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Benznidazole is recommended in Brazil for the treatment of Trypanosoma cruzi infection in acute and early chronic phases of Chagas' disease. Observations by others have indicated a higher incidence of neoplasias in immunosuppressed patients, presenting Chagas' disease reactivation, submitted to treatment with benznidazole. In the present study, we investigated whether there is a potentiation in the generation of lymphomas in chronically infected mice, treated with immunosuppressive drugs and benznidazole. For this, 142 Swiss mice chronically infected with the 21 SF strain of T. cruzi and 72 normal Swiss mice were used. Both infected and normal mice were divided into experimental groups and submitted to one of the following treatment regimens: benznidazole alone; immunosuppressive drugs (azathioprine, betamethasone and cyclosporin); a combination of immunosuppressive drugs and benznidazole; and untreated controls. In the infected group treated with benznidazole, one mouse developed a non-Hodgkin's lymphoma. This finding has been interpreted as a spontaneous tumor of mice. The study of the chronically infected mice treated with the combination of immunosuppressive drugs and benznidazole demonstrated an absence of lymphomas or other neoplasias. These findings support the indication of benznidazole, as the drug of choice, for immunosuppressed patients that develop a reactivation of Chagas' disease.

Eflornithine is the only new molecule registered for the treatment of human African trypanosomiasis over the last 50 years. It is the drug used mainly as a back-up for melarsoprol refractory Trypanosoma brucei gambiense cases. The most commonly used dosage regimen for the treatment of T. b. gambiensesleeping sickness consists of 100 mg kg(-1) body weight at intervals of 6 h for 14 days (150 mg kg(-1) body weight in children) of eflornithine given as short infusions. Its efficacy against Trypanosoma brucei rhodesiense is limited due to the innate lack of susceptibility of this parasite based on a higher ornithine decarboxylase turnover. Adverse drug reactions during eflornithine therapy are frequent and the characteristics are similar to other cytotoxic drugs for the treatment of cancer. Their occurrence and intensity increase with the duration of treatment and the severity of the general condition of the patient. Generally, adverse reactions to eflornithine are reversible after the end of treatment. They include convulsions (7%), gastrointestinal symptoms like nausea, vomiting and diarrhea (10%-39%), bone marrow toxicity leading to anemia, leucopenia and thrombocytopenia (25-50%), hearing impairment (5% in cancer patients) and alopecia (5-10%). The drug arrests embryonic development in mice, rats and rabbits but the extent of excretion into breast milk is unknown. The mean half-life is around 3-4 h and the volume of distribution in the range of 0.35 l kg(-1). Renal clearance is about 2 ml min kg(-1) (i.v.) and accounts for more than 80% of drug elimination. Bioavailability of an orally administered 10 mg kg(-1) dose was estimated at 54%. One of the major determinants of successful treatment seems to be the cerebrospinal fluid drug level reached during treatment, and it was shown that levels above 50 micro mol l(-1) must be reached to attain the consistent clearance of parasites. Based on its trypanostatic rather than trypanocidal mode of action, it is a rather slow-acting drug.

Devastating epidemics of human African trypanosomiasis are currently re-emerging in many sub-Saharan countries. In the past three decades, clinical research into this important disease has been neglected, as have urgently needed initiatives on drug development, disease surveillance and vector control. Recent impetus has aimed to provide a free supply of antitrypanosomal drugs, to develop a new orally active trypanocidal agent and to attack the tsetse vector with modern technology. In addition, pan-African initiatives to co-ordinate control efforts have begun. These all provide some hope for the future, but they might not be enough to reverse the resurgence of this deadly disease in the heart of Africa.

Human African trypanosomiasis (HAT), or sleeping sickness, is currently on the rise. HAT develops in two stages, the first involving the hemolymphatic system, and the second, the neurological system. Left untreated, HAT is invariably fatal. There have been no therapeutic advances in more than 40 years. Stage 1 can be treated with pentamidine and suramin, but stage 2 can only be treated with melarsoprol, a toxic arsenic derivative that has a 2-12% incidence of fatal side-effects (encephalopathy). Eflornithine has never achieved widespread use because it is difficult to administer under field conditions. Nifurtimox has been used successfully in the treatment of American trypanosomiasis, or Chagas disease, but only in small studies or as a compassionate use treatment. There is little research and development for new drugs in this area: only one prodrug is in the clinical development phase, a pentamidine analog that offers hope for the replacement of injectable pentamidine with an orally administered drug. Current efforts appear to be focused on reevaluating older drugs. A course of treatment with melarsoprol for 10 days at 2.2 mg/kg/day is now in the multicenter evaluation phase. Orally administered eflornithine is also slated for reevaluation. In addition, studies of drug combinations are recommended to determine possible combined or synergistic effects and find ways to reduce toxicity.

During June-July 2000, an outbreak of surra occurred on an equine breeding farm in Khonkaen Province, Thailand. Forty-two percent of pregnant mares aborted or gave stillbirth and 40% (19/47) of horses and 10% (1/10) of mules died from surra. In August 2000 Trypanosoma evansi were detected in the remaining animals (28 horses and nine mules) on the farm by blood smear and/or the haematocrit centrifuge technique. All animals were treated with diminazene aceturate at 3.5 mg/kg body weight by intramuscular injection on days 0 and 41 of the study. Blood samples of eight randomly selected horses and mules were collected on days 0, 1 and once a week until day 56 and examined for T. evansi by various parasitological techniques. The sera were tested for antibodies against T. evansi using an indirect enzyme linked immunosorbent assay (ELISA).The results revealed that diminazene aceturate at 3.5 mg/kg appeared to be effective in the first treatment of horses and mules infected with T. evansi. Parasites were cleared from the peripheral blood of horses on days 1 and 7 and mules on days 1 and 14. Thereafter the number of positive animals increased. After the second treatment, 50% of horses and 25% of mules were still positive to surra 24 h after treatment demonstrating that diminazene had no protective effect. Mild to severe toxicity of diminazene was seen in the horses and mules after injection.

In the search for antiprotozoal compounds from natural sources, Triclisia patens displayed activity against L. donovani promastigotes (IC(50) = 1.5 microg/mL) and T. b. brucei blood stream trypomastigote forms (IC(50) = 31.25 microg/mL). In addition, a total of 20 bisbenzylisoquinoline alkaloids were screened for antileishmanial and antitrypanosomal activity in vitro. Fangchinoline (IC(50) = 0.39 microM) was found to be as active as the standard pentamidine against Leishmania donovani promastigotes. Phaeanthine was three-fold more active (IC(50) = 2.41 microM; 1.5 microg/mL) than the standard drug Pentostam against L. donovani amastigotes, but at this concentration was toxic to murine macrophages. In contrast, cocsoline (IC(50) = 12.3 microM; 6.76 microg/mL) was as active as Pentostam, and was not toxic to macrophages at this concentration. Thalisopidine showed the strongest activity (IC(50) = 1.14 microM) against Trypanosoma brucei brucei blood stream form trypomastigotes, but was less active than pentamidine., (Copyright 2002 John Wiley & Sons, Ltd.)

Human African trypanosomiasis re-emerged in the 1980s. However, little progress has been made in the treatment of this disease over the past decades. The first-line treatment for second-stage cases is melarsoprol, a toxic drug in use since 1949. High therapeutic failure rates have been reported recently in several foci. The alternative, eflornithine, is better tolerated but difficult to administer. A third drug, nifurtimox, is a cheap, orally administered drug not yet fully validated for use in human African trypanosomiasis. No new drugs for second-stage cases are expected in the near future. Because of resistance to and limited number of current treatments, there may soon be no effective drugs available to treat trypanosomiasis patients, especially second-stage cases. Additional research and development efforts must be made for the development of new compounds, including: testing combinations of current trypanocidal drugs, completing the clinical development of nifurtimox and registering it for trypanosomiasis, completing the clinical development of an oral form of eflornithine, pursuing the development of DB 289 and its derivatives, and advancing the pre-clinical development of megazol, eventually engaging firmly in its clinical development. Partners from the public and private sector are already engaged in joint initiatives to maintain the production of current drugs. This network should go further and be responsible for assigning selected teams to urgently needed research projects with funds provided by industry and governments. At the same time, on a long term basis, ambitious research programmes for new compounds must be supported to ensure the sustainable development of new drugs.

Zentaris (formerly Asta Medica) has developed and launched miltefosine, a phospholipid derivative, in various European countries [173324], [254947] and in Brazil in 1997 [332428], [366795] as a treatment for breast cancer. As of January 2002, phase III trials for treatment of leishmaniaisis were ongoing [435767]. In February 1999, Lehman Brothers predicted miltefosine would be launched for treatment of leishmaniasis in 2002, with peak sales expected in 2010 [319225].

The aim of this article is to present an investigation of cure rate, after long follow up, of specific chemotherapy with benznidazole in patients with both acute and chronic Chagas disease, applying quantitative conventional serological tests as the base of the criterion of cure. Twenty one patients with the acute form and 113 with one or other of the various chronic clinical forms of the disease were evaluated, after a follow up period of 13 to 21 years, for the acute, and 6 to 18 years, for the chronic patients. The duration of the acute as well as the chronic disease, a condition which influences the results of the treatment, was determined. The therapeutic schedule was presented, with emphasis on the correlation between adverse reactions and the total dose of 18 grams, approximately, as well as taking into consideration precautions to assure the safety of the treatment. Quantitative serological reactions consisting of complement fixation, indirect immunofluorescence, indirect hemagglutination, and, occasionally, ELISA, were used. Cure was found in 76 per cent of the acute patients but only in 8 per cent of those with chronic forms of the disease. In the light of such contrasting results, fundamentals of the etiological therapy of Chagas disease were discussed, like the criterion of cure, the pathogenesis and the role of immunosuppression showing tissue parasitism in long standing chronic disease, in support of the concept that post-therapeutic consistently positive serological reactions mean the presence of the parasite in the patient's tissues. In relation to the life-cycle of T. cruzi in vertebrate host, there are still some obscure and controversial points, though there is no proof of the existence of resistant or latent forms. However, the finding over the last 15 years, that immunosuppression brings about the reappearance of acute disease in long stand chronic patients justifies a revision of the matter. Facts were quoted in favor of the treatment of chronic patients.

This paper gives an overview of the treatment of Human African Trypanosomiasis from the early 20th century until today.

Encephalopathies are the most feared complications of sleeping sickness treatment with melarsoprol. To investigate the existence of risk factors, the incidence of encephalopathic syndromes and the relationship between the development of different types of encephalopathies and the clinical outcome was studied in a clinical trial with 588 patients under treatment with melarsoprol. The 38 encephalopathy cases were classified into three types according to the leading clinical picture: coma type, convulsion type and psychotic reactions. Nine patients were attributed to the convulsion type, defined as a transient event of short duration with convulsions followed by a post-ictal phase, without signs of a generalized disease. None of these patients died from the reaction. Febrile reactions in the 48 h preceding the reaction were generally not observed in this group. Twenty-five patients were attributed to the coma type, which is a progredient coma lasting several days. Those patients often had signs of a generalized disease such as fever (84%), headache (72%) or bullous skin (8%) reactions. The risk of mortality was high in this group (52%). About 14/16 patients with encephalopathic syndrome of the coma type were infected with malaria. Patients with psychotic reactions or abnormal psychiatric behaviour (3/38) and one patient who died after alcohol intake were excluded from the analysis. The overall rate of encephalopathic syndromes in the cases analysed (n=34) was 5.8%, of which 38.2% died. We did not find any parameters of predictive value for the risk of developing an encephalopathic syndrome based on the symptoms and signs before treatment initiation. The appearance during treatment of febrile reactions (RR 11.5), headache (RR 2.5), bullous eruptions (RR 4.5) and systolic hypotension (RR 2.6) were associated with an increased risk for the occurrence of encephalopathic syndromes especially of the coma type.

Background: Melarsoprol remains the first-choice drug for trypanosomiasis (human African sleeping sickness). To contribute to the sparse pharmacologic data and to better understand the cause of the frequent serious adverse reactions, we investigated the metabolism of this 50-year-old organoarsenic compound., Results: The half-life of melarsoprol determined by HPLC was <1 hour compared with 35 hours determined by bioassay and atomic absorption spectroscopy, indicating the existence of active metabolites. One metabolite, melarsen oxide, was identified by ultraviolet HPLC after incubation of melarsoprol with microsomes. The maximum plasma concentration of melarsenoxide was reached 15 minutes after administration; the clearance was 21.5 mL/min/kg and the half-life of free melarsen oxide was 3.9 hours. Either melarsen oxide or a yet-undiscovered active metabolite is irreversibly bound to proteins, as shown by ultrafiltration, precipitation experiments, and atomic absorption spectroscopy. Because of the poor pharmaceutical properties of melarsoprol, the therapeutic potential of melarsen oxide was investigated. In a rodent model of acute infection, 20 of 20 mice were cured (0.1 to 1 mg/kg intravenously or 2.2 mg/kg intraperitoneally). In a rodent model of central nervous system infection, five of six mice survived for more than 180 days (5 mg/kg intravenously), indicating a sufficient melarsen oxide penetration across the blood-brain barrier., Conclusion: The prospects for the future of trypanosomiasis treatment are deplorable. Investigations on the improvement of the use of the old drugs are therefore required. The results of this study may build a basis for further research on the cause of severe adverse reactions.

Background: African trypanosomiasis is a fatal disease caused by protozoan parasites of the species Trypanosoma brucei. The disease has reached epidemic dimensions in various countries of central Africa. Treatment of the second stage is long and complicated, and is hampered by severe adverse reactions to the first-line drug, melarsoprol. Despite these problems, melarsoprol is likely to remain the drug of choice for the next decade. We therefore did a randomised trial comparing the standard treatment schedule with a new, concise regimen., Methods: The safety and efficacy of the new schedule were assessed in patients presenting to a hospital in Kwanza Norte, Angola with sleeping sickness. The control group followed the 26-day standard Angolan schedule of three series of four daily injections of melarsoprol at doses increasing from 1.2 to 3.6 mg/kg within each series, with a 7-day interval between series. The new treatment schedule comprised 10 daily injections of 2.2 mg/kg. Primary outcomes assessed were elimination of parasites, deaths attributed to treatment, and rate of encephalopathy. Analysis was by intention to treat., Findings: Of 767 patients with second-stage disease, 500 were enrolled: 250 were assigned the standard schedule, and 250 the new schedule. 40 patients on the standard schedule and 47 on the new schedule had adverse events which resulted in treatment disruption or withdrawal. 50 patients on the standard regimen deviated or withdrew from treatment, compared with two on the new regimen. Parasitological cure 24 h after treatment was 100% in both groups; there were six deaths (all due to encephalopathy) 30 days after treatment in each group. The number of patients with encephalopathic syndromes was also the same in each group (14). Skin reactions were more common with the new treatment, but all could be resolved by additional medication or withdrawal of treatment., Interpretation: Considering the economic and practical advantages of the new 10-day schedule over the standard 26-day treatment schedule, and the similarity of treatment outcome, the new schedule is a useful alternative to the present standard, especially in epidemic situations and in locations with limited resources.

Although therapeutic strategies for trypanosomiasis appear to be straightforward, their application in the field raises a number of questions which are successively examined below. After a quick reminder of the available drugs, we discuss: Criteria for eligibility: problems of beginning treatment for immunological suspects and determination of the development phase. Present-day problems: availability of drugs; side effects; therapeutic failures. While efforts should be continued to make existing drugs available, it is important that fundamental research be carried out to enhance their utilisation as well as to develop new active molecules.

