Herbal extracts differentially inhibit oxidative effects caused by the biotransformation of nifurtimox, nitrofurantoin and acetaminophen on rat liver microsomes / Extractos herbales inhiben diferencialmente los efectos oxidativos causados por la biotransformación de nifurtimox, nitrofurantoína y acetaminofeno en microsomas hepáticos de rata]

Inflammation is a cellular defensive mechanism associated to oxidative stress. The administration of nitrofurantoin, nifurtimox and acetaminophen generates oxidative stress by their biotransformation through CYP450 system. The main adverse effect described for the first two drugs is gastrointestinal inflammation and that of the last, hepatitis. Therefore, standardised dry extracts from Rosmarinus officinalis, Buddleja globosa Hope, Cynara scolymus L., Echinacea purpurea and Hedera helix were tested to evaluate their capacity to decrease drug-induced oxidative stress. For that, rat liver microsomes were incubated with drugs in the presence of NADPH (specific CYP450 system cofactor) to test oxidative damage on microsomal lipids, thiols, and GST activity. All drugs tested induced oxidation of microsomal lipids and thiols, and inhibition of GST activity. Herbal extracts prevented these phenomena in different extension. These results show that antioxidant phytodrugs previously evaluated could alleviate drugs adverse effects associated to oxidative stress.

Inflamación es un mecanismo de defensa el cual está asociado a estrés oxidativo. La administración de nitrofurantoína, nifurtimox y paracetamol genera estrés oxidativo al metabolizarse a través del sistema CYP450. El principal efecto adverso de los dos primeros fármacos es inflamación gastrointestinal y del tercero, hepatitis. Por lo tanto, utilizamos diversos extractos herbales para disminuir el estrés oxidativo inducido por estos fármacos. Para esto se incubaron microsomas hepáticos de rata con dichos fármacos en presencia de NADPH (cofactor específico del sistema CYP450) y se evaluó el daño oxidativo generado sobre los lípidos, los tioles y la actividad GST microsómica. Todos los fármacos indujeron oxidación de los lípidos y los tioles microsómicos e inhibieron la actividad GST. Los extractos herbales previnieron estos fenómenos oxidativos en diferente extensión. Estos resultados indican que fitofármacos antioxidantes previamente evaluados, podrían aliviar los efectos adversos asociados a estrés oxidativo de los fármacos.

Experiencia terapéutica en un centro para la enfermedad de Chagas / Therapeutic experience in a Chagas disease center

American Trypanosomiasis or Chagas Disease is a major public health problem, endemic in the American continent since prehistoric times. Its natural course is towardschronicity in the immunocompetent host, often leading to severe cardiopathy or bowelinvolvement. Pharmacologic therapy is restricted to two drugs and only one of themis currently available in Chile. Both have poor effectiveness in the chronic stages ofthe disease and cause frequent adverse reactions. Many physicians avoid their use,despite published evidences about the usefulness. We herein report the experienceof our Center in the treatment of Chronic Chagas Disease in adults using the drugnifurtimox, emphasizing its degree of acceptability and its secondary effects.

Nifurtimox therapy for Chagas disease does not cause hypersensitivity reactions in patients with such previous adverse reactions during benznidazole treatment.

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.

A phase 1 study of nifurtimox in patients with relapsed/refractory neuroblastoma.

The primary aim of this phase 1 study was to determine the maximum tolerated dose (MTD) and evaluate the safety of nifurtimox alone and in combination with cyclophosphamide and topotecan in multiple relapsed/refractory neuroblastoma pediatric patients. The secondary aim was to evaluate the pharmacokinetics of nifurtimox and the treatment response. To these ends, we performed a phase 1 dose escalation trial of daily oral nifurtimox with toxicity monitoring to determine the MTD, followed by 3 cycles of nifurtimox in combination with cyclophosphamide and topotecan. Samples were collected to determine the pharmacokinetic parameters maximum concentration, time at which maximum concentration is reached, and area under the curve between 0 and 8 hours. Treatment response was evaluated by radiographic and radionuclide (I-metaiodobenzylguanidine) imaging, measurement of urinary catecholamines, and clearance of bone marrow disease. We determined the MTD of nifurtimox to be 30 mg/kg/d. The non-dose-limiting toxicities were mainly nausea and neuropathy. The dose-limiting toxicities of 2 patients at 40 mg/kg/d were a grade 3 pulmonary hemorrhage and a grade 3 neuropathy (reversible). Overall, nifurtimox was well tolerated by pediatric patients at a dose of 30 mg/kg/d, and tumor responses were seen both as a single agent and in combination with chemotherapy. A Phase 2 study to determine the antitumor efficacy of nifurtimox is currently underway.

Tratamento etiológico da doença de Chagas no Brasil / Etiologic treatment of Chagas disease in Brazil

Nosso grupo de pesquisa tem desenvolvido experiências de monitoramento de reações adversas em pacientes chagásicos em tratamento com benznidazol. A proposta de produção deste artigo nasceu da constatação da escassez de artigos que reunissem vários aspectos relacionados ao tratamento etiológico da doença de Chagas. Portanto, foram realizadas buscas de artigos originais e revisões indexadas, nas bases do Medline e Lilacs, de publicações relativas ao tratamento etiológico da doença de Chagas desde os primeiros ensaios terapêuticos até o momento incluindo mecanismo de ação, reações adversas, critérios de cura e indicações de tratamento do consenso brasileiro. Os medicamentos nifurtimox e benznidazol, utilizados atualmente no tratamento da doença de Chagas, apresentam eficácia acima de 80por cento na fase aguda e de 8por cento a 30por cento na fase crônica. O sucesso da terapêutica esbarra em alguns pontos tais como: esquema terapêutico prolongado, reações adversas, variabilidade genética dos parasitos e cepas naturalmente resistentes aos fármacos. Os resultados desta atualização revelam a necessidade do desenvolvimento de novos fármacos com atividade anti-T. cruzi que, por um lado, apresentem menor toxicidade, e por outro, maior eficácia na fase crônica.

Benznidazole biotransformation in rat heart microsomal fraction without observable ultrastructural alterations: comparison to Nifurtimox-induced cardiac effects

Benznidazole (Bz) and Nifurtimox (Nfx) have been used to treat Chagas disease. As recent studies have de-monstrated cardiotoxic effects of Nfx, we attempted to determine whether Bz behaves similarly. Bz reached the heart tissue of male rats after intragastric administration. No cytosolic Bz nitroreductases were detected, although microsomal NADPH-dependent Bz nitroreductase activity was observed, and appeared to be mediated by P450 reductase. No ultrastructurally observable deleterious effects of Bz were detected, in contrast to the overt cardiac effects previously reported for Nfx. In conclusion, when these drugs are used in chagasic patients, Bz may pose a lesser risk to heart function than Nfx when any cardiopathy is present.

Trypanocide treatment among adults with chronic Chagas disease living in Santa Fe city (Argentina), over a mean follow-up of 21 years: parasitological, serological and clinical evolution

The efficacy of treatment with nifurtimox and/or benznidazole among adults with chronic Chagas disease with no previous electrocardiographic disturbances was evaluated over a mean follow-up of 21 years, by means of conventional serology, xenodiagnosis, clinical examination, electrocardiograms and chest X-ray. One hundred and eleven patients, between 17 and 46 years old, were studied: 54 underwent treatment (nifurtimox 27, benznidazole 27) and 57 remained untreated (control group). Xenodiagnosis was performed on 65 percent of them: 36/38 of the treated and 9/34 of the untreated patients had previous positive xenodiagnosis. Post-treatment, 133 xenodiagnoses were performed on 41 patients, all resulting negative. In the control group, 29 xenodiagnoses were performed on 14 patients; 2 resulted positive. Sera stored during the follow-up were simultaneously analyzed through conventional serology tests (IHA; DA-2ME; IIF). The serological evolution in the treated group was: a) 37 percent underwent negative seroconversion (nifurtimox 11, benznidazole 9); b) 27.8 percent decreased titers (nifurtimox 9, benznidazole 6), 9 showed inconclusive final serology (nifurtimox 7, benznidazole 2); c) 35.2 percent remained positive with constant titers (nifurtimox 7; benznidazole 12). The control group conserved the initial antibody levels during the follow-up. In the clinical evolution, 2/54 (3.7 percent) of the treated and 9/57 (15.8 percent) of the untreated patients showed electrocardiographic disturbances attributable to Chagas myocardiopathy, with a statistically relevant difference (p<0.05). Treatment caused deparasitation in at least 37 percent of the chronically infected adults and a protective effect on their clinical evolution.

