What Powers Trastuzumab's Cardiotoxicity? Decoding Mitochondrial-Related Gene Expression Through Integrative Review and Meta-Analysis in Cardiomyocytes.

Trastuzumab is a monoclonal antibody used in oncotherapy for HER2-positive tumors. However, as an adverse effect, trastuzumab elevates the risk of heart failure, implying the involvement of energy production and mitochondrial processes. Past studies with transcriptome analysis have offered insights on pathways related to trastuzumab safety and toxicity but limited study sizes hinder conclusive findings. Therefore, we meta-analyzed mitochondria-related gene expression data in trastuzumab-treated cardiomyocytes. We searched the transcriptome databases for trastuzumab-treated cardiomyocytes in the ArrayExpress, DDBJ Omics Archive, Gene Expression Omnibus, Google Scholar, PubMed, and Web of Science repositories. A subset of 1270 genes related to mitochondrial functions (biogenesis, organization, mitophagy, and autophagy) was selected from the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology Resource databases to conduct the present meta-analysis using the Metagen package (Study register at PROSPERO: CRD42021270645). Three datasets met the inclusion criteria and 1243 genes were meta-analyzed. We observed 69 upregulated genes after trastuzumab treatment which were related mainly to autophagy (28 genes) and mitochondrial organization (28 genes). We also found 37 downregulated genes which were related mainly to mitochondrial biogenesis (11 genes) and mitochondrial organization (24 genes). The present meta-analysis indicates that trastuzumab therapy causes an unbalance in mitochondrial functions, which could, in part, help explain the development of heart failure and yields a list of potential molecular targets. These findings contribute to our understanding of the molecular mechanisms underlying the cardiotoxic effects of trastuzumab and may have implications for the development of targeted therapies to mitigate such effects.

Safety Assessment of an Oral Therapeutic Dose of Firocoxib on Healthy Horses.

Firocoxib is a non-steroidal anti-inflammatory drug specifically formulated for veterinary medicine and selectively acts on inhibiting the cyclooxygenase 2 enzyme (COX-2). This study evaluated the possible adverse effects of administering oral therapeutic firocoxib on gastric mucosa, hematological parameters, coagulation cascade, and hepatic and renal biochemistry in healthy horses. Nine clinically healthy Arabian horses, approximately 9 years old, received 0.1 mg/kg of oral firocoxib for 14 days. The gastroscopic examination was conducted 1 day before starting treatment (D0) and two days after the last blood collection (D23). Venous blood samples were obtained for laboratory tests on day 1, immediately prior to the initiation of treatment (D1), after 7 and 14 days of treatment (D7 and D14), and 7 days after the conclusion of treatment (D21. No changes were found in the gastroscopic and hematological tests. Coagulation and serum biochemistry levels remain between these species' average values. However, the increased activated partial thromboplastin time (aPTT) and prothrombin time (PT) indicate reduced blood coagulation capacity, which contradicts the expected effect of treatment with selective COX-2 inhibitors, as these drugs theoretically promote coagulation. Administering firocoxib to horses is safe as it does not cause significant adverse reactions. Therefore, it is a suitable option for managing inflammatory conditions in these animals with attention to an unexpected adverse anti-coagulopathy effect, and further study is warranted.

Chemotherapy-Induced Peripheral Neuropathy Impacts Quality Of Life And Activities Of Daily Living Of Brazilian Multiple Myeloma Patients.

BACKGROUND: Survival in multiple myeloma (MM) has improved in the past years with the introduction of immunomodulators and proteasome inhibitors. However, chemotherapy-induced peripheral neuropathy (CIPN) is associated with both drug classes affecting Health-Related Quality of Life (HRQoL) and activities of daily living (ADL). OBJECTIVE: We evaluated CIPN in MM patients to identify associated factors and impacts on HRQoL and ADL. METHODS: This is a cross-sectional study with Brazilian patients from public and private health services. Patients were interviewed using validated tools to measure CIPN and HRQoL, along with sociodemographic and clinical questions. Logistic regression was used to assess the association of CIPN with sociodemographic, clinical, and HRQoL variables. RESULTS: In total, 217 patients were eligible for the study. The median age was 67, 50.9% were women, 51.6% had low income, 47.5% had low education, and 55.3% attended private health services. The chemotherapy regimen most used was the combination of cyclophosphamide, thalidomide, and dexamethasone (17.5%) among the 24 types of regimens found. Most patients (90.3%) had at least one CIPN symptom: 62.7% were severe, and 51.62% were extremely bothered ADL. Numbness was the most common symptom (40.6%). CIPN was independently associated with education, hospitalization, chemotherapy, side effects, disease symptoms, and global health status in HRQoL. CONCLUSION: MM patients showed a high frequency of CIPN, which affected ADL and impaired HRQoL. Early and accurate detection of CIPN and dose management in patients with thalidomide and bortezomib-based regimens should be performed to provide better treatment outcomes and avoid permanent disabilities.

Real-world effectiveness and safety of multiple myeloma treatments based on thalidomide and bortezomib: A retrospective cohort study from 2009 to 2020 in a Brazilian metropolis.

BACKGROUND: Multiple myeloma (MM) is an incurable cancer of plasma cells; the survival of which has improved over the years with the emergence of new treatments. In Brazil, the availability of treatment-regimens is different from developed countries. Real-world evidence with Brazilian patients is lacking. OBJECTIVES: Our aim was to evaluate the effectiveness and the safety of MM treatments in a Brazilian metropolis. METHODS: This was a retrospective cohort study with MM patients, beginning MM treatment from 2009 to 2020 (i.e., before bortezomib became available in public health services). Patients' medical records were revised to obtain clinical variables. The primary outcomes were Overall Survival (OS) and Progression Free Survival (PFS, measured as time to next treatment), and the secondary outcomes were Adverse Events (AE). Kaplan-Meier curves were obtained and the Cox proportional hazards model was performed for univariate and multivariate analyses. The incidence of AE was estimated and the chi-squared test was performed to evaluate the association between AE and MM regimens. RESULTS: In total, 278 patients participated in the study with median age of 64 years; 50.4 % were females, 55.8 % attended a private clinic, 34.9 % received autologous stem cell transplantation (ASCT) and 32.4 % were on polypharmacy. Most patients from public services used thalidomide-based regimens (40.3 %) and at private clinics used bortezomib-based regimens (38.1 %) as first-line treatment. Patients had a median OS of 99 months. Patients had median PFS of 28 months in first-line treatment, which was significantly different for age (p = 0.0055), polypharmacy (p = 0.0094) and ASCT (p < 0.0001). PFS was independently associated to polypharmacy and ASCT. The incidence of peripheral neuropathy (39.6 %) was high. In contrast, the incidence of severe AE was low. We found significant difference between first-line T + B-based regimens and leukopenia (p = 0.012). CONCLUSION: Our study showed that patients on polypharmacy and who did not receive ASCT had worse PFS. Similar to other Latin countries, most patients used thalidomide- and bortezomib-based regimens as first-line treatments having similar OS and PFS. Treatments were considered relatively safe, especially regarding serious AE.

Utilidad estadística de los estudios de farmacovigilancia para evaluar reacciones adversas a medicamentos

Introducción: la detección oportuna y la evaluación de las reacciones adversas de los medicamentos es cada vez más importante. En Cuba existe la necesidad de profundizar y extender con alcance nacional los estudios de Farmacovigilancia, por tal motivo se expone como objetivo fundamentar sustentados en la estadística el uso de estudios de farmacovigilancia para la detección, registro, notificación y evaluación de las sospechas de las reacciones adversas de los medicamentos valorando su seguridad. Desarrollo: se brinda un resumen de tipos de estudios de farmacovigilancia con ejemplos de objetivos de investigaciones realizadas y publicadas en revistas científicas posibles a considerar y aplicar a las condiciones reales que tenga cada investigador, se presentan variables que ya han sido establecidas en otros estudios que se deben tener en cuenta para estudiar seguridad de los medicamentos y técnicas estadísticas teniendo en cuenta los tipos de variables a relacionar. Conclusiones: se concluye que resulta un logro científico conocer formas de profundizar y extender los estudios de Farmacovigilancia para tomar conocimiento de la seguridad de los fármacos y promover un uso racional, científico y adecuado de los mismos, en beneficio de la comunidad.

