Prevention of hypertension in patients with pre-hypertension: Protocol for the PREVER-prevention trial

Background: Blood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age. Non-drug interventions to prevent hypertension have had low effectiveness. In individuals with previous cardiovascular disease or diabetes, the use of BP-lowering agents reduces the incidence of major cardiovascular events. In the absence of higher baseline risk, the use of BP agents reduces the incidence of hypertension. The PREVER-prevention trial aims to investigate the efficacy, safety and feasibility of a population-based intervention to prevent the incidence of hypertension and the development of target-organ damage.Methods: This is a randomized, double-blind, placebo-controlled clinical trial, with participants aged 30 to 70 years, with pre-hypertension. The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. The primary outcomes will be the incidence of hypertension, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new sub-clinical atherosclerosis, and sudden death. The study will last 18 months. The sample size was calculated on the basis of an incidence of hypertension of 14% in the control group, a size effect of 40%, power of 85% and P alpha of 5%, resulting in 625 participants per group. The project was approved by the Ethics committee of each participating institution.Discussion: The early use of blood pressure-lowering drugs, particularly diuretics, which act on the main mechanism of blood pressure rising with age, may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension. If this intervention shows to be effective and safe in a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil.Trial Registration: Clinical Trials NCT00970931. © 2011 Fuchs et al; licensee BioMed Central Ltd.

Prevention of soil-transmitted helminth infection

Soil-transmitted helminths (STHs) form one of the most important groups of infectious agents and are the cause of serious global health problems. The most important STHs are roundworms (Ascaris lumbricoides), whipworms (Trichuris trichiura) and hookworms (Necator americanus or Ancylostoma duodenale); on a global level, more than a billion people have been infected by at least one species of this group of pathogens. This review explores the general concepts of transmission dynamics and the environment and intensity of infection and morbidity of STHs. The global strategy for the control of soil-transmitted helminthiasis is based on (i) regular anthelminthic treatment, (ii) health education, (iii) sanitation and personal hygiene and (iv) other means of prevention with vaccines and remote sensoring. The reasons for the development of a control strategy based on population intervention rather than on individual treatment are discussed, as well as the costs of the prevention of STHs, although these cannot always be calculated because interventions in health education are difficult to measure. An efficient sanitation infrastructure can reduce the morbidity of STHs and eliminates the underlying cause of most poverty-related diseases and thus supports the economic development of a country.

Effects of the ethyl acetate fraction of Alchornea triplinervia on healing gastric ulcer in rats

Alchornea triplinervia (Spreng.) Muell. Arg (Euphorbiaceae) is a medicinal plant commonly used by people living in the Cerrado region of Brazil to treat gastrointestinal ulcers. We previously described the gastroprotective action of methanolic extract (ME) of Alchornea triplinervia and the ethyl acetate fraction (EAF) in increasing of prostaglandin E 2 (PGE 2) gastric levels in the mucosa. In this work we evaluated the effect of EAF in promoting the healing process in rats with acetic acid-induced gastric ulcers. In addition, toxicity was investigated during treatment with EAF. After 14 days of treatment with EAF, the potent stimulator of gastric cell proliferation contributed to the acceleration of gastric ulcer healing. Upon immunohistochemical analysis, we observed a pronounced expression of COX-2, mainly in the submucosal layer. The 14-day EAF treatment also significantly increased the number of neutrophils in the gastric mucosa regeneration area. The EAF induced angiogenesis on gastric mucosa, observed as an increase of the number of blood vessels supplying the stomach in rats treated with EAF. Oral administration for 14 days of the ethyl acetate fraction from Alchornea triplinervia accelerated the healing of gastric ulcers in rats by promoting epithelial cell proliferation, increasing the number of neutrophils and stimulation of mucus production. This fraction, which contained mainly phenolic compounds, contributed to gastric mucosa healing. © 2011 by the authors; licensee MDPI, Basel, Switzerland.