Avaliamos a eficácia do nifurtimox e/ou benznidazol, durante 21 anos em média, em adultos chagásicos crônicos sem alterações eletrocardiográficas iniciais, mediante sorologia convencional, xenodiagnóstico, exames clínicos, eletrocardiográficos e radiografia do tórax. Estudamos 111 pacientes (17 a 46 anos): 54 foram tratados (27 com nifurtimox e 27 com benznidazol) e 57 formaram o grupo controle. Foram submetidos ao xenodiagnóstico 65 por cento dos pacientes estudados: 36/38 tratados e 9/34 do grupo controle com xenodiagnóstico positivo prévio. Após tratamento, foram realizados 133 xenodiagnósticos em 41 pacientes, sendo todos negativos. Foram realizados 29 xenodiagnósticos em 14 pacientes do grupo controle, 2 foram positivos. A sorologia convencional foi realizada em soros estocados durante o seguimento. Evolução sorológica. Grupo tratado: a) 37 por cento negativaram (nifurtimox 11, benznidazol 9); b) 27,8 por cento diminuíram a titulação (nifurtimox 9, benznidazol 6), 9 deles apresentaram sorologia final discordante (nifurtimox 7, benznidazol 2; c) 35,2 por cento permaneceram positivos com titulação constante (nifurtimox 7, benznidazol 12). Grupo controle: conservou os níveis iniciais de anticorpos durante o seguimento. Evolução clínica: 2/54 (3,7 por cento) pacientes tratados e 9/57 não tratados apresentaram alterações eletrocardiográficas atribuíveis a miocardiopatia chagásica. Diferenças estatisticamente significantes (p<0,05). O tratamento produziu efeito de combate ao parasita em pelo menos 37 por cento dos infetados crônicos adultos e efeito protetor na evolução clínica.

Toxic side effects of drugs used to treat Chagas' disease (American trypanosomiasis).

Chagas' disease (American trypanosomiasis) is an endemic parasitic disease in some areas of Latin America. About 16-18 million persons are infected with the aetiological agent of the disease, Trypanosoma cruzi, and more than 100 million are living at risk of infection. There are different modes of infection: (1) via blood sucking vector insects infected with T. cruzi, accounting for 80-90% of transmission of the disease; (2) via blood transfusion or congenital transmission, accounting for 0.5-8% of transmission; (3) other less common forms of infection, eg, from infected food or drinks or via infected organs used in transplants. The acute phase of the disease can last from weeks to months and typically is asymptomatic or associated with fever and other mild nonspecific manifestations. However, life-threatening myocarditis or meningoencephalitis can occur during the acute phase. The death rate for persons in this phase is about 10%. Approximately 10-50% of the survivors develop chronic Chagas' disease, which is characterized by potentially lethal cardiopathy and megacolon or megaoesophagus. There are two drugs available for the aetiological treatment of Chagas' disease: nifurtimox (Nfx) and benznidazole (Bz). Nfx is a nitrofurane and Bz is a nitroimidazole compound. The use of these drugs to treat the acute phase of the disease is widely accepted. However, their use in the treatment of the chronic phase is controversial. The undesirable side effects of both drugs are a major drawback in their use, frequently forcing the physician to stop treatment. The most frequent adverse effects observed in the use of Nfx are: anorexia, loss of weight, psychic alterations, excitability, sleepiness, digestive manifestations such as nausea or vomiting, and occasionally intestinal colic and diarrhoea. In the case of Bz, skin manifestations are the most notorious (e.g., hypersensitivity, dermatitis with cutaneous eruptions, generalized oedema, fever, lymphoadenopathy, articular and muscular pain), with depression of bone marrow, thrombocytopenic purpura and agranulocytosis being the more severe manifestations. Experimental toxicity studies with Nfx evidenced neurotoxicity, testicular damage, ovarian toxicity, and deleterious effects in adrenal, colon, oesophageal and mammary tissue. In the case of Bz, deleterious effects were observed in adrenals, colon and oesophagus. Bz also inhibits the metabolism of several xenobiotics biotransformed by the cytochrome P450 system and its reactive metabolites react with fetal components in vivo. Both drugs exhibited significant mutagenic effects and were shown to be tumorigenic or carcinogenic in some studies. The toxic side effects of both nitroheterocyclic derivatives require enzymatic reduction of their nitro group. Those processes are fundamentally mediated by cytochrome P450 reductase and cytochrome P450. Other enzymes such as xanthine oxidoreductase or aldehyde oxidase may also be involved.

