Chemotherapy and chemoprophylaxis of African trypanosomiasis

Williamson, J.

doi:10.1016/0014-4894(62)90046-2

Cited by 23 publications

(14 citation statements)

References 375 publications

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“…The ca-GP system mediating terminal respiration and the recycling of NADH in bruceisubgroup trypanosomes has been proposed as a likely chemotherapeutic target, since it is essential for survival of the parasite but not for the survival of the host (18). Williamson (35) suggested that anticancer agents might find use in trypanosome chemotherapy. The drugs used here specifically inhibit mammalian cancer cell a-GPDH (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…Effects of trypanocides, especially arsenicals, on trypanosome glycolytic enzymes have hardly been investigated (35). The few previous investigations of their mode of action have not correlated growth inhibition with enzyme inhibition (7,8,10,21,27).…”

Section: Discussionmentioning

confidence: 99%

“…Their mode of action is unclear, and their inhibition of trypanosome glycolytic enzymes is incompletely charted (18,35). Few practical drugs have been developed for African human trypanosomiasis during the past decade.…”

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confidence: 99%

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Effects of Some Antitumor Agents on Growth and Glycolytic Enzymes of the Flagellate Crithidia

1969

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Some antitumor agents known to specifically inhibit certain tumor cell enzymes were examined for activity against glycolytic enzymes and growth of the insect trypanosomatid, Crithidia fasciculata. The cytoplasmic enzymes hexokinase, a-glycerophosphate dehydrogenase, malic dehydrogenase, and glucose-6-phosphate dehydrogenase were tested. Agaricic acid (2-hydroxy-1 ,2,3-nonadecane tricarboxylic acid) was highly inhibitory (50 to 100%) to malic and a-glycerophosphate dehydrogenases at 3 x 10-5 M; 2-(p-hydroxyphenyl)-2-phenylpropane (2 X 10-M), and 5,6-dichloro-2-benzoxazolinone (5 X 10-4 M) were less effective (50% inhibition) against them. The antiprotozoal agents primaquine (4 X 10-4 M) and Melarsoprol (8 X 10-4 M) were 30 to 40% inhibitory. Agaricic acid, 2-(p-hydroxyphenyl)-2-phenylpropane, and 5,6-dichloro-2-benzoxazolinone inhibited growth of Crithidia at less than 10-4 M. Eight other test compounds from the Cancer Chemotherapy National Service Center (CCNSC) were not toxic to cell growth, although two (4-biphenylcarboxylic acid and 1-[p-chlorobenzyl]-2-ethyl-5-methyl-indole-3acetic acid) inhibited Crithidia a-glycerophosphate dehydrogenase below 1 mM. All of the compounds used specifically inhibited cancer cell a-glycerophosphate dehydrogenase. The corresponding enzyme in pathogenic African trypanosomes is important in their terminal respiration. C. fasciculata may be useful in preliminary evaluation of chemotherapeutic agents as potential trypanocides. 11, 12) and arsenicals on glycolytic enzymes and cells of C. fasciculata. This trypanosomatid 23

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of Some Antitumor Agents on Growth and Glycolytic Enzymes of the Flagellate Crithidia

1969

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“…Ironically, trypanosomes were among the first organisms to be targeted by synthetic drugs and Paul Ehrlich, ‘the father of chemotherapy’ (Drews, 2004), chose these organisms as a model on which to test his ideas. During the first two‐thirds of the twentieth century, several compounds were introduced to treat HAT (Williamson, 1962, 1970; Apted, 1970). Sanofi‐Aventis and Bayer between them currently produce all of the licensed anti‐HAT drugs and donate them free of charge to the World Health Organization (WHO) who distributes them in Africa.…”

Section: Introductionmentioning

confidence: 99%

Human African trypanosomiasis: pharmacological re‐engagement with a neglected disease

Barrett

Boykin

Brun

et al. 2007

British J Pharmacology

289

355

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This review discusses the challenges of chemotherapy for human African trypanosomiasis (HAT). The few drugs registered for use against the disease are unsatisfactory for a number of reasons. HAT has two stages. In stage 1 the parasites proliferate in the haemolymphatic system. In stage 2 they invade the central nervous system and brain provoking progressive neurological dysfunction leading to symptoms that include the disrupted sleep wake patterns that give HAT its more common name of sleeping sickness. Targeting drugs to the central nervous system offers many challenges. However, it is the cost of drug development for diseases like HAT, that afflict exclusively people of the world's poorest populations, that has been the principal barrier to new drug development and has led to them becoming neglected. Here we review drugs currently registered for HAT, and also discuss the few compounds progressing through clinical trials. Finally we report on new initiatives that might allow progress to be made in developing new and satisfactory drugs for this terrible disease.

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“…Seventeen years later, adoption of even a small improvement in treatment regimes is a step forward. As the trypanosome biochemist Jim Williamson so cogently remarked “there have been many more reviews of trypanosome chemotherapy than new drugs” [7]. However, the challenge of the eflornithine/nifurtimox option, even if this combination therapy is available as an “essential drug,” is classic: transport of a weighty product; the difficulties of intravenous administration in rural settings where health facilities are minimal; drug availability and affordability; the intensity of the specialised medical care required for patients; the monitoring of side effects and the potential for relapses requiring regular follow-up: all costly activities where patients are beyond the end of the road.…”

mentioning

confidence: 99%