ascorbic-acid and Chagas-Disease

Benznidazole is an effective drug in the trypanocidal treatment of acute and chronic indeterminate Chagas' disease (CD). However, adverse drug reactions (ADR) are common and frequently cause patients to discontinue treatment.. We hypothesized that antioxidant supplementation could mitigate benznidazole-induced toxicity.. We co-supplemented an adult traveller with chronic indeterminate CD who experienced benznidazole ADR with ascorbic acid (AA), 1000 mg/day. We measured selected serum biomarkers of oxidative stress [total antioxidant status (TAS), total oxidative status (TOS), nuclear factor erythroid 2-related factor 2 (Nrf2), malondialdehyde (MDA), extracellular glutathione peroxidase (GPX3), catalase (CAT) and total superoxide dismutase (T-SOD)] at timepoints before and throughout benznidazole treatment and after AA co-supplementation.. AA co-supplementation effectively mitigated benznidazole-induced ADR during the aetiological treatment of chronic indeterminate CD. The kinetics of serum biomarkers of oxidative stress suggested significantly decreased oxidative insult in our patient.. We hypothesize that the key pathophysiological mechanism of benznidazole-associated toxicity is oxidative stress, rather than hypersensitivity. AA co-supplementation may improve adherence to benznidazole treatment of chronic indeterminate (or acute) CD. Oxidative stress biomarkers have the potential to guide the clinical management of CD. Prospective studies are needed to establish the benefit of antioxidant co-supplementation to benznidazole treatment of CD in reducing benznidazole toxicity, parasite clearance and the prevention of end-organ damage.

Topics: Adult; Antioxidants; Ascorbic Acid; Biomarkers; Chagas Disease; Dietary Supplements; Drug-Related Side Effects and Adverse Reactions; Humans; Nitroimidazoles; Oxidative Stress

The protozoan parasite Trypanosoma cruzi is the causative agent of American trypanosomiasis, otherwise known as Chagas disease. To survive in the host, the T. cruzi parasite needs antioxidant defense systems. One of these is a hybrid heme peroxidase, the T. cruzi ascorbate peroxidase-cytochrome c peroxidase enzyme (TcAPx-CcP). TcAPx-CcP has high sequence identity to members of the class I peroxidase family, notably ascorbate peroxidase (APX) and cytochrome c peroxidase (CcP), as well as a mitochondrial peroxidase from Leishmania major (LmP). The aim of this work was to solve the structure and examine the reactivity of the TcAPx-CcP enzyme. Low temperature electron paramagnetic resonance spectra support the formation of an exchange-coupled [Fe(IV)=O Trp

Topics: Antioxidants; Ascorbate Peroxidases; Ascorbic Acid; Chagas Disease; Cytochrome-c Peroxidase; Cytochromes c; Heme; Humans; Peroxidase; Peroxidases; Substrate Specificity; Trypanosoma cruzi

Trypanosoma cruzi infection stimulates inflammatory mediators which cause oxidative stress, and the use of antioxidants can minimize the sequelae of Chagas disease. In order to evaluate the efficacy of vitamin C in minimizing oxidative damage in Chagas disease, we orally administered ascorbic acid to Swiss mice infected with 5.0 × 10

Topics: Acute Disease; Animals; Antioxidants; Ascorbic Acid; Bilirubin; Chagas Disease; Chronic Disease; Disease Models, Animal; Inflammation; Iron; Male; Mice; Nitric Oxide; Oxidative Stress; Parasitemia; Peroxynitrous Acid; Trypanosoma cruzi

Topics: Animals; Antioxidants; Ascorbic Acid; Chagas Disease; Drug Therapy, Combination; Inflammation; Lipid Peroxidation; Male; Mice; Nitroimidazoles; Oxidation-Reduction; Reactive Oxygen Species; Trypanocidal Agents; Trypanosoma cruzi

Drugs currently used for the treatment of Chagas' disease, nifurtimox and benznidazole, have a limited effectiveness and toxic side effects. With the aim of finding new therapeutic approaches, in vitro and in vivo anti-Trypanosoma cruzi activity of vitamin C alone and combined with benznidazole were investigated.. The trypanocidal activity on epimastigote and trypomastigote forms was evaluated by counting parasites in a Neubauer chamber after treatment with the compounds. For the amastigote stage, transgenic parasites expressing β-galactosidase were used and quantified by measuring the β-galactosidase activity. The cytotoxicity of compounds was tested on Vero cells. The redox state of the parasite was evaluated by determining the reduced thiol levels (spectrophotometric assay) and the intracellular oxidative state (by flow cytometry). The in vivo trypanocidal activity was evaluated on a murine model of Chagas' disease. The trypanocidal activity of vitamin C and benznidazole was similar for the three parasite forms. When combining both drugs, vitamin C did not induce any change in the antiparasitic activity of benznidazole on trypomastigotes; however, on mammal cells, vitamin C diminished the cytotoxicity degree of benznidazole. Two mechanisms of action may be postulated for vitamin C: a lethal pro-oxidant effect on the parasite when used alone, and an antioxidant effect, when combined with benznidazole. A similar behavior was observed on infected mice; i.e., parasite counts in infected mice treated with vitamin C were lower than that of the control group. Animals treated with benznidazole presented lower parasitemia levels, as compared with those treated with vitamin C alone. Again, vitamin C did not cause any effect on the antiparasitic profile of benznidazole. Even though a combined treatment was employed, the antioxidant effect of vitamin C on the host was evidenced; a 100% survival was observed and the weight loss occurring during the acute phase of the infection was reduced.. Based on these results, the combination of vitamin C with benznidazole could be considered as an alternative treatment for Chagas' disease. These preliminary results encourage further research to improve the treatment of Chagas' disease.