Introduction: timely detection and evaluation of adverse drug reactions is increasingly important. In Cuba there is a need to deepen and extend pharmacovigilance studies nationwide. That is why it is stated, based on statistics, the use of studies for the detection, registration, notification and evaluation of suspected adverse drug events, assessing their safety. Development: a summary of types of pharmacovigilance studies is provided with examples of objectives of research works already done and published in scientific magazines likely to consider and use in actual conditions each researcher has, and there are also presented variables that have already been established in other studies, which must be taken into account to study drug safety and statistical techniques considering the types of variables to be related. Conclusion: it is concluded that knowing ways to deepen and spread the Pharmacovigilance studies in order to be aware of drug safety and foster their rational, scientific and adequate use in the interests of the community is indeed a scientific accomplishment.

Introdução: a detecção e avaliação oportunas de reações adversas a medicamentos está se tornando cada vez mais importante. Em Cuba há uma necessida de de aprofundar e ampliar os estudos de farmacovigilância com âmbito nacional, por esta razão é declarado como um objetivo fundamentar com base em estatísticas o uso de estudos de farmacovigilância para a detecção, registro, notificação e avaliação de suspeitas de reações adversas de medicamentos que avaliam sua segurança. Desenvolvimento: um resumo dos tipos de estudos de farmacovigilância é fornecido com exemplos de objetivos de pesquisa realizados e publicados em possíveis revistas científicas a serem consideradas e aplicadas às condições reais que cada pesquisador possui, variáveis que já foram estabelecidas em outros estudos que devem ser levadas em conta para estudar a segurança de medicamentos e técnicas estatísticas levando em conta os tipos de variáveis a serem relacionadas. Conclusões: conclui-se que é uma conquista científica conhecer formas de aprofundar e ampliar os estudos de farmacovigilância para tomar conhecimento da segurança dos medicamentos e promover um uso racional, científico e adequado dos mesmos, em benefício da comunidade.

Definition of self-medication: a scoping review.

Self-medication (SM) is a global and growing phenomenon. It represents a public health problem due to antibiotic resistance, risk of adverse drug reactions, drug-drug interactions, disease masking, and increased morbidity. There is not a consensus on the definition of SM. The definitions found in different studies make it difficult to address this problem from a theoretical perspective and therefore find an adequate solution to this public health problem. The aim of this article is to search the medical literature to characterize the current understanding of SM in the medical community. We conducted a scoping review of definitions of SM by searching on PubMed - Medline, Embase, and LILACS using the following combination of keywords: 'self-prescription' or 'self prescription', 'self-medication' or 'self medication', or 'automedication' and 'definition' or 'explanation'. The search was limited to articles containing the definition of SM, with no limit on language or year. Duplicate studies and those that did not mention the definition of SM were excluded from the final review. A total of 65 studies were included in the final selection. We found a vast heterogeneity in the definition of SM. Most articles based their definition of SM on the process of obtaining the drug, the nonparticipation of a specific health professional, the source of the medication, and the reason for SM. Other interesting concepts such as self-care, nonadherence to a prescription, reuse of stored drugs, and sharing and lending medicines were also considered forms of SM by other authors, however. This study highlights the need to reach a consensus regarding the definition of SM to adequately propose strategies to address this global health problem. This study shows the diverse concepts that need to be included in a future definition of SM. Plain Language Summary: Definition of self-medication: a review with systematic methodology Self-medication (SM) is a global and growing phenomenon that represents a public health problem due to antibiotic resistance, risk of dangerous side effects, interactions between drugs, and disease masking. Currently, there is not a consensus on the definition of SM, which makes it difficult to address this problem and therefore find an adequate solution. Making a standard definition would allow the development of programs focused on addressing drug-related problems associated with self-medication behavior. The purpose of this article is to search the medical literature to define the current understanding of SM in the medical community. We included a total of 65 studies and found a great variance in the definition of SM. Most articles based their definition of SM on the process of obtaining the drug, the nonparticipation of a specific health professional, the source of the medication, and the reason for SM. Other interesting concepts such as self-care, not following a prescription, reuse of stored drugs, and sharing and lending medicines were also considered forms of SM by other authors, however. Furthermore, this study highlights that SM is a wider concept that goes beyond aiming to promote and restore health, as aesthetic and recreational purposes are also reasons for SM that can put individuals at risk and compromise the correct and safe use of medications.

