In-Hospital Safety in Field Conditions of Nifurtimox Eflornithine Combination Therapy (NECT) for T. b. gambiense Sleeping Sickness
Caecilia SchmidAndrea KuemmerleJohannes BlumSalah GhabriVictor KandéWilfried MutomboMédard IlungaIsmael LumpunguSylvain MutandaPathou NganzoboDigas Ngolo TeteNono MubwaMays KisalaSéverine BlessonOlaf Valverde Mordt
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Abstract:
Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2(nd) stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use.In a multicentre, open label, single arm, phase IIIb study of the use of NECT for 2(nd) stage T.b. gambiense HAT, all patients admitted to the trial centres who fulfilled inclusion criteria were treated with NECT. The primary outcome was the proportion of patients discharged alive from hospital. Safety was further assessed based on treatment emergent adverse events (AEs) occurring during hospitalisation.629 patients were treated in six HAT treatment facilities in the Democratic Republic of the Congo (DRC), including 100 children under 12, 14 pregnant and 33 breastfeeding women. The proportion of patients discharged alive after treatment completion was 98.4% (619/629; 95%CI [97.1%; 99.1%]). Of the 10 patients who died during hospitalisation, 8 presented in a bad or very bad health condition at baseline; one death was assessed as unlikely related to treatment. No major or unexpected safety concerns arose in any patient group. Most common AEs were gastro-intestinal (61%), general (46%), nervous system (mostly central; 34%) and metabolic disorders (26%). The overall safety profile was similar to previously published findings.In field conditions and in a wider population, including children, NECT displayed a similar tolerability profile to that described in more stringent clinical trial conditions. The in-hospital safety was comparable to published results, and long term efficacy will be confirmed after 24 months follow-up.The trial is registered at ClinicalTrials.gov, number NCT00906880.Keywords:
Eflornithine
Nifurtimox
sleeping sickness, also called human African trypanosomiasis (HAT), results from the infection of humans with either of two protozoan parasites, Trypanosoma brucei gambiense and T. b. rhodesiense. HAT is transmitted by tsetse flies (Glossina spp) and, like the vector, is found exclusively in Africa between the latitudes 14° North and 29° South. A total of 50 million people live in foci where active transmission is possible and are therefore at risk of infection; however, the annual incidence and estimated prevalence currently stand at 7139 and 30 000 cases respectively. When trypanosomes are inoculated into a human host, the resulting clinical disease is classified into a first (early) stage in which trypanosomes are localised within the haemo-lymphatic system and a second (late) stage in which trypanosomes have crossed the blood brain barrier (BBB) and invaded the central nervous system (CNS). Currently, pentamidine and suramin are used to treat the first stage of T. b. gambiense and T. b. rhodesiense HAT, respectively. On the other hand, eflornithine and the nifurtimox eflornithine combination therapy (NECT) are the prefered treatments for second stage T. b. gambiense HAT. The organoarsenic drug melarsoprol may be used for both forms of HAT but is mainly used against T. b. rhodesiense. Clearly, the therapeutic options for HAT are very limited. In addition, available drugs are associated with different levels of toxicity, especially melarsoprol which causes a post treatment reactive encephalopathy (PTRE) in 5-10% of treated patients, up to 50% of PTRE patients may die. There are also reports of high melarsoprol treatment failure rates in some foci and there is a lack of easy to use oral formulations for all the drugs. We have carried out biological and pharmacological investigations of potential new drug candidates in animal models of HAT with the objective of contributing to the development of safe, efficacious and easy to use treatments for HAT. The studies were carried out in the context of a PhD programme at the Swiss TPH/University of Basel and were anchored onto an ongoing diamidines development project of the Consortium for Parasitic Drug Development (CPDD). Vervet monkeys (Chlorocebus [Cercopithecus] aethiops) were the main model for this study. To prepare for the studies in monkeys, one prodrug (DB289) was evaluated in mouse models of first stage HAT. We obtained good activities against different trypanosome isolates, including the one that is used in the monkey model, T. b. rhodesiense KETRI2537. We further evaluated the metabolism of the prodrugs in monkey liver microsomes. In all cases, prodrugs were metabolized to generate expected intermediate and active metabolites, thus allowing us to proceed to test the compounds for safety in un-infected monkeys. We determined that in monkeys: i) diamidine toxicity was dependent on the dose and duration of dosing, ii) the plasma concentrations of active metabolites were potentially therapeutic for HAT, and iii) the dose level at which there were no observed adverse effects (NOAEL). Three prodrugs (DB289, DB844 and DB868) and one active compound (DB829) were subsequently evaluated for efficacy at dose rates that were equal or below NOAEL. In general, the prodrugs were highly active against first stage HAT after oral administration and one prodrug (DB844) had additionally an improved activity (43%) in the second stage monkey HAT model in comparison with pentamidine (0%). The intramuscularly administered parent compound DB829 was fully curative in the second stage HAT model at 2.5 mg/kg x 5 days. Our findings suggest that the two compounds (oral DB868 and intramuscular DB829) should be recommended to enter the regulatory phase of development as potential HAT drugs. Oral DB868 cured the first stage HAT model at a daily dose of 3 mg/kg for 7 days (cumulative dose, CD = 21 mg/kg) compared to a maximum tolerated daily dose of 30 mg/kg for 10 days (CD = 300 mg/kg). The efficacy, safety and pharmacokinetic profiles suggest that this compound would be a useful clinical candidate using an optimal dosing duration of 5-7 days. The second compound, intramuscular DB829, cured the second stage HAT model at a daily dose of 2.5 mg/kg for 5 days and was tolerated at 5 mg/kg for 5 days (CD = 25 mg/kg). Pharmacokinetic analysis indicated the intramuscular administration of DB829 resulted in better systemic bioavailability, thus accounting for the improved efficacy in comparison with oral dosing.
