Novel drug design and repurposing: An opportunity to improve translational research in cardiovascular diseases?

Drug repurposing is defined as the use of approved therapeutic drugs for indications different from those for which they were originally designed. Repositioning diminishes both the time and cost for drug development by omitting the discovery stage, the analysis of absorption, distribution, metabolism, and excretion routes, as well as the studies of the biochemical and physiological effects of a new compound. Besides, drug repurposing takes advantage of the increased bioinformatics knowledge and availability of big data biology. There are many examples of drugs with repurposed indications evaluated in in vitro studies, and in pharmacological, preclinical, or retrospective clinical analyses. Here, we briefly review some of the experimental strategies and technical advances that may improve translational research in cardiovascular diseases. We also describe exhaustive research from basic science to clinical studies that culminated in the final approval of new drugs and provide examples of successful drug repurposing in the field of cardiology.

Validez y confiabilidad de un instrumento para identificar factores que influyen en la adherencia al tratamiento en personas con factores de riesgo cardiovascular

Introducción: Es necesario contar con instrumentos válidos y confiables para identificar los factores que influyen en la adherencia al tratamiento en personas con factores de riesgo cardiovascular. En Colombia, Bonilla y Gutiérrez diseñaron un instrumento que cuenta con validez facial y de contenido. Sin embargo, no se ha demostrado la validez de constructo. Objetivo: Determinar la validez de constructo y confiabilidad del instrumento, factores que influyen en la adherencia al tratamiento farmacológico y no farmacológico en personas con factores de riesgo cardiovascular. Metodología: Investigación metodológica. Participaron 694 personas con factores de riesgo de enfermedad cardiovascular residentes en tres ciudades de Colombia (Neiva, Espinal y Tunja). Se realizó un análisis factorial exploratorio (extracción de componentes principales y rotación Varimax), análisis factorial confirmatorio (estimación de máxima verosimilitud) y una prueba de confiabilidad global y por dimensiones (alfa de Cronbach y Test-retest). Resultados: El análisis factorial exploratorio reportó un instrumento de 30 ítems con estructura de 4 factores (varianza total acumulada de 42,6 %). Los índices de ajuste del modelo propuesto indicaron ajuste absoluto excelente y ajuste incremental aceptable. El alfa de Cronbach global fue 0,86, lo que indica alta confiabilidad. Discusión: El estudio proporciona evidencia de un instrumento más robusto que otras versiones. Los instrumentos estandarizados para medir factores que influyen en la adherencia pueden ser muy útiles para la investigación y la práctica si cumplen con pruebas psicométricas de fiabilidad y validez. Conclusión: Se pone a disposición de los investigadores y del personal de salud un instrumento válido y confiable. Se recomienda su uso en poblaciones similares a la de este estudio.

Introduction: It is necessary to have valid and reliable instruments to identify the factors that influence adherence to treatment in people with cardiovascular risk factors. In Colombia, Bonilla y Gutierrez designed an instrument that has face and content validity. However, construct validity has not been demonstrated. Objective: To determine the construct validity and reliability of the instrument, factors that influence adherence to pharmacological and non-pharmacological treatment in people with cardiovascular risk factors. Methodology: Methodological research. A total of 694 people with risk factors for cardiovascular disease residing in three Colombian cities (Neiva, Espinal and Tunja) participated. Exploratory factor analysis (extraction of principal components and Varimax rotation), confirmatory factor analysis (maximum likelihood estimation) and global and dimensional reliability test (Cronbach's alpha and Test-retest) were performed. Results: The exploratory factor analysis reported a 30-item instrument with a 4-factor structure (total cumulative variance of 42.6%). The fit indices of the proposed model indicated excellent absolute fit and acceptable incremental fit. The overall Cronbach's alpha was 0.86, indicating high reliability. Discussion: The study provides evidence of a more robust instrument than other versions. Standardized instruments to measure factors that influence adherence can be very useful for research and practice if they meet psychometric tests of reliability and validity. Conclusion: A valid and reliable instrument is made available to researchers and health personnel. Its use is recommended in populations similar to that of this study.

Cardiovascular effects of hyoscine butylbromide in patients under general anaesthesia.