Safety of biological therapy in patients with rheumatoid arthritis in administrative health databases: A systematic review and meta-analysis.

Background: Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects the synovial fluid of joints, tendons, and some extra-articular sites. Biologic agents have been highly effective and are comparable in reducing RA symptoms, slowing disease progression, and improving physical function; however, concerns have been raised about the risks of several potential adverse effects. Thus, this study aimed to assess the safety of biological therapy in patients with rheumatoid arthritis in observational studies using administrative health databases. Methods: PubMed, Embase, Lilacs, Ovid, Scopus, and Web of Science were searched from inception to 21 October 2021. The analysis was divided into five groups: tumor necrosis factor inhibitors (TNFi) versus non-TNFi; TNFi versus csDMARDs; bDMARDs versus csDMARDs; abatacept versus bDMARDs; and TNFi versus Janus kinase inhibitors (JAKi). The adverse events were cancer, cardiovascular events, infection, herpes zoster, tuberculosis, and death. The methodological quality of the studies was assessed by the Newcastle-Ottawa Scale. A random-effects model estimated risk ratios with 95% confidence intervals. Results: Thirty-one studies were eligible for inclusion in the present systematic review, published from 2014 to 2021. A total of 1,039,398 RA patients were assessed. The 31 studies evaluated eleven different biological drugs. No significant differences were found regarding safety between TNFi versus non-TNFi (RR 1.08; 95% CI 0.92-1.28; p < 0.01; I2 = 93.0%), TNFi versus csDMARDs (RR 0.91; 95% CI 0.75-1.10; p < 0.01; I2 = 87.0%), bDMARDs versus csDMARDs (RR 0.99; 95% CI 0.82-1.20; p < 0.01; I2 = 93.0%), abatacept versus bDMARDs (RR 0.80; 95% CI 0.54-1.18; p < 0.01; I2 = 90.0%), and TNFi versus JAKi (RR 3.54; 95% CI 0.30-42.09; p = 0.01; I2 = 81.0%). In the subgroup analysis, among studies comparing abatacept to TNFi, a lower risk of cardiovascular events was associated with abatacept (RR 0.37; 95% CI 0.24-0.55). Conclusion: Our results do not suggest an increased risk of adverse events associated with biological therapy in treating RA patients, indicating a lower risk of cardiovascular events with abatacept than TNFi. However, these findings must be interpreted with caution given the limitations of this study and the low/very low certainty of the evidence. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?, identifier [CRD42020190838].

Conocimientos, actitudes y prácticas de farmacovigilancia en el contexto de la COVID-19 en profesionales de la salud del Seguro Social del Perú / Knowledge, attitudes and practices of pharmacovigilance in the context of COVID-19 in health professionals of the peruvian social insurance

RESUMEN El estudio tuvo como objetivo evaluar el conocimiento, las actitudes y prácticas de un grupo de profesionales de la salud sobre la farmacovigilancia en el contexto de la COVID-19 en el Seguro Social de Salud del Perú (EsSalud). Se realizó un análisis secundario descriptivo de una base de datos que incluía las respuestas de una encuesta en línea realizada por el Centro de Referencia Institucional de Farmacovigilancia y Tecnovigilancia de EsSalud. De 144 participantes, el 66% mostró alto nivel de conocimiento y el 81,2%, actitud positiva; sin embargo, el 71,5% tuvo un inadecuado nivel de práctica de farmacovigilancia. Si bien los profesionales de EsSalud demostraron tener alto conocimiento y actitud positiva para implementar farmacovigilancia, esto no se ve reflejado en la práctica de esta actividad en la época de pandemia por el SARS-CoV-2. Se deben emplear estrategias para integrar a la farmacovigilancia en las actividades asistenciales en beneficio de la seguridad del paciente.