In this study is presented the comparative therapeutical experience comparing the Allopurinol, Benznidazol y Nifurtimox, in a prospective following in a long term, considering the responses to the parasitemia, specific serology and evolution of the clinic manifestations and complementaries in the 535 chronic chagasic cases (44.5%), instead of 668 patients who did not get any treatment (1203 chagasic cases followed for more than 5 years average). This study was done between April 1984 and April 1994 in patients with and without cardiopathy, in the Córdoba Hospital and the Salud Estudiantil Direccion, Universidad Nacional de Córdoba (U.N.C.); from them, 309 patients were given Allopurinol, 130 were given Benznidazol, and 96 were given Nifurtimox, with usual doses of Benznidazol and Nifurtimox, but with Allopurinol it was made an study evaluating the answering-doses, with a following time of post-therapeutic average of 55.6 months (D.S. = + -57 m.) The comparative parameters were the starting clinic characteristics, the qualitative and quantitative for Chagas, the pre-treatment xerodiagnostic, the treatment fulfillment, the treatment duration, the adverse effects, the treatment abandon, the time of postreatment longitudinal following till the last clinic-complementary evaluation, the clinic characteristics at the end of the following period; quantitative and qualitative serology for Chagas after the treatment, and post-treatment xerodiagnostic. It was observe a prevalence of Electrocardiographic Changes in the ECG in rest, in the first complementary evaluation in 76 of the 535 "Treated" and in the 225 "No-treated" patients, being Electrocardiographic abnormality proportion much more in the "No-treated" patients (P = 0.000000). After the end of the following period it was thought to have been found Miocardic Damage Progression in 120 patients "No-treated" and in 31 "Treated" patients (17.9% and 5.8% respectively) (P = 0.0000000). The complications in the evolution course were proved in 113 of the "No-treated" and in 19 of the "Treated" patients (16.9% and 3.5%, being this a statistically significant difference (P = 0.0000000). The mortality along the evolution was proved in 37 of the "No-Treated:" patients and in 7 of the "Treated" patients (5.5% and 1.3%), being this a statistically significant difference (P = 0.00019). The most tolerated drug and the one with the least incidence of therapeutic abandons was the Allopurinol. The xerodiagnostic negativization percentages were 72.5% for Allopurinol, 76.4% for Benznidazol and 76.5% for Nifurtimox (non-significant differences). A year and two years after the end of the treatment was made a titled serology with the Inmunofluorescence and Indirect Hemoaglutination Tests, getting significant statistical differences between the three drugs, resulting lower the values obtain after the treatment with Benznidazol and Nifurtimox than with Allopurinol (P = 0.0042 and P = 0.00039), respectively). The biggest proportion of Progression in the Cardiopathies, Complications, General Mortality and Attributed Mortality in "No Treated" (specially in older than 30 years) significant both for infected patient and slight cardiopathy, stabilises the possibility of stopping or reducing the morbid course of the Chronic Chagasic Cardiopathy, specially relevant in the formers, where the pathogenic process seems to be accelerated related to the latters. The negativation of the parasitemia and the parasitemia and the title disminution of the specific serology like effectiveness treatment parameters, and the stopping in the progression or dissemination of the incidence in new cases of Chronic Chagasic Cardiopathies were considered to be the real benefit of the antiparasitaric therapeutic in the Chagas Disease. As a conclusion, it is thought that the further the instauration of the specific antiparasitaric treatment the more the possibilities of effectiveness, as well as the increase in the probabilities of preventing or reducing the incidence of cardiopathy in chronic infected, or to stop its evolution and reduce its morbimortality in patients with already installed cardiopathy.

Objective: A randomized controlled trial was conducted to determine whether 7 days of intravenous eflornithine (100 mg/kg every 6 h) was as effective as the standard 14-day regimen in the treatment of late-stage Trypanosoma brucei gambiense trypanosomiasis., Methods: A total of 321 patients (274 new cases, 47 relapsing cases) were randomized at four participating centres in Congo, Côte d'Ivoire, the Democratic Republic of the Congo, and Uganda to one of these treatment regimens and followed up for 2 years., Results: Six patients died during treatment, one of whom was on the 7-day regimen, whereas the other five had been on the 14-day regimen (P = 0.2). The response to eflornithine differed markedly between Uganda and other countries. Among new cases in Uganda, the 2-year probability of cure was 73% on the 14-day course compared with 62% on the 7-day regimen (hazard ratio (HR) for treatment failure, 7-day versus 14-day regimen: 1.45, 95% CI: 0.7, 3.1, P = 0.3). Among new cases in Côte d'Ivoire, Congo, and the Democratic Republic of the Congo combined, the 2-year probability of cure was 97% on the 14-day course compared with 86.5% on the 7-day regimen (HR for treatment failure, 7-day vs 14-day: 6.72, 95% confidence interval (CI): 1.5, 31.0, P = 0.003). Among relapsing cases in all four countries, the 2-year probability of cure was 94% with 7 days and 100% with 14 days of treatment. Factors associated with a higher risk of treatment failure were: a positive lymph node aspirate (HR 4.1; 95% CI: 1.8-9.4), a cerebrospinal fluid (CSF) white cell count > or = 100/mm3 (HR 3.5; 95% CI: 1.1-10.9), being treated in Uganda (HR 2.9; 95% CI: 1.4-5.9), and CSF trypanosomes (HR 1.9; 95% CI: 0.9-4.1). Being stuporous on admission was associated with a lower risk of treatment failure (HR 0.18; 95% CI: 0.02-1.4) as was increasing age (HR 0.977; 95% CI: 0.95-1.0, for each additional year of age)., Discussion: The 7-day course of eflornithine is an effective treatment of relapsing cases of Gambian trypanosomiasis. For new cases, a 7-day course is inferior to the standard 14-day regimen and cannot be recommended.