BACKGROUND: Cardiovascular effects for drugs such as hyoscine butylbromide are poorly documented in the literature, unlike atropine, which is considered the antimuscarinic of choice in the presence of intraoperative bradycardia. AIM: The aim of the study was to describe the dose-related cardiovascular effect of hyoscine butylbromide in patients between 18 and 65 years of age, with low perioperative risk undergoing elective surgery under general anaesthesia on an outpatient basis or hospitalised at our institution between 1 January and 31 May 2019. METHODS: Descriptive, cross-sectional, retrospective study; 28 patients with low perioperative risk who underwent general anaesthesia were selected. Changes in heart rate and blood pressure were analysed during the first 6 minutes after the administration of hyoscine butylbromide. The data obtained was recorded in a Microsoft Excel database and analysed using the Excel analysis tool and IBM SPSS. RESULTS: The average dose of 0.15mg/kg of hyoscine butylbromide achieved an increase in heart rate and mean arterial pressure in 96% and 92.8%, respectively, in the first 6 minutes after the administration. Significant changes in heart rate and blood pressure were obtained during the first 6 minutes at doses between 0.05mg/kg and 0.15mg/kg. CONCLUSION: Hyoscine butylbromide generates positive effects on the heart rate and blood pressure of patients under general anaesthesia, representing a possible alternative in the management of intraoperative bradycardia.

Vortex-assisted liquid-liquid microextraction combined with liquid chromatography tandem mass spectrometry for simultaneous determination of cardiovascular drugs in human plasma.

Hypertension and dyslipidemias are among the main risk factors for the development of cardiovascular diseases, which are responsible for the death of approximately 17 million people each year. There are several drugs available for the treatment of these diseases. Therefore, methods for the simultaneous analysis of several of these drugs are useful in a wide range of situations. In this context, this study aimed to develop a modern method for the simultaneous determination of eight cardiovascular drugs in human plasma. A vortex-assisted liquid-liquid microextraction (VALLME) procedure, combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Mass spectrometry conditions, chromatographic separation, and sample preparation were optimized. For VALLME optimization, pH, sodium chloride concentration, volume of buffer solution, extraction solvent (type and volume), and vortex stirring time were evaluated. The method proved to be simple, fast, and environmentally friendly since low volumes of organic solvent were employed. Furthermore, the VALLME procedure required small sample volume, which is desirable when large volumes are scarce. Suitable recoveries and lower limits of quantification were achieved with a chromatographic run of only 8 min. The method was validated, showing to be selective, precise, and accurate. Furthermore, the analytical curves were well fitted to the selected models and the matrix effect did not affect method reliability. The developed method was successfully applied for the analysis of plasma samples obtained from volunteers attending a hospital service.

Cardiovascular drugs and analysis of potential risk factors associated with mortality in severe coronavirus disease 2019 patients

SUMMARY OBJECTIVES: Cardiovascular diseases are also considered to increase the risk of death in COVID-19 patients. However, real-world data concerning the risk factors for death in patients with severe COVID-19 still remain vague. This study aimed to identify the potential risk factors associated with mortality in severe COVID-19 patients. METHODS: All consecutive patients admitted to the intensive care unit (ICU) of our institute for COVID-19 for severe COVID-19 pneumonia from April 1, 2020 to July 20, 2020 were included in the analysis. Patient characteristics, including complete medical history and comorbid diseases, blood test results during admission and on day 7, and clinical characteristics were compared between survivors and nonsurvivors. RESULTS: There was no significant difference between survivors and nonsurvivors regarding age, gender, and preexisting cardiovascular diseases. Moreover, the rate of the medications including angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blockers did not differ between survivors and nonsurvivors. The peak C-reactive protein (CRP), procalcitonin, fibrinogen, and d-dimer levels and the rate for chronic renal failure were significantly higher in nonsurvivors compared with survivors. Intubated patients had a higher risk of death than the others had. CONCLUSIONS: This study failed to demonstrate a significant difference in preexisting cardiovascular diseases and cardiovascular medications between survivors and nonsurvivors who were admitted to ICU for severe COVID-19. Our findings indicate that the presence of chronic renal failure, a high peak ferritin concentration, and the need for invasive mechanical ventilation appear predictive for mortality. We propose that these risk factors should be taken into account in defining the risk status of severe COVID-19 patients admitted to the ICU.