ABSTRACT The study aimed to evaluate a group of health professionals' knowledge, attitudes, and practices on pharmacovigilance in the context of COVID-19 in the Peruvian Social Health Insurance (EsSalud). A descriptive secondary analysis was carried out on a database that included responses from an online survey conducted by the Institutional Referral Center for Pharmacovigilance and Technovigilance of EsSalud. Of 144 participants, 66% showed a high level of knowledge and 81.2% had a positive attitude; however, 71.5% had an inadequate level of pharmacovigilance practice. Although EsSalud professionals demonstrated a high level of knowledge and positive attitude to implement pharmacovigilance, this is not reflected in the practice of this activity during the SARS-CoV-2 pandemic. Strategies should be implemented to integrate pharmacovigilance into healthcare activities to benefit patient safety.

A Drug Safety Surveillance Study of a Ciprofloxacin/Dexamethasone Ophthalmic Fixed Combination in Peruvian Population.

(1) Background: drugs provide a significant benefit for patients who require medical treatment; however, their use implies an intrinsic potential danger, with the possibility of causing unwanted effects. These effects are known as adverse drug reactions (ADRs). Post-marketing drug safety surveillance detects unknown risks that have not been identified in clinical trials, and it is necessary to monitor marketed medications under real-life practice. Due to the scarce information about fixed combination of ciprofloxacin 0.3%/dexamethasone 0.1% (SDO), we performed a drug safety surveillance study. (2) Methods: A prospective non-controlled drug safety surveillance study was conducted in Peruvian population. A total of 236 patients prescribed SDO were included derived from 12 sites. Patients' standardized information was collected through two phone calls, including demographics, medical history, prescribing patterns of SDO, concomitant medication, and ADRs in detail. The ADRs were classified by causality and severity, followed by outcome measures to identify new risk. (3) Results: 236 patients prescribed with SDO participated in the study and 220 were included. A total of 82 ADRs/220 patients were reported after the use of SDO, presenting a ratio 0.37 ADR/patient. The most frequent ADR with SDO administration was eye irritation (30%). All ADRs were classified as non-serious, and 97.5% (n = 80) were classified as mild while 2.5% as moderate (n = 2). No cases under the severe category were identified. (4) Conclusion: No new risks were found in the population where this study was conducted.

Prevalence and risk factors of long-term proton pump inhibitors-associated hypomagnesemia: a cross-sectional study in hospitalized patients.

BACKGROUND: Proton pump inhibitors (PPI)-related hypomagnesemia is a potentially life-threatening adverse event first described in 2006. PPIs are widely used in the general population. Information regarding prevalence and risk factors is scarce. We conducted a cross-sectional study in inpatients to evaluate prevalence and associated factors with hypomagnesemia in chronic PPIs users. This is a cross-sectional study of hospitalized adult patients with chronic use of PPIs from January 01, 2012, to December 31, 2018. Chronic use was defined as taking PPIs at least 6 months before hospital admittance. Data were collected from informatized medical records from a University Hospital (Hospital Italiano de Buenos Aires). Hypomagnesemia was defined as a value equal to or less than 1.7 mg/dl. The first hospitalization measurement was retrieved. Thirty-six percent of patients (95% CI 30-43) with chronic PPI use presented hypomagnesemia at admission. Patients with hypomagnesemia presented a higher prevalence of chronic kidney disease (18.6% vs 8%, p < 0.05), more use of oral magnesium supplementation (20.9% vs 8%, p < 0.05), use of corticosteroids (32.6% vs 19.3%, p = 0.06) and calcineurin inhibitors (17.4% vs 6.7%, p < 0.05). Regarding laboratory findings, they presented lower hematocrit (28.7% vs 32.8%, p < 0.05), phosphatemia (3 mg/dl vs 3.4 mg/dl, p < 0.05), natremia (135 mg/dl vs 136 mg/dl, p < 0.05) and albumin levels (2.8 g/dl vs 3.2 g/dl p < 0.05) when compared to those who presented normomagnesemia. Hypocalcemia was more frequent among patients with hypomagnesemia (57% vs 38.7%, p < 0.05). In the multivariate analysis, hyponatremia, decreasing levels of hematocrit (odds ratio, OR 0.93-CI 95% 0.88-0.98) and malignant bone compromise (OR 2.83-CI 95% 1.04-7.7) were associated with hypomagnesemia. Adult patients with long-term use of PPIs have a high prevalence of hypomagnesemia. Increasing age, female sex, concomitant use of drugs that impair tubular function and chronic kidney disease may enhance this phenomenon. Anemia, hyponatremia and malignant bone compromise were associated factors with PPIs-related hypomagnesemia.

Early preclinical screening using zebrafish (Danio rerio) reveals the safety of the candidate anti-inflammatory therapeutic agent TnP.

The patented anti-inflammatory peptide TnP had its effectiveness recently confirmed in vivo in a murine model of multiple sclerosis and asthma. In this work, the safety of the TnP was evaluated in investigative toxicology tests using zebrafish (Danio rerio) as a model. We conducted the OECD #236 test to investigate effects of the TnP on the survival, hatching performance, and morphological formation of zebrafish embryos. After determining these endpoints, morphometric analysis termination of locomotion eartbeat rate in zebrafish larvae were evaluated to identify adverse effects such as neurotoxicity and cardiotoxicity. The results highlight a wide therapeutic index for TnP with non-lethal and safe doses rom 1 nM to 10 µM, without causing neurotoxicity or cardiotoxic effect. The low frequencyf abnormalities by TnP was associated with high safety of the molecule and the developing embryo's ability to process and eliminate it. TnP crossed the blood-brain barrier without disturbing the normal architecture of forebrain, midbrain and hindbrain. Our data reinforce the importance of zebrafish as an accurate investigative toxicology model to assess acute toxicity as well as cardiotoxicity and neurotoxicity of molecules in the preclinical phase of development.

Profile of entrectinib in the treatment of ROS1-positive non-small cell lung cancer: Evidence to date.

ROS proto-oncogene 1 (ROS1) encodes a type I integral membrane protein with tyrosine kinase activity and whose activating alterations are involved in the aggressiveness of several tumor types. Fusions involving ROS1 gene are present in 1-2% of lung adenocarcinomas and other solid tumors. Entrectinib, also known as RXDX-101, is a potent second-generation, multitarget oral inhibitor against NTRK1, NTRK2, NTRK3, ALK, and ROS1 with the ability to cross the blood-brain barrier. Results of Phase I and II trials have led the Food and Drug Administration to grant approval to entrectinib for the treatment of patients with metastatic, ROS1-positive non-small cell lung cancer (NSCLC). In this review, we will describe the biology of ROS1, as well as results of the efficacy and safety of different clinical trials evaluating entrectinib in ROS1-positive NSCLC.

Investigation of topical intranasal cocaine for sinonasal procedures: a randomized, phase III clinical trial.

BACKGROUND: The objective of this trial was to demonstrate the clinical efficacy and safety of topical cocaine as part of the effort to gain regulatory approval from the United States Food and Drug Administration. METHODS: This phase III, randomized, prospective, double-blind, multicenter, single-dose, placebo- and dose-controlled, parallel-group study aimed to evaluate the safety and efficacy of topical intranasal cocaine (RX0041-002). A total of 925 subjects were screened and a total of 648 subjects were randomized: 95 to placebo; 275 to 4% RX0041-002; and 278 to 8% RX0041-002. Efficacy was assessed with subjective pain intensity scores using the visual numeric rating scale and objectively using the von Frey filament test. Adverse events (AEs), vital signs, Holter monitoring, nasal irritation on visual examination, and smell assessment were recorded. The placebo and experimental groups were compared using a two-tailed Fisher's exact test. RESULTS: Topical 4% and 8% cocaine achieved significant subject analgesia, the primary efficacy endpoint. Both doses were safe and well-tolerated, with a safety profile similar to placebo. In the 4% and 8% groups, headache (1.5% and 2.5%, respectively), epistaxis (0.7% and 1.1%), and anxiety (0.7% and 0%) were the only AEs reported by >1 subject. No cardiovascular AEs, serious AEs, or deaths occurred. A higher percentage of subjects in the 4% and 8% groups compared with the placebo group had a modest increase in either systolic or diastolic blood pressure. CONCLUSION: Topical 4% and 8% cocaine is an effective anesthetic that can be safely administered for nasal procedures.