Dromedaries are particularly susceptible to toxicity from certain drugs at doses harmless to other ruminants. The pharmacokinetics of drugs may be different in dromedary and in cattle. This paper reviews the toxicity and adverse reactions of certain therapeutic agents to dromedary.

Background: Heart transplantation is a new therapeutic procedure to treat heart failure resulting from Chagas' disease. Experimental studies have demonstrated neoplastic effects of benznidazole, which is used for treatment of Trypanosoma cruzi infection. We compared the incidence and characteristics of neoplasia after heart transplantation for treatment of chronic Chagas' disease with those of other diseases., Methods: Sixteen patients with Chagas' disease and 75 patients with other diseases underwent heart transplantation. Benznidazole was administered to 14 patients with Chagas's disease either for prophylaxis (4 patients) or for treatment of Chagas' disease reactivation (10 patients)., Results: The survival rate of patients in the nonchagasic group was 90% at 1 year and 82.4% at 2 years, and the survival rate in the chagasic group was 63% at 1 year and 57% at 2 years. Six of 16 patients (37.5%) with Chagas' disease had malignant tumors after a mean follow-up time of 25.3+/-2.1 months in contrast to 2 of 75 patients (2.7%) in the nonchagasic group after 34.6+/-3.6 months of follow-up. In the chagasic group, lymphoproliferative disorder was diagnosed in three patients, Kaposi's sarcoma in two, and squamous cell carcinoma in one patient. Reactivation of T. cruzi infection was diagnosed in all patients who had lymphoproliferative disorder. One patient without Chagas' disease had lymphoproliferative disorder in the lung, and another had malignant schwannoma affecting the skin., Conclusions: We found a higher incidence of malignant neoplasia after heart transplantation for treatment of chronic Chagas' disease. It is likely that the neoplasia is the result of chronic infection with an immunomodulator protozoan, immunosuppression, reactivation of the T. cruzi infection, or the toxicity of therapeutic intervention with benznidazole.

Although there have been recent molecular biological studies for evidence of possible changes in trypanosome biochemistry, such studies are not yet complemented by parallel clinical studies to determine the possible implications to the sleeping sickness patient. The study of the duration of symptoms and the case fatality of T. b. rhodesiense showed that the disease progressed to the stage of central nervous system involvement between three weeks to two months of infection. Most (> 80%) deaths occurred within six months of illness. The case fatality rate of treated sleeping sickness patients was 6% of which the rate in the late-stage of sleeping sickness was more than two and a half times that in the early stage. The incidence of melarsoprol encephalopathy was 2.5% and case fatality due to this condition was 1.0% and similar to previous findings. Thus it appears the virulence of T. b. rhodesiense circulating in south east Uganda has not changed during the past decades.

This study enrolled 28 CNS-involved patients with Trypanosoma brucei rhodesiense at the Kenya Trypanosomiasis Research Institute (Alupe, Kenya) to examine treatment efficacy and toxicity of melarsoprol in relation to renal excretion/dose relationships. This study complied with World Health Organization treatment recommendations, initially treating with suramin followed by three courses of melarsoprol. Traced study patients had a relapse rate of 4.1%. The toxicity and crude death rate was 7.1%. Total urine arsenic output was measured between 24 and 48 hr after the last dose for each course. The range of means of total urine arsenic output between the three treatment courses was 356-511 micrograms. There was no correlation comparing melarsoprol dose, estimated creatine clearance, or urine arsenic output. Urinary pharmacokinetic parameters are not predictive of toxicity or therapeutic efficacy.

A controlled clinical trial was carried out to evaluate the therapeutic efficacy and tolerance of nifurtimox and benznidazole in patients with chronic Chagas' disease. All patients had immunofluorescence and complement fixation reactions positives for T. cruzi antibodies and at least two xenodiagnoses positives in three performed before treatment, and they were submitted to clinical examinations, ECG and X-ray of the heart and esophagus. Of 77 patients studied, 27 were treated with nifurtimox and 26 with benznidazole in the dosage of 5 m/kg/day for 30 consecutive days, and 24 received a placebo in tablets similar to benznidazole. From the 77 patients, 64 (83.1%) accomplished the treatment: 23 (88.4%) with benznidazole, 19 (70.3%) with nifurtimox and 22 (91.6%) with placebo. The patients were evaluated, clinically, serologically and parasitologically (six xenodiagnoses within one year after treatment). The benznidazole group showed only 1.8% of positive xenodiagnoses post-treatment, the nifurtimox 9.6% and the placebo 34.3%. All serologic reactions continued positive and there were no clinical, ECG or X-ray changes one year after treatment.

