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Objectives: Chagas disease (CD) treatment is limited to two therapeutic options: benznidazole (generally the first option in Spain) and nifurtimox. Both drugs present high rates of adverse reactions and treatment discontinuation and there is no consensus regarding the most effective administration schedule for benznidazole or how to prevent and manage treatment toxicity. We aim to compare the tolerability and treatment discontinuation rate between two different treatment schemes with benznidazole., Methods: This was a prospective observational study of adult patients with CD, enrolled from January 2014 to March 2018 in two referral centres in Madrid (Spain). Participants were treated either with benznidazole 5 mg/kg/day (full dose) over 60 days (benznidazole standard dose scheme (BSD)), or with an escalating dose lasting 5 days up to a maximum of 300 mg/day (benznidazole increasing dose scheme (BID))., Results: 471 patients were analysed: 201 in the BSD group and 270 in the BID group. There were no significant differences regarding age (40.4 (SD 8.7) vs 41 (SD 8.2) years), sex (74.1% (149/201) vs 68.5% (185/270) women), weight (69.4 (SD 12.8) vs 68.9 (SD 11) kg) or nationality (97.5% (196/201) vs 96.7% (261/270) Bolivians) between groups. There were also no differences in adverse reactions rate (55.2% (111/201) vs 55.6% (150/270)), number of adverse reactions per patient, adverse reactions type (except for arthralgias and myalgias which occurred more frequently in the BID group (0% (0/111) BSD vs 8% (12/150) BID; p 0.002)) and degree and time to first adverse reactions. There was significantly more treatment discontinuation (49.8% (100/201) vs 33.0% (89/270); p <0.001) in the BSD group, but not during the first 30 days of treatment (32.3% (65/201) vs 25.6% (69/270); p 0.08)., Conclusion: The use of increasing doses of benznidazole for 5 days and a maximum dose of 300 mg, does not significantly improve drug tolerability. However, while the treatment discontinuation rates were similar during the first 30 days of treatment, it may improve the treatment completion rate at 60 days., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Caused by Trypanosoma cruzi, Chagas disease is responsible for public health problems greater in magnitude than those attributed to malaria, schistosomiasis, or leishmaniasis. A factor in the socioeconomic development of poor countries, Chagas disease can cause death due to a high parasitic burden during its acute phase due and irreversible damage in organs such as the heart, esophagus, and colon during its chronic phase, even when the number of parasites is minimal. For treating Chagas disease, benznidazole (BNZ) remains the drug of choice and, in Latin America, the only drug on the market for treating the disease. However, BNZ has exhibited insufficient activity in the chronic phase of Chagas disease, required administration in large doses, prolonged treatment, and shown a high incidence of adverse reactions (vomiting, rash, peripheral neuropathy, and spinal cord depression), toxicity, and low solubility in water. As an antidote, pharmaceutical technologies have been introduced that can improve BNZ's solubility and dissolution, as well as reduce side effects in light of its bioavailability, all of which can enhance therapy for Chagas disease. In response to that trend, by conducting a literature review, we sought to identify current pharmaceutical technologies used in tandem with BNZ to improve therapy for Chagas disease. Documented techniques include emulsion and microemulsion formation, solutions, parenteral formulas, micronization, and drug delivery systems supported by the development of nanoparticles and cyclodextrins, solid dispersions, and the use of metal-organic frameworks as innovative excipients. Such technologies increase the water solubility of BNZ by 4-25-fold on dissolution and an 85% release with efficacy in only a few minutes, as recorded during a viability experiment with nanoparticle suspensions. That experiment demonstrated the need for a lower concentration of BNZ to kill 50% of trypomastigote forms of T. cruzi, described in terms of the formation of BNZ-cyclodextrin complexes, and modulating and vectoring of the antichagasic by using metal-organic frameworks. Altogether, the promising results of research identified can enable strategies to improve solubility and efficacy of BNZ, as well as therapy for Chagas disease., (Copyright © 2018. Published by Elsevier B.V.)

Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory response observed from the beginning of infection, is critical for the control of parasite proliferation and evolution of Chagas disease. Peroxisome proliferator-activated receptors (PPAR)-α, are known to modulate inflammation. In this study we investigated whether a PPAR-α agonist, Fenofibrate, improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricular end-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-α and NOS2) and heart remodeling mediators (MMP-9 and CTGF), and reduced serum creatine kinase activity. The fact that Fenofibrate partially inhibited NOS2 expression and NO release in the presence of a PPAR-α non-competitive inhibitor, suggested it also acted through PPAR-α-independent pathways. Since IκBα cytosolic degradation was inhibited by Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate that Fenofibrate acts through PPAR-α-dependent and -independent pathways. Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chagas disease, caused by Trypanosoma cruzi, is the main cause of dilated cardiomyopathy in the Americas. Antiparasitic treatment mostly relies on benznidazole (Bzl) due to Nifurtimox shortage or unavailability. Both induce adverse drug effects (ADE) of varied severity in many patients, leading to treatment discontinuation or abandonment. Since dosage may influence ADE, we aimed to assess Bzl efficacy in terms of parasiticidal and anti-inflammatory activity, using doses lower than those previously reported. BALB/c mice infected with the T. cruzi RA strain were treated with different doses of Bzl. Parasitaemia, mortality and weight change were assessed. Parasite load, tissue infiltrates and inflammatory mediators were studied in the heart. Serum creatine kinase (CK) activity was determined as a marker of heart damage. The infection-independent anti-inflammatory properties of Bzl were studied in an in vitro model of LPS-treated cardiomyocyte culture. Treatment with 25 mg/kg/day Bzl turned negative the parasitological parameters, induced a significant decrease in IL-1β, IL-6 and NOS2 in the heart and CK activity in serum, to normal levels. No mortality was observed in infected treated mice. Primary cultured cardiomyocytes treated with Bzl showed that inflammatory mediators were reduced via inhibition of the NF-κB pathway. A Bzl dose lower than that previously reported for treatment of experimental Chagas disease exerts adequate antiparasitic and anti-inflammatory effects leading to parasite clearance and tissue healing. This may be relevant to reassess the dose currently used for the treatment of human Chagas disease, aiming to minimize ADE.

Current therapies against African and American trypanosomiasis are problematic and with no immediate prospect of a vaccine there is an urgent need for cheap, more effective treatments. To aid the drug discovery pipeline, we report a novel in vivo screening approach using zebrafish (Danio rerio) embryos as a means of rapidly assessing a compounds developmental toxicity. This technique, amenable to high-throughput screening, was validated using several trypanocidal nitroaromatic prodrugs including nifurtimox and benznidazole., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Currently, only two drugs are approved for treating Trypanosoma cruzi infection: benznidazole and nifurtimox. Adverse reactions are frequent with both drugs: they have chemical similarities and common metabolic pathways making cross reactions a possibility. Our objective was to describe the safety/tolerability profile of nifurtimox in patients who had previously discontinued benznidazole due to hypersensitivity reactions. We performed a prospective observational study from September 2009 to December 2011. Patients who discontinued benznidazole therapy due to hypersensitivity reactions (HR) and were later treated with nifurtimox were included. HR to benznidazole were defined as presence of a rash with or without mucosal involvement, fever or laboratory abnormalities (such as eosinophilia, leucopaenia or impaired liver function tests). The drugs were prescribed for 60 days (benznidazole) or 60-90 days (nifurtimox). The National Cancer Institute criteria (CTCAE, 2006, Version 3.0) were used for grading and reporting of adverse reactions (AR). Eighteen patients (16 females, two males, median age 35.5 years, range 15-50 years) with asymptomatic late chronic infection, were included. Median time between benznidazole interruption and start of therapy with nifurtimox was 121.5 days (IQR 72-223 days). Fifteen patients (83.3%) developed an AR to nifurtimox, gastrointestinal complaints and anorexia being the most common, and 13 patients (72%) completed the treatment schedule. Five patients interrupted therapy (27.8%) mainly because of gastrointestinal intolerance and/or nervous system toxicity. Only one patient developed skin lesions, a mild maculopapular rash not requiring specific therapy or treatment withdrawal. There was no severe AR. Nifurtimox as second line therapy in patients who discontinued benznidazole specifically due to HR appears to be safe and does not seem to be associated with a higher incidence of AR., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Gambian (Trypanosoma brucei gambiense) human African trypanosomiasis (HAT) evolves from the hemolymphatic stage 1, treated with pentamidine, to the meningoencephalitic stage 2, often treated with melarsoprol. This arseniate may provoke a deadly reactive encephalopathy. It is therefore crucial to diagnose precisely the stages of HAT, especially when clinical and biological examinations are doubtful. We present here the case of a 30-month old girl (E20 KOLNG) diagnosed with stage 1 HAT during a field survey in June 2007 in Congo. She was followed-up every six months for 18 months in a village dispensary facility at Mpouya. Her health status deteriorated in December 2008, although cerebrospinal fluid (CSF) white blood cell (WBC) count was normal. The child was hospitalized at Brazzaville and a daytime polysomnographic recording (electroencephalogram, electrooculogram, and electromyogram) was performed (Temec Vitaport 3® portable recorder) to avoid a new lumbar puncture. The child presented a complete polysomnographic syndrome of HAT with a major disturbance of the distribution of sleep and wake episodes and the occurrence of sleep onset REM periods (SOREMPs). The relapse at stage 2 was confirmed by a new CSF examination that showed an elevated WBC count (23cells·μL(-1)) with the presence of B lymphocytes. Melarsoprol treatment was undertaken. A post-treatment recording was immediately performed, showing the resolution of sleepwake pattern abnormalities. Another polysomnography, taken four months later, confirmed the normalization of sleep-wake patterns indicating healing. We therefore propose that polysomnography, being a non-invasive technique, should be used in children to alleviate burden caused by HAT staging procedures, especially regarding lumbar punctures in remote African villages., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: There is no consensus regarding large-scale use of benznidazole to treat Chagas disease, because of its toxicity and low efficacy during the chronic phase., Objectives: To evaluate heart rate variability in chronic Chagas patients before and after treatment with benznidazole., Methods: Twenty-one Chagas patients with positive blood cultures and/or PCR received benznidazole (5 mg/kg twice daily for 60 days) and were matched for age and gender with 24 Chagas individuals with negative blood cultures, as controls. R-R intervals were assessed in time and frequency domains using an autoregressive algorithm under three different conditions: baseline, cold face and active tilt tests. Power spectral densities in low and high-frequency bands were estimated in absolute and normalized units. Data were expressed as mean±SD or medians (lower and upper quartiles). Groups were compared using non-paired or paired Student's T, Mann-Whitney or Wilcoxon tests, as required. The significance level was 5%., Results: The groups were comparable regarding age, gender and clinical disease forms. There were no differences in temporal and spectral indices between groups in baseline and cold face tests. Treated patients presented significantly lower tachycardic responses in mean R-R intervals during the active tilt test (p=0.0200) than controls did. Genetic characterization of T. cruzi isolates from treated group samples showed that 100% belonged to genotype II., Conclusion: For the first time in the medical literature, we detected sympathetic impairment during the active tilt test in chronic Chagas patients treated with benznidazole. This finding may be partially explained by benznidazole neurotoxicity., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Baccharis dracunculifolia (Asteraceae), the most important plant source of the Brazilian green propolis (GPE), displayed in vitro activity against Leishmania donovani, with an IC(50) value of 45 microg/mL, while GPE presented an IC(50) value of 49 microg/mL. Among the isolated compounds of B. dracunculifolia, ursolic acid, and hautriwaic acid lactone showed IC(50) values of 3.7 microg/mL and 7.0 microg/mL, respectively. Uvaol, acacetin, and ermanin displayed moderate antileishmanial activity. Regarding the antiplasmodial assay against Plasmodium falciparum, BdE and GPE gave similar IC(50) values (about 20 microg/mL), while Hautriwaic acid lactone led to an IC(50) value of 0.8 microg/mL (D6 clone).

