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

Efectos de la administración crónica de carvedilol sobre la variabilidad de la presión arterial y el daño de órgano blanco en ratas con desnervación sinoaórtica

Background: Increased blood pressure variability is a novel risk factor for the development of target organ injury both in hypertensive and normotensive subjects, so its reduction should be considered as a new therapeutic goal. Objective: The aim of this study was to evaluate the effect of long-term oral carvedilol treatment on blood pressure, blood pressure variability and target organ injury in the left ventricle and thoracic aorta in a model of blood pressure liability. Methods: Twelve male Wistar rats submitted to sinoaortic denervation were treated during 8 weeks with a single dose of carvedilol 30 mg/kg or vehicle. At the end of treatment, echocardiographic evaluation and blood pressure and short-term variability measurements were performed. Left ventricular and thoracic aortic weights were determined and histological samples were prepared from both tissues. Metalloproteinase MMP-2 and transforming growth factor β (TGF-β) were quantified in the left ventricle and thoracic aorta. Results: Carvedilol reduced systolic blood pressure and its variability in sinoaortic-denervated rats compared with the control group (126±5 vs. 142±11 mmHg, p<0.05; SD: 2.9±0.5 vs. 6.0±0.5 mmHg; p<0.05). A lower amount of connective tissue was found in carvedilol-treated animals. The expression of TGF-β decreased in both organs after carvedilol treatment. Conclusions: Chronic carvedilol treatment significantly reduces systolic blood pressure and its short-term variability in sinoaorticdenervated rats, decreasing the degree of left ventricular fibrosis.Fil: del Mauro, Julieta Sofía. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Santander Plantamura, Yanina Alejandra. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Bertera, Facundo Martin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Carranza, Maria Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Donato, Pablo Martín. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gorzalczany, Susana Beatriz. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Gelpi, Ricardo Jorge. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiopatología Cardiovascular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentin

Pharmacokinetic and Pharmacodynamic Profile of Nebivolol in an Animal Model of Metabolic Syndrome

Con el objetivo en este estudio de evaluar los efectos cardiovasculares y la farmacocinética del nebivolol en ratas hipertensas por sobrecarga de fructosa y en ratas control, se registraron los efectos de la administración intravenosa de nebivolol, 3 mg/kg o 10 mg/kg, sobre la presión arterial, la frecuencia cardíaca y la variabilidad de la presión arterial a corto plazo y latido-a-latido, y se evaluó la farmacocinética enantioselectiva a partir del análisis de la concentración plasmática de los enantiómeros d-nebivolol y l-nebivolol. La variabilidad de la presión arterial a corto plazo y latido-a-latido se evaluó mediante la desviación estándar y el análisis espectral del registro de la presión arterial, respectivamente. El estado hipertensivo alteró la farmacocinética del nebivolol, evidenciado por una reducción en el aclaramiento del nebivolol en el grupo fructosa respecto del grupo control luego de la administración de la dosis más alta. El efecto antihipertensivo del nebivolol fue similar en ambos grupos, en tanto que el efecto bradicardizante fue mayor en las ratas del grupo control. Aunque no se observaron diferencias significativas en la variabilidad de la presión arterial latido-a-latido, la reducción de la variabilidad de la presión arterial a corto plazo inducida por el nebivolol fue significativamente superior en las ratas del grupo fructosa en comparación con los animales normotensos (-57,9% ± 11,8% vs. -19,6% ± 9,2%; p < 0,05). En conclusión, si bien el nebivolol reduce la presión arterial y la variabilidad de la presión arterial en ambos grupos, no se encontraron diferencias significativas en las ratas con sobrecarga de fructosa en cuanto a la farmacocinética y los efectos cardiovasculares, a excepción de una eficacia bradicardizante menor y una reducción mayor de la variabