Multitarget-Directed Ligands Hitting Serotonin Receptors: A Medicinal Chemistry Survey.

Serotonin (5-hydroxytryptamine, 5-HT) is a ubiquitous neurotransmitter in the human body. In the central nervous system, 5-HT affects sleep, pain, mood, appetite, and attention, while in the peripheral nervous system, 5-HT modulates peristalsis, mucus production, and blood vessel dilation. Fourteen membrane receptors mediate 5-HT activity. In agreement with the crucial roles played by 5-HT, many drugs target 5-HT receptors (5-HTRs). Therefore, it is unsurprising that many efforts have been devoted to discovering multitarget-directed ligands (MTDLs) capable of engaging one or more 5-HTRs plus another target phenotypically linked to a particular disease. In this review, we will describe medicinal chemistry efforts in designing MTDLs encompassing activity for one or more 5-HTRs, starting with atypical antipsychotics and moving to dual 5-HT1AR/serotonin transporter ligands, 5-HT6R antagonists/acetyl cholinesterases inhibitors, and 5-HT4R agonists/acetyl cholinesterases inhibitors. We will also provide an outlook on the most recent efforts made in the field.

El fragmento N-terminal del propéptido natriurético cerebral es el mejor predictor de mortalidad intrahospitalaria en pacientes con sepsis y bajo riesgo de lesión orgánica / The N-terminal pro brain natriuretic peptide is the best predictor of mortality during hospitalization in patients with low risk of sepsis-related organ failure

Introducción: El objetivo de este estudio fue investigar el valor del fragmento N-terminal del propéptido natriurético cerebral (NT-proBNP), proteína C reactiva (PCR) y procalcitonina (PCT) para predecir la mortalidad en pacientes sépticos durante la hospitalización con un riesgo de mortalidad<10% evaluado por el Sepsis-related Organ Failure Assessment (SOFA). Material y métodos: Estudio observacional prospectivo realizado en pacientes hospitalizados con sepsis y riesgo SOFA<10%. Los biomarcadores se obtuvieron en las primeras 72h después del ingreso en el hospital. Todos fueron monitorizados durante la hospitalización o hasta la muerte. Se utilizaron las curvas ROC para determinar el área bajo la curva (ABC) e identificar las mejores concentraciones de corte para predecir la mortalidad. Resultados: Se analizaron un total de 174 pacientes. Diecisiete (9,8%) pacientes murieron durante la hospitalización. El ABC de NT-proBNP fue 0,793 (IC 95% 0,686-0,9; p<0,0005) en comparación con el ABC de la PCR (0,728; IC 95% 0,617-0,839; p=0,004) y el ABC del PCT (0,684; IC 95% 0,557-0,811; p=0,019). Los factores asociados a la mortalidad hospitalaria fueron: tener un NT-proBNP>1.330pg/ml (OR=23,23; IC 95% 2,92-182,25; p=0,003) y tener factores predisponentes para presentar sepsis (OR=3,05; IC 95% 1,3-9,3; p=0,044). Conclusiones: En pacientes con bajo riesgo de mortalidad según la puntuación SOFA, los niveles de NT-proBNP obtenidos en las primeras 72h después del ingreso son un poderoso predictor de mortalidad. Su implementación en la práctica clínica podría mejorar la capacidad predictiva de la puntuación de gravedad clínica en estos pacientes (AU)

Introduction: The purpose of this study was to investigate the value of N-terminal pro brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP) and procalcitonin (PCT) in predicting mortality in septic patients during hospitalization with mortality risk<10% evaluated by Sepsis-related Organ Failure Assessment (SOFA). Material and methods: Prospective, observational study performed in sepsis patients with SOFA risk<10%. We obtained levels of biomarkers in the first 72h after admission in hospital. All patients were monitored during hospitalization or until death. We used ROC curves to determine area under curve (AUC) and identify the best cutoff concentrations to predict mortality. Results: A total of 174 patients were analyzed. Seventeen (9.8%) patients died during hospitalization. The AUC of NT-proBNP was 0.793 (95% CI 0.686-0.9; P<.0005) compared to AUC of CRP (0.728; 95% CI 0.617-0.839; P=.004) and AUC of PCT (0.684; 95% CI 0.557-0.811; P=.019). Factors independently associated with in-hospital mortality were NT-proBNP>1,330pg/ml (OR=23.23; 95% CI 2.92-182.25; P=.003) and to have predisposing factors (OR=3.05; 95% CI 1.3-9.3; P=.044). Conclusions: In patients with low mortality risk according to SOFA score, NT-proBNP obtained in the first 72h after admission prove to be a powerful predictor of mortality. Their implementations in clinical practice would improve the predictive ability of clinical severity scores (AU)

The N-terminal pro brain natriuretic peptide is the best predictor of mortality during hospitalization in patients with low risk of sepsis-related organ failure. / El fragmento N-terminal del propéptido natriurético cerebral es el mejor predictor de mortalidad intrahospitalaria en pacientes con sepsis y bajo riesgo de lesión orgánica.

INTRODUCTION: The purpose of this study was to investigate the value of N-terminal pro brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP) and procalcitonin (PCT) in predicting mortality in septic patients during hospitalization with mortality risk<10% evaluated by Sepsis-related Organ Failure Assessment (SOFA). MATERIAL AND METHODS: Prospective, observational study performed in sepsis patients with SOFA risk<10%. We obtained levels of biomarkers in the first 72h after admission in hospital. All patients were monitored during hospitalization or until death. We used ROC curves to determine area under curve (AUC) and identify the best cutoff concentrations to predict mortality. RESULTS: A total of 174 patients were analyzed. Seventeen (9.8%) patients died during hospitalization. The AUC of NT-proBNP was 0.793 (95% CI 0.686-0.9; P<.0005) compared to AUC of CRP (0.728; 95% CI 0.617-0.839; P=.004) and AUC of PCT (0.684; 95% CI 0.557-0.811; P=.019). Factors independently associated with in-hospital mortality were NT-proBNP>1,330pg/ml (OR=23.23; 95% CI 2.92-182.25; P=.003) and to have predisposing factors (OR=3.05; 95% CI 1.3-9.3; P=.044) CONCLUSIONS: In patients with low mortality risk according to SOFA score, NT-proBNP obtained in the first 72h after admission prove to be a powerful predictor of mortality. Their implementations in clinical practice would improve the predictive ability of clinical severity scores.