[Interventional study in the natural evolution of Chagas disease. Evaluation of specific antiparasitic treatment. Retrospective-prospective study of antiparasitic therapy]. / Estudio de intervención en la evolución natural de la enfermedad de Chagas. Evaluación del tratamiento antiparasitario específico. Estudio retrospectivo-prospectivo de terapéutica antiparasitaria.

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.

Tratamiento de la enfermedad de Chagas / Treatment of Chagas disease

En la actualidad se acepta que la enfermedad de Chagas humana debe ser tratada en cualquier período de su evolución con la única excepción del período crónico terminal. En el período agudo clínico, infección de menos de 2 meses así como en el biológico: pesquisa de parásitos al fresco, frotis, gota gruesa y con serología convencional positiva e IgM(+). El ideal de tratamiento es con nifurtimox (NF) 8-10 mg/kg día en adultos y 15 mg/kg día en niños por 60-90 días. La dosis se reparte en tres tomas. La curación clínica y serológica es de un 60 por ciento. En Brasil donde se utiliza este fármaco se trata con benznidazol (BNZ) 5 mg/kg día (adultos) y 5-10 mg/kg día en niños por 60 días. En las infecciones congénitas la terapia debe ser precoz en cuanto se realice el diagnóstico por clínica y pesquisa del parásito al fresco, frotis, microstraut etc. Muchas veces el diagnóstico se efectúa por persistenica de la serología por más de 6 meses y el recién nacido ya esta en etapa crónica de la infección. Es necesario efectuar seguimiento clínico serológico y parasitológico de los casos. Las infecciones accidentales deben ser tratadas por 10 días. En los trasplantes de órganos en que el receptor o dador es chagásico se debe indicar terapia con NF o BNZ a igual dosis y tiempo que la señalada anteriormente. Las reactivaciones en los casos crónicos ejem: que adquieren un SIDA o que presentan depresiones del sistema inmunidad celular como leucemias, Hodgkin, etc se deben tratar como cuadros agudos con NF ó NBZ por períodos prolongados de 5 ó más meses. En estos casos obviamente la prevención es lo ideal: hacer serología para Chagas a los pacientes con SIDA, etc

Estudo comparativo controlado com emprego de benznidazole, nifurtimox e placebo, na forma crônica da doença de Chagas, em uma área de campo com transmissäo interrompida: I. avaliaçäo preliminar / A controlled comparative study using benznidazole, nifurtimox and placebo in chronic Chaga's disease patients, in a field area with interrupted transmission: I. preliminary evaluation

Foi realizado um estudo controlado para avaliar a eficácia terapêutica e a tolerância do nifurtimox e do benznidazole em pacientes com a doença de Chagas crônica. Todos os pacientes tinham as reaçöes de imunofluorescência e fixaçäo do complemento positivas para anticorpos anti-T. cruzi e pelo menos dois xenodiagnósticos positivos em três realizados, antes do tratamento, e foram submetidos a exames clínicos, eletrocardiográficos do coraçäo e do esôfago. De 77 pacientes estudados, 27 foram tratados com nifurtimox, 26 com benznidazole, ambos na dose de 5mg/kg/dia, durante 30 dias consecutivos, e 24 receberam um placebo em comprimidos semelhantes aos do benznidazole. Dos 77 pacientes, 64 (83,1 por cento) completaram o tratamento: 23 (88,4 por cento) com benznidazole, 19 (70,3 por cento) com niturtimox e 22 (91,6 por cento) com placebo. Os pacientes foram avaliados clinicamente, sorologicamente e parasitologicamente (seis xenodiagnósticos no período de um ano após o tratamento). O grupo do benznidazole mostrou apenas 1,8 por cento de xenodiagnósticos positivos pós-tratamento, o grupo do nifurtimox 9,6 por cento e o do placebo 34,3 por cento. Todas as reaçöes sorológicas continuam positivas e näo houve alteraçöes clínicas, eletrocardiográficas ou radiológicas um ano após o tratamento