Background: Human African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are toxic, ineffective, or impractical. We assessed the efficacy and safety of nifurtimox-eflornithine combination therapy (NECT) for second-stage disease compared with the standard eflornithine regimen., Methods: A multicentre, randomised, open-label, active control, phase III, non-inferiority trial was done at four HAT treatment centres in the Republic of the Congo and the Democratic Republic of the Congo. Patients aged 15 years or older with confirmed second-stage T b gambiense infection were randomly assigned by computer-generated randomisation sequence to receive intravenous eflornithine (400 mg/kg per day, every 6 h; n=144) for 14 days or intravenous eflornithine (400 mg/kg per day, every 12 h) for 7 days with oral nifurtimox (15 mg/kg per day, every 8 h) for 10 days (NECT; n=143). The primary endpoint was cure (defined as absence of trypanosomes in body fluids and a leucocyte count

Drug therapy for late-stage (encephalitic) human African trypanosomiasis (HAT) is currently very unsatisfactory with the most commonly used drug, melarsoprol, having a 5% overall mortality. There is evidence in a mouse model of HAT that Substance P (SP) receptor antagonism reduces the neuroinflammatory reaction to CNS trypanosome infection. In this study we investigated the effects of combination chemotherapy with melarsoprol and a humanised SP receptor antagonist aprepitant (EMEND) in this mouse model. The melarsoprol/aprepitant drug combination did not produce any clinical signs of illness in mice with CNS trypanosome infection. This lack of any additional or unexpected CNS toxicity in the mouse model of CNS HAT provides valuable safety data for the future possible use of this drug combination in patients with late-stage HAT.

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.

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.

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.

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.

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.

Chromosomal aberrations and induction of micronuclei were analyzed from cultures of peripheral lymphocytes in 2 groups of chagasic children, before and after treatment with benznidazole. The median incidence of micronucleated interphase lymphocytes (20 patients) and chromosomal aberrations (10 patients) increased from control values of 5/1000 and 3% to 11.5/1000 and 6%, respectively, at a significance of P = 0.05.