Scientific publications 2006

New Azasterols against Trypanosoma brucei: Role of 24-Sterol Methyltransferase in Inhibitor Action by Gros L, Castillo-Acosta VM, Jimenez Jimenez C, Sealey-Cardona M, Vargas S, Manuel Estevez A, Yardley V, Rattray L, Croft SL, Ruiz-Perez LM, Urbina JA, Gilbert IH, Gonzalez-Pacanowska D. Antimicrob Agents Chemother. 2006 Aug; 50(8):2595-601.
A series of azasterol derivatives, designed as potential inhibitors of the Δ24 –sterol methyltransferase enzyme (24-SMT), were synthesized and evaluated for their activities against parasitic protozoa. We conclude that the designed compounds act at sites other than 24-SMT in Trypanosoma brucei.
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Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents by Vicik R, Hoerr V, Glaser M, Schultheis M, Hansell E, McKerrow JH, Holzgrabe U, Caffrey CR, Ponte-Sucre A, Moll H, Stich A, Schirmeister T. Bioorg. Med. Chem. Lett. 2006 May 15;16(10):2753-7. Epub 2006 Mar 3.
The protozoan parasite Trypanosoma brucei causes Human African trypanosomiasis, which is fatal if left untreated. Due to the toxicity of currently used drugs and emerging drug resistance, there is an urgent need for novel therapies. The major trypanosome papain-like cysteine protease expressed by the parasite (e.g., rhodesain in T. b. rhodesiense) is considered an important target for the development of new trypanocidal drugs.
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Discovery of Trypanocidal Compounds by Whole Cell HTS of Trypanosoma brucei by Mackey ZB, Baca AM, Mallari JP, Apsel B, Shelat A, Hansell EJ, Chiang PK, Wolff B, Guy KR, Williams J, McKerrow JH. Chem Biol Drug Des. 2006 May;67(5):355-63.
One potentially rapid and cost-effective approach to identifying and developing new trypanocidal drugs would be high throughput-screening of existing drugs already approved for other uses, as well as clinical candidates in late development. A screen was performed in a collection of 2160 FDA approved drugs, bioactive compounds and natural products to identify hits that were cytotoxic to cultured Trypanosoma brucei at a concentration of 1lM or less. From the screen, 35 hits from seven different drug categories were identified.
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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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Inhibition of Trypanosoma cruzi Hexokinase by Bisphosphonates by Hudock MP, Sanz-Rodriguez CE, Song Y, Chan JM, Zhang Y, Odeh S, Kosztowski T, Leon-Rossell A, Concepcion JL, Yardley V, Croft SL, Urbina JA, Oldfield E. J Med Chem. 2006 Jan 12;49(1):215-23.
Hexokinase is the first enzyme involved in glycolysis in most organisms, including the etiological agents of Chagas disease (Trypanosoma cruzi) and African sleeping sickness (Trypanosoma brucei). The T. cruzi enzyme is unusual since, unlike the human enzyme, it is inhibited by inorganic diphosphate (PPi).
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Use of weight-for-age-data to optimize tablet strength and dosing regimens for a new fixed-dose artesunate-amodiaquine combination for treating falciparum malaria by Taylor WR, Terlouw DJ, Olliaro PL, White NJ, Brasseur P, ter Kuile FO. Bull World Health Organ. 2006 Dec;84(12):956-64.
The objective of this study was to test a novel methodology to define age-based dosing regimens for the treatment of malaria with a new, user-friendly, blister-packaged fixed-dose combination of artesunate and amodiaquine. The proposed method to use weight-for-age reference data from countries where malaria is endemic is a useful tool for designing age based dosing regimens for antimalarial drugs for drug registration and field use.
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An open label randomized comparison of mefloquine–artesunate as separate tablets vs. a new co-formulated combination for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand by Ashley EA, Lwin KM, McGready R, Simon WH, Phaiphun L, Proux S, Wangseang N, Taylor W, Stepniewska K, Nawamaneerat W, Thwai KL, Barends M, Leowattana W, Olliaro P, Singhasivanon P, White NJ, Nosten F. Trop Med Int Health. 2006 Nov;11(11):1653-60.
Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug resistant falciparum malaria.
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Population Pharmacokinetic Assessment of a New Regimen of Mefloquine Used in Combination Treatment of Uncomplicated Falciparum Malaria by Ashley EA, Stepniewska K, Lindegardh N, McGready R, Hutagalung R, Hae R, Singhasivanon P, White NJ, Nosten F. Antimicrob Agents Chemother. 2006 Jul;50(7):2281-5.
A fixed artesunate-mefloquine combination, comprising three daily doses of 8 mg of mefloquine/kg of body weight and 4 mg of artesunate/kg, has been developed recently. This study was designed to construct a population pharmacokinetic model describing this new dosage regimen of mefloquine given as loose tablets together with artesunate. This new regimen is well tolerated and results in an equivalent therapeutic response.
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Accessibility and affordability of malaria intervention, treatment and prevention in Africa by Koech DK. Afr J Health Sci. 2006;13(1-2):i.
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Evaluation of Azasterols as Anti-Parasitics by Gros L, Lorente SO, Jimenez CJ, Yardley V, Rattray L, Wharton H, Little S, Croft SL, Ruiz-Perez LM, Gonzalez-Pacanowska D, Gilbert IH. J Med Chem. 2006 Oct 5;49(20):6094-103.
In this article, the design and synthesis of some novel azasterols is described, followed by their evaluation against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donoVani, and Plasmodium falciparum, the causative agents of human African trypanosomiasis, Chagas disease, leishmaniasis, and malaria, respectively. Some of the compounds showed anti parasitic activity.
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Endemic tropical diseases: comtemporary health problem due to abandoned diseases in the developing world by Ohta N. Kansenshogaku Zasshi. 2006 Sep;80(5):469-74. Review.
There are two kinds of infectious diseases in the world; diseases being paid attention and neglected diseases. The former diseases include HIV/AIDS, tuberculosis and malaria, the latter group include many parasitic, fungal, bacterial and some of viral infections. "Neglected Infectious Diseases", which have been renamed as Endemic Tropical Diseases by WHO, are endemic in the developing world are not newly appeared diseases, but diseases affecting humans in these decades. However, those diseases were not recognized as serious health problems because of socio-economical and/or scientific reasons. Considering that issues of "Neglected Infectious Diseases" are urgent to be solved and also are challenging for modern medicine and medical sciences, researchers in the developed countries including Japan should make efforts to promote more active researches in this field.
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To Fully Tackle the Gang of Four, Needs-Driven R&D is Essential by Torreele E, Royce C, Don R, Sevcsik AM, Croft S. PLoS Med. 2006 Jun;3(6):e282; author reply e284.
In this correspondence, the authors address the challenges set to the global health audience to address neglected tropical diseases affecting the poor and powerless in resource-poor settings. To tackle the gang of four, adequate and field-adapted health tools must be available, and governments must prioritize needs-driven R&D for those diseases where no such tools exist.
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Global framework on essential health R&D by Chirac P and Torreele E. Lancet. 2006 May 13;367:1560-1.
One of the critical issues to be discussed at the next World Health Assembly ( Geneva , May 22-26) will be a resolution about a global framework on essential health research and development. Over the past years, the crisis in research and development in the worldwide pharmaceutical industry, and in particular the absence of research and development for new medicines targeting diseases that mainly affect people in developing countries (neglected diseases), has become a global concern.
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New initiatives against Africa’s worms by Fenwick A. Trans R Soc Trop Med Hyg. 2006 Mar;100(3):200-7. Epub 2005 Dec 15.
Since 1999, the funding available for the control of diseases of poverty (neglected diseases) has increased mainly due to leverage resulting from donations by the Bill and Melinda Gates Foundation and loans from the World Bank. Many countries have embarked on control programmes on a national scale due to drug donation by pharmaceutical companies through vertical programmes.
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No drugs in an age of plenty: urging governments to redress the balance by Torreele E. Interdisciplinary Science Reviews. 2006 Mar;31(1):3-8.
35,000 people die every day from diseases that disproportionately affect the poor in Latin America, Africa, and Asia , and that have been neglected by the pharmaceutical industry and governments. Although scientific knowledge exists to develop new treatments, political will and the profit-driven pharmaceutical model have not sufficiently supported these efforts. Instead, it has been left to generous philanthropic efforts, but this is unsustainable. Public leadership and support is urgently needed.
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