Background: Benznidazole, a nitroimidazole derivative, has been recommended for the treatment of acute and congenital Trypanosoma cruzi infection (Chagas' disease). We have examined the safety and efficacy of this drug in the treatment of the early chronic phase of T cruzi infection., Methods: Between 1991 and 1995, we carried out a randomised, double-blind, placebo-controlled trial in a rural area of Brazil with endemic Chagas' disease. 82% of 2434 schoolchildren (aged 7-12 years) identified in a census were screened for antibodies to T cruzi by indirect immunofluorescence, indirect haemagglutination, and ELISA. 130 were positive in all tests and were randomly assigned benznidazole (7.5 mg/kg daily for 60 days by mouth) or placebo. The primary endpoint for efficacy was the disappearance of specific antibodies (negative seroconversion) by the end of 3-year follow-up. The secondary endpoint was the reduction of antibody titres on repeated serological tests. One child moved away from the area just after randomisation and was excluded from the analyses. Insecticidal measures were taken throughout the trial to reduce the risk of reinfection., Findings: Minor side-effects requiring no specific medication were recorded in a small proportion of individuals. On a chemiluminescent ELISA with purified trypomastigote glycoconjugate, serum from all participants was positive at the beginning of the trial. At the end of follow-up, 37 (58%) of the 64 benznidazole-treated participants and 3 (5%) of those who received placebo were negative for T cruzi antibodies. The efficacy of benznidazole treatment estimated by intention to treat was 55.8% (95% CI 40.8-67.0). At the end of follow-up, children who received benznidazole had five-fold lower geometric mean titres by indirect immunofluorescence than placebo-treated children (196[147-256] vs 1068[809-1408], p < 0.00001)., Interpretation: The trial showed that a 60-day course of benznidazole treatment of early chronic T cruzi infection was safe and 55.8% effective in producing negative seroconversion of specific antibodies. The results are very encouraging and justify the recommendation of treatment for seropositive children as public health policy.

1. The safety profile of terbinafine, the first orally active allylamine, was monitored in the UK in a post-marketing setting. The study recruited 10,361 patients, a number which is approximately 5% of the population who received oral terbinafine in the UK during the period of the study. 2. Follow-up data were available on 9,879 patients. During the course of the study 14.5% patients reported medical events. 49% were thought to be possibly or probably related to terbinafine treatment. Seventy-four of the events (< 1%) were classified as 'serious' and of these only five were assessed as possibly or probably related to treatment. 3. Taste disturbance occurred in 0.6% of the patients and emerged as the only new adverse reaction probably attributable to terbinafine: this was significantly commoner in females and reversible on stopping treatment, with a median time to recovery of 42 days. 4. The study approach successfully combined hospital based dermatology outpatient and general practice centres. Source data verification was conducted on 13% of the cohort selected randomly. 5. Overall, the denominator-based description of the safety profile in actual practice shows terbinafine to be well-tolerated against a wide background of age and coexisting illness.

The diagnostic and clinical aspects of congenital Chagas' disease were studied in 71 children in Buenos Aires. The children's ages ranged from 2 days to 10 years. In infants < 6 months old, the disease was diagnosed by detection of Trypanosoma cruzi in the blood; the microhematocrit test was positive in 38 (97.4%) of 39 cases. This test was the fastest and most reliable diagnostic method in this group, whereas two conventional serological methods were useful in children > or = 6 months of age. Forty-six (64.8%) of the 71 children had no clinical signs of infection. The clinical sign most frequently documented was hepatomegaly (18.3%). Three children were coinfected with human immunodeficiency virus; the latter infection was severe in two instances. Nifurtimox (10-15 mg/[kg.d] for 2 months) was used for parasiticidal treatment, and use of this drug resulted in mild adverse effects.

Combinations of DL-alpha-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% 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-drug-refractory cases of East African sleeping sickness.

Since 1988, the french non-governmental organisation Médecins Sans Frontières is running a control program of human african trypanosomiasis in the district of Moyo, North-Uganda. Between 1988 and 1993, more than 7,000 patients were diagnosed and treated. Since 1988, it has been noted that incidence of melarsoprol reaction had increased systematically between June and October of each year, indicating strong seasonal variation. In 1992 and 1993, two outbreaks of arsenical reactive encephalopathy (ARE) occurred in the sleeping sickness center of Adjumani. The incidence of ARE suddenly exceeded 10% of the patients treated by melarsoprol during August 1992 and September 1993. The onset of 80% of those "epidemic" cases, occurred between the 5th and the 11th day of treatment. Two retrospective studies were conducted in 1992 (75 cases) and in 1993 (51 cases). Among the risk factors studied, two appear to increase the risk of ARE: the prescription of thiabendazole to treat strongyloidiasis during the melarsoprol cure and the bad general clinical conditions of patients. These observations suggest that exogenous co-factors could be involved in the occurrence of ARE. Recommendations were to avoid administration of diffusible anti-helminthic treatment during the cure, and to improve the general conditions of patients before the cure of melarsoprol.