Mutagenic and genotoxic effect of hydroxyurea

The hydroxyurea, a cytotoxic drug, is the mainly available therapeutical strategy for the treatment of sickle cell disease. This study aimed to evaluate the mutagenic and genotoxic potential of the hydroxyurea through the Salmonella/Microsome assay and micronucleus test in peripheral blood of mice. The doses were evaluated at 29.25-468 μmol/plate in Salmonella/Microsome assay in presence and absence of metabolic activation the drug. In the micronucleus test the doses were evaluated at 12.5; 25; 50; 75 and 100 mg/kg. The results show that hydroxyurea present mutagenic activity in TA98 and TA100 in doses above 117 μmol/plate and 234 μmol/plate respectively. The drug induced a significant increase in the frequency of micronuclei in reticulocytes of mice at concentrations of 50, 75 and 100 mg/kg, compared to negative control (water). These results demonstrated the mutagenic and genotoxic potential of hydroxyurea. © 2011 Santos et al.

Ventricular systolic reserve in asymptomatic children previously treated with low doses of anthracyclines: A longitudinal, prospective exercise echocardiography study

Background: The time course of mild cardiotoxicity induced by anthracycline remains unknown. The aim of this study was to evaluate the long-term evolution of decreased myocardial reserve in children previously treated with a cumulative dose of anthracycline up to 100mg/m 2. Patients and Methods: Twenty-seven asymptomatic cancer survival patients (25 with lymphoblastic leukemia), in continuous remission and off treatment for >12 months with no alterations in conventional echocardiograms were evaluated by exercise echocardiography at 37±15.4 months (T1) and 101±24 months (T2) after finishing treatment (ADRIA group). This group was compared with 25 healthy individuals (control group) similar to the ADRIA group with respect to age and body surface area (BSA). All individuals underwent treadmill exercise testing according to Bruce protocol. Echocardiograms were performed before and immediately after exercise. Results: The groups were similar regarding cardiac structure and left ventricular (LV) systolic function at rest at T1 and T2. The growth of LV posterior wall thickness related to BSA was lower in the ADRIA group at T2. Post exercise, smaller LV ejection indexes and attenuated changes in the afterload in ADRIA group were observed at T1 and T2. Conclusion: The decreased systolic reserve induced by a low dose of anthracycline in asymptomatic children and adolescents remains unaffected over a 5-year period, suggesting that positive outcomes in chronic cardiotoxicity would be expected in patients with mild impairment after anthracycline treatment. © 2011 Wiley Periodicals, Inc.

Síndrome antifosfolípide e trombocitopenia na infância

Objective: To report the case of a child diagnosed with antiphospholipid syndrome associated with severe thrombocytopenia, and to review the literature on the subject. Case description: Child aged nine years and eight months old with severe thrombocytopenia associated with a positive anticardiolipin antibody. Data were collected by clinical history, physical examination, and laboratorial exams. Diagnosis was confirmed according to criteria established for the antiophospholipid syndrome, associated with the presence of the most common manifestations of the syndrome in children: livedo reticularis and thrombocytopenia. Comments: The antiphospholipid syndrome is an uncommon pediatric disease, and clinical manifestations such as decreased platelet number should be considered.

Tachycardia-induced cardiomyopathy

Tachycardia-induced cardiomyopathy (TIC) is an important cause of heart failure as it is potentially reversible after ventricular rate control. A 66-year-old hypertensive woman presented with a 15-day history of tachycardia, dyspnoea and oedema. ECG revealed atrial fibrillation with ventricular frequency of 130 beats per minute (bpm). Echocardiogram showed dilated left ventricle (LV) with 0.39 ejection fraction. Angiography revealed non-obstructed coronary arteries. Heart rate and cardiac failure were controlled with amiodarone, digoxine, captopril, metoprolol and furosemide. During follow-up, despite drug dose optimisation, the patient kept complaining of tachycardia and dyspnoea with a ventricular rate between 108 and 120 bpm. Medical staff suspected she was not taking her medicines properly. Two months later, the patient was asymptomatic and had converted to sinus rhythm (heart rate of 76 bpm). Echocardiogram showed normal LV size and function. Patient 's diagnosis was TIC. Although rare, TIC should be considered in all cases of systolic dysfunction associated with tachyarrhythmia. Copyright 2012 BMJ Publishing Group. All rights reserved.

Biocompatible microemulsion modifies the pharmacokinetic profile and cardiotoxicity of doxorubicin

Doxorubicin (DOX) is an anthracycline antibiotic with a broad antitumor spectrum. However, the clinical use of DOX is limited because of its cardiotoxicity, a dose-dependent effect. Colloidal drug delivery systems, such as microemulsions (MEs), allow the incorporation of drugs, modifying the pharmacokinetic (PK) profile and toxic effects. In this study, we evaluated the PK profile and cardiotoxicity of a new DOX ME (DOX-ME). The PK profile of DOX-ME was determined and compared with that of the conventional DOX after single-dose administration (6mg/kg, intravenous) in male Wistar rats (n = 12 per group). The cardiotoxicity of DOX formulations was evaluated by serum creatine kinase MB (CKMB) activity in both animal groups before and after drug administration. The plasma DOX measurements were performed by high-performance liquid chromatography with fluorescence detection, and the CKMB levels were assayed using the CKMB Labtest® kit. The ME system showed a significant increase in plasma DOX concentrations and lower distribution volume when compared with conventional DOX. Serum CKMB activity increased after conventional DOX administration but was unchanged in the DOX-ME group. These results demonstrate modifications in drug access to susceptible sites using DOX-ME. DOX-ME displayed features that make it a promising system for future therapeutic application. © 2012 Wiley Periodicals, Inc.

Gastroprotective effect of the ethanolic extract and fractions obtained from syngonanthus bisulcatus Rul

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High dosage folic acid supplementation, oral cleft recurrence and fetal growth

Objectives: To evaluate the effects of folic acid supplementation on isolated oral cleft recurrence and fetal growth. Patients and Methods: The study included 2,508 women who were at-risk for oral cleft recurrence and randomized into two folic acid supplementation groups: 0.4 and 4 mg per day before pregnancy and throughout the first trimester. The infant outcome data were based on 234 live births. In addition to oral cleft recurrence, several secondary outcomes were compared between the two folic acid groups. Cleft recurrence rates were also compared to historic recurrence rates. Results: The oral cleft recurrence rates were 2.9% and 2.5% in the 0.4 and 4 mg groups, respectively. The recurrence rates in the two folic acid groups both separately and combined were significantly different from the 6.3% historic recurrence rate post the folic acid fortification program for this population (p = 0.0009 when combining the two folic acid groups). The rate of cleft lip with palate recurrence was 2.9% in the 0.4 mg group and 0.8% in the 4 mg group. There were no elevated fetal growth complications in the 4 mg group compared to the 0.4 mg group. Conclusions: The study is the first double-blinded randomized clinical trial (RCT) to study the effect of high dosage folic acid supplementation on isolated oral cleft recurrence. The recurrence rates were similar between the two folic acid groups. However, the results are suggestive of a decrease in oral cleft recurrence compared to the historic recurrence rate. A RCT is still needed to identify the effect of folic acid on oral cleft recurrence given these suggestive results and the supportive results from previous interventional and observational studies, and the study offers suggestions for such future studies. The results also suggest that high dosage folic acid does not compromise fetal growth. © 2013 by the authors; licensee MDPI, Basel, Switzerland.

Influence of gasoline inhalation on the enantioselective pharmacokinetics of fluoxetine in rats

Fluoxetine is used clinically as a racemic mixture of (+)-(S) and (-)-(R) enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose-only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10-mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC-MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)-(S)-fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC(+)-(S)/(-)-(R) = 1.68). In animals exposed to gasoline, we observed an increase in AUC0-∞ for both enantiomers, with a sharper increase seen for the (-)-(R)-fluoxetine enantiomer (enantiomeric ratio AUC(+)-(S)/(-)-(R) = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (-)-(R)-fluoxetine enantiomer (55% vs. 30%). Chirality 25:206-210, 2013. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.

