Treatment outcomes and risk factors for relapse in patients with early-stage human African trypanosomiasis (HAT) in the Republic of Congo

Balasegaram, Manica; Harris, Steve; Checchi, Francesco; Hamel, Catherine; Karunakara, Unni

doi:10.2471/blt.05.028399

Cited by 32 publications

(22 citation statements)

References 11 publications

(11 reference statements)

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“…A slow uptake of pentamidine into human brain also has been described, which might be a reflection of the trapping effect of the BBB, with it only being detectable ϳ30 days after the start of a daily regimen (ϳ4 mg/kg/day pentamidine isethionate) in AIDS patients (Donnelly et al, 1988). Furthermore, tissue and plasma protein binding of pentamidine is established and contributes to its long-lasting prophylactic effect in humans (Donnelly et al, 1988;Balasegaram et al, 2006) with pentamidine having a half-life of 22 to 47 h (Bronner et al, 1991). Pentamidine is not metabolized significantly in humans or mice , and this investigation supports this because we found no HPLC evidence of [ 3 H]pentamidine being metabolized in brain tissue.…”

Section: Discussionmentioning

confidence: 99%

Pentamidine Movement across the Murine Blood-Brain and Blood-Cerebrospinal Fluid Barriers: Effect of Trypanosome Infection, Combination Therapy, P-Glycoprotein, and Multidrug Resistance-Associated Protein

Sanderson¹,

Dogruel²,

Rodgers³

et al. 2009

J Pharmacol Exp Ther

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During the first stage of human African trypanosomiasis (HAT),Trypanosoma brucei gambiense is found mainly in the blood, and pentamidine treatment is used. Pentamidine is predominantly ineffective once the parasites have invaded the central nervous system (CNS). This lack of efficacy is thought to be due to the inability of pentamidine to cross the blood-brain barrier, although this has never been explored directly. This study addresses this using brain perfusion in healthy mice, P-glycoprotein-deficient mice, and in a murine model of HAT (T. brucei brucei). The influence of additional antitrypanosomal drugs on pentamidine delivery to the CNS also was investigated. Results revealed that [ 3 H]pentamidine can cross the blood-brain barrier, although a proportion was retained by the capillary endothelium and failed to reach the healthy or trypanosome-infected brain (up to day 21 p.i.). The CNS distribution of pentamidine was increased in the final (possibly terminal) stage of trypanosome infection, partly because of loss of barrier integrity (days 28 -35 p.i.) as measured by [14 C]sucrose and [ 3 H]suramin. Furthermore, pentamidine distribution to the CNS involved influx and efflux [via P-glycoprotein and multidrug resistance-associated protein (MRP)] transporters and was affected by the other antitrypanosomal agents, suramin, melarsoprol, and nifurtimox, but not eflornithine. These interactions could contribute to side effects or lead to the development of parasite resistance to the drugs. Thus, great care must be taken when designing drug combinations containing pentamidine or other diamidine analogs. However, coadministration of P-glycoprotein and/or MRP inhibitors with pentamidine or other diamidines might provide a means of improving efficacy against CNS stage HAT.

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Section: Discussionmentioning

confidence: 99%

Pentamidine Movement across the Murine Blood-Brain and Blood-Cerebrospinal Fluid Barriers: Effect of Trypanosome Infection, Combination Therapy, P-Glycoprotein, and Multidrug Resistance-Associated Protein

Sanderson¹,

Dogruel²,

Rodgers³

et al. 2009

J Pharmacol Exp Ther

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“…15 In the Republic of the Congo, fol--lowing a period of civil war in the 1990s, Médecins Sans Frontières (MSF) assisted the Ministry of Health in implementing 16 This was accompanied by a formal change in the programme's protocol in 2003. 16,17 Both melarsoprol and eflornithine were available throughout the dura--tion of the programme but melarsoprol remained the first-line therapy until August 2003; eflornithine was reserved for patients whom clinicians felt were too ill for melarsoprol. Internal analysis of the MSF programme results at this time led to eflornithine becoming the first-line therapy at all MSF sites as a result of a high case-fatality rate and relapse rate among patients treated with melarsoprol: 3/46 (6.5%) patients treated with eflornithine died or relapsed compared with 46/429 (10.7%) treated with melarsoprol.…”