Monitoring compliance with Clinical Protocol and Therapeutic Guidelines for Alzheimer's disease.

Dementia is a chronic neurodegenerative disease and Alzheimer's disease (AD) is the most prevalent type. OBJECTIVE: To describe the drug monitoring of patients enrolled in a Clinical Protocol and Therapeutic Guidelines of Alzheimer's Disease (PCDTDA) in Brazil. METHODS: A descriptive study based on interviews conducted in 2017 was performed. Patients diagnosed with Alzheimer's disease (AD) enrolled on the PCDTDA were included. The variables assessed were age, sex, time since diagnosis, clinical parameters of Mini-Mental State Exam (MMSE) and Clinical Dementia Rating (CDR), drug therapy used and AD drug collection. RESULTS: The drug monitoring of 143 patients was evaluated. Observing the requirements of the screening tests for patient enrolment on the PCDTDA, all patients had scores for at least one MMSE and CDR assessment at protocol admission. None of the patients underwent the first reassessment of the effectiveness of AD drug therapy or the semiannual reassessment. CONCLUSION: Although PCDTDA provides the best evidence of AD treatment, the data showed failures in the monitoring of the effectiveness of AD drug therapy at dispensing.

A demência é uma doença crônica e neurodegenerativa, e a doença de Alzheimer (DA) é a mais prevalente. OBJETIVO: Descrever o monitoramento da farmacoterapia de pacientes inseridos no Protocolo Clínico e Diretrizes Terapêuticas da Doença de Alzheimer (PCDTDA), Brasil. MÉTODOS: Estudo descritivo, conduzido por meio de entrevistas em 2017. Foram incluídos pacientes com diagnóstico da doença de Alzheimer (DA) inseridos no PCDTDA. As variáveis foram idade; sexo; tempo de diagnóstico e farmacoterapia da DA; os parâmetros clínicos Mini-exame do estado mental (MEEM) e Clinical Dementia Rating (CDR); e farmacoterapia em uso. RESULTADOS: O monitoramento de 143 pacientes foi avaliado. Considerando a exigência dos testes de rastreio para a inserção do paciente no PCDTDA, observou-se que todos os pacientes tinham pelo menos um escore no MEEM e no CDR na admissão no protocolo. Nenhum paciente foi submetido à primeira reavaliação da efetividade da farmacoterapia da DA e nem à reavaliação semestral. CONCLUSÃO: Apesar do PCDTDA ser a maior evidência do tratamento da DA, dados evidenciam falhas no monitoramento da efetividade da farmacoterapia da DA na dispensação.

Monitoring compliance with Clinical Protocol and Therapeutic Guidelines for Alzheimer's disease / Monitoramento do cumprimento do protocolo clínico e diretrizes terapêuticas da doença de alzheimer

ABSTRACT Dementia is a chronic neurodegenerative disease and Alzheimer's disease (AD) is the most prevalent type. Objective: To describe the drug monitoring of patients enrolled in a Clinical Protocol and Therapeutic Guidelines of Alzheimer's Disease (PCDTDA) in Brazil. Methods: A descriptive study based on interviews conducted in 2017 was performed. Patients diagnosed with Alzheimer's disease (AD) enrolled on the PCDTDA were included. The variables assessed were age, sex, time since diagnosis, clinical parameters of Mini-Mental State Exam (MMSE) and Clinical Dementia Rating (CDR), drug therapy used and AD drug collection. Results: The drug monitoring of 143 patients was evaluated. Observing the requirements of the screening tests for patient enrolment on the PCDTDA, all patients had scores for at least one MMSE and CDR assessment at protocol admission. None of the patients underwent the first reassessment of the effectiveness of AD drug therapy or the semiannual reassessment. Conclusion: Although PCDTDA provides the best evidence of AD treatment, the data showed failures in the monitoring of the effectiveness of AD drug therapy at dispensing.