Ethopharmacological evaluation of the rat exposure test: A prey-predator interaction test

The rat exposure test (RET) is a prey (mouse)-predator (rat) situation that activates brain defensive areas and elicits hormonal and defensive behavior in the mouse. Here, we investigated possible correlations between the spatiotemporal [time spent in protected (home chamber and tunnel) and unprotected (surface) compartments and frequency of entries into the three compartments] and ethological [e.g., duration of protected and unprotected stretched-attend postures (SAP), duration of contact with the rat's compartment] measures (Experiment 1). Secondly, we investigated the effects of systemic treatment with pro- or anti-aversive drugs on the behavior that emerged from the factor analysis (Experiment 2). The effects of chronic (21 days) imipramine and fluoxetine on defensive behavior were also investigated (Experiment 3). Exp. 1 revealed that the time in the protected compartment, protected SAP and rat contacts loaded on factor 1 (defensive behavior), while the total entries and unprotected SAP loaded on factor 2 (locomotor activity). Exp. 2 showed that alprazolam (but not diazepam) selectively changed the defensive factor. Caffeine produced a mild proaversive-like effect, whereas yohimbine only decreased locomotor activity (total entries). Fluoxetine (but not imipramine) produced a weak proaversive-like effect. 5-HT1A/5-HT2 receptor ligands did not change any behavioral measure. In Exp. 3, chronic fluoxetine (but not imipramine) attenuated the defensive behavior factor without changing locomotion. Given that the defensive factor was sensitive to drugs known to attenuate (alprazolam and chronic fluoxetine) and induce (caffeine) panic attack, we suggest the RET as a useful test to assess the effects of panicolytic and panicogenic drugs. © 2012 Elsevier B.V.

Systematic review of randomized controlled trials of new anticoagulants for venous thromboembolism prophylaxis in major orthopedic surgeries, compared with enoxaparin

Background: In the past 10 years, new anticoagulants (NACs) have been studied for venous thromboembolism (VTE) prophylaxis. Objective: To evaluate the risk/benefit profile of NACs versus enoxaparin for VTE prophylaxis in major orthopedic surgery. Methods: A systematic review of double-blind randomized phase III studies was performed. The search strategy was run from 2000 to 2011 in the main medical electronic databases in any language. Independent extraction of articles was performed by 2 authors using predefined data fields, including study quality indicators. Results: Fifteen published clinical trials evaluating fondaparinux, rivaroxaban, dabigatran, and apixaban were included. Primary efficacy (any deep vein thrombosis [DVT], nonfatal pulmonary embolism, or all-cause mortality) favored fondaparinux (relative risk [RR] 0.50; 95% CI, 0.39, 0.63) and rivaroxaban (RR, 0.50; 95% CI, 0.34, 0.73) over enoxaparin, although significant heterogeneity was observed in both series. The primary efficacy of dabigatran at 220 mg, apixaban, and bemiparin were similar, with RRs of 1.02 (95% CI, 0.86, 1.20), 0.63 (95% CI, 0.39, 1.01), and 0.87 (95% CI, 0.65, 1.17), respectively. The primary efficacy of dabigatran at 150 mg (RR, 1.20; 95% CI, 1.03, 1.41), was inferior to enoxaparin. The incidence of proximal DVT favored apixaban (RR, 0.45; 95% CI, 0.27, 0.75) only. Rivaroxaban (RR, 0.45; 95% CI, 0.27, 0,77) and apixaban (RR, 0.38; 95% CI, 0.16, 0.90) produced significantly lower frequencies of symptomatic DVT. The incidence of major VTE favored rivaroxaban (RR, 0.44; 95% CI, 0.25, 0.81), only. Bleeding risk was similar for all NACs, except fondaparinux (RR, 1.27; 95% CI, 1.04, 1.55), which exhibited a significantly higher any-bleeding risk compared with enoxaparin, and apixaban (RR, 0.88; 95% CI, 0.79, 0.99), which was associated with a reduced risk of any bleeding. Alanine amino transferase was significantly lower with 220 mg of dabigatran, (RR, 0.67; 95% CI, 0.79, 0.99) than with enoxaparin. Conclusions: NACs can be considered alternatives to conventional thromboprophylaxis regimens in patients undergoing elective major orthopedic surgery, depending on clinical characteristics and cost-effectiveness. The knowledge of some differences concerning efficacy or safety profile, pointed out in this systematic review, along with the respective limitations, may be useful in clinical practice. © 2013 Elsevier Inc. All rights reserved.