Human African trypanosomiasis (HAT) is a major public health problem in 36 sub-Saharan African countries and around 50 million people are classed as "at risk". About 25,000 new cases of the disease are reported annually by the World Health Organisation (WHO). This disease is fatal if untreated. As for now, chemotherapy is unsatisfactory and relies on a few drugs which show two major problems. The first is pharmacokinetics involving the passage through the blood-brain barrier. The second concerns toxicity and adverse side-effects of drugs used to treat this disease. New trypanocides should be safe, effective without toxicity. This study reports the action of 45 drugs, known to pass through the blood-brain barrier and belonging to different therapeutic classes, and also the megazol, a nitrothiadiazole derivative, on Trypanosoma brucei brucei AnTat 1-9 in vitro in acellular semi-defined medium. Results showed that some drugs did not modify the parasitic growth, and others were either trypanostatic or trypanocide. These last drugs were tested in vivo on T. b. brucei An-Tat 1-9 infected Swiss mice. Only megazol was shown to be effective and trypanocide. This compound might trigger the production of oxygen derivatives and free radicals-which have toxic effects on the trypanosome metabolism.

The use of a rapid curative chemotherapeutic regimen for experimental infection of the central nervous system (CNS) of mice by Trypanosoma brucei has indicated that this 'aggressive' treatment does not precipitate the development of post-treatment meningo-encephalopathy. If meningoencephalitis is already established at the time of the treatment there is no exacerbation of the reaction and the CNS pathology rapidly returns to normal. Paralysis is not precipitated by the rapid curative treatment of either primary or relapse infections, in contrast to non-curative treatments. Mice showing this overt clinical paralysis in addition to histological meningoencephalitis soon regain mobility and the CNS pathology is rapidly resolved after curative chemotherapy. These experiments provide no support for the concept that the rapid release of trypanosome antigens in situ in the brain exacerbates the post-treatment encephalopathy. They do support the concept that it is viable trypanosomes remaining in the brain which are responsible.

The treatment of human African sleeping sickness is complicated by a post-treatment meningoencephalitis that may be fatal. Using a mouse model this study assesses the use of the non-steroidal anti-inflammatory drug, azathioprine, in the management of this post-treatment reaction. Female NIH mice treated with the trypanocidal compound diminazene aceturate (40 mg/kg), 28 days after infection, developed a similar post-treatment reaction to that seen in humans. Administration of azathioprine (100 mg/kg) for 5 days before and 5 days after trypanocidal chemotherapy abrogated the pathology in the central nervous system although this returned approximately 15 days after cessation of azathioprine. Activated astrocytes associated with the later stages of the infection did not appear to be affected by the use of azathioprine.

The treatment of late-stage African sleeping sickness in man is often complicated by a post-treatment reactive encephalopathy. The bases of this pathological reaction was investigated in a mouse model of African trypanosomiasis. Subcurative treatment with diminazene aceturate, which did not clear parasites from the central nervous system, resulted in a post-treatment meningoencephalitis similar to that seen in man. By contrast, a curative regimen of melaminylthioarsenite and 5-nitroimidazole, which cleared parasites from the central nervous system, did not cause any pathological reaction in the mice. This result indicates that subcurative treatment leads to the development of the post-treatment encephalopathy. Evidence that this may also be the case in man was provided by the detection of trypanosome DNA with the polymerase chain reaction in the brains of 9 patients who had died as the result of a post-treatment reaction. Our findings suggest that more aggressive treatment regimens, which ensure the elimination of trypanosomes from the central nervous system, may prevent post-treatment reactions in patients.

No studies exist on sister-chromatid exchange (SCE) formation in chagasic patients therapeutically exposed to nifurtimox (NFX) or benznidazol (BZ). In the present study SCE was analyzed in cultures of peripheral lymphocytes of patients aged 11 months to 11 years treated with NFX 12-15 mg/kg/d for 60 days or with BZ 5 mg/kg/d for 30 days. Chagasic patients before treatment constituted a control group. A mean of 30 metaphases were examined for each individual. All treated patients compared with untreated controls did not show a significant increase in SCE frequency. Compared with the percentage of chromosomal aberrations in these patients and others belonging to the same epidemic protocol, SCE seems to be less sensitive in the detection of lymphocyte chromosomal damage caused by NFX or BZ.

Forty buffaloes naturally infected with Trypanosoma evansi in the South of China were treated with a single dose of a new arsenical. Cymelarsan (Mel Cy) at 0.25 mg/kg to 3.0 mg/kg by intramuscular injection. All animals were cured, with the exception of two out of four animals treated with 0.25 mg/kg Mel Cy which relapsed two months after drug administration. Two out of eight buffaloes in control groups treated with a single dose of diminazene aceturate (Berenil), 3.5 mg/kg, relapsed two months after treatment. All cured animals showed no trypanosomes in their blood when tested within one to three years after administration. A scleroma about 2 to 3.5 cm in diameter was found at the site of injection at the dose of 1.5 mg/kg Mel Cy in three of eight animals. At a dose of 3 mg/kg, Mel Cy induced obvious necrosis of the tissue at the site of injection. The results of field application proved that Mel Cy is a very active trypanocidal drug against T. evansi.

