Scientific publications Archives

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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Antitrypanosomal, Antileishmanial, and Antimalarial Activities of Quaternary Arylalkylammonium 2-Amino-4-Chlorophenyl Phenyl Sulfides, a New Class of Trypanothione Reductase Inhibitor, and of N-Acyl Derivatives of 2-Amino-4 Chlorophenyl Phenyl Sulfide by Parveen S, Khan MO, Austin SE, Croft SL, Yardley V, Rock P, Douglas KT. J Med Chem. 2005 Dec 15;48(25):8087-97.
Quaternization of the nitrogen atom of 2-amino-4-chlorophenyl phenyl sulfide analogues of chlorpromazine improved inhibition ~40-fold (3’,4’-dichlorobenzyl-[5-chloro-2 phenylsulfanylphenylamino)-propyl]-dimethylammonium chloride inhibited trypanothione reductase from Trypanosoma cruzi with a linear competitive Ki value of 1.7 ( 0.2 íM). The phenothiazine and diaryl sulfide quaternary compounds were also powerful antimalarials, providing a new structural framework for antimalarial design.
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Government action needed to step up research and development for world's most neglected diseases by Pecoul B. Expert Rev Anti Infect Ther. 2005 Dec;3(6):841-3.
Neglected and most neglected diseases affect millions of people in the world's poorest countries, yet we do not have safe, affordable, and field-adapted vaccines, diagnostics and drugs to tackle them.
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Public-private partnership: from there to here by Croft SL. Trans R Soc Trop Med Hyg. 2005 Oct; 99 Suppl 1:S9-14.
Major changes in research and development (R&D) for drugs to treat tropical and neglected diseases have occurred in the past five years. Public-private partnerships have proved that they can move compounds quickly through the R&D pipeline. The challenge is to ensure that the products are delivered to the people who need them and to ensure that scientists in endemic countries are involved in the whole process.
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DNDi in the British Medical Journal, July 2005: Prioritising Neglected Diseases Related to Poverty by Rhona MacDonald. BMJ. 2005 Jul; 331:12.
Bernard Pécoul, director of the Drugs for Neglected Diseases Initiative, tells Rhona MacDonald how his organisation is hoping to help millions of people living in poverty worldwide.
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Drugs for Neglected Diseases Initiative. Wasunna KM. Afr J Health Sci. 2005 Jan-Jun;12(1-2):i-ii.
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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. Click here to download the full article [PDF]