RESUMO A demência é uma doença crônica e neurodegenerativa, e a doença de Alzheimer (DA) é a mais prevalente. Objetivo: Descrever o monitoramento da farmacoterapia de pacientes inseridos no Protocolo Clínico e Diretrizes Terapêuticas da Doença de Alzheimer (PCDTDA), Brasil. Métodos: Estudo descritivo, conduzido por meio de entrevistas em 2017. Foram incluídos pacientes com diagnóstico da doença de Alzheimer (DA) inseridos no PCDTDA. As variáveis foram idade; sexo; tempo de diagnóstico e farmacoterapia da DA; os parâmetros clínicos Mini-exame do estado mental (MEEM) e Clinical Dementia Rating (CDR); e farmacoterapia em uso. Resultados: O monitoramento de 143 pacientes foi avaliado. Considerando a exigência dos testes de rastreio para a inserção do paciente no PCDTDA, observou-se que todos os pacientes tinham pelo menos um escore no MEEM e no CDR na admissão no protocolo. Nenhum paciente foi submetido à primeira reavaliação da efetividade da farmacoterapia da DA e nem à reavaliação semestral. Conclusão: Apesar do PCDTDA ser a maior evidência do tratamento da DA, dados evidenciam falhas no monitoramento da efetividade da farmacoterapia da DA na dispensação.

Early preclinical screening using zebrafish (Danio rerio) reveals the safety of the candidate anti-inflammatory therapeutic agent TnP

The patented anti-inflammatory peptide TnP had its effectiveness recently confirmed in vivo in a murine model of multiple sclerosis and asthma. In this work, the safety of the TnP was evaluated in investigative toxicology tests using zebrafish (Danio rerio) as a model. We conducted the OECD #236 test to investigate effects of the TnP on the survival, hatching performance, and morphological formation of zebrafish embryos. After determining these endpoints, morphometric analysis termination of locomotion eartbeat rate in zebrafish larvae were evaluated to identify adverse effects such as neurotoxicity and cardiotoxicity. The results highlight a wide therapeutic index for TnP with non-lethal and safe doses rom 1 nM to 10 μM, without causing neurotoxicity or cardiotoxic effect. The low frequencyf abnormalities by TnP was associated with high safety of the molecule and the developing embryo's ability to process and eliminate it. TnP crossed the blood-brain barrier without disturbing the normal architecture of forebrain, midbrain and hindbrain. Our data reinforce the importance of zebrafish as an accurate investigative toxicology model to assess acute toxicity as well as cardiotoxicity and neurotoxicity of molecules in the preclinical phase of development.

Montelukast and Neuropsychiatric Events in Children with Asthma: A Nested Case-Control Study.

OBJECTIVE: To examine the association between montelukast prescription and neuropsychiatric events in children with asthma. STUDY DESIGN: A matched, nested case-control design was used to identify cases and controls from a cohort of children aged 5-18 years with physician-diagnosed asthma from 2004 to 2015, in Ontario, Canada, prescribed an asthma maintenance medication. Cases were children with a hospitalization or emergency department visit for a neuropsychiatric event. Cases were matched to up to 4 controls on birth year, year of asthma diagnosis, and sex. The exposures were dispensed prescriptions for montelukast (yes/no) and number of dispensed montelukast prescriptions in the year before the index date. Conditional logistic regression was used to measure the unadjusted OR and aOR and 95% CIs for montelukast prescription and neuropsychiatric events. Covariates in the adjusted model included sociodemographic factors and measures of asthma severity. RESULTS: In total, 898 cases with a neuropsychiatric event and 3497 matched controls were included. Children who experienced a new-onset neuropsychiatric event had nearly 2 times the odds of having been prescribed montelukast, compared with controls (OR 1.91, 95% CI 1.15-3.18; P = .01). Most cases presented for anxiety (48.6%) and/or sleep disturbance (26.1%). CONCLUSIONS: Children with asthma who experienced a new-onset neuropsychiatric event had nearly twice the odds of having been prescribed montelukast in the year before their event. Clinicians should be aware of the association between montelukast and neuropsychiatric events in children with asthma, to inform prescribing practices and clinical follow-up.