An investigation was conducted on the therapeutic and prophylactic activity of isometamidium chloride (SamorinR) in Boran (Bos indicus) cattle against a Trypanosoma congolense clone, IL 3270. This clone was derived, without drug selection, from a stock originally isolated in Burkina Faso and has previously been shown to be resistant to isometamidium in both cattle and mice using an infection and treatment regimen. A group of 5 cattle were treated intramuscularly with 1.0 mg kg-1 isometamidium chloride and 28 days later challenged with Glossina morsitans centralis infected with T. congolense IL 3270. All 5 cattle and 17 untreated cattle challenged on the same day became parasitaemic by day 16 post challenge, indicating that prophylaxis did not extend to 28 days post treatment. The cattle were then treated with isometamidium chloride at one of the following doses and by different routes of administration; 1.0 or 2.0 mg kg-1 intramuscularly, 0.25, 0.5, 0.75 or 1.0 mg kg-1 intravenously. Infections relapsed in all cattle at an interval of 12-21 days following treatment, with the exception of those treated with 2.0 mg kg-1 intramuscularly in which the development of relapse infections was delayed. Similar studies were also conducted with a highly sensitive clone of T. congolense, IL 1180. Infections in cattle with this clone were eliminated by intravenous treatment with 0.25 mg kg-1 isometamidium chloride or intramuscular treatment with 0.5 mg kg-1 isometamidium chloride. Thus, although intravenous administration of isometamidium eliminated a fully sensitive infection, treatment by this route appeared not to enhance the therapeutic efficacy of the drug in the treatment of a T. congolense clone which expresses a high level of resistance.

Benznidazole (bz) is the active component of the antichagasic drug Rochagan. Tests were carried out to detect the induction of chromosomal aberrations and micronuclei in rodent bone marrow cells and peripheral blood cells, respectively. Rats were exposed to acute treatment with Rochagan by gavage at total doses of 150, 300, 1500, 2000 and 3000 mg bz/kg body weight and killed at different times. In the chronic treatments, healthy and chagasic Balb/c mice were treated with Rochagan by gavage at a dose of 100 mg bz/kg/day for 10 and 25 days. No significant increase in frequency of chromosomal aberrations in bone marrow cells or of micronuclei in peripheral blood cells was detected in the animals acutely or chronically exposed to Rochagan in vivo.

The disposition and adverse effects of the anti-trypanosomal drug isometamidium in pigs were evaluated. Following intramuscular administration of the drug at doses of 0.5, 15 and 35 mg kg-1, the drug was rapidly absorbed within 15 to 30 minutes to reach maximum plasma concentrations of 12 to 477 (n = 6), 302 to 655 (n = 4) and 1620 (n = 1) ng ml-1, respectively. No drug was detectable in plasma (less than 5 ng ml-1) 24 hours after drug administration at the three doses used. The half-lives of disappearance of the drug from plasma during the terminal phase were 7.12 h for the pigs given a dose of 15 mg kg-1, and 7.20 h for the pig which received a dose of 35 mg kg-1. At all the intramuscular injection sites, high drug concentrations were found six weeks after administration. The most dramatic adverse reactions observed were: one death after intramuscular administration at a dose of 35 mg kg-1 to two animals, and two deaths after intravenous administration at a dose of 2 mg kg-1 to two animals. For all these cases, the immediate cause of death was acute cardiovascular collapse. Biochemical analyses and gross and histological examinations showed that the animals that tolerated the high doses of 15 and 35 mg kg-1 given intramuscularly had extensive and severe tissue damage at the injection sites. Significant increases in plasma gamma-glutamyltransferase and alanine aminotransferase following drug administration suggested a degree of hepatobiliary damage.

Laboratory and animal studies have demonstrated that pyrazolopyrimidines have significant activity against Trypanosoma cruzi. This clinical investigation was to ascertain the efficacy of allopurinol in the treatment of chronic Chagas' disease. Of 307 patients studied, 91 were untreated; the remaining 216 were divided into 4 treatment groups. These corresponded to 600 or 900 mg/day of allopurinol for 60 days and benznidazole or nifurtimox at conventional dosage regimens. Patients were evaluated clinically, serologically, and parasitologically. Allopurinol was found to be as efficacious as the conventional therapeutic modalities in eliminating the parasitemia and rendering patients seronegative. Adverse reactions occurred in 11% of patients who received allopurinol and in 30% of those receiving nitrofurans. Reactions with the conventional therapy were more frequent and of a more serious nature. Oral allopurinol is as effective as the nitrofurans, but has none of the side effects.

Administration of the trypanocidal drug, Benznidazole (N-benzyl-2-nitro-imidazoleacetamide) to Trypanosoma cruzi-infected rabbits did not arrest the destructive Chagas' heart myocarditis. A typical feature of lymphocytic infiltrates associated with non-parasitized heart cell lysis was present in both treated and untreated groups of rabbits. Benznidazole-treated rabbits had their survival time shortened, probably as a consequence of Chagas' heart disease and of the development of lymphomas. The survival time of untreated T. cruzi-infected rabbits was 765 +/- 639 days and those treated with Benznidazole in the chronic phase of infection survived for 392 +/- 571 days. Malignant, non-Hodgkin's lymphomas were present in 38% of the rabbits that received the nitroarene therapy. Testicular atrophy was observed in 2 out of 10 nitroarene-treated rabbits. Benznidazole administration caused severe cell-mediated immunosuppression in T. cruzi-infected and BCG-immunized rabbits. Specific antibodies against the parasite and an unrelated antigen were detected in high levels, regardless of the nitroarene administration.