Liver Fibrosis Stages Affect Organic Cation Transporter 1/2 Activities in Hepatitis C Virus-Infected Patients.

This study aims to evaluate the impact of liver fibrosis stages of chronic infection with hepatitis C virus (HCV) on the in vivo activity of organic cation transporters (hepatic OCT1 and renal OCT2) using metformin (MET) as a probe drug. Participants allocated in Group 1 (n = 15, mild to moderate liver fibrosis) or 2 (n = 13, advanced liver fibrosis and cirrhosis) received a single MET 50 mg oral dose before direct-acting antiviral (DAA) drug treatment (Phase 1) and 30 days after achieving sustained virologic response (Phase 2). OCT1/2 activity (MET AUC0-24) was found to be reduced by 25% when comparing the two groups in Phase 2 (ratio 0.75 (0.61-0.93), p < 0.05) but not in Phase 1 (ratio 0.81 (0.66-0.98), p > 0.05). When Phases 1 and 2 were compared, no changes were detected in both Groups 1 (ratio 1.10 (0.97-1.24), p > 0.05) and 2 (ratio 1.03 (0.94-1.12), p > 0.05). So, this study shows a reduction of approximately 25% in the in vivo activity of OCT1/2 in participants with advanced liver fibrosis and cirrhosis after achieving sustained virologic response and highlights that OCT1/2 in vivo activity depends on the liver fibrosis stage of chronic HCV infection.

Deprescripción en el anciano con demencia / Deprescribing in the elderly with dementia

Resumen Introducción: La polifarmacia inapropiada en adultos mayores con demencia es un problema de salud pública global. En este artículo se describen las indicaciones y se dan pautas para la deprescripción de potenciadores cognitivos (inhibidores de acetilcolinesterasa y memantina) y psicofármacos en pacientes con demencia. Materiales y métodos: Esta es una revisión narrativa a partir del estado del arte sobre la deprescripción en el anciano con demencia. Resultados: La deprescripción no significa limitar esfuerzos terapéuticos, por el contrario, consiste en una estrategia de prevención cuaternaria para reducir el riesgo de reacciones adversas e identificar escenarios donde el beneficio clínico es marginal. Para esto, es necesario rastrear activamente a pacientes con demencia con indicación de deprescripción (falta de respuesta clínica adecuada, desaparición del beneficio con el uso prolongado, estadio de demencia grave o fase terminal). Discusión: Los procesos de deprescripción varían según el grupo farmacológico e incluyen disminuciones progresivas de la medicación, así como el seguimiento y la monitorización para evitar el empeoramiento clínico. Se requiere de programas de educación médica en deprescripción para estudiantes y profesionales en ejercicio, especialmente en servicios de atención primaria en áreas rurales o dispersas, lo cual configura un llamado urgente a la neurología, la psiquiatría y la geriatría. Conclusión: El proceso de deprescripción en el paciente con demencia puede implementarse bajo criterios específicos y de una forma organizada.

Abstract Introduction: Inappropriate polypharmacy in older adults with dementia is a global public health problem. This article describes the indications and gives guidelines for the deprescription of cognitive enhancers (acetylcholinesterase inhibitors and memantine), and psychotropic drugs in patients with dementia. Materials and methods: This is a narrative review article based on the state of the art on deprescribing in the elderly with dementia. Results: Deprescribing does not mean limiting therapeutic efforts; on the contrary, it consists of a quaternary prevention strategy to reduce the risk of adverse reactions and identify scenarios where the clinical benefit is marginal. For this, it is necessary to actively track patients with dementia with an indication for deprescription (lack of adequate clinical response, disappearance of benefit with prolonged use, severe dementia, or palliative phase). Discussion: Deprescribing processes vary depending on the pharmacological group and include progressive reductions in medication, as well as follow-up and monitoring to avoid clinical worsening. Medical education programs in deprescribing are required for students and practicing professionals, especially in primary care services in rural or dispersed areas, which constitutes an urgent call for neurology, psychiatry, and geriatrics. Conclusion: The deprescription process in patients with dementia can be implemented under specific criteria and in an organized manner.

Validation of a method to assess the severity of medication administration errors in Brazil.

