtual biotechnology company for identifying and optimizing drug leads.
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Drug Screening for Kinetoplastid Diseases: A Training Manual for Screening in Neglected Diseases by Ioset JR, Brun R, Wenzler T, Kaiser M, Yardley V. DNDi and Pan-Asian Screening Network 2009 Apr: 74pp.
The production of this research manual is one of the deliverables of the Pan-Asian Network for Drugs for Neglected Diseases from Natural Substances. This comprehensive manual is a practical and user-friendly guide for essays available to screen natural products against pathogens responsible for some of the neglected diseases. It brings recommendations and protocols related to these essays, describes the principles of good scientific practice, and lists information about materials requested for the essays, institutions using them as well as key references.
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2008

Natural Products for Neglected Diseases: A Review by Ioset JR. Current Organic Chemistry 2008 May; 12 (8): 643-666.
Neglected diseases are responsible for high mortality and morbidity each year in low-income countries. Due to the lack of vaccines and of safe, effective and affordable treatments, there is an urgent need to reinforce the existing therapeutic arsenal against these killers. One of the main opportunities is through the discovery of new molecules from natural origin. The gaps identified in the R&D process aiming to deliver new medicines for neglected diseases however also apply to natural products. A key review of the most promising antiprotozoal molecules recently discovered from natural resources is presented here together with a critical update on their current development status.


2007

Kala-Azar Outbreak in Libo Kemkem, Ethiopia: Epidemiologic and Parasitologic Assessment by Alvar J, Bashaye S, Argaw D, Cruz I, Aparicio P, Kassa A, Orfanos G, Parreno F, Babaniyi O, Gudeta N, Canavate C, Bern C. Am J Trop Med Hyg. 2007 Aug; 77(2): 275-82.
In May 2005, visceral leishmaniasis (VL) was recognized for the first time in Libo Kemkem, Ethiopia. In October 2005, a rapid assessment was conducted using data from 492 patients with VL treated in the district health center and a household survey of 584 residents of four villages. Local transmission resulted from multiple introductions, is now well established, and will be difficult to eradicate.
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Consultative meeting to develop a strategy for treatment of cutaneous leishmaniasis. Institut Pasteur, Paris, 13–15 June, 2006 by Modabber F, Buffet PA, Torreele E, Milon G, Croft SL. Kinetoplastid Biol Dis. 2007 Apr 24; 6:3.
A meeting was organized by Drugs for Neglected Diseases initiative (DNDi) and the Institute Pasteur (IP), Paris, to review the treatment for all forms of cutaneous leishmaniasis (CL) and to propose a strategy for the development of new efficacious and affordable treatments. Short and long-term objectives and activities were defined as a part of meeting recommendations.
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Topical buparvaquone formulations for the treatment of cutaneous leishmaniasis by Garnier T, Mantyla A, Jarvinen T, Lawrence MJ, Brown MB, Croft SL. J Pharm Pharmacol. 2007 Jan; 59(1):41-9.
As the part of a study to develop buparvaquone (BPQ) formulations for the treatment of cutaneous leishmaniasis, the topical delivery of BPQ and one of its prodrugs from a range of formulations was evaluated. The results confirm that BPQ and its prodrug 3-POM-BPQ can penetrate the skin from several formulations, making them potentially interesting candidates for further investigation of topical formulations using in-vivo models of cutaneous leishmaniasis.
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2006