Cost-effectiveness comparison between pituitary down-regulation with a gonadotropin-releasing hormone agonist short regimen on alternate days and an antagonist protocol for assisted fertilization treatments

Objective: To compare cost-effectiveness between pituitary down-regulation with a GnRH agonist (GnRHa) short regimen on alternate days and GnRH antagonist (GnRHant) multidose protocol on in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcome. Design: Prospective, randomized. Setting: A private center. Patient(s): Patients were randomized into GnRHa (n = 48) and GnRHant (n = 48) groups. Intervention(s): GnRHa stimulation protocol: administration of triptorelin on alternate days starting on the first day of the cycle, recombinant FSH (rFSH), and recombinant hCG (rhCG) microdose. GnRHant protocol: administration of a daily dose of rFSH, cetrorelix, and rhCG microdose. Main Outcome Measure(s): ICSI outcomes and treatment costs. Result(s): A significantly lower number of patients underwent embryo transfer in the GnRHa group. Clinical pregnancy rate was significantly lower and miscarriage rate was significantly higher in the GnRHa group. It was observed a significant lower cost per cycle in the GnRHa group compared with the GnRHant group ($5,327.80 ± 387.30 vs. $5,900.40 ± 472.50). However, mean cost per pregnancy in the GnRHa was higher than in the GnRHant group ($19,671.80 ± 1,430.00 vs. $11,328.70 ± 907.20). Conclusion(s): Although the short controlled ovarian stimulation protocol with GnRHa on alternate days, rFSH, and rhCG microdose may lower the cost of an individual IVF cycle, it requires more cycles to achieve pregnancy. Clinical Trial Registration Number: NCT01468441. © 2013 by American Society for Reproductive Medicine.

Índice preditor de reserva ovariana (ORPI) para controle de estimulação ovariana individualizado

Objective: to expand the evaluation of a new ovarian response prediction index (ORPI), which was based on the AMH, AFC and age, and to verify its reability as a predictor of ovarian response to stimulation in assisted reproductive technology (ART) cycles. Methods: A total of 129 patients enrolled in the ICSI programme were included. The ORPI values were calculated by multiplying the AMH level (ng/ml) by the number of antral follicles (2-9 mm), and the result was divided by the age (years) of the patient (ORPI=(AMH × AFC)/Patient age). Results: Spearman's test revealed significant correlations (P<0.0001) between the ORPI and the number of oocytes collected and the number of follicles. Logistic regression revealed that ORPI values were significantly associated with the likelihood of collecting ≥4 oocytes (OR=45.56), ≥4 MII oocytes (OR=6.01) and ≥15 oocytes (OR=6.15; P<0.0001). Based on the ROC curves, the ORPI accurately predicted a low ovarian response (<4 oocytes retrieved; area under the curve (AUC):0.91), collection of ≥4 MII oocytes (AUC:0.85) and an excessive ovarian response (≥15 oocytes retrieved; AUC:0.89). Conclusions: The ORPI exhibited an excellent ability to predict a low ovarian response and a good ability to predict a collection of ≥ 4 MII oocytes, an excessive ovarian response. The ORPI might be used to improve the cost-benefit ratio of ovarian stimulation regimens by guiding the selection of medications and by modulating the doses and regimens according to the actual needs of the patients. © Todos os direitos reservados a SBRA - Sociedade Brasileira de Reprodução Assistida.