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De Lima Barros M.B.,Evandro Chagas Clinical Research Institute | Schubach A.O.,Evandro Chagas Clinical Research Institute | De Vasconcellos Carvalhaes De Oliveira R.,Evandro Chagas Clinical Research Institute | Martins E.B.,Oswaldo Cruz Institute | And 2 more authors.
Clinical Infectious Diseases

Background. Itraconazole has become the first choice for treatment of cutaneous sporotrichosis. However, this recommendation is based on case reports and small series. The safety and efficacy of itraconazole were evaluated in 645 patients who received a diagnosis on the basis of isolation of Sporothrix schenckii in Rio de Janeiro, Brazil. Methods. A standard regimen of itraconazole (100 mg/day orally) was used. Clinical and laboratory adverse events were assessed a grades 1-4. A multivariate Cox model was used to analyze the response to treatment. Results. The median age was 43 years. Lymphocutaneous form occurred in 68.1% and fixed form in 23.1%. Six hundred ten patients (94.6%) were cured with itraconazole (50-400 mg/day): 547 with 100 mg/day, 59 with 200-400 mg/day, and 4 children with 50 mg/day. Three patients switched to potassium iodide, 2 to terbinafine, and 4 to thermotherapy. Twenty-six were lost to follow-up. Clinical adverse events occurred in 18.1% of patients using 100 mg/day and 21.9% of those using 200-400 mg/day. The most frequent clinical adverse events were nausea and epigastric pain. Laboratory adverse events occurred in 24.1%; the most common was hypercholesterolemia, followed by hypertriglyceridemia. Four hundred sixty-two patients (71.6%) completed clinical follow-up, and all remained cured. Only 2 variables were significant in explaining the cure: patients with erythema nodosum healed faster, and lymphocutaneous form took longer to cure.Conclusions.In the current series, the therapeutic response was excellent with the minimum dose of itraconazole, and there was a low incidence of adverse events and treatment failure. © 2011 The Author. Source

Zanini G.M.,La Jolla Bioengineering Institute | Zanini G.M.,Evandro Chagas Clinical Research Institute | Martins Y.C.,La Jolla Bioengineering Institute | Martins Y.C.,Federal University of Rio de Janeiro | And 5 more authors.
Journal of Neuroimmune Pharmacology

Administration of the exogenous nitric oxide (NO) donor dipropylenetriamine-NONOate (DPTA-NO) to mice during Plasmodium berghei ANKA (PbA) infection largely prevents development of experimental cerebral malaria (ECM). However, a high dose (1 mg/mouse twice a day) is necessary and causes potent side effects such as marked hypotension. In the present study we evaluated whether an alternative, physiologically relevant NO donor, S-nitrosoglutathione (GSNO), was able to prevent ECM at lower doses with minimal side effects. Prophylactic treatment with high (3.5 mg), intermediate (0.35 mg) or low (0.035 mg) doses of GSNO decreased incidence of ECM in PbA-infected mice, decreasing also edema, leukocyte accumulation and hemorrhage incidence in the brain. The high dose inhibited parasite growth and also induced transient hypotension. Low and intermediate doses had no or only mild effects on parasitemia, blood pressure, and heart rate compared to saline-treated mice. PbA infection decreased brain total and reduced (GSH) glutathione levels. Brain levels of oxidized (GSSG) glutathione and the GSH/GSSG ratio were positively correlated with temperature and motor behavior. Low and intermediate doses of GSNO failed to restore the depleted brain total glutathione and GSH levels, suggesting that ECM prevention by GSNO was probably related to other effects such as inhibition of inflammation and vascular protection. These results indicate that ECM is associated with depletion of the brain glutathione pool and that GSNO is able to prevent ECM development in a wide range of doses, decreasing brain inflammation and inducing milder cardiovascular side effects. © Springer Science+Business Media, LLC 2011. Source

Ong P.K.,La Jolla Bioengineering Institute | Melchior B.,La Jolla Bioengineering Institute | Martins Y.C.,La Jolla Bioengineering Institute | Hofer A.,La Jolla Bioengineering Institute | And 7 more authors.
PLoS Pathogens

