Jorge Atouguiaa & Frank Jenningsb
a Centre de Malária e outras Doencas Tropicais and Departamento de Clínica das Doenças Tropicais, Institute de Higiene e Medicina Tropical, R. da Junqueira, 96 1400-Lisboab Department of Veterinary Parasitology, University of Glasgow, Glasgow G61 1QH, Scotland.
Introduction
New compounds
Combination chemotherapy
Topical treatments
Melarsoprol and nitrofuranes
Melarsoprol and nitroimidazoles
Future prospects
References
Human African trypanosomiasis, caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, is usually characterised by two stages, the "early" and the "late" stage. In the early stage the parasites are confined to the blood, lymph and tissues, and can be easily cured with pentamidine, used exclusively for Trypanosoma brucei gambiense infections, and diminazene aceturate (berenil) or suramin, used in both infections. As the disease progresses, the trypanosomes progressively enter the central nervous system (CNS), and the drugs in use at this (late) stage are melarsoprol, eflornithine (DFMO) or the nitrofuranes, nitrofurazone and nifurtimox. Treatment of late stage trypanosomiasis with these drugs is not satisfactory. Side-effects are important: the intravenous melarsoprol is associated with a reactive encephalopathy, occurring in 4-8% of patients (Pepin and Milord, 1994) and local problems at the injection site, due to the propylene glycol solvent; the oral nitrofuranes are responsible for gastrointestinal tract symptoms, polyneuropathies and haemolysis; eflornithine doesn't have much toxicity but is not effective in the Rhodesian form of the disease, and is very expensive (a complete treatment costs US $500), making its use as a first choice drug almost impossible in Africa.
New compounds have been studied, some of them with trypanocidal effect in vitro and in animal models. None has been approved for use in humans.
The nitroimidazoles L611.744, MK-436, L634.549, fexinidazole, and Ro-15-0216 had good trypanocidal activity (even in T. cruzi infections) but their developmental work has been suspended based on their potential mutagenic and teratogenic properties. At the present time the only nitroimidazole under development is megazol (Bouteille et al, 1995). Recently investigated compounds include the spiroarsoranes (Loiseau et al, 1993), IMOL 881, also effective on the animal trypanosomes T. evansi and T. equiperdum (Maes et al, 1993), inhibitors of DNA topoisomerases (Shapiro, 1993), cis-Pt pentamidine (Dreyfuss et al, 1993), MDL 73811, an S-adenosylmethionine decarboxylase inhibitor (Bacchi et al, 1992) and D0879, an inhibitor of sterol biosynthesis (TDR, 1996).
In an effort to increase the efficacy of chemotherapy, studies on drug combinations were carried out using animal models. Good results have been obtained with eflornithine combined with bleomycin, suramin, melarsoprol and other arsenicals, antimonials, and berenil (Jennings, 1990).
Unfortunately, the most successful combinations are those which combine an arsenical with the nitroimidazoles, which are not approved in human medicine. The melarsoprol/MK-436 or cymelarsen/MK-436 combinations are the reference for curative treatment in the CNS-trypanosomiasis mouse model (Jennings, 1990).
Some drug combinations have been used in humans: pentamidine or berenil with suramin (Pepin and Khonde, 1996) metronidazole with suramin (Arroz and Djedje, 1988; Foulkes, 1996), eflornithine with suramin, (results to be published) and eflornithine combined with melarsoprol (Simarro and Asumu, 1996). Some relative success has been obtained with metronidazole/suramin combination, but this treatment requires further studies (Foulkes, 1996). At the present time, eflornithine with melarsoprol is the only clearly effective combination. Unfortunately, eflornithine, due to its price and production problems, is not widely available, leaving this and other eflornithine combinations without much future. In practical terms, the first choice, and, in most of the African countries, the only, drug to treat late stage infections of human African trypanosomiasis is melarsoprol.
The difficulty of using intravenous routes of administration in Africa, added to the serious venous damage provoked by melarsoprol treatment (Ginoux et al, 1984), was the reason for studies in the efficacy of topically applied melarsoprol. Using the CNS-trypanosomiasis mouse model (Jennings and Gray, 1983), permanent cures were obtained with the solution of the commercially available melarsoprol in 3.6% propylene glycol (Jennings et al, 1993), or the same solution made into a gel with the addition of hydroxypropylcellulose (Atouguia et al, 1995), when applied directly on the skin of CNS-trypanosomiasis mice.
Nitrofurazone and nifurtimox can be dissolved in dimethylsuphoxide (DMSO) and will be absorbed through the skin. When applied together with melarsoprol (3.6% in propylene glycol) they can cure late stage trypanosomiasis in mice. These solutions can be converted into gels by the addition of hydroxypropylcellulose, facilitating the ease and accuracy of administration. A one day treatment with 0.05ml (60mg/kg) of melarsoprol plus 0.1ml (200mg/ml) nitrofurazone gel cured 50% of mice, and 100% cures were obtained with a two-day treatment. Using the same doses, but in monotherapy, melarsoprol and nitrofurazone were ineffective. Nifurtimox/melarsoprol combination produced permanent cures which were superior to melarsoprol monotherapy. Nitrofurazone was more effective in clearing trypanosomes from the circulation than nifurtimox. However, when used in combination with melarsoprol, nifurtimox was superior in eliminating trypanosomes in the CNS.
Gels of MK-436, fexinidazole and megazol when used with melarsoprol gel, are capable of curing CNS-trypanosomiasis with a single day treatment.
The use of melarsoprol/MK-436 was more efficient than melarsoprol/fexinidazole gels. A single treatment with 0.1ml (104 mg/kg) melarsoprol gel combined with 0.1 ml (114.3 mg/kg) fexinidazole gel or 0.1ml (28.6 mg/kg) MK-436 gel cured 100% of mice. Although the nitroimidazoles are dissolved in DMSO and melarsoprol in propylene glycol, a combined gel of melarsoprol/MK-436 has been produced, and this mixture was also effective as a single treatment (Jennings et al, 1996a).
In addition, the melarsoprol/MK-436 combined gel resolved the hind-leg paralysis and post-treatment reactive encephalopathy caused by non-curative treatment of the CNS-trypanosomiasis.
A single application of 0.1 ml of melarsoprol gel plus 0.1 ml of either 8 or 16 mg/ml megazol gel successfully treated experimental CNS-trypanosomiasis while two consecutive days' treatment with 0.05 ml melarsoprol and 0.1 ml of 16 or 32 mg/ml megazol gels also produced satisfactory cures (Jennings et al, 1996b).
It is unlikely that a new drug for human African trypanosomiasis will be available in the foreseeable future. New drug development is an extremely expensive process, and no pharmaceutical company is interested in spending millions in the investigation of a new treatment for a disease which only exists in Africa. The only remote possibility is the development of a compound which is active against diseases prevalent in the developed countries, which could be used in human trypanosomiasis.
The nitroimidazoles, which are active against T. cruzi and a range of protozoan diseases and which proved to be effective, at least in combination with existing drugs, in experimental T. brucei infections, are not being developed. Thus, chemotherapy resources have to rely on the existing drugs and their combinations, as well as new therapeutic approaches using new dosages, new treatment periods and new administration methods.
Anonymous, TDR News, November 1996.
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