Treatment of arsenical refractory Rhodesian sleeping sickness in Kenya

Bales, James D.; Harrison, SM; Mbwabi, D.; Schecter, P. J.

doi:10.1080/00034983.1989.11812414

Cited by 33 publications

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“…Melarsoprol, which is effective against the second stage of the disease, causes encephalopathy in 5-10% of treated patients [2]. Eflornithine, also a second stage specific drug, is less toxic however is not effective against T.b.rhodesiense [3]. Suramin, pentamidine, melarsoprol and eflornithine all require intravenous injection for treatment which is not practical considering the poor medical facilities in most of the disease endemic areas.…”

Section: Introductionmentioning

confidence: 99%

A luciferase based viability assay for ATP detection in 384-well format for high throughput whole cell screening of Trypanosoma brucei brucei bloodstream form strain 427

Sykes

Avery

2009

Parasites Vectors

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BackgroundHuman African Trypanosomiasis (HAT) is caused by two trypanosome species, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Current drugs available for the treatment of HAT have significant issues related to toxicity, administration regimes with limited effectiveness across species and disease stages, thus there is a considerable need to find alternative drugs. A well recognised approach to identify new drug candidates is high throughput screening (HTS) of large compound library collections.ResultsWe describe here the development of a luciferase based viability assay in 384-well plate format suitable for HTS of T.b.brucei. The parameters that were explored to determine the final HTS assay conditions are described in detail and include DMSO tolerability, Z', diluents and cell inoculum density. Reference compound activities were determined for diminazene, staurosporine and pentamidine and compared to previously published IC50 data obtained. The assay has a comparable sensitivity to reference drugs and is more cost effective than the 96-well format currently reported for T.b.brucei.ConclusionDue to the reproducibility and sensitivity of this assay it is recommended for potential HTS application. As it is commercially available this assay can also be utilised in many laboratories for both large and small scale screening.

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Section: Introductionmentioning

confidence: 99%

A luciferase based viability assay for ATP detection in 384-well format for high throughput whole cell screening of Trypanosoma brucei brucei bloodstream form strain 427

Sykes

Avery

2009

Parasites Vectors

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“…This is particularly true in East Africa, which has undergone recent epidemics in Uganda, north of Lake Victoria and along the Kenya-Uganda border, in Zaire, and in the Sudan (7, 26). Chemotherapy for East African sleeping sickness is unreliable: drug resistance to arsenical drugs is common (7,26), and clinical strains refractory to DL-a-difluoromethylomithine (DFMO; eflornithine; Ornidyl) and diamidines have also been documented (5,7,26). Clearly, there is a pressing need for alternatives to existing treatment methods.…”

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“…Major lapses in control activities have resulted from military activities in some areas so that 80% of the at-risk population is not covered by diagnostic or vector control measures (24). This is particularly true in East Africa, which has undergone recent epidemics in Uganda, north of Lake Victoria and along the Kenya-Uganda border, in Zaire, and in the Sudan (7,26). Chemotherapy for East African sleeping sickness is unreliable: drug resistance to arsenical drugs is common (7,26), and clinical strains refractory to DL-a-difluoromethylomithine (DFMO; eflornithine; Ornidyl) and diamidines have also been documented (5,7,26).…”

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Combination chemotherapy of drug-resistant Trypanosoma brucei rhodesiense infections in mice using DL-alpha-difluoromethylornithine and standard trypanocides