Eflornithine
Pentamidine
Trypanosoma brucei rhodesiense
Diminazene
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Nifurtimox
Diminazene
Pentamidine
Eflornithine
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The main problem in the treatment of human African trypanosomiasis remains the toxicity of the universal and effective drug melarsoprol (4% to 8% lethality during treatment). Other drugs do not penetrate the central nervous system, where the trypanosome migrate very early in the infection before any inflammatory signs appear in the cerebrospinal fluid. DL-α-Difluoromethylornithine provides an efficient and safe alternative for Trypanosoma brucei gambiense infection, while Trypanosoma brucei rhodesiense is more resistant. Moreover, the administration scheme is spread over 5 weeks including 14 days of intravenous injections. Nifurtimox taken orally for 1 or 2 months has a marked effect on the T. brucei gambiense infection. Too frequent relapses are observed in some trials. Imidazoles, new arsenicals, and antimitotics, were successfully tested in experimental models. Combinations of drugs with additive or potentiating effects mainly based on decarboxylase enzymes or methylating molecules seem promising.
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Background. Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are either highly toxic or impracticable in field conditions. We compared the efficacy and safety of the nifurtimox-eflornithine drug combination with the standard eflornithine regimen for the treatment of second-stage disease.
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Nifurtimox
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Eflornithine
Trypanosoma brucei rhodesiense
Human disease
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Trypanocidal agent
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In a multiclinic trial in Brazzaville, Congo, 14 patients with late-stage Trypanosoma brucei gambiense trypanosomiasis were treated with eflornithine. All cases had previously been treated with one or several courses of melarsoprol. Eflornithine treatment consisted of 400 mg/kg/day intravenously for 14 days followed by 300 mg/kg/day orally for 21 days. After treatment all patients had a disappearance of trypanosomes from cerebrospinal fluid (CSF), a normalization of CSF WBC count, and, where present prior to study, a clear, rapid and lasting amelioration of neurological signs. Neither clinical nor biological adverse effects necessitated modifying or discontinuing treatment. These encouraging results in melarsoprol-refractory cases demonstrate, despite certain logistical problems, the interest of eflornithine in the treatment of human African trypanosomiasis.
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Human African trypanosomiasis (HAT, better called as sleeping sickness), caused by two morphologically identicalprotozoan parasite Trypanosoma bruceiis transmitted by the bite of tsetse flies of Glossinagenus, mainly in the rural areas of the sub-Saharan Africa. HAT is one of the neglected tropical diseases and is characterized by sleep disturbance as the main symptom, hence is called as sleeping sickness. As it is epidemic in the poorest population of Africa, there is limited availability of safe and cost-effective tools for controlling the disease. Trypanosoma bruceigambiense causes sleeping sickness in Western and Central Africa, whereas Trypanosoma bruceirhodesiense is the reason for prevalence of sleeping sickness in Eastern and Southern Africa. For the treatment of sleeping sickness, only five drugs have been approved suramin, pentamidine, melarsoprol, eflornithine and nifurtimox. Various small molecules of diverse chemical nature have been synthesized for targeting HAT and many of them are in the clinical trialsincluding fexinidazole (phase I completed) and SCYX-7158 (advanced in phase I). The present work has been planned to review various types of small molecules developed in the last 10 years having potent antitrypanosoma activity likely to be beneficial in sleeping sickness along with different natural anti-HAT agents.
Nifurtimox
Eflornithine
Pentamidine
Trypanosoma brucei rhodesiense
Neglected Tropical Diseases
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Eflornithine
Trypanosoma brucei rhodesiense
Pentamidine
Trypanosoma evansi
Tsetse fly
Nifurtimox
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Abstract Human African trypanosomiasis (sleeping sickness) is caused by subspecies of the protozoan parasite Trypanosoma brucei. The disease is restricted to tropical Africa where it is transmitted by the bite of infected tsetse flies (Glossina spp.). Control programmes in the 1960s were very effective, but subsequent relaxation of control measures led to recurrence of epidemic proportions in the 1980s and 1990s. Control is now being regained. Untreated human African trypanosomiasis is almost invariably fatal. Specific treatment depends on the trypanosome subspecies and the stage of the disease. Drugs used for stage 1 include pentamidine and suramin, and for stage 2 include melarsoprol, eflornithine, and nifurtimox, but regimens are not standardized, and treatment is difficult and dangerous; all of the drugs used have many side effects, some potentially lethal.
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