Perspectivas actuales del tratamiento específico de la enfermedad de Chagas / Present perspectives of specific treatment of Chagas's disease

The evolution of the specific treatment of Chagas's disease, including the numerous drugs tested, is briefly summarized. Since 1969 laboratory and clinical studies have persistently demostrated that nifurtimox (NFX) and benznidazole (BNL) are the best agents for treating trypanosoma cruzi huamn infection, even though they cannot be considered ideal drugs. The main indications for NFX and BNL are: acute phase of the infection, congenital form, reactivation associated with inmunosuppresion, recently acquired infection, mostly in children and young adults, and in transfusions and organ transplant situations. Both drugs may also be indicated for the treatment of some patients in the indeterminated asymptomatic form of the chronic infection with mild heart involvement, or in clinical megaesophagus patients who previously need symptomatic treatmentto ensure the appropriate absortion of the medication. The most used dosage schedules are: NFX, for 60-90 days, 8-10 mg/kg/day in adults and < 15 mg/kg/day in children. BNL, for 60 days, 5 mg/kg/day in adults and < 10 mg/kg/day in children. Both drugs are taken orally and must be given divided into 2-3 fracctions after meals. Both drugs are well tolerated by children, and particularly in the acute phase of the disease. Adverse reactions may be observed, i.e. disturbances associated to the digestive tract such as hiporexia, nausea, vomiting and loss of weigth with NFX, and dermopathy and polineuropathy, with BNL. The main limitations of both drugs are in the long course od adminitration and the ocurrence of adverse side affects. A series of promising new drugs for the treatment of human Chagas's disease in beign tested. Because the relativa lack of interest of the pharmaceutical industry in the research for new drugs for the treatment of the parasitosis, which affects 16-18 million people in Latin America, Universities and Research Governmental Institution should stimulate the investigation for the development of new drugs and the clinical evaluation of drugs experimentally known and not yet tested.

Therapeutic efficacy of allopurinol in patients with chronic Chagas' disease.

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.

Malignant, non-Hodgkin's lymphomas in Trypanosoma cruzi-infected rabbits treated with nitroarenes.

Use of 2-nitroimidazole, 5-nitrofuran and 5-nitroimidazole compounds in T. cruzi-infected rabbits resulted in a reduction in duration of parasitaemia in comparison with untreated, infected rabbits. The chronic myocarditis associated with Chagas' disease was not, however, prevented in nitroarene-treated rabbits; lymphocytic infiltrates associated with cardiac cell lysis, in the absence of parasites in situ, were present in both treated and untreated rabbits. The carcinogenic effect of each trypanocidal nitroarene used in this study was also assessed. Administration of nitroarenes to rabbits resulted in the appearance of solid tumours in 37.8 per cent of animals that received drug therapy. Untreated, control rabbits in this series did not show tumour growth. Furthermore, malignant, mixed-cell type, non-Hodgkin's lymphomas were seen in 32.4 per cent of the treated rabbits. It seems that a direct relationship could be present between the presence of the nitro group, the trypanocidal cytotoxicity and the prevalence of tumours. Benznidazole cleared up parasitaemias in the shortest time and was associated with 41.6 per cent of lymphoma growths, whereas MK-436 required twice as much time to clear blood parasites, and showed lymphomas in 25 per cent of experimental rabbits. The demonstration of a high prevalence of malignant tumours in addition to the chronic myocarditis of Chagas' disease in nitroarene-treated rabbits is important since indiscriminate use of such compounds currently used to treat T. cruzi infections in man could increase the risk of lymphoma.

