Cardiovascular drugs inducing QT prolongation: facts and evidence

Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking IKr. Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.Fil: Taira, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Mayer, Marcos Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentin

Phytochemistry and bioactivity of Chiliotrichum diffusum (Astereaceae), a native species from the Andean Patagonian

Chiliotrichum diffusum (Asteraceae), "mata negra", habita el sur de Argentina. Se han descripto usos étnicos rituales y medicinales de la especie. Las partes aéreas evidenciaron la presencia de flavonoides, taninos, hidratos de carbono, proteínas, antraquinonas, saponinas, cianoglicósidos y esteroides. El análisis de los flavonoides demostró una importante variabilidad estructural. Los grupos de flavonoides detectados fueron principalmente flavonas y flavonoles 7-O-glicosilados, dihidroflavonoles e isoflavonas. El extracto alcohólico y sus fracciones, mostraron actividad frente al bioensayo de citotoxicidad de la Artemia salina. La actividad antimicrobiana fue moderada frente a Staphylococcus aureus.Chiliotrichum diffusum (Asteraceae), "mata negra?, inhabits the south of Argentina. Ethnic rituals and medicinal uses have been described for this species. Flavonoids, tannins, carbohydrates, proteins, anthraquinones, saponins, cyanoglycosides and steroids were detected in the aerial parts. The analysis of the flavonoid fraction demonstrated an important structural variability. The principal flavonoid groups detected were flavones and flavonol 7-O-glycosides, dihydroflavonols and isoflavones. The alcoholic extract and their fractions showed activity against Artemia salina cytotoxicity bioassay. The antimicrobial activity was moderate against Staphylococcus aureus.Chiliotrichum diffusum (Asteraceae), "mata negra?, habita el sur de Argentina. Se han descripto usos étnicos rituales y medicinales de la especie. Las partes aéreas evidenciaron la presencia de flavonoides, taninos, hidratos de carbono, proteínas, antraquinonas, saponinas, cianoglicósidos y esteroides. El análisis de los flavonoides demostró una importante variabilidad estructural. Los grupos de flavonoides detectados fueron principalmente flavonas y flavonoles 7-O-glicosilados, dihidroflavonoles e isoflavonas. El extracto alcohólico y sus fracciones, mostraron actividad frente al bioensayo de citotoxicidad de la Artemia salina. La actividad antimicrobiana fue moderada frente a Staphylococcus aureus.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Muscarinic receptors and central cholinergic stimulation in rats with sinoaortic denervation

Estos estudios evaluaron la participación de receptores muscarínicos centrales en la respuesta presora a la administración central de neostigmina, un anticolinesterásico cuaternario, en ratas conscientes con operación simulada o con desnervación sinoaórtica. El efecto presor dependiente de dosis de neostigmina (0,l-1 µg, icv) fue significativamente mayor en las ratas con desnervación sinoaórtica que en aquellas con la operación simulada. El antagonista de receptores muscarínicos M3 4- DAMP (0,3 nmol icv), pero no el antagonista M1 pirenzepina (0,3 nmol icv), previno el efecto presor de neostigmina (0,l - 1 µg icv) en ambos grupos de ratas. Las diferencias en el efecto presor de neostigmina (icv) entre las ratas con operación simulada y las desnervadas podrían deberse a una actividad diferente de las vías colinérgicas. Los resultados también sugieren una participación de receptores muscarínicos M3 cerebrales en el efecto presor de neostigmina (icv) en ambos grupos de ratasThese studies evaluated the participation of central muscarinic receptors in the pressor effect of centrally injected neostigmine, a quaternary anticholinestemse, in conscius sham operated and siiioaortic denervated rats. Dose-dependent pressor effect of neostigmine (0,l-1 µg icv) was significantly greater in sinoaortic denervated rats than in sham operated animals. The M3 muscarinic receptor antagonist 4-DAMP (0,3 nmol icv), but not the M1 antagonist pirenzepine (0,3 nmol icv), prevented the pressor effect of neostigmine (0,l - 1 µg icv) in both groups of rats. Differences in the pressor effect of neostigmine (icv) between sham and sinoaortic denervated rats could be due to a different activity of cholinergic pathways. The results also suggest a brain M3 muscarinic receptors involvement in the pressor'effect of neostigmine (icv) in both groups of ratsColegio de Farmacéuticos de la Provincia de Buenos Aire

Muscarinic receptors and central cholinergic stimulation in rats with sinoaortic denervation