INTRODUCTION: Medication errors are frequent and have high economic and social impacts; however, some medication errors are more likely to result in harm than others. Therefore, it is critical to determine their severity. Various tools exist to measure and classify the harm associated with medication errors; although, few have been validated internationally. METHODS: We validated an existing method for assessing the potential severity of medication administration errors (MAEs) in Brazil. Thirty healthcare professionals (doctors, nurses and pharmacists) from Brazil were invited to score 50 cases of MAEs as in the original UK study, regarding their potential harm to the patient, on a scale from 0 to 10. Sixteen cases with known harmful outcomes were included to assess the validity of the scoring. To assess test-retest reliability, 10 cases (of the 50) were scored twice. Potential sources of variability in scoring were evaluated, including the occasion on which the scores were given, the scorers, their profession and the interactions among these variables. Data were analysed using generalisability theory. A G coefficient of 0.8 or more was considered reliable, and a Bland-Altman analysis was used to assess test-retest reliability. RESULTS: To obtain a generalisability coefficient of 0.8, a minimum of three judges would need to score each case with their mean score used as an indicator of severity. The method also appeared to be valid, as the judges' assessments were largely in line with the outcomes of the 16 cases with known outcomes. The Bland-Altman analysis showed that the distribution was homogeneous above and below the mean difference for doctors, pharmacists and nurses. CONCLUSION: The results of this study demonstrate the reliability and validity of an existing method of scoring the severity of MAEs for use in the Brazilian health system.

Role of pharmacists in the context of rare diseases: a scoping review protocol.

INTRODUCTION: Rare diseases are chronic conditions, generally incurable, progressive and disabling, which may result in early death. Access to therapeutic products, both medicines and appropriate medical devices, is essential to prevent the progression of the disease and maintain the patients' quality of life. Pharmacists can be part of health teams, in charge of guiding patients' journey, monitoring pharmacotherapy and identifying risks. This scoping review aims to identify and summarise evidence on the role of pharmacists and its impact in the field of rare diseases. METHODS AND ANALYSIS: The searches will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline for protocols. Three electronic databases will be consulted. Studies reporting on qualitative and/or quantitative data from any world region will be considered. There will be no language or initial time limit for studies inclusion, until December 2022. To be eligible for inclusion, studies must focus on the role pharmacists in clinical services aimed at promote the access to medicines, prevention and resolution of problems related to pharmacotherapy. No assessments of items' quality will be made, as the purpose of this scoping review is to synthesise and describe the coverage of the evidence. Clinical, humanistic or economic outcomes from studies that meet the inclusion criteria will be included in the review. The analysis will synthesise the available evidence and may be able to push pharmaceutical practice forward, aiding professionals, educators and managers in the implementation of new approaches to better meet the needs of rare diseases and providing opportunities for future research. ETHICS AND DISSEMINATION: Primary data will not be collected in this study and formal ethical approval is not required. The findings of this study will be disseminated through peer-reviewed publications and conference presentations.

Temporal profile of adverse drug reactions and associated clinical factors: a prospective observational study in a neonatal intensive care unit.

OBJECTIVE: Although adverse drug reactions (ADRs) are quite common in hospitalised neonates, pharmacovigilance activities in this public are still incipient. This study aims to characterise ADRs in neonates in a neonatal intensive care unit (NICU), identifying causative drugs, temporal profile and associated factors. DESIGN: Prospective observational study. SETTING: NICU of a public maternity hospital in Natal/Brazil. PARTICIPANTS: All neonates admitted to the NICU for more than 24 hours and using at least one medication were followed up during the time of hospitalisation. PRIMARY OUTCOME MEASURES: Incidence rate and risk factors for ADRs. The ADRs were detected by an active search in electronic medical records and analysis of spontaneous reports in the hospital pharmacovigilance system. RESULTS: Six hundred neonates were included in the study, where 118 neonates had a total of 186 ADRs. The prevalence of ADRs at the NICU was 19.7% (95% CI 16.7% to 23.0%). The most common ADRs were tachycardia (30.6%), polyuria (9.1%) and hypokalaemia (8.6%). Tachycardia (peak incidence rate: 57.1 ADR/1000 neonates) and hyperthermia (19.1 ADR/1000 neonates) predominated during the first 5 days of hospitalisation. The incidence rate of polyuria and hypokalaemia increased markedly after the 20th day, with both reaching a peak of 120.0 ADR/1000 neonates. Longer hospitalisation time (OR 0.018, 95% CI 0.007 to 0.029; p<0.01) and number of prescribed drugs (OR 0.127, 95% CI 0.075 to 0.178; p<0.01) were factors associated with ADRs. CONCLUSION: ADRs are very common in NICU, with tachycardia and hyperthermia predominant in the first week of hospitalisation and polyuria and hypokalaemia from the third week onwards.

