Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Chagas' disease: lymphoma growth in rabbits treated with Benznidazole. 211 56

Chagas' heart disease (CHD), caused by the parasite Trypanosoma cruzi, is the most common form of myocarditis in Central America and South America. Some humans and experimental animals develop both humoral and cell-mediated cardiac-specific autoimmunity during infection. Benznidazole, a trypanocidal drug, is effective at reducing parasite load and decreasing the severity of myocarditis in acutely infected patients. We hypothesized that the magnitude of autoimmunity that develops following T. cruzi infection is directly proportional to the amount of damage caused by the parasite. To test this hypothesis, we used benznidazole to reduce the number of parasites in an experimental model of CHD and determined whether this treatment altered the autoimmune response. Infection of A/J mice with the Brazil strain of T. cruzi leads to the development of severe inflammation, fibrosis, necrosis, and parasitosis in the heart accompanied by vigorous cardiac myosin-specific delayed-type hypersensitivity (DTH) and antibody production at 21 days postinfection. Mice succumbed to infection within a month if left untreated. Treatment of infected mice with benznidazole eliminated mortality and decreased disease severity. Treatment also reduced cardiac myosin-specific DTH and antibody production. Reinfection of treated mice with a heart-derived, virulent strain of T. cruzi or immunization with myosin led to the redevelopment of myosin-specific autoimmune responses and inflammation. These results provide a direct link between the levels of T. cruzi and the presence of autoimmunity and suggest that elimination of the parasite may result in the reduction or elimination of autoimmunity in the chronic phase of infection.
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PMID:Modulation of autoimmunity by treatment of an infectious disease. 1748 57

Nifurtimox (Nfx) and Benznidazole (Bz) are being used for the treatment of the acute phase of Chagas' disease. Recently, they were also considered for use in the indeterminate phase. Both the nitroheterocyclic drugs have serious toxic side effects. The mechanism of Nfx toxicity is associated with the formation of reactive oxygen species (ROS) generated during nitroreduction. Potential effects on cardiac function have not been established yet, despite the well-known cardiopathy often produced by the disease itself. We describe experiments testing some acute effects of Nfx on the male Sprague Dawley rat heart. Nifurtimox was present in the heart at 1, 3 and 6 h after intragastric (i.g) treatment. In vitro studies on Nfx microsomal and cytosolic nitroreductase activities showed that only the microsomal fraction had the ability to nitroreduce it. Cytochrome P450 and cytochrome P450 reductase would be involved in the process as suggested by their response to specific inhibitors. Nifurtimox increased the cardiac protein carbonyl content at 1 and 3 h and decreased the protein sulfhydryl content at 3 h. In addition, 24 h after treatment ultrastructural alterations such as marked cytoplasmic vacuolization, separation and loss of myofibrils and mitochondrial swelling were observed. Results suggest that Nfx administration might aggravate pre-existing adverse cardiac conditions. Human & Experimental Toxicology (2007) 26, 781 -788.
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PMID:Early nifurtimox-induced biochemical and ultrastructural alterations in rat heart. 1802 49

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.
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PMID:Benznidazole biotransformation in rat heart microsomal fraction without observable ultrastructural alterations: comparison to Nifurtimox-induced cardiac effects. 1894 24

Chronic chagasic cardiac patients are exposed to oxidative stress that apparently contributes to disease progression. Benznidazole (BZN) is the main drug used for the treatment of chagasic patients and its action involves the generation of reactive species. 41 patients with Chagas' heart disease were selected and biomarkers of oxidative stress were measured before and after 2 months of BZN treatment (5 mg/kg/day) and the subsequent antioxidant supplementation with vitamin E (800 UI/day) and C (500 mg/day) during 6 months. Patients were classified according to the modified Los Andes clinical hemodynamic classification in groups IA, IB, II and III, and the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) and glutathione reductase (GR), as well as the contents of reduced glutathione (GSH), thiobarbituric acid reactive species (TBARS), protein carbonyl (PC), vitamin E and C and nitric oxide (NO), myeloperoxidase (MPO) and adenosine deaminase (ADA) activities were measured in their blood. Excepting in group III, after BZN treatment SOD, CAT, GPx and GST activities as well as PC levels were enhanced while vitamin E levels were decreased in these groups. After antioxidant supplementation the activities of SOD, GPx and GR were decreased whereas PC, TBARS, NO, and GSH levels were decreased. In conclusion, BZN treatment promoted an oxidative insult in such patients while the antioxidant supplementation was able to attenuate this effect by increasing vitamin E levels, decreasing PC and TBARS levels, inhibiting SOD, GPx and GR activities as well as inflammatory markers, mainly in stages with less cardiac involvement.
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PMID:Antioxidant therapy attenuates oxidative insult caused by benzonidazole in chronic Chagas' heart disease. 1962 91

Among the pathophysiological derangements operating in the chronic phase of Chagas disease, parasite persistence is likely to constitute the main mechanism of myocardial injury in patients with chronic chagasic cardiomyopathy. The presence of Trypanosoma cruzi in the heart causes a low-grade, but relentless, inflammatory process and induces myocardial autoimmune injury. These facts suggest that trypanocidal therapy may positively impact the clinical course of patients with chronic Chagas heart disease. However, the experimental and clinical evidence currently available is insufficient to support the routine use of etiologic treatment in these patients. The BENEFIT project--Benznidazole Evaluation for Interrupting Trypanosomiasis--is an international, multicenter, double-blind, placebo-controlled trial of trypanocidal treatment with benznidazole in patients with chronic Chagas heart disease. This project is actually comprised of two studies. The pilot study investigates whether etiologic treatment significantly reduces parasite burden, as assessed by polymerase chain reaction-based techniques and also determines the safety and tolerability profile of the trypanocidal drug in this type of chagasic population. The full-scale study determines whether antitrypanosomal therapy with benznidazole reduces mortality and other major cardiovascular clinical outcomes in patients with chronic Chagas heart disease.
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PMID:The BENEFIT trial: testing the hypothesis that trypanocidal therapy is beneficial for patients with chronic Chagas heart disease. 1975 91