Estos estudios evaluaron la participación de receptores muscarínicos centrales en la respuesta presora a la administración central de neostigmina, un anticolinesterásico cuaternario, en ratas conscientes con operación simulada o con desnervación sinoaórtica. El efecto presor dependiente de dosis de neostigmina (0,l-1 µg, icv) fue significativamente mayor en las ratas con desnervación sinoaórtica que en aquellas con la operación simulada. El antagonista de receptores muscarínicos M3 4- DAMP (0,3 nmol icv), pero no el antagonista M1 pirenzepina (0,3 nmol icv), previno el efecto presor de neostigmina (0,l - 1 µg icv) en ambos grupos de ratas. Las diferencias en el efecto presor de neostigmina (icv) entre las ratas con operación simulada y las desnervadas podrían deberse a una actividad diferente de las vías colinérgicas. Los resultados también sugieren una participación de receptores muscarínicos M3 cerebrales en el efecto presor de neostigmina (icv) en ambos grupos de ratasThese studies evaluated the participation of central muscarinic receptors in the pressor effect of centrally injected neostigmine, a quaternary anticholinestemse, in conscius sham operated and siiioaortic denervated rats. Dose-dependent pressor effect of neostigmine (0,l-1 µg icv) was significantly greater in sinoaortic denervated rats than in sham operated animals. The M3 muscarinic receptor antagonist 4-DAMP (0,3 nmol icv), but not the M1 antagonist pirenzepine (0,3 nmol icv), prevented the pressor effect of neostigmine (0,l - 1 µg icv) in both groups of rats. Differences in the pressor effect of neostigmine (icv) between sham and sinoaortic denervated rats could be due to a different activity of cholinergic pathways. The results also suggest a brain M3 muscarinic receptors involvement in the pressor'effect of neostigmine (icv) in both groups of ratsColegio de Farmacéuticos de la Provincia de Buenos Aire

Subtypes of adrenoceptors involved in the cardiovascular responses to Clonidine

La clonidina es un fármaco utilizado en el tratamiento antihipertensivo y su acción se debería a estimulación de receptores imidazólicos de la médula caudoventrolateral. Sin embargo, cuando se la administra a ratas conscientes y normotensas se obtiene un efecto presor. El objetivo del presente trabajo fue analizar las respuestas cardiovasculares y caracterizar el subtipo de receptor comprometido en las acciones de clonidina cuando se administra por la vía intracerebroventricular en ratas, normotensas y conscientes. Nuestros resultados sugieren que la clonidina produce una respuesta presora y bradicardia que estarían mediadas por una población heterogenea de receptores a nivel del sistema nervioso central: imidazólicos y adrenérgicos alfa 2 y alfa 1A.Clonidine is an antihypertensive drug with action on imidazolic receptors in the caudoventrolateral medula. However, this drug also shows a pressor effect in conscious normotensive rats. It was interesting to study alpha adrenoceptors and imidazolic receptors involvement in the cardiovascular response to intracerebroventricular injection of clonidine in conscious normotensive rats. Results suggest that pressor response and bradycardia to clonidine could be mediated by imidazolic receptors and alpha 1A and alpha 2 adrenoceptors.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Subtypes of adrenoceptors involved in the cardiovascular responses to Clonidine

La clonidina es un fármaco utilizado en el tratamiento antihipertensivo y su acción se debería a estimulación de receptores imidazólicos de la médula caudoventrolateral. Sin embargo, cuando se la administra a ratas conscientes y normotensas se obtiene un efecto presor. El objetivo del presente trabajo fue analizar las respuestas cardiovasculares y caracterizar el subtipo de receptor comprometido en las acciones de clonidina cuando se administra por la vía intracerebroventricular en ratas, normotensas y conscientes. Nuestros resultados sugieren que la clonidina produce una respuesta presora y bradicardia que estarían mediadas por una población heterogenea de receptores a nivel del sistema nervioso central: imidazólicos y adrenérgicos alfa 2 y alfa 1A.Clonidine is an antihypertensive drug with action on imidazolic receptors in the caudoventrolateral medula. However, this drug also shows a pressor effect in conscious normotensive rats. It was interesting to study alpha adrenoceptors and imidazolic receptors involvement in the cardiovascular response to intracerebroventricular injection of clonidine in conscious normotensive rats. Results suggest that pressor response and bradycardia to clonidine could be mediated by imidazolic receptors and alpha 1A and alpha 2 adrenoceptors.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Effect of α-methyldopa on striatal doparninergic neurotransmision

Se estudió el efecto del inhibidor de la decarboxilasa de aminoácidos aromáticos α-metildopa sobre la neurotransmisión dopaminérgica en el cuerpo estriado de ratas mediante la técnica de perfusión por microdiálisis. La α-metildopa, que a la dosis de 100 mg/kg (i.p.) sólo muestra una acción cardíaca, induce la acumulación de la l-dopa en el cuerpo estriado de ratas, sugiriendo una inhibición de la síntesis de dopamina, pero al mismo tiempo provoca también un incremento de la concentración de dopamina en las muestras de perfusato. Este último efecto podría deberse a alguna accibn de la droga sobre la liberación del neurotransmisor.The effect of α-methyIDOPA, an inhibitor of aromatic aminoacid decarboxilase on dopaminergic neurotransmision, was studied in rat striatum by using the technique of microdialysis perfusion. At a dose (100 mg/kg, i.p.) with only cardiac action, α-Methyldopa induces striatal accumulation of l- dopa, suggesting an inhibition of doparnine synthesis in rat striatum. However, an increase of dopamine level was also seen which could be due by an action of α-methyIDOPA on the neurotransmitter release.Colegio de Farmacéuticos de la Provincia de Buenos Aire