Bacchi

Nathan

Yarlett

et al. 1994

Antimicrob Agents Chemother

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Combinations of DL-ot-difluoromethylornithine (DFMO; eflornithine; Ornidyl) with either suramin or melarsen oxide were found to be effective against acute laboratory model infections with Trypanosoma brucei rhodesiense. We used clinical isolates known to be resistant to these drugs when used singly. An infection with a melarsen oxide-refractory isolate was cured by a combination of low-dose DFMO (0.5% in the drinking water) plus low-dose suramin (1 mg/kg of body weight given intraperitoneally). Another strain, moderately resistant to arsenical drugs, was cured with combinations of 4% DFMO with 5 mg of melarsen oxide per kg. Furthermore, a combination of DFMO (2% in the drinking water) and suramin (20 mg/kg) provided a 100%S cure rate in a central nervous system model, although the same doses of these drugs used singly were completely ineffective. The synergism of DFMO and suramin against an acute infection was improved when suramin was given at the end of the DFMO administration. No adverse interactions were observed when high doses of DFMO combined with high doses of suramin were administered to uninfected mice. These results suggest that combinations of DFMO and suramin should be examined clinically for activity in arsenical-drugrefractory cases of East African sleeping sickness.Sleeping sickness remains a serious health problem in equatorial Africa. Major lapses in control activities have resulted from military activities in some areas so that 80% of the at-risk population is not covered by diagnostic or vector control measures (24). This is particularly true in East Africa, which has undergone recent epidemics in Uganda, north of Lake Victoria and along the Kenya-Uganda border, in Zaire, and in the Sudan (7, 26). Chemotherapy for East African sleeping sickness is unreliable: drug resistance to arsenical drugs is common (7,26), and clinical strains refractory to DL-a-difluoromethylomithine (DFMO; eflornithine; Ornidyl) and diamidines have also been documented (5,7,26). Clearly, there is a pressing need for alternatives to existing treatment methods.The newest drug to be approved by the U.S. Food and Drug Administration for use against African trypanosomiasis is DFMO. DFMO is an irreversible inhibitor of ornithine decarboxylase, a key enzyme of polyamine biosynthesis. Although this compound was originally designed as an antitumor agent, it has proven to be highly effective against Trypanosoma brucei gambiense infections (22,24,26

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“…DFMO is a clinically effective agent for the treatment of early-and late-stage Trypanosoma brucei gambiense infections in West Africa (18,20); however, it has not been as effective against East African disease caused by Trypanosoma brucei rhodesiense (5,20). In light of the demonstrated resistance of T. brucei rhodesiense to DFMO and standard trypanocidal agents (3,20), there is a need for a novel agent which is effective against this form of the disease.…”

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Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor

Bacchi

Nathan

Yarlett

et al. 1992

Antimicrob Agents Chemother

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The compound 5'-{[(Z)-4-amino-2-butenyl]methylamino}-5'-deoxyadenosine (MDL73811), a potent inhibitor of S-adenosylmethionine decarboxylase, was effective in mice against six of eight clinical isolates of 7rypano-soma brucei rhodesiense, the causative agent of East African sleeping sickness. In combination with the ornithine decarboxylase inhibitor DL-e-dfloromethylornithine (DFMO; Ornidyl), MDL73811 acted synergistically to cure seven of eight infections. MDL73811 was effective when given singly at 50 to 100 mg/kg of body weight per day for 7 days (osmotic pumps). In combination with subcurative DFMO levels (0.25 to 1.0% in drinking water for 7 days), the curative MDL73811 dose could be lowered to 25 or 50 mgkg, depending on the isolate. Oral administration of the MDL73811-DFMO combination was also effective in an acute infection and in a long-term central nervous system model of 1fypansoma brucei brucei infection. These data indicate that MDL73811 may be effective therapeutically in drug-refractory and late-stage East African typanosomiasis.

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Treatment of arsenical refractory Rhodesian sleeping sickness in Kenya

Cited by 33 publications

References 0 publications

A luciferase based viability assay for ATP detection in 384-well format for high throughput whole cell screening of Trypanosoma brucei brucei bloodstream form strain 427

A luciferase based viability assay for ATP detection in 384-well format for high throughput whole cell screening of Trypanosoma brucei brucei bloodstream form strain 427

Combination chemotherapy of drug-resistant Trypanosoma brucei rhodesiense infections in mice using DL-alpha-difluoromethylornithine and standard trypanocides

Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor

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