El caso de infecciosas: Leishmaniasis cutanea / The case of infectious: Leishmaniasis cutaneous

Se presenta el caso de un agricultor quien padecio lesion cutanea ulcerosa cronica producida por Leishmaniasis sp. la cual curo con tratamiento con Metilglucamina mas Cimetidina

Comportamento da parasitemia avaliada pelo método de Strout modificado em chagásicos agudos em tratamento / Changes in parasitemia evaluated using the modified Strout method in patients with acute Chagas' disease under treatment

Em 18 pacientes com doença de Chagas aguda foi semiquantificada a parasitemia, pelo método de Strout modificado, antes e durante o tratamento. Antes da terapêutica a parasitemia variou entre 1 e 104 tripanossomos, e após o nício do tratamento a parasitemia foi lida repetidamente com um intervalo, na maioria dos casos, entre dois e cinco dias, até a negativaçäo. A dose inicial dos medicamentos foi de 10 a 15 mg/kg/dia de Nifurtimox para sete pacientes, e 10 a 20 mg/kg%dia Benzonidazol para onze indivíduos. Após início do tratamento com Nifurtimox um paciente ficou o mínimo de cinco e dois o máximo de 23 dias com parasitemia enquanto com o Benzonidazol um paciente peraneceu o máximo de 15 dias com parasitemia patente. O Benzonidazol baixou a parasitemia mais rapidamente que o Nifurtimox

Toxic effects of nifurtimox and benznidazole, two drugs used against American trypanosomiasis (Chagas' disease).

American trypanosomiasis (Chagas' disease) is an endemic parasitic disease afflicting more than 20 million persons in Latin America. Two drugs are currently being used for treatment of the acute phase of Chagas' disease: 4-[(5-nitrofurfurylidene)amino-3-methylthiomorpholine-1,1-di oxide] (Nifurtimox; Nfx) and (N-benzl-2-nitro-1-imidazole acetamide) (Benznidazole; Bz). Nfx and Bz have serious undesirable effects, which have been reported during their clinical use, including anorexia and weight loss, nausea and vomiting, nervous excitation, insomnia, psyche depressions, convulsions, vertigo, headache, sleepiness, myalgias, arthralgias, loss of balance, disorientation, forgetfulness, paresthesias, adynamia, acoustic phenomena, peripheral neuropathies, gastralgia, mucosal edema, hepatic intolerance, skin manifestations, and intolerance to drinking alcohol. Effects in the central and peripheral nervous system of Nfx were also reproduced in animals. Signs of testicular and ovarian injury were reported for both Nfx and Bz, the effects of Bz being in general less intense than those of Nfx. Both drugs evidenced mutagenicity. In light of the present knowledge about the toxicity of Nfx and Bz, further studies on the mutagenic, teratogenic, carcinogenic, and reproductive effects of both drugs are recommended. Lack of information is particularly serious for Bz. Studies on Nfx and Bz biotransformation, activation to reactive metabolites, and potential mechanisms for their toxic effects were analyzed. Risk-benefit considerations of the use of Nfx and Bz were made and an analysis of the need for research on Chagas' disease chemotherapy was also performed.

Enfermedad de Chagas: efecto clastogénico de nifurtimox y benznidazol en niños / Chagas' disease: clastogenic effect of nifurtimox and benznidazole in children

Se realizaron estudios citogenéticos en 10 pacientes que padecieron enfermedad de Chagas aguda, para evaluar el daño cromosómico antes, durantre y posterior al tratamiento con Nifurtimox o Benznidazol. Se demostró el efecto clastogénico de ambos farmacos durante el tratamiento al observarse que producen un elelvado porcentaje de micronúcleos y una frecuencia aumentada de expresión de Sitios Frágiles (SF) localizados con técnica de bandeo G en: 1p31, 2p24, 314, 5q34, 6q25, 7q32, 8q24, 14q24, 16q23, Xp22 todos ellos ubicados en áreas cromosómicas lindantes con proto-oncogenes o con puntos de rotura específicos en cáncer. Estas observaciones indican que existe un riesgo potencial para la población tratada con nifurtimox o Benznidazol