Topics: Animals; Ascorbic Acid; Body Weight; Chagas Disease; Chlorocebus aethiops; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Female; Mice, Inbred C3H; Nitroimidazoles; Parasite Load; Parasitemia; Survival Analysis; Treatment Outcome; Trypanocidal Agents; Trypanosoma cruzi; Vero Cells

Chagas' disease is an infection that is caused by the protozoan Trypanosoma cruzi, affecting millions of people worldwide. Because of severe side effects and variable efficacy, the current treatments for Chagas' disease are unsatisfactory, making the search for new chemotherapeutic agents essential. Previous studies have reported various biological activities of naphthoquinones, such as the trypanocidal and antitumor activity of vitamin K3. The combination of this vitamin with vitamin C exerted better effects against various cancer cells than when used alone. These effects have been attributed to an increase in reactive oxygen species generation. In the present study, we evaluated the activity of vitamin K3 and vitamin C, alone and in combination, against T. cruzi. The vitamin K3 + vitamin C combination exerted synergistic effects against three forms of T. cruzi, leading to morphological, ultrastructural, and functional changes by producing reactive species, decreasing reduced thiol groups, altering the cell cycle, causing lipid peroxidation, and forming autophagic vacuoles. Our hypothesis is that the vitamin K3 + vitamin C combination induces oxidative imbalance in T. cruzi, probably started by a redox cycling process that leads to parasite cell death.

Topics: Animals; Ascorbic Acid; Cell Line; Chagas Disease; Drug Synergism; Macaca mulatta; Oxidation-Reduction; Reactive Oxygen Species; Trypanosoma cruzi; Vitamin K 3

Chagas disease is still an important endemic disease in Brazil, and the cardiac involvement is its more severe manifestation.. To verify whether the concomitant use of carvedilol will enhance the antioxidant effect of vitamins E and C in reducing the systemic oxidative stress in chronic Chagas heart disease.. A total of 42 patients with Chagas heart disease were studied. They were divided into four groups according to the modified Los Andes classification: 10 patients in group IA (normal electrocardiogram and echocardiogram; no cardiac involvement); 20 patients in group IB (normal electrocardiogram and abnormal echocardiogram; mild cardiac involvement); eight patients in group II (abnormal electrocardiogram and echocardiogram; no heart failure; moderate cardiac involvement); and four patients in group III (abnormal electrocardiogram and echocardiogram with heart failure; severe cardiac involvement). Blood levels of markers of oxidative stress were determined before and after a six-month period of treatment with carvedilol, and six months after combined therapy of carvedilol with vitamins E and C. The markers analyzed were as follows: activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase and reductase, myeloperoxidade and adenosine deaminase; and the levels of reduced glutathione, thiobarbituric-acid reactive substances, protein carbonyls, vitamin E, and nitric oxide.. After treatment with carvedilol, all groups showed significant decrease in protein carbonyls and reduced glutathione levels, whereas nitric oxide levels and adenosine activity increased significantly only in the less severely affected group (IA). In addition, the activity of most of the antioxidant enzymes was decreased in the less severely affected groups (IA and IB). By combining the vitamins with carvedilol, a reduction in protein damage, in glutathione levels, and in the activity of most of the antioxidant enzymes were observed.. The decrease in oxidative stress levels observed by means of the markers tested was more significant when carvedilol was used in combination with the antioxidant vitamins. The findings suggest that both carvedilol alone and in combination with the vitamins were effective in attenuating the systemic oxidative stress in patients with Chagas heart disease, especially those less severely affected, thus suggesting the possibility of synergism between these compounds.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Analysis of Variance; Antioxidants; Ascorbic Acid; Biomarkers; Carbazoles; Carvedilol; Chagas Disease; Chronic Disease; Drug Synergism; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Oxidative Stress; Propanolamines; Prospective Studies; Time Factors; Treatment Outcome; Vitamin E; Young Adult

To evaluate the efficacy of vitamin C in reducing the consequences generated by the production of free radicals in the acute and chronic phases of Chagas disease, two different doses of ascorbic acid were administered orally to 60 mice infected by Trypanosoma cruzi QM2 strain.. The animals were divided into six groups: G1, G2, and G3 for the acute phase study, and G'1, G'2, and G'3 for the chronic stage. The groups G1 and G'1 received 8.6 x 10⁻⁴ mg/g of vitamin C daily, whereas G2 and G'2 received 7.14 x 10⁻³ mg/g daily. The other groups, G3 and G'3, were considered placebos and received 10 µL of mineral water.. The study of the acute phase showed statistically significant differences between G1 and the other groups at various count days of the parasitemia evolution. The multiplying parasite was slower in G1 until the 11th day, but on the 22nd day it had greater parasitemia than in G2 and G3, and from the 36th day on, parasitemia stabilized at higher levels. However, when the histopathology of acute and chronic phases is considered, one does not note significant differences.. The administration of two different doses of vitamin C was not able to protect mice and to contain the oxidative stress caused by free radicals formed by the metabolism of oxygen (reactive oxygen species) and nitrogen (reactive nitrogen species).