Design and synthesis of peptidomimetic protein farnesyltransferase inhibitors as anti-Trypanosoma brucei agents by Ohkanda J, Buckner FS, Lockman JW, Yokoyama K, Carrico D, Eastman R, de Luca-Fradley K, Davies W, Croft SL, Van Voorhis WC, Gelb MH, Sebti SM, Hamilton AD. J Med Chem. 2004 Jan 15;47(2):432-45.
On the basis of the structure of the CVIM tetrapeptide substrate of mammalian protein farnesyltransferase, a series of imidazole-containing peptidomimetics was designed and synthesized, and their inhibition activity against Trypanosoma brucei protein farnesyltransferase (TbPFT) was evaluated.
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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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Efficacy of therapeutic combinations with artemisinin derivatives in the treatment of non complicated malaria in Burundi by Ndayiragije A, Niyungeko D, Karenzo J, Niyungeko E, Barutwanayo M, Ciza A, Bosman A, Moyou-Somo R, Nahimana A, Nyarushatsi JP, Barihuta T, Mizero L, Ndaruhutse J, Delacollette C, Ringwald P, Kamana J. Trop Med Int Health. 2004 Jun; 9(6): 673-9.
Faced with the problem of resistance to chloroquine and sulfadoxine-pyrimethamine, the Ministry of Public Health of Burundi decided to study the efficacy of two artemisinin-based combinations, the fixed combination of artemether-lumefantrine and the combination of amodiaquine + artesunate. During a consensus workshop, the Ministry of Public Health agreed on the combination of artesunate and amodiaquine as the first line drug for the treatment of uncomplicated falciparum malaria in Burundi including epidemic outbreak.
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Combined antimalarial therapy using artemisinin by Majori G. Parassitologia. 2004 Jun;46(1-2):85-7.
The existing armamentarium of drugs for the treatment and prevention of malaria is limited primarily by resistance (and cross-resistance between closely related drugs). However, most of these drugs still have a place and their life-span could be prolonged if better deployed and used, and also by rationally combining them based on pharmacodynamic and pharmacokinetic properties. Newer compounds are also being developed. The nature of malaria disease and its prevalence in the developing world call for innovative approaches to develop new affordable drugs and to safeguard the available ones.
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Developing artemisinin based drug combinations for the treatment of drug resistant falciparum malaria: A review by Olliaro PL, Taylor WR. J Postgrad Med. 2004 Jan-Mar; 50(1):40-4. Review.
The emergence and spread of drug resistant malaria represents a considerable challenge to controlling malaria. To date, malaria control has relied heavily on a comparatively small number of chemically related drugs, belonging to either the quinoline or the antifolate groups. Controlling resistance is key to ensuring that the investment put into developing new antimalarial drugs is not wasted. This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin-based combinations to those that need them most.
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New Drugs for Neglected Diseases: From Pipeline to Patients by Bernard Pécoul. PLoS Med. 2004 Oct; 1(1):e6. Epub 2004 Oct 19.
In wealthy countries,state-funded research has yielded breakthroughs in molecular biology,chemistry,and engineering.These advances have been taken up by the pharmaceutical industry and applied to drug development for a growing range of illnesses and conditions.As a result, patients have access to new drugs that are better tolerated, more specific,and more effective than old ones.
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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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Antimalarial compounds: from bench to bedside by Olliaro PL, Taylor WR. J Exp Biol. 2003 Nov;206(Pt 21):3753-9.
The emergence and spread of drug-resistant malaria parasites is the major threat to effective malaria control. Experience has shown that resistance eventually curtails the life span of antimalarial drugs. If measures are not applied to contain resistance, the investment put into the development of new drugs will be squandered. This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin-based combinations to those that need them most.
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Recent advances in research and control of malaria, leishmaniasis, trypanosomiasis and schistosomiasis by Croft SL, Vivas L, Brooker S. East Mediterr Health J. 2003 Jul;9(4):518-33. Review.
In the Eastern Mediterranean Region of the World Health Organization (WHO), malaria, schistosomiasis, leishmaniasis and trypanosomiasis are the parasitic diseases of major importance. Our review focuses on recent advances in the control and treatment of these diseases with particular reference to diagnosis, chemotherapy, vaccines, vector and environmental control.
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Initiative launched to develop drugs for neglected diseases by Frankish H. Lancet. 2003 Jul 12; 362(9378):135.
A new initiative that aims to develop drugs to tackle diseases that affect the world's poorest people was launched in Geneva on July 3. The Drugs for Neglected Diseases Initiative (DNDi) aims to identify drugs to combat diseases such as trypanosomiasis, visceral leishmaniasis, and Chagas disease, which affect more than 350 million people every year.
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2002