Miltefosine: issues to be addressed in the future by Berman J, Bryceson AD, Croft S, Engel J, Gutteridge W, Karbwang J, Sindermann H, Soto J, Sundar S, Urbina JA. Trans. R. Soc. Trop. Med. Hyg. 2006 Dec;100 Suppl 1:S41-4. Epub 2006 Jun 5.
Future issues that need to be addressed for miltefosine are efficacy against non-Indian visceral leishmaniasis, efficacy in HIV-coinfected patients, efficacy against the many forms of cutaneous and mucosal disease, effectiveness under clinical practice conditions, generation of drug resistance and the need to provide a second antileishmanial agent to protect against this disastrous event, and the ability to maintain reproductive contraceptive practices under routine clinical conditions.
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Miltefosine — discovery of the antileishmanial activity of phospholipid derivatives by Croft SL, Engel J. Trans R Soc Trop Med Hyg. 2006 Dec;100 Suppl 1:S4-8. Epub 2006 Aug 14. Review.
Miltefosine (hexadecylphosphocholine, ImpavidoTM), a novel antiprotozoal drug used for the treatment of visceral and cutaneous leishmaniasis, was identified and evaluated independently in the early 1980s as a potential anticancer drug in Germany and as an antileishmanial drug in the UK. Miltefosine is active against most Leishmania species, including those that cause cutaneous disease.
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Liposomal Amphotericin B for the Treatment of Visceral Leishmaniasis by Bern C, Adler-Moore J, Berenguer J, Boelaert M, den Boer M, Davidson RN, Figueras C, Gradoni L, Kafetzis DA, Ritmeijer K, Rosenthal E, Royce C, Russo R, Sundar S, Alvar J. Clin Infect Dis. 2006 Oct 1;43(7):917-24. Epub 2006 Aug 28.
During the past decade, liposomal amphotericin B has been used with increasing frequency to treat visceral leishmaniasis (VL). In Europe, liposomal amphotericin B is widely used to treat VL. In Africa and Asia, the VL disease burden is high and drug access is poor; liposomal amphotericin B is available only through preferential pricing for nonprofit groups in East Africa. The public health community should work to broaden access to preferential liposomal amphotericin B pricing by public sector VL treatment programs.
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In-vitro and in-vivo studies on a topical formulation of sitamaquine dihydrochloride for cutaneous leishmaniasis by Garnier T, Brown MB, Lawrence MJ, Croft SL. J Pharm Pharmacol. 2006 Aug;58(8):1043-54.
The efficacy of topical formulations of the 8-aminoquinoline, sitamaquine dihydrochloride, in both in vitro and in in-vivo models of cutaneous leishmaniasis is reported.
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Mechanisms of experimental resistance of Leishmania to miltefosine: Implications for clinical use by Perez-Victoria FJ, Sanchez-Canete MP, Seifert K, Croft SL, Sundar S, Castanys S, Gamarro F. Drug Resist Updat. 2006 Feb-Apr;9(1-2):26-39. Review.
Miltefosine (hexadecylphosphocholine, MIL), registered as Impavido®, has become the first oral drug for the treatment of visceral and cutaneous leishmanasis. MIL is a simple molecule, very stable, relatively safe and highly efficient in clinical trials. However, MIL requires a long treatment course (28 days) and has a long half-life (around 150 h), which might accelerate the emergence of drug resistance in case of inadequate use.
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Current scenario of drug development for leishmaniasis by Croft SL, Seifert K, Yardley V. Indian J Med Res. 2006 Mar; 123(3):399-410. Review.
As part of research to identify better treatments for VL and cutaneous leishmaniasis (CL), alternative and potentially cheaper formulations of amphotericin B, alklyphosphocholines other than miltefosine and improved formulations of paromomycin for CL have been identified. The process for discovery and development of new antileishmanials would also benefit from improved models, for example, transfected parasites, and non invasive methods of measuring parasite load in rodent models of infection.
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Drug resistance in leishmaniasis by Croft SL, Sundar S, Fairlamb AH. Clin Microbiol Rev. 2006 Jan;19(1):111-26.
Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. It is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.
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In Vitro and In Vivo Interactions between Miltefosine and Other Antileishmanial Drugs by Seifert K, Croft SL. Antimicrob Agents Chemother. 2006 Jan;50(1):73-9.
The interaction of miltefosine with amphotericin B, sodium stibogluconate, paromomycin, and sitamaquine was assessed in vitro and additionally for the first three combinations in vivo.
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Situational analysis of leishmaniases research in Kenya by Tonui WK. Afr J Health Sci. 2006;13(1-2):7-21.
Leishmaniasis has been known to be endemic in parts of Kenya from as far back as early in the 20th century. Since 1980, the Kenya Medical Research Institute (KEMRI) has spearheaded research on leishmaniases research in Kenya focusing on various aspects including characterization of Leishmania species, biology, and ecology of sand fly vectors, development of biological strategies for sand fly control, identification of animal reservoirs, diagnosis, new treatment strategies, new chemotherapeutic agents, and vaccine-related studies.
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Chemotherapy in the Treatment and Control of Leishmaniasis by Alvar J, Croft S, Olliaro P. Adv. Parasitol. 2006; 61:223-74.
Drugs remain the most important tool for the treatment and control of both visceral and cutaneous leishmaniasis. Although there have been several advances in the past decade, with the introduction of new therapies by liposomal amphotericin, oral miltefosine and paromomycin (PM), these are not ideal drugs, and improved shorter duration, less toxic and cheaper therapies are required.
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2005