Análisis del programa de Farmacología Clínica en el plan de estudio E para la carrera de Medicina / Analysis of the program of Clinical Pharmacology in the E plan study for the Medicine career i: en

Introducción: En Cuba han existido varias concepciones sobre planes de estudio. La necesidad de revisar y proponer cambios que aseguren los niveles de calidad deseados en el proceso de formación integral de los futuros profesionales motivó a investigar los elementos teóricos y metodológicos que regulan y orientan el proceso de enseñanza-aprendizaje en la asignatura Farmacología Clínica. Objetivo: Analizar el programa de Farmacología Clínica del plan de estudio E para la carrera de Medicina desde un enfoque crítico y sistematizado. Métodos: Se realizó un estudio cualitativo del programa de estudio de la asignatura Farmacología Clínica según el plan E, vigente en la Universidad de Ciencias Médicas de Santiago de Cuba, durante el 2022, para lo cual se utilizaron los métodos de revisión documental, los documentos rectores del proceso docente en la educación superior y la metodología propuesta por algunos autores. Resultados: Varios temas enunciaban un número excesivo de objetivos específicos sin tener en cuenta el nivel de asimilación; la forma de organización de la enseñanza más utilizada fue la conferencia. En las evaluaciones frecuentes no se tuvo en cuenta el trabajo investigativo independiente; en tanto, la bibliografía básica correspondió a una edición del 2002. Conclusiones: El programa no requirió trasformaciones temáticas, pero desde el punto de vista didáctico deben modificarse componentes del proceso de enseñanza-aprendizaje y, además, se debe actualizar la bibliografía básica pertinente.

Introduction: In Cuba several conceptions have existed on the study plans. The necessity to revise and propose changes that assure the levels of quality wanted in the process of integral formation of the future professionals motivated to investigate the theoretical and methodological elements that regulate and guide the teaching-learning process in the Clinical Pharmacology subject. Objective: To analyze the program of Clinical Pharmacology of the E plan study for the medicine career, from a critical and systematized approach. Methods: A qualitative study of the study program in the Clinical Pharmacology subject was carried out according to the E plan, effective in the University of Medical Sciences in Santiago de Cuba, during 2022, for which the methods of documental review, the rector documents of the teaching process in higher education and the methodology proposed by some authors were used. Results: Several topics enunciated an excessive number of specific objectives without taking into account the level of assimilation; the form of organization most used in teaching was the conference. Independent investigative work was not taken into account in frequent evaluations; meanwhile, the basic bibliography corresponded to an edition from 2002. Conclusions: The program did not require of thematic transformations, but from the didactic point of view components of the teaching-learning process should be modified, besides updating the pertinent basic literature.

Factors associated with higher quality of clinical practice guidelines and their recommendations for the pharmacological treatment of depression: a systematic review.

OBJECTIVE: The objective of this study was to assess the quality of clinical practice guidelines (CPGs) for the pharmacological treatment of depression along with their recommendations and factors associated with higher quality. DESIGN: We conducted a systematic review that included CPGs for the pharmacological treatment of depression in adults. DATA SOURCES: We searched for publications from 1 January 2011 to 31 December 2021, in MEDLINE, Cochrane Library, Embase, PsycINFO, BVS and 12 other databases and guideline repositories. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included CPGs containing recommendations for the pharmacological treatment of depression in adults at outpatient care setting, regardless of whether it met the U.S. National Academy of Medicine criteria, or not. If a CPG included recommendations for both children and adults, they were considered. No language restriction was applied. DATA EXTRACTION AND SYNTHESIS: Data extraction was also conducted independently and in duplicate, a process that was validated in a previous project. The quality of the CPGs and their recommendations were assessed by three independent reviewers using Appraisal of Guidelines for Research and Evaluation (AGREE II) and Appraisal of Guidelines for Research and Evaluation-Recommendations Excellence (AGREE-REX). A CPG was considered to be of high quality if AGREE II Domain 3 was ≥60%; while their recommendations were considered high if AGREE-REX Domain 1 was ≥60%. RESULTS: Seventeen out of 63 (27%) CPGs were classified as high quality, while 7 (11.1%) had high-quality recommendations. The factors associated with higher-scoring CPGs and recommendations in the multiple linear regression analyses were 'Handling of conflicts of interest', 'Multiprofessional team' and 'Type of institution'. 'Inclusion of patient representative in the team' was also associated with higher-quality recommendations. CONCLUSIONS: The involvement of professionals from diverse backgrounds, the handling of conflicts of interest, and the inclusion of patients' perspectives should be prioritised by developers aiming for high-quality CPGs for the treatment of depression.

Direct Oral Anticoagulants: An Updated Systematic Review of Their Clinical Pharmacology and Clinical Effectiveness and Safety in Patients With Nonvalvular Atrial Fibrillation.

Direct oral anticoagulants have been an increasingly used class of drugs in the setting of nonvalvular atrial fibrillation, defying vitamin K antagonists' monopoly when it comes to anticoagulation due to its several limitations. Direct oral anticoagulants (DOACs) have entered the market as a noninferior and safer option in comparison with vitamin K antagonists, as their respective phase III clinical trials proved. The aim of this article was to update and summarize data on their clinical pharmacology and to review real-world data to know their comparative effectiveness and safety. We performed a systematic review using PubMed, Google Scholar, Embase, and Web of Science as search engines. Regarding pharmacodynamics, there were no substantial changes reported from their original profile. There were many advances in the knowledge about clinical pharmacokinetics of DOACs that have had a direct impact on their clinical use, mainly related to drug-drug interactions. In a real-world setting, DOACs have shown to be noninferior in preventing thromboembolic events compared to vitamin K antagonists. In regards to safety, DOACs have shown a lower bleeding risk relative to warfarin. Comparison between DOACs has demonstrated rivaroxaban to have the highest bleeding risk. Overall, the evidence gathered showed few changes from the original data presented in phase III clinical trials, concluding that their real-world use coincides greatly with them.

Sedación del paciente pediátrico / Sedation in pediatrics

Sedation consists in the administration of different types of drugs that produce central nervous system depression, decreasing alertness and anxiety, to allow medical procedures to be performed, which may or not be painful and require some degree of immobility. The physician in charge of the sedation of pediatric patients must know the physiological changes of the child, the pharmacokinetics and pharmacodynamics of the different medications to be used, as well as the possible complications that may occur before, during and after sedation, in order to provide a safe and quality care.

La sedación consiste en la administración de diferentes tipos de fármacos que producen depresión del sistema nervioso central, disminuyendo el estado de alerta y ansiedad, para permitir la realización de procedimientos médicos, que pueden ser dolorosos o no y que requieren algún grado de inmovilidad. El médico encargado de la sedación de pacientes pediátricos debe conocer los cambios fisiológicos del niño, la farmacocinética y farmacodinámica de los diferentes medicamentos a utilizar, además de las posibles complicaciones que se pueden presentar antes, durante y después de la sedación, con el fin de brindar una atención segura y de calidad.

Effect of bortezomib on the treatment of multiple myeloma: a systematic review protocol.

INTRODUCTION: Multiple myeloma (MM) is an incurable malignant neoplasm that accounts for approximately 1% of all cancers and 10% of haematological malignancies. Bortezomib is one of the most commonly used medications in first-line treatment and subsequent relapses, either as a single agent or in combination with other therapies. This study aims to assess the effects of bortezomib on the overall survival (OS), progression-free survival, overall response rate, time to next treatment, health-related quality of life, compliance, adverse events and treatment-related death in patients with MM. METHODS AND ANALYSIS: We have performed a systematic review and meta-analysis and will include both randomised and non-randomised controlled studies where the effect of bortezomib was compared in similar or dissimilar background therapies in each arm. General and adaptive search strategies have been created for the following electronic health databases: Embase, Medline, LILACS and CENTRAL. Two reviewers have independently selected eligible studies, will assess the risk of bias, and will extract data from the included studies. Similar outcomes will be plotted in the meta-analysis using the Stata Statistical Software V.17. The relative risk will be calculated with a 95% CI as the effect size of bortezomib. For the OS and progression-free survival, we calculate the overall OR from the HRs of each included study. Peto's one-step OR will be calculated for event rates below 1%. We will use the Grading of Recommendations Assessment, Development and Evaluation system to evaluate the certainty of evidence. ETHICS AND DISSEMINATION: As no primary data collection will be undertaken, formal ethical assessment is not required. We plan to present the results of this systematic review in a peer-reviewed scientific journal, conferences and popular press. PROSPERO REGISTRATION NUMBER: CRD42020151142.