Treatment of human African trypanosomiasis—present situation and needs for research and development by Legros, D. et al., Lancet Infect Dis 2002 2: 437–40.
Human African trypanosomiasis (sleeping sickness) re-emerged in the 1980s. However, little progress has been made in the treatment of this disease over the past decades. Research and development efforts must be made for the development of new compounds. At the same time, on a long term basis, ambitious research programmes for new compounds must be supported to ensure the sustainable development of new drugs.
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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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Reflection & Reaction by Alimuddin Zumla, Lancet Infect Dis 2002 July, 2:393.
Recent global partnership initiatives have focused on stimulating further interest in the development and provision of drugs for the world's top three killer infectious diseases: AIDS/HIV, malaria, and tuberculosis. The “most neglected” diseases (where there are no affordable, effective, easy to use medicines available) continue to cause significant morbidity and mortality in developing countries. This paper is a short introduction to a series of articles outlining research and development priorities for sleeping sickness, visceral leishmaniasis and malaria.
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The world's most neglected diseases. Ignored by the pharmaceutical industry and by public­private partnerships by Yamey G, Torreele E. BMJ. 2002 Jul 27;325(7357):176-7.
The article discusses issues about the “most neglected” diseases as still being ignored not just by the pharmaceutical industry but also by public-private partnerships.
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Drug development for neglected diseases: a deficient market and a public-health policy failure by Trouiller, P. et al., June 2002, Lancet, 359: 2188–94.
There is a lack of effective, safe, and affordable pharmaceuticals to control infectious diseases that cause high mortality and morbidity among poor people in the developing world. This paper analyses outcomes of pharmaceutical research and development over the past 25 years, and reviews current public and private initiatives aimed at correcting the imbalance in research and development that leaves diseases that occur predominantly in the developing world largely unaddressed.
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2001

Availability and affordability of treatment for Human African Trypanosomiasis by Etchegorry MG, Helenport JP, Pecoul B, Jannin J, Legros D. Trop Med Int Health. 2001 Nov;6(11):957-9.
Human African Trypanosomiasis (HAT) is a re-emerging disease whose usual treatments are becoming less efficient because of the increasing parasite resistance. Availability of HAT drugs is poor and their production in danger because of technical, ecological and economic constraints.
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Neglected diseases of global importance by Ford N, Torreele E. JAMA. 2001 Dec 19;286(23):2943-4.
In this letter to the editor, the authors raise the need of increased responsibility from the private and public sectors in order to ensure that people’s health needs are met, and the importance of non-for-profit drug development initiatives to address the imbalance in the burden of infectious diseases between rich and poor countries.
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Drugs for neglected diseases: a failure of the market and a public health failure? By Trouiller P, Torreele E, Olliaro P, White N, Foster S, Wirth D, Pecoul B. Trop Med Int Health. 2001 Nov;6(11):945-51. Review.
Infectious diseases cause the suffering of hundreds of millions of people, especially in tropical and subtropical areas. Effective, affordable and easy-to-use medicines to fight these diseases are nearly absent. Although science and technology are sufficiently advanced to provide the necessary medicines, very few new drugs are being developed. An urgent reorientation of priorities in drug development and health policy is needed. New and creative strategies involving both the public and the private sector are needed to ensure that affordable medicines for today's neglected diseases are developed.
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Public-private partnerships for health: their main targets, their diversity, and their future directions. Widdus R. Bull World Health Organ. 2001;79(8):713-20. Epub 2001 Oct 24.
The global burden of disease, especially the part attributable to infectious diseases, disproportionately affects populations in developing countries. Inadequate access to pharmaceuticals plays a role in perpetuating this disparity. A large variety of public-private partnerships, combining the skills and resources of a wide range of collaborators, have arisen for product development, disease control through product donation and distribution, or the general strengthening or coordination of health services. Suggestions are made for public, private, and joint activities that could help to improve the access of poor populations to the pharmaceuticals and health services they need.
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1999

Antiparasitic agents: challenges of sleeping sickness, hopes for malaria by Croft SL. Curr Opin Infect Dis. 1999 Dec; 12(6):557-8.
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Access to Essential Drugs in Poor Countries – A Lost Battle ? ” by Pécoul, B. et al., JAMA, January 27, 1999—Vol 281, No. 4.
This article focuses on the problems of access to quality drugs for the treatment of diseases that predominantly affect the developing world: (1) poor-quality and counterfeit drugs; (2) lack of availability of essential drugs due to fluctuating production or prohibitive cost; (3) need to develop field-based drug research to determine optimum utilization and remotivate research and development for new drugs for the developing world; and (4) potential consequences of recent World Trade Organization agreements on the availability of old and new drugs.
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