Chemotherapy of trypanosomiases and leishmaniasis by Croft SL, Barrett MP, Urbina JA. Trends Parasitol. 2005 Nov;21(11):508-12.
New formulations, therapeutic switching of the established drugs amphotericin B and paromomycin, and the serendipitous discovery of miltefosine have markedly improved leishmaniasis chemotherapy in the past 21 years. The situation for the two trypanosomiases has been less encouraging. However, the appearance of not-for-profit product-development partnerships offers a new paradigm for bringing new drugs to patients.
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Advances in leishmaniasis by Murray HW, Berman JD, Davies CR, Saravia NG. Lancet. 2005 Oct 29-Nov 4;366(9496):1561-1577.
Diagnosis relies on visualising parasites in tissue or serology; culture and detection of parasite DNA are useful in the laboratory. Despite tangible advances in diagnosis, treatment, and basic scientific research, leishmaniasis is embedded in poverty and neglected. Current obstacles to realistic prevention and proper management include inadequate vector (sandfly) control, no vaccine, and insufficient access to or impetus for developing affordable new drugs.
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Control of mucocutaneous leishmaniasis, a neglected disease: results of a control programme in Satipo Province, Peru by Guthmann JP, Arlt D, Garcia LM, Rosales M, de Jesus Sanchez J, Alvarez E, Lonlas S, Conte M, Bertoletti G, Fournier C, Huari R, Torreele E, Llanos-Cuentas A. Trop Med Int Health. 2005 Sep;10(9):856-62.
Mucocutaneous leishmaniasis (MCL) is an important health problem in many rural areas of Latin America, but there are few data on the results of programmatic approaches to control the disease. We report the results of a control programme in San Martin de Pangoa District, which reports one of the highest prevalences of MCL in Peru.
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The sensitivity of clinical isolates of Leishmania from Peru and Nepal to miltefosine by Yardley V, Croft SL, De Doncker S, Dujardin JC, Koirala S, Rijal S, Miranda C, Llanos-Cuentas A, Chappuis F. Am J Trop Med Hyg. 2005 Aug;73(2):272-5.
Clinical isolates of Leishmania, from visceral leishmaniasis (VL) cases in Nepal and from cutaneous leishmaniasis (CL) cases in Peru, were cultured using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) to type species and strain. The study demonstrates a notable difference in the intrinsic sensitivity of Leishmania species to miltefosine in vitro.
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Preparation of transition-state analogues of sterol 24-methyl transferase as potential anti-parasitics by Lorente SO, Jimenez CJ, Gros L, Yardley V, de Luca-Fradley K, Croft SL, A Urbina J, Ruiz-Perez LM, Pacanowska DG, Gilbert IH. Bioorg. Med. Chem. 2005 Jul, 13: 5435-5453.
In this paper we discuss the design, synthesis and evaluation of potential transition state analogues of the enzyme D24(25)-methyltransferase (24-SMT). This enzyme is essential for the biosynthesis of ergosterol, but not required for the biosynthesis of cholesterol. A series of compounds were successfully synthesised in which mimics of the S-adenosyl methionine co-factor were attached to the sterol nucleus.
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Visceral Leishmaniasis: New Health Tools Are Needed by Hailu A, Musa A.M, Royce C, Wasunna M. PLoS Med. 2005 Jul; 2(7):e211.
Visceral leishmaniasis (VL), commonly known as kala azar, from the Hindu vernacular, is a human systemic disease caused by parasitic protozoan species of the genus Leishmania. Transmitted by the bite of the tiny and seemingly innocuous female phlebotomine sandfly, the parasite enters macrophages, where it multiplies and establishes the infection.
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2004

Novel Azasterols as Potential Agents for Treatment of Leishmaniasis and Trypanosomiasis by Lorente SO, Rodrigues JC, Jimenez Jimenez C, Joyce-Menekse M, Rodrigues C, Croft SL, Yardley V, de Luca-Fradley K, Ruiz-Perez LM, Urbina J, de Souza W, Gonzalez Pacanowska D, Gilbert IH. Antimicrob Agents Chemother. 2004 Aug;48(8):2937-50.
This paper describes the design and evaluation of novel azasterols as potential compounds for the treatment of leishmaniasis and other diseases caused by trypanosomatid parasites. The compounds prepared showed activity at micromolar and nanomolar concentrations when tested against Leishmania spp. and Trypanosoma spp. The compounds were also found to be active against the bloodstream form (trypomastigotes) of Trypanosoma brucei rhodesiense, a causative agent of African trypanosomiasis.
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Synthesis and antileishmanial activity of novel buparvaquone oxime derivatives by Mantyla A, Rautio J, Nevalainen T, Vepsalainen J, Juvonen R, Kendrick H, Garnier T, Croft SL, Jarvinen T. Bioorg Med Chem. 2004 Jul 1;12(13):3497-502.
Novel oxime derivatives (2, 3 and 5) of buparvaquone (1) and O-methyl-buparvaquone (4) were synthesized and their in vitro activities against Leishmania donovani, the causative agent of visceral leishmaniasis (VL), were determined. Buparvaquoneoxime (2) was also studied as a bioreversible prodrug structure of buparvaquone (1).
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2003

Leishmaniasis-current chemotherapy and recent advances in the search for novel drugs by Croft SL, Coombs GH. Trends Parasitol. 2003 Nov;19(11):502-8
The chemotherapy currently available for leishmaniasis is far from satisfactory. Resistance to the pentavalent antimonials, which have been the recommended drugs for the treatment of both visceral (VL) and cutaneous leishmaniasis (CL) for >50 years, is now widespread in India. Although new drugs have become available in recent years for the treatment of VL, treatment problems remain. The search for new drugs continues. Many potential drug targets have been identified in biochemical and molecular studies, and some have been validated. Attempts to exploit these targets are in progress.
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2002

Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda by Guérin P. et al, August 2002, Lancet Infect Dis 2002; 2 : 494–501.
Visceral leishmaniasis is common in less developed countries, with an estimated 500 000 new cases each year. Because of the diversity of epidemiological situations, no single diagnosis, treatment, or control will be suitable for all. This article reviews the current situation and perspectives for diagnosis, treatment, and control of visceral leishmaniasis, and lists some priorities for research and development.
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