Cerebrovascular dysfunction plays a key role in the pathogenesis of cerebral malaria. In experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA, cerebrovascular dysfunction characterized by vascular constriction, occlusion and damage results in impaired perfusion and reduced cerebral blood flow and oxygenation, and has been linked to low nitric oxide (NO) bioavailability. Here, we directly assessed cerebrovascular function in ECM using a novel cranial window method for intravital microscopy of the pial microcirculation and probed the role of NOS isoforms and phosphorylation patterns in the impaired vascular responses. We show that pial arteriolar responses to endothelial NOS (eNOS) and neuronal NOS (nNOS) agonists (Acetylcholine (ACh) and N-Methyl-D-Aspartate (NMDA)) were blunted in mice with ECM, and could be partially recovered by exogenous supplementation of tetrahydrobiopterin (BH4). Pial arterioles in non-ECM mice infected by Plasmodium berghei NK65 remained relatively responsive to the agonists and were not significantly affected by BH4 treatment. These findings, together with the observed blunting of NO production upon stimulation by the agonists, decrease in total NOS activity, augmentation of lipid peroxidation levels, upregulation of eNOS protein expression, and increase in eNOS and nNOS monomerization in the brain during ECM development strongly indicate a state of eNOS/nNOS uncoupling likely mediated by oxidative stress. Furthermore, the downregulation of Serine 1176 (S1176) phosphorylation of eNOS, which correlated with a decrease in cerebrovascular wall shear stress, implicates hemorheological disturbances in eNOS dysfunction in ECM. Finally, pial arterioles responded to superfusion with the NO donor, S-Nitroso-L-glutathione (GSNO), but with decreased intensity, indicating that not only NO production but also signaling is perturbed during ECM. Therefore, the pathological impairment of eNOS and nNOS functions contribute importantly to cerebrovascular dysfunction in ECM and the recovery of intrinsic functionality of NOS to increase NO bioavailability and restore vascular health represents a target for ECM treatment. © 2013 Ong et al. Source

Cabrales P.,La Jolla Bioengineering Institute | Cabrales P.,University of California at San Diego | Martins Y.C.,La Jolla Bioengineering Institute | Ong P.K.,La Jolla Bioengineering Institute | And 5 more authors.

Ischemia and hypoxia have been implicated in cerebral malaria (CM) pathogenesis, although direct measurements of hypoxia have not been conducted. C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) develop a neurological syndrome known as experimental cerebral malaria (ECM), whereas BALB/c mice are resistant to ECM. In this study, intravital microscopy methods were used to quantify hemodynamic changes, vascular/tissue oxygen (O2) tension (PO2), and perivascular pH in vivo in ECM and non-ECM models, employing a closed cranial window model. ECM mice on day 6 of infection showed marked decreases in pial blood flow, vascular (arteriolar, venular), and perivascular PO2, perivascular pH, and systemic hemoglobin levels. Changes were more dramatic in mice with late-stage ECM compared with mice with early-stage ECM. These changes led to drastic decreases in O2 delivery to the brain tissue. In addition, ECM animals required a greater PO2 gradient to extract the same amount of O2 compared with non-infected animals, as the pial tissues extract O2 from the steepest portion of the blood O2 equilibrium curve. ECM animals also showed increased leukocyte adherence in post-capillary venules, and the intensity of adhesion was inversely correlated with blood flow and O2 extraction. PbA-infected BALB/c mice displayed no neurological signs on day 6 and while they did show changes similar to those observed in C57BL/6 mice (decreased pial blood flow, vascular/tissue PO2, perivascular pH, hemoglobin levels), non-ECM animals preserved superior perfusion and oxygenation compared with ECM animals at similar anemia and parasitemia levels, resulting in better O2 delivery and O2 extraction by the brain tissue. In conclusion, direct quantitative assessment of pial hemodynamics and oxygenation in vivo revealed that ECM is associated with severe progressive brain tissue hypoxia and acidosis. © 2013 Landes Bioscience. Source

Kinsler J.J.,University of California at Los Angeles | Cunningham W.E.,University of California at Los Angeles | Nurena C.R.,National Major San Marcos University | Nadjat-Haiem C.,University of California at Los Angeles | And 5 more authors.
AIDS and Behavior

Conjoint Analysis (CJA), a statistical market-based technique that assesses the value consumers place on product characteristics, may be used to predict acceptability of hypothetical products. Rectal Microbicides (RM)-substances that would prevent HIV infection during receptive anal intercourse-will require acceptability data from potential users in multiple settings to inform the development process by providing valuable information on desirable product characteristics and issues surrounding potential barriers to product use. This study applied CJA to explore the acceptability of eight different hypothetical RM among 128 MSM in Lima and Iquitos, Peru; Guayaquil, Ecuador; and Rio de Janeiro, Brazil. Overall RM acceptability was highest in Guayaquil and lowest in Rio. Product effectiveness had the greatest impact on acceptability in all four cities, but the impact of other product characteristics varied by city. This study demonstrates that MSM from the same region but from different cities place different values on RM characteristics that could impact uptake of an actual RM. Understanding specific consumer preferences is crucial during RM product development, clinical trials and eventual product dissemination. © 2011 Springer Science+Business Media, LLC. Source

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