Section: ‫صفحة‬ ‫يف‬ ‫بالعربية‬ ‫امللخص‬ ‫عىل‬ ‫االطالع‬ ‫ميكن‬mentioning

confidence: 99%

Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of Congo

Balasegaram

Harris

Checchi

et al. 2006

Bull World Health Organ

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Objective To compare the effectiveness of melarsoprol and eflornithine in treating late-stage Gambian trypanosomiasis in the Republic of the Congo. Methods We analysed the outcomes of death during treatment and relapse within 1 year of discharge for 288 patients treated with eflornithine, 311 patients treated with the standard melarsoprol regimen and 62 patients treated with a short-course (10-day) melarsoprol regimen between April 2001 and April 2005. Findings A total of 1.7% (5/288) of patients treated with eflornithine died compared with 4.8% (15/311) of those treated with standard melarsoprol and 6.5% (4/62) of those treated with short-course melarsoprol. Patients treated with eflornithine tended to be younger and were more likely to have trypanosomes or higher white blood cell counts in their cerebrospinal fluid. The cumulated incidence of relapse among patients who attended at least one follow-up visit 1 year after discharge was 8.1% (11/136) for those treated with eflornithine, 14% (36/258) for those treated with standard melarsoprol and 15.5% (9/58) for those treated with shortcourse melarsoprol. In a multivariate analysis, when compared with eflornithine, standard melarsoprol was found to be a risk factor for both death (odds ratio (OR) = 2.87; 95% confidence interval (CI) = 1.03-8.00) and relapse (hazard ratio (HR) = 2.47; 95% CI = 1.22-5.03); when compared with eflornithine, short-course melarsoprol was also found to be a risk factor for death (OR = 3.90; 95% CI = 1.02-14.98) and relapse (HR = 6.65; 95% CI = 2.61-16.94). Conclusion The effectiveness of melarsoprol treatment appears to have diminished. Eflornithine seems to be a better first-line therapy for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. IntroductionAfrican trypanosomiasis is a public health hazard in many countries in sub-Saharan Africa, with an incidence of around 20 000 new cases a year.1,2 The disease is fatal if untreated. Control programmes have been severely weakened by war and civil instability in many of the countries with the highest prevalence. 3,4 In central and west Africa the disease is predominantly caused by the protozoan Trypanosoma brucei gambiense and is transmitted by the tsetse fly (Glossina spp.) in a human-fly-human cycle. Pentamidine, first-line treatment for early-stage disease, cannot be used if the parasites have invaded the central nervous system because the drug does not cross the blood-brain barrier. The principal treatment options for late-stage (or stage-2) disease are either melarsoprol (an organoarsenic compound that in--hibits parasite glycolysis) or eflornithine (an irreversible inhibitor of ornithine decarboxylase which is necessary for the parasite's synthesis of DNA and RNA). Both drugs must be adminis--tered intravenously over a period of 1-4 weeks, which is logistically challenging in health-care systems in the developing world. Melarsoprol is a highly toxic drug that causes encephalopathy in 5-10% of patients and approximately 40% of these patients will die. 1,5 Eflo...

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“…Due to the high potency of pentamidine and the low drug levels detected in the CSF (Bronner et al 1991) the use to treat 'intermediate stage' patients (up to 10 or 20 white blood cells (WBC) mm − 3 in CSF) was suggested (Doua et al 1996). The resulting efficacy in respective studies is equivocal (Ruiz et al 2002;Lejon et al 2003;Balasegaram et al 2006b). Hence the use of pentamidine for patients with 5-20 cells mm − 3 should not be generally recommended, but should be restricted to areas where melarsoprol is still in use, and where a very good adherence to follow up and rapid access to rescue treatment is guaranteed.…”

Section: P E N T a M I D I N Ementioning

confidence: 99%

Chemotherapy against human African trypanosomiasis: Is there a road to success?

Burri

2010

Parasitology

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S U M M A R YFor over fifty years, human African trypanosomiasis (HAT, sleeping sickness) has been treated with suramin, pentamidine and the very toxic organo-arsenical melarsoprol that was the only drug available for effective treatment of the second stage of the disease. Recently there have been significant efforts using molecular and biochemical approaches to drug design, including high-throughput screening, but the number of lead compounds with promising activity against T. brucei spp. and an acceptable toxicity index has remained astonishingly small. Clinical research continues to be difficult due to the economic constraints and the complexity of trials on a low prevalence disease in remote and impoverished African regions. Despite those limitations the situation for the patients is improving thanks to the combination of a number of critical factors. By the late 1990s the disease had reached epidemic levels that triggered political support. WHO would sign a donation agreement with the manufacturers for all drugs to treat HAT. A result of this agreement was that eflornithine which is much safer than melarsoprol became available and widely used by non-governmental organizations. The IMPAMEL I and II programmes demonstrated that against all odds the conduct of clinical trials on HAT was feasible. This allowed the initiation of trials on combination therapies which eventually resulted in the nifurtimox-eflornithine combination treatment (NECT). This combination is currently being introduced as first line treatment, and there is even the prospect of having a new compound, fexinidazole, in the development pipeline. This review summarizes the key information about the existing drugs and gives a comprehensive summary about the recent and currently ongoing efforts towards new drugs.

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Treatment outcomes and risk factors for relapse in patients with early-stage human African trypanosomiasis (HAT) in the Republic of Congo

Cited by 32 publications

References 11 publications

Pentamidine Movement across the Murine Blood-Brain and Blood-Cerebrospinal Fluid Barriers: Effect of Trypanosome Infection, Combination Therapy, P-Glycoprotein, and Multidrug Resistance-Associated Protein

Pentamidine Movement across the Murine Blood-Brain and Blood-Cerebrospinal Fluid Barriers: Effect of Trypanosome Infection, Combination Therapy, P-Glycoprotein, and Multidrug Resistance-Associated Protein

Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of Congo

Chemotherapy against human African trypanosomiasis: Is there a road to success?

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