Topics: Acute Disease; Animals; Antioxidants; Ascorbic Acid; Chagas Disease; Chronic Disease; Disease Models, Animal; Male; Mice; Parasitemia

The tissue changes that occur in Chagas disease are related to the degree of oxidative stress and antioxidant capacity of affected tissue. Studies with vitamin C supplementation did not develop oxidative damage caused by Chagas disease in the host, but other studies cite the use of peroxiredoxins ascorbate - dependent on T. cruzi to offer protection against immune reaction. Based on these propositions, thirty "Swiss" mice were infected with T. cruzi QM1 strain and treated with two different vitamin C doses in order to study the parasitemia evolution, histopathological changes and lipid peroxidation biomarkers during the acute phase of Chagas disease. The results showed that the parasite clearance was greater in animals fed with vitamin C overdose. There were no significant differences regarding the biomarkers of lipid peroxidation and inflammatory process or the increase of myocardium in animals treated with the recommended dosage. The largest amount of parasite growth towards the end of the acute phase suggests the benefit of high doses of vitamin C for trypomastigotes. The supplementation doesn't influence the production of free radicals or the number of amastigote nests in the acute phase of Chagas disease.

Topics: Acute Disease; Animals; Antioxidants; Ascorbic Acid; Chagas Disease; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Lipid Peroxidation; Male; Mice; Parasitemia; Time Factors; Trypanosoma cruzi

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.

Topics: Antioxidants; Ascorbic Acid; Chagas Disease; Chronic Disease; Humans; Nitroimidazoles; Oxidative Stress; Thiobarbituric Acid Reactive Substances; Vitamin E

Allogeneic blood transfusions are the second most frequent route of Chagas' disease transmission in countries where the disease is endemic. The prevention of transfusion-associated Chagas' disease has been attempted through clinical and serologic screening of blood donors and/or by the addition of trypanomicidal substances such as gentian violet (GV) to stored blood for 24 hours. The present study describes an alternative method of chemoprophylaxis of transfusion-associated Chagas' disease that reduces the sterilization time by using a combination of low-concentration GV, ascorbic acid (AA), and photoradiation with visible light.. To better reproduce the conditions of blood transfusion in developing areas, normal human blood was collected in blood collection bags, infected with different concentrations of Trypanosoma cruzi, and treated with GV, AA, and photoradiation. Mice were then inoculated with the T. cruzi-infected human blood that had been stored at different incubation intervals. Active parasites were sought in mouse blood for parasitologic diagnosis and serologic evaluation (mice inoculation, blood culture, and indirect immunofluorescence).. The association of GV (250 micrograms/mL), and photoradiation with visible light (75W) sterilized T. cruzi-infected blood even after treatment for less than 30 minutes and even when chagasic blood was treated with low-concentration GV (62.5 micrograms/mL for 30 min). Moreover, the trypanomicidal activity of GV associated with AA and photoradiation with visible light was found even when blood was infected with a 10-fold parasite concentration.. The proposed alternative prophylactic method is reproducible, easy to perform, and inexpensive, and it may have practical importance in endemic areas where serologic screening of donor blood is not always available. In addition, the reduction of the GV trypanomicidal concentration might further minimize the potential for GV-related side effects.

Topics: Animals; Ascorbic Acid; Blood Transfusion; Chagas Disease; Dose-Response Relationship, Drug; Gentian Violet; Humans; Light; Mice; Sterilization; Time Factors; Trypanosoma cruzi

Blood transfusion is the second most important mechanism of transmission of Chagas' disease, and crystal violet is currently used in blood banks in endemic areas in attempts to eliminate such transmission. A photodynamic action of crystal violet against Trypanosoma cruzi trypomastigotes in blood has been detected. This action was enhanced by addition of sodium ascorbate. Photoirradiation of whole blood containing crystal violet increased the concentration of ascorbyl radical and the generation of superoxide anion. Similar results were observed in incubations containing ascorbate and crystal violet in the absence of blood. Hydrogen peroxide generation was also detected in these incubations, thus confirming redox cycling of crystal violet under aerobic conditions. Since photoirradiation and addition of sodium ascorbate reduces significantly the effective dose and time of contact of crystal violet with T. cruzi-infected blood, a possible practical application of these findings is envisaged.

Topics: Animals; Ascorbic Acid; Chagas Disease; Drug Synergism; Electron Spin Resonance Spectroscopy; Free Radicals; Gentian Violet; Mice; Oxidation-Reduction; Oxygen; Photochemistry; Transfusion Reaction; Trypanosoma cruzi