Efficacy and safety of the pharmacotherapy used in the management of hyperkalemia: a systematic review

Background: Although the management of hyperkalemia follows expert guidelines, treatment approaches are based on traditionally accepted practice standards. New drugs have been assessed such as sodium zirconium cyclosilicate and patiromer; however, their safety and efficacy or effectiveness have not yet been compared to traditional pharmacotherapy. Objective: The present systematic review had the purpose to evaluate the efficacy, effectiveness, and safety of hyperkalemia pharmacotherapies. Methods: PubMed, LILACS, Cochrane Library, and ClinicalTrials were searched through November 2018. Clinical trial, cohort and case-control were searched. The risk of bias (RoB v2.0 and ROBINS-I) and quality of evidence (GRADE) at the level of outcomes were assessed. Results: Sixteen clinical trials and one retrospective cohort were identified regarding efficacy and safety of 24 different alternatives. The management of hyperkalemia remains empirical and off-label, since sodium zirconium cyclosilicate and patiromer are not available in several countries and further studies are required to assess efficacy, effectiveness and safety. Sodium or calcium polystyrene sulfonate (moderate confidence), sodium zirconium cyclosilicate (moderate confidence), and insulin plus dextrose (moderate confidence) showed superior efficacy to, respectively, placebo, no treatment, placebo, and dextrose. Other therapies (low confidence) showed similar efficacy compared to active or inactive alternatives. Most of the adverse events reported were nonspecific, so it was not possible to assign the cause and to classify as defined or probable. Conclusions: Comparative cohort and case-control studies are need to evaluate the safety and effectiveness of new and traditional pharmacotherapies to support the development of guidelines about acute and chronic hyperkalemia, with high-quality evidence

Reliability in long-term clinical studies of disease-modifying therapies for relapsing-remitting multiple sclerosis: A systematic review

Background Although relapsing-remitting multiple sclerosis (RRMS) has a chronic course, little information is known about the comparison between the disease-modifying therapies (DMT) for long-term outcomes. We aimed to conduct a systematic review of randomized clinical trial (RCT) extension and observational studies to examine the efficacy and safety of all available DMT for RRMS, compare the evidence with that derived from mid-term studies, and investigate whether the published long-term data are robust and reliable enough to inform clinical decision-making concerning RRMS treatment. Method PubMed, Scopus, and manual searches were performed until October 2019. The clinical outcomes of long- and mid-term studies were compared. ROBINS-I was used to assess the methodological qualities of the long-term studies. PROSPERO number CRD42019123361. Results Nineteen long-term studies (9,018 participants) were included in the systematic review. All studies presented serious or critical risks of bias that were mainly due to confounding, selection, and missing data biases. The annualised relapse rates (ARR) observed in the long-term studies are lower (better) than those from the mid-term studies for most treatments. The main reason for this ARR decrease could be a selection bias for good responders in the long-term studies, since many studies show a loss of patients between the mid- and long-term phases. The safety profiles depend on the study, follow-up, report, and outcome (i.e., discontinuation or number of patients with at least one serious adverse event). Conclusion The currently available long-term data for patients with RRMS exhibit serious or critical risks of bias that preclude robust comparisons between long-term studies. High quality comparative observational studies with long-term follow-ups or RCT extensions with intention-to-treat analyses are needed to support clinical and regulatory practice. Until reliable long-term evidence is available, neurologists should continue to base their conduct on mid-term studies, patients experience and, most importantly, patients needs and predictor factors, according to personalized medicine

Deficiency of vitamins C and E in women of childbearing age in Brazil: a systematic review and meta-analysis

Background: Despite current policies of salt iodination, iodine deficiency is still a global public health problem, especially in women. So far, conflicting evidence has been suggested for the prevalence of iodine deficiency in Brazil. Objective: To estimate the prevalence of iodine deficiency and associated factors in women of childbearing age in Brazil. Methods: A systematic review was conducted using databases (PubMed, LILACS, WHO, Scopus, and Capes dissertation and thesis), from inception to May 2020. Meta-analyses of proportions were performed using the variance inverse for the fixed model. Reporting and methodological quality were assessed using the Joanna Briggs Institute tool to prevalence studies. Results: Our review identified seven studies published between 2002 e 2017, including 1354 participants, especially pregnant women. All studies presented at least one quality limitation, mainly regarding the sampling method (i.e., convenience) and small sample size. The prevalence of iodine deficiency ranged among studies from 16% to 62%. In contrast, the meta-analysis identified a mean prevalence of 40% (95% confidence interval, CI 37%-43%) for pregnant women and 13% (95% CI 4%-24%) for non-pregnant women. Cumulative meta-analysis suggests a tendency of higher iodine deficiency prevalence from 2018 in pregnant women. Conclusions: Although this systematic review identified studies with poor methodological and reporting quality, a high prevalence of iodine deficiency was identified in pregnant women, reinforcing the importance of national nutritional policies for monitoring iodine status in this population. Future studies should consider random probabilistic sampling, appropriate sample size, and pre-defined subgroup analysis to adequately inform the prevalence of iodine deficiency and associated factors in women of childbearing age and support health policies

Iodine deficiency in women of childbearing age in Brazil: systematic review and meta-analysis

Background: Despite current policies of salt iodination, iodine deficiency is still a global public health problem, especially in women. So far, conflicting evidence has been suggested for the prevalence of iodine deficiency in Brazil. Objective: To estimate the prevalence of iodine deficiency and associated factors in women of childbearing age in Brazil. Methods: A systematic review was conducted using databases (PubMed, LILACS, WHO, Scopus, and Capes dissertation and thesis), from inception to May 2020. Meta-analyses of proportions were performed using the variance inverse for the fixed model. Reporting and methodological quality were assessed using the Joanna Briggs Institute tool to prevalence studies. Results: Our review identified seven studies published between 2002 e 2017, including 1354 participants, especially pregnant women. All studies presented at least one quality limitation, mainly regarding the sampling method (i.e., convenience) and small sample size. The prevalence of iodine deficiency ranged among studies from 16% to 62%. In contrast, the meta-analysis identified a mean prevalence of 40% (95% confidence interval, CI 37%-43%) for pregnant women and 13% (95% CI 4%-24%) for non-pregnant women. Cumulative meta-analysis suggests a tendency of higher iodine deficiency prevalence from 2018 in pregnant women. Conclusions: Although this systematic review identified studies with poor methodological and reporting quality, a high prevalence of iodine deficiency was identified in pregnant women, reinforcing the importance of national nutritional policies for monitoring iodine status in this population. Future studies should consider random probabilistic sampling, appropriate sample size, and pre-defined subgroup analysis to adequately inform the prevalence of iodine deficiency and associated factors in women of childbearing age and support health policies.</jats:p

Consequences of Eukaryotic Enhancer Architecture for Gene Expression Dynamics, Development, and Fitness

The regulatory logic of time- and tissue-specific gene expression has mostly been dissected in the context of the smallest DNA fragments that, when isolated, recapitulate native expression in reporter assays. It is not known if the genomic sequences surrounding such fragments, often evolutionarily conserved, have any biological function or not. Using an enhancer of the even-skipped gene of Drosophila as a model, we investigate the functional significance of the genomic sequences surrounding empirically identified enhancers. A 480 bp long “minimal stripe element” is able to drive even-skipped expression in the second of seven stripes but is embedded in a larger region of 800 bp containing evolutionarily conserved binding sites for required transcription factors. To assess the overall fitness contribution made by these binding sites in the native genomic context, we employed a gene-replacement strategy in which whole-locus transgenes, capable of rescuing even-skipped- lethality to adulthood, were substituted for the native gene. The molecular phenotypes were characterized by tagging Even-skipped with a fluorescent protein and monitoring gene expression dynamics in living embryos. We used recombineering to excise the sequences surrounding the minimal enhancer and site-specific transgenesis to create co-isogenic strains differing only in their stripe 2 sequences. Remarkably, the flanking sequences were dispensable for viability, proving the sufficiency of the minimal element for biological function under normal conditions. These sequences are required for robustness to genetic and environmental perturbation instead. The mutant enhancers had measurable sex- and dose-dependent effects on viability. At the molecular level, the mutants showed a destabilization of stripe placement and improper activation of downstream genes. Finally, we demonstrate through live measurements that the peripheral sequences are required for temperature compensation. These results imply that seemingly redundant regulatory sequences beyond the minimal enhancer are necessary for robust gene expression and that “robustness” itself must be an evolved characteristic of the wild-type enhancer

Systematic review and meta-analysis of the efficacy and safety of amfepramone and mazindol as a monotherapy for the treatment of obese or overweight patients

© 2017 CLINICS. The aim of this study was to evaluate efficacy and safety of amfepramone, fenproporex and mazindol as a monotherapy for the treatment of obese or overweight patients. A systematic review of primary studies was conducted, followed by a direct meta-analysis (random effect) and mixed treatment comparison. Medline and other databases were searched. Heterogeneity was explored through I2 associated with a p-value. Of 739 identified publications, 25 were included in the meta-analysis. The global evaluation of Cochrane resulted in 19 studies with a high level of bias and six with unclear risk. Due to the lack of information in primary studies, direct meta-analyses were conducted only for amfepramone and mazindol. Compared to placebo, amfepramone resulted in higher weight loss in the short-term (<180 days; mean difference (MD) -1.281 kg; p<0.05; I2: 0.0%; p=0.379) and long-term (≥180 days; MD -6.518 kg; p<0.05; I2: 0.0%; p=0.719). Only studies with long-term follow up reported efficacy in terms of abdominal circumference and 5-10% weight reduction. These results corroborated the finding that the efficacy of amfepramone is greater than that of placebo. Treatment with mazindol showed greater short-term weight loss than that with placebo (MD -1.721 kg; p<0.05; I2: 0.9%; p=0.388). However, metabolic outcomes were poorly described, preventing a meta-analysis. A mixed treatment comparison corroborated the direct meta-analysis. Considering the high level of risk of bias and the absence of important published outcomes for anti-obesity therapy assessments, this study found that the evaluated drugs showed poor evidence of efficacy in the treatment of overweight and obese patients. Robust safety data were not identified to suggest changes in their regulatory status

Self-perception of knowledge and adherence reflecting the effectiveness of antiretroviral therapy

Carolina Dagli-Hernandez,1 Rosa Camila Lucchetta,1 Tales Rubens de Nadai,2 Jos&eacute; Carlos Fernandez Galdur&oacute;z,3 Patricia de Carvalho Mastroianni1 1Department of Drugs and Medications, School of Pharmaceutical Sciences of the UNESP &ndash; Univ Estadual Paulista, Araraquara, 2Department of Surgery and Anatomy, Americo Brasiliense State Hospital, 3Department of Psychobiology, Universidade Federal de S&atilde;o Paulo (UNIFESP), S&atilde;o Paulo, Brazil Objectives: To evaluate which indirect method for assessing adherence best reflects highly active antiretroviral therapy (HAART) effectiveness and the factors related to adherence. Method: This descriptive, cross-sectional study was performed in 2012 at a reference center of the state of S&atilde;o Paulo. Self-report (simplified medication adherence questionnaire [SMAQ]) and drug refill parameters were compared to the viral load (clinical parameter of the effectiveness of pharmacotherapy [EP]) to evaluate the EP. The &ldquo;Cuestionario para la Evaluaci&oacute;n de la Adhesi&oacute;n al Tratamiento Antiretroviral&rdquo; (CEAT-VIH) was used to evaluate factors related to adherence and the EP and, complementarily, patient self-perception of adherence was compared to the clinical parameter of the EP. Results: Seventy-five patients were interviewed, 60 of whom were considered as adherent from the clinical parameter of the EP and ten were considered as adherent from all parameters. Patient self-perception about adherence was the instrument that best reflected the EP when compared to the standardized self-report questionnaire (SMAQ) and drug refill parameter. The level of education and the level of knowledge on HAART were positively correlated to the EP. Forgetfulness, alcohol use, and lack of knowledge about the medications were the factors most frequently reported as a cause of nonadherence. Conclusion: A new parameter of patient self-perception of adherence, which is a noninvasive, inexpensive instrument, could be applied and assessed as easily as self-report (SMAQ) during monthly drug refill, since it allows monitoring adherence through pharmaceutical assistance. Therefore, patient adherence to HAART could be evaluated using self-perception (CEAT-VIH) and the viral load test. Keywords: health literacy, anti-HIV agents, patient compliance, antiretroviral therapy, highly active, acquired immunodeficiency syndrom

Safety outcomes of disease-modifying therapies for relapsing–remitting multiple sclerosis: A network meta-analysis

© 2019 Background: Randomised clinical trials (RCTs) and observational studies have reported adverse events that preclude the use of disease-modifying therapies (DMTs) in relapsing–remitting multiple sclerosis (RRMS) in the long term or in specific populations, however, little is known about the relationship between the use of DMTs and frequency of undesirable events. We aimed to conduct a systematic review and network meta-analyses (NMAs) of RCTs and observational studies to synthesise the evidence on the safety of all available DMTs for patients with RRMS. Methods: PubMed, Scopus and a manual search were performed. Bayesian NMAs of safety outcomes reported in RCTs and observational studies assessing DMTs as monotherapies were conducted. Results: Forty-seven studies were included in the systematic review. Considering all studies, 368 and 149 different safety outcomes were reported for at least one study and two studies, respectively. Considering clinical trials, 22 NMAs were conducted for 16 outcomes. Regarding geometry metrics, the median number of studies, DMTs, common comparator, strong edge, and patients were 5 (IQR 5–9), 5 (IQR 4–8), 44%, 33%, and 3998 (IQR 3380–6761). In summary, most comparisons showed similar risk of safety events for DMTs and placebo for all outcomes. Considering cohort studies, only three meta-analyses were conducted. Conclusion: Safety outcomes are poorly reported in primary studies of DMTs in RRMS, precluding the conduction of robust meta-analyses. Therefore, the current available data on safety of these drugs is not contributing to regulatory and clinical decision making, with adverse event reports underbalanced compared to efficacy outcomes

Diethylpropion and mazindol: An end to the discussion?

Antiobesity pharmacotherapy remains the main point of disagreement among both scientists and regulators. This is probably due to small sample sizes, high levels of heterogeneity, and low methodological quality. For many years, Brazil was one of the largest consumers of appetite suppressants worldwide, with evidence of irrational use of this drug class. Therefore, the country was the scene of a debate that divided the Brazilian Health Surveillance Agency (Anvisa - Agência Nacional de Vigilância Sanitáia) and medical societies over the maintenance record of diethylpropion, mazindol and fenproporex. In this context, this commentary presents new arguments to contribute to the discussion, as well as recommendations for future studies