Implementation of good practices for administering vasoactive amines: a quasi-experimental study / Implementación de buenas prácticas para la administración de aminas vasoactivas: un estudio cuasi-experimental / Implementação de boas práticas para administração de aminas vasoativas: um estudo quase-experiemental

ABSTRACT Objective to analyze the implementation of training on good practices for administering vasoactive amines when facing undesirable clinical events in patients of a cardiointensive unit. Method this is a quasi-experimental study (before and after), carried out in three stages at a university hospital located in Rio de Janeiro, Brazil. An observation was performed in the first stage about the team's adherence to good practices in administering vasoactive amines. Training was conducted with the nursing team in the second stage to implement the actions, and adherence to good practices in administering vasoactive amines was evaluated in the third stage. Data collection was performed from October 2019 to July 2021. The McNemar test and the Wilcoxon non-parametric test were used to compare the differences in the pre- and post-intervention groups. Results a total of 280 patients were infused with vasoactive amines, 97 in the first stage (pre-intervention) and 183 after the intervention. The variables related to the administration in an exclusive way and the identification of the infusion pump obtained 100% assertiveness. A total of 37 (13.2%) undesirable clinical events related to the use of vasoactive amines were identified, 27 (27.8%) in the control group (pre-intervention) and 10 (5.5%) after the intervention, evidencing a significant reduction (p-value = 0.0001). Conclusion the implementation of the intervention significantly contributed to reducing the occurrence of undesirable clinical events related to administering vasoactive amines, contributing to safer drug therapy.

RESUMEN Objetivo analizar la implementación de capacitaciones sobre buenas prácticas para la administración de aminas vasoactivas ante la ocurrencia de eventos clínicos indeseables en pacientes de una unidad cardiointensiva. Método se trata de un estudio cuasi-experimental (antes y después), realizado en tres etapas en un hospital universitario ubicado en Río de Janeiro, Brasil. En la primera etapa, se realizó una observación sobre la adherencia del equipo a las buenas prácticas en la administración de aminas vasoactivas. En la segunda etapa, se realizó capacitación con el equipo de enfermería para la implementación de las acciones y, en la tercera etapa, se evaluó la adherencia a las buenas prácticas en la administración de aminas vasoactivas. La recolección de datos fue de octubre de 2019 a julio de 2021. Para comparar las diferencias en los grupos pre y post intervención se utilizó la prueba de McNemar y la prueba no paramétrica de Wilcoxon. Resultados 280 pacientes fueron infundidos con aminas vasoactivas, 97 en la primera etapa (preintervención) y 183 después de la intervención. Las variables relacionadas con la administración de forma exclusiva y la identificación de la bomba de infusión obtuvieron 100% de asertividad. Se identificaron un total de 37 (13,2%) eventos clínicos indeseables relacionados con el uso de aminas vasoactivas, 27 (27,8%) en el grupo control (preintervención) y 10 (5,5%) después de la intervención, evidenciándose una reducción significativa (valor p = 0,0001). Conclusión la implementación de la intervención contribuyó significativamente para la reducción de la ocurrencia de eventos clínicos indeseables relacionados con la administración de aminas vasoactivas, contribuyendo para una terapia farmacológica más segura.

RESUMO Objetivo analisar a implementação de um treinamento sobre boas práticas para administração de aminas vasoativas frente à ocorrência de eventos clínicos indesejáveis em pacientes de uma unidade cardiointensiva. Método trata-se de um estudo quase-experimental (antes e depois), realizado em três etapas em um hospital universitário localizado no Rio de Janeiro, Brasil. Na primeira etapa, fez-se uma observação sobre adesão da equipe às boas práticas na administração de aminas vasoativas. Na segunda etapa, realizou-se um treinamento com a equipe de enfermagem para implementação das ações e, na terceira etapa, avaliou-se a adesão às boas práticas na administração de aminas vasoativas. A coleta de dados foi de outubro de 2019 a julho de 2021. Para comparar as diferenças nos grupos pré e pós-intervenção, utilizou-se o teste de McNemar e o teste não paramétrico de Wilcoxon. Resultados observaram-se 280 pacientes em infusão de aminas vasoativas, sendo 97 na primeira etapa (pré-intervenção) e 183 após a intervenção. As variáveis relacionadas à administração em via exclusiva e a identificação da bomba infusora obtiveram 100% de assertividade. Identificaram-se ao todo 37 (13,2%) eventos clínicos indesejáveis relacionados ao uso das aminas vasoativas, sendo 27 (27,8%) no grupo controle (pré- intervenção) e 10 (5,5%) após a intervenção, evidenciando uma redução significativa (p valor =0,0001). Conclusão a implementação da intervenção corroborou de forma significativa para redução da ocorrência de eventos clínicos indesejáveis relacionados à administração de aminas vasoativas, contribuindo para uma terapia medicamentosa mais segura.

Adverse effects, pharmacological interactions, and cardiovascular drugs in COVID-19 treatment.

In severe coronavirus disease (COVID)-19 patients, an extraordinary systemic inflammatory response is seen. It could impact in multiple organ disorders, specially a severe myocardial injury, an acute myocarditis results in focal or global myocardial inflammation and necrosis. Those events can be present in healthy subjects or cardiovascular (CV) patients. It is clinically associated with ventricular dysfunction exacerbation or worsening and tachyarrhythmias. It is also related to a poor outcome for CV patients with ischemic heart disease, hypertensión, and heart failure. COVID-19 patients require multiple and complex treatment that alleviates symptoms, the vast variety of agents interacts with diseases and CV drugs. Our purpose is to correlate in guidance synopsis: Adverse effects, pharmacological interactions, and CV drugs in COVID-19 treatment.

En pacientes con COVID-19 grave se ha observado una extraordinaria respuesta inflamatoria sistémica. Este impacto se traduce en múltiples trastornos de órganos, especialmente cardíacos, por lesión miocárdica grave, miocarditis aguda que resulta en inflamación focal o miocárdica global, necrosis cardiaca. Estos tremendos eventos son observados en sujetos sanos como pacientes cardiovasculares. Clínicamente asociados con nueva presentación o empeoramiento de la disfunción ventricular y taquiarritmias. Relacionado a un predictor principal de malos resultado en pacientes cardiovasculares (CV), especialmente en aquellos con cardiopatía isquémica, hipertensión e insuficiencia cardíaca. Los enfermos con COVID-19 requieren múltiples y complejos tratamientos que alivien los síntomas, esta gran variedad de agentes interactúa con enfermedades y medicamentos CV. Nuestro propósito es correlacionar, en una guía sinóptica: efectos adversos, interacciones farmacológicas y fármacos cardiovasculares en el tratamiento del COVID-19.

Farmacogenómica: aplicaciones cardiovasculares / Pharmacogenomics: cardiovascular applications

Las enfermedades cardiovasculares constituyen un importante problema de salud pública al ser la principal causa de morbilidad y mortalidad en el mundo. Por ello, existe la creciente necesidad de tratamientos farmacoterapéuticos más eficaces y seguros. Sin embargo, a pesar de que los médicos prescriben fármacos sobre la base de las características farmacológicas del medicamento y la probabilidad de obtener resultados clínicamente reproducibles, muchos de los fármacos son eficaces sólo entre 25-60% de los pacientes. En este sentido es que la Farmacogenómica, a través del estudio de variantes genéticas de proteínas involucradas en la farmacocinética y farmacodinamia de los medicamentos, persigue maximizar su eficacia y seguridad, Este trabajo pretende dar una visión general acerca de farmacogenómica cardiovascular y la posibilidad de utilizar, en la consulta clínica, herramientas genéticas para apoyar la decisión farmacoterapéutica, con el objeto de mejorar la respuesta al tratamiento de enfermedades cardiovasculares, un paso hacia la medicina personalizada en Chile.

Cardiovascular disease is a major public health problem being the leading cause of morbidity and mortality worldwide. Therefore, there is a growing need for safer and more effective pharmacotherapeutic treatments. However, although physicians prescribe drugs based on pharmacological properties of each drug and the probability of obtaining clinically reproducible results, many drugs are effective only in 25-60% of patients. In this respect, pharmacogenomics, through the study of genetic variants of proteins involved in the pharmacokinetics and pharmacodynamics of drugs, pursues to maximize their efficacy and safety, This paper aims to give an overview of cardiovascular pharmacogenomics and the possibility to use, in clinical practice, genetic tools to support pharmacotherapeutical decisions, in order to improve the response to treatment of cardiovascular diseases, a step toward personalized medicine in Chile.