Avaliação dos preditores da falha dos antivirais de ação direta como mais um passo para programas de eliminação de VHC mais eficiente: o polimorfismo genético IL28B (IFNL4) não tem destaque, enquanto maior liberação estimada do "clearence" de creatinina é um fator esquecido / Assessing predictors of directly acting antivirals' failure as a further step towards more efficient hcv elimination programs: il28b (ifnl4) gene polymorphism has no role while higher estimated creatinine clearance is a forgotten factor

ABSTRACT Background: Sustained virologic response (SVR) rates after directly acting antivirals (DAAs) for hepatitis C virus (HCV) exceed 95%. This encouraged policymakers to put plans to achieve HCV elimination by 2030. The remaining percentage of non-SVR12 can affect HCV eradication strategies in the real-world especially the compliance of large numbers of treated persons to follow up for assessment of virologic response cannot be guaranteed. Objective: We aimed to assess predictors of failure to achieve SVR after receiving sofosbuvir plus NS5A inhibitor as an important step towards achieving better HCV eradication strategies. Methods: During the period from 1st November 2018 to 1st November 2019, 1581 treatment-naive patients received sofosbuvir plus daclatasvir ± ribavirin at our unit and 10 patients were referred to us with HCV relapse after the same regimens. A total of 163 out of the 1581 patients were lost for follow-up before assessment of virologic response and excluded from the analysis. 20 out of the remaining patients failed to achieve SVR12. Data from the 30 patients with non-SVR12 were included in the case-control analysis. Results: Every unit increase in estimated creatinine clearance using modification of diet in renal disease study (MDRD) score, total bilirubin, and INR was associated with 1.03, 13.92, and 80.08 times greater odds of non-SVR12 (P<0.001, P=0.0016, P=0.02) respectively. The presence of liver cirrhosis on ultrasonography increases the odds by 10.03. (P=0.009). Conclusion: Higher MDRD score, INR, total bilirubin, and presence of sonographic features of liver cirrhosis are predictors of failure to achieve SVR12 using sofosbuvir plus NS5A inhibitor.

RESUMO Contexto: As taxas de resposta virológica sustentada (SVR) após ação direta de antivirais (DAAs) para o vírus da hepatite C (VHC) excedem 95%. Isso encorajou os formuladores de políticas a colocar planos para alcançar a eliminação do VHC até 2030. O percentual remanescente de não-respondedores pode afetar as estratégias de erradicação do VHC no mundo real, especialmente a conformidade de um grande número de pessoas tratadas para acompanhamento para avaliação da resposta virológica não pode ser garantida. Objetivo: Nosso objetivo foi avaliar os preditores de não atingir o SVR após receber o inibidor sofosbuvir mais NS5A como um passo importante para alcançar melhores estratégias de erradicação do VHC. Métodos: No período de 1º de novembro de 2018 a 1º de novembro de 2019, 1581 pacientes receberam sofosbuvir mais daclatasvir ± ribavirin em nossa unidade e 10 pacientes foram encaminhados por recaída do VHC após os mesmos regimes. Um total de 163 dos 1581 pacientes foram perdidos para o acompanhamento antes da avaliação da resposta virológica e excluídos da análise. 20 dos demais pacientes não conseguiram a resposta virológica sustentada (SVR12). Os dados de 30 pacientes com não SVR12 foram incluídos na análise caso-controle. Resultados: Cada unidade aumentada no clearence estimado de creatinina usando o escore do estudo Modificação da Dieta em Doença Renal (MDRD), bilirrubina total e INR foram associadas a 1,03, 13,92 e 80,08 vezes maiores chances de não-SVR12 (P<0,001, P=0,0016, P=0,02) respectivamente. A presença de cirrose hepática na ultrassonografia aumenta as chances em 10,03. (P=0,009). Conclusão: Maior escore de MDRD, INR, bilirrubina total e presença de características sonográficas de cirrose hepática são preditores de falha na realização do SVR12 utilizando o inibidor sofosbuvir mais NS5A.

Quality of clinical practice guidelines for inadequate response to first-line treatment for depression according to AGREE II checklist and comparison of recommendations: a systematic review.

OBJECTIVE: To assess similarities and differences in the recommended sequence of strategies among the most relevant clinical practice guidelines (CPGs) for the treatment of depression in adults with inadequate response to first-line treatment. DATA SOURCES: We performed a systematic review of the literature spanning January 2011 to August 2020 in Medline, Embase, Cochrane Library and 12 databases recognised as CPGs repositories. CPGs quality was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II). STUDY SELECTION: The eligibility criteria were CPGs that described pharmacological recommendations for treating depression for individuals aged 18 years or older in outpatient care setting. We included CPGs considered of high-quality (≥80% in domain 3 of AGREE II) or recognised as clinically relevant. DATA EXTRACTION: Two independent researchers extracted recommendations for patients who did not respond to first-line pharmacological treatment from the selected CPGs. RESULTS: We included 46 CPGs and selected 8, of which 5 were considered high quality (≥80% in domain 3 of AGREE II) and 3 were recognised as clinically relevant. Three CPGs did not define inadequate response to treatment and 3 did not establish a clear sequence of strategies. The duration of treatment needed to determine that a patient had not responded was not explicit in 3 CPGs and was discordant in 5 CPGs. Most CPGs agree in reassessing the diagnosis, assessing the presence of comorbidities, adherence to treatment, and increase dosage as first steps. All CPGs recommend psychotherapy, switching antidepressants, and considering augmentation/combining antidepressants. CONCLUSION: Relevant CPGs present shortcomings in recommendations for non-responders to first-line antidepressant treatment including absence and divergencies in definition of inadequate response and sequence of recommended strategies. Overall, most relevant CPGs recommend reassessing the diagnosis, evaluate comorbidities, adherence to treatment, increase dosage of antidepressants, and psychotherapy as first steps. PROSPERO REGISTRATION NUMBER: CRD42016043364.

Sex differences and adverse events of antiretrovirals in people living with HIV/AIDS: a systematic review and meta-analysis protocol.

INTRODUCTION: Antiretroviral therapy (ART) for HIV/AIDS is associated with adverse events (AEs). However, little is known about the differences in the risk of AEs between women and men living with HIV/AIDS. This study aims to determine (1) whether there are sex differences in the risk of AEs in people with HIV/AIDS treated with ART and (2) the prevalence of AEs to the reproductive system and bone mineral density in women. METHODS AND ANALYSIS: This systematic review (SR) will include randomised trials evaluating ART in people living with HIV/AIDS with at least 12 weeks of duration follow-up. Searches will be conducted in Medline, Embase, Cochrane Library, Epistemonikos, Lilacs, trial registries and grey literature databases, without restriction on publication status, year of publication and language. The primary outcome will be the risk of ART discontinuation or drop-outs/withdrawals of ART due to AEs and the number of any treatment-emergent AE. The secondary outcomes are the incidence of serious clinic or laboratory (grade 3 and/or 4) treatment-emergent AEs, hospitalisation, death and AEs specific to the reproductive system and bone mineral density (osteoporosis, osteopenia and fractures) of women. Selection, data extraction and quality assessment will be performed by pairs of reviewers. Cochrane collaboration tools will be used to assess the risk of bias. If appropriate, a meta-analysis will be conducted to synthesise results. The overall quality of the evidence for each outcome will be determined by the Grades of Recommendation, Assessment, Development and Evaluation. ETHICS AND DISSEMINATION: The results of this SR will assist the formulation of public policies aimed at the management and monitoring of AEs of ART in people living with HIV/AIDS. A deliberative dialogue will be scheduled with the Department of Chronic Conditions and Sexually Transmitted Infections of Brazil's Ministry of Health to align the project with policymakers' interests. PROSPERO REGISTRATION NUMBER: CRD42021251051.

Review of pharmacological options for the treatment of Chagas disease.

Chagas disease (CD) is a worldwide problem, with over 8 million people infected in both rural and urban areas. CD was first described over a century ago, but only two drugs are currently available for CD treatment: benznidazole (BZN) and nifurtimox (NF). Treating CD-infected patients, especially children and women of reproductive age, is vital in order to prevent long-term sequelae, such as heart and gastrointestinal dysfunction, but this aim is still far from being accomplished. Currently, the strongest data to support benefit-risk considerations come from trials in children. Treatment response biomarkers need further development as serology is being questioned as the best method to assess treatment response. This article is a narrative review on the pharmacology of drugs for CD, particularly BZN and NF. Data on drug biopharmaceutical characteristics, safety and efficacy of both drugs are summarized from a clinical perspective. Current data on alternative compounds under evaluation for CD treatment, and new possible treatment response biomarkers are also discussed. Early diagnosis and treatment of CD, especially in paediatric patients, is vital for an effective and safe use of the available drugs (i.e. BZN and NF). New biomarkers for CD are urgently needed for the diagnosis and evaluation of treatment efficacy, and to guide efforts from academia and pharmaceutical companies to accelerate the process of new drug development.

Mechanism of Action and Efficacy of Immunosupressors in Lupus Nephritis.

Approximately 70% of the patients with systemic lupus erythematosus will have clinical evidence of kidney damage during their evolution. Patients with impaired renal function at onset and those with recurrent flares have a poor prognosis. Understanding the mechanism of action of immunosuppressants is essential for proper prescription. Steroids inhibit the DNA sequence that promotes the release of inflammatory cytokines. Phosphoramide mustard, metabolite of cyclophosphamide, cross-link with the DNA, causing the aggregation of an alkyl group, causing cell death. Mycophenolate inhibits inosine monophosphate dehydrogenase, prevents de novo synthesis of guanine, inducing cell arrest in S phase. Azathioprine blocks the synthesis of purines and induces apoptosis. Calcineurin inhibitors prevent the dephosphorylation of NFAT and reduce the production of interleukin 2. Antimalarials alter the enzymatic release of lysosomes by increasing intravesicular pH. The mechanism of action of rituximab is related to complement-dependent cytotoxicity and the elimination of anti-CD20-labeled B cells. Progress in the knowledge and management of low doses of steroids may change the current paradigm and reduce the frequency of related adverse events. Mycophenolate seems to be a better choice than cyclophosphamide for induction, it is also preferred over azathioprine as a maintenance immunosuppressive agent, although azathioprine is preferred in women with a desire for conception, those pregnant, or with low resources. For treatment-resistant cases, tacrolimus, rituximab or belimumab may be effective. Ongoing clinical trials with new drugs offer promising results.

Effectiveness and safety of ivermectin in the treatment of COVID-19: protocol for a systematic review and meta-analysis.

INTRODUCTION: Ivermectin is a drug with antiviral properties and has been proposed as an alternative treatment for patients with COVID-19, in some countries; however, there is limited evidence to support its clinical use. Accordingly, the aim of this review and meta-analysis is to obtain superior evidence on the effectiveness and safety of ivermectin in treatment of COVID-19. METHODS AND ANALYSIS: We will search in the medical databases and International Clinical Trials Registry Platform databases for randomised clinical trials and quasi-randomised trials published from December 2019. The criteria for inclusion are that infection needs to be confirmed by a real-time PCR or serology test, and the effect of ivermectin has been compared with placebo, symptomatic treatment or no treatment. We will exclude observational studies and clinical trials that involved patients with symptoms suggestive of COVID-19, but without a laboratorial diagnosis. Outcomes of interest include mortality, time to symptom resolution, time of hospitalisation, frequency of invasive mechanical ventilation and extracorporeal membrane oxygenation, incidence of severe acute respiratory syndrome, admission to intensive care unit, viral load, PCR-negative status, percentage of infection after prophylactic use, and total incidence of adverse and side effects. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two reviewers will independently select the studies and assess their eligibility. Two other reviewers will independently extract data from each study. Meta-analysis will then be carried out using fixed-effects or random-effects model, using the mean difference for continuous outcomes and the relative risk for dichotomous outcomes. Bias risk will be assessed using the Cochrane risk-of-bias tool. The quality of evidence for each outcome will be assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. Review Manager V.5.3.5 will be used for synthesis and subgroup analysis. ETHICS AND DISSEMINATION: Owing to the nature of the review, ethical approval is not required. The results will be disseminated through peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42020197395.

Lag times in the publication of network meta-analyses: a survey.

OBJECTIVE: We assessed the extent of lag times in the publication and indexing of network meta-analyses (NMAs). STUDY DESIGN: This was a survey of published NMAs on drug interventions. SETTING: NMAs indexed in PubMed (searches updated in May 2020). PRIMARY AND SECONDARY OUTCOME MEASURES: Lag times were measured as the time between the last systematic search and the article submission, acceptance, online publication, indexing and Medical Subject Headings (MeSH) allocation dates. Time-to-event analyses were performed considering independent variables (geographical origin, Journal Impact Factor, Scopus CiteScore, open access status) (SPSS V.24, R/RStudio). RESULTS: We included 1245 NMAs. The median time from last search to article submission was 6.8 months (204 days (IQR 95-381)), and to publication was 11.6 months. Only 5% of authors updated their search after first submission. There is a very slightly decreasing historical trend of acceptance (rho=-0.087; p=0.010), online publication (rho=-0.080; p=0.008) and indexing (rho=-0.080; p=0.007) lag times. Journal Impact Factor influenced the MeSH allocation process, but not the other lag times. The comparison between open access versus subscription journals confirmed meaningless differences in acceptance, online publication and indexing lag times. CONCLUSION: Efforts by authors to update their search before submission are needed to reduce evidence production time. Peer reviewers and editors should ensure authors' compliance with NMA standards. The accuracy of these findings depends on the accuracy of the metadata used; as we evaluated only NMA on drug interventions, results may not be generalisable to all types of studies.

New prophylaxis regimen for SARS-CoV-2 infection in health professionals with low doses of hydroxychloroquine and bromhexine: a randomised, double-blind placebo clinical trial (ELEVATE Trial).

INTRODUCTION: SARS-CoV-2 infection in Mexico has caused ~2.7 million confirmed cases; around 20%-25% of health workers will be infected by the virus at their workplace, with approximately 4.4% of mortality. High infectivity of SARS-CoV-2 is related with cell entry mechanism, through the ACE receptor. SARS-CoV-2 requires transmembrane protease serine 2 to cleave its spike glycoprotein and ensure fusion of host cell and virus membrane. We propose studying prophylactic treatment with hydroxychloroquine (HCQ) and bromhexine (BHH), which have been shown to be effective in preventing SARS-CoV-2 infection progression when administered in early stages. The aim of this study is to assess the efficacy of HCQ and BHH as prophylactic treatments for SARS-CoV-2 infection in healthy health workers exposed to the virus. METHODS AND ANALYSIS: Double-blind randomised clinical trial, with parallel allocation at a 1:1 ratio with placebo, of low doses of HCQ plus BHH, for 60 days. Study groups will be defined as follows: (1) HCQ 200 mg/day+BHH 8 mg/8 hours versus (2) HCQ placebo plus BHH placebo. Primary endpoint will be efficacy of both interventions for the prevention of SARS-CoV-2 infection, determined by the risk ratio of infected personnel and the absolute risk. At least a 16% reduction in absolute risk is expected between the intervention and placebo groups; a minimum of 20% infection is expected in the placebo group. The sample size calculation estimated a total of 214 patients assigned: two groups of 107 participants each. ETHICS AND DISSEMINATION: This protocol has been approved by the local Medical Ethics Committee (National Institute of Rehabilitation 'Luis Guillermo Ibarra Ibarra', approval number INRLGII/25/20) and by the Federal Commission for Protection against Sanitary Risks (COFEPRIS, approval number 203 300 410A0058/2020). The results of the study will be submitted for publication in peer-reviewed journals and disseminated through conferences. TRIAL REGISTRATION NUMBER: NCT04340349.

Effectiveness and safety of oral sedation in adult patients undergoing dental procedures: a systematic review.

OBJECTIVES: It can be challenging to manage patients who are anxious during dental procedures. There is a lack of evidence regarding the effectiveness and safety of oral sedation in adults. This study evaluated the effectiveness and safety of oral sedation in patients undergoing dental procedures. DESIGN: Systematic review. METHODS: Randomised clinical trials (RCTs) compared the oral use of benzodiazepines and other medications with a placebo or other oral agents in adult patients. A search of the Cochrane (CENTRAL), MEDLINE (via Ovid), EMBASE (via Ovid) and Cumulative Index to Nursing and Allied Health Literature (via Ovid) databases was conducted, without any restrictions on language or date of publication. The primary outcomes included the adverse effects and anxiety level. The secondary outcomes included sedation, satisfaction with the treatment, heart rate, respiratory rate, blood pressure and oxygen saturation. Reviewers, independently and in pairs, assessed each citation for eligibility, performed the data extraction and assessed the risk of bias. A narrative synthesis of the data was provided. RESULTS: A number of RCTs (n=327 patients) assessed the use of benzodiazepines (n=9) and herbal medicines (n=3). We found good satisfaction with treatment after the use of midazolam 7.5 mg or clonidine 150 µg and reduced anxiety with alprazolam (0.5 and 0.75 mg). Midazolam 15 mg promoted greater anxiety reduction than Passiflora incarnata L. 260 mg, while Valeriana officinalis 100 mg and Erythrina mulungu 500 mg were more effective than a placebo. More patients reported adverse effects with midazolam 15 mg. Diazepam 15 mg and V. officinalis 100 mg promoted less change in the heart rate and blood pressure than a placebo. CONCLUSIONS: Given the limitations of the findings due to the quality of the included studies and the different comparisons made between interventions, further RCTs are required to confirm the effectiveness and safety of oral sedation in dentistry. PROSPERO REGISTRATION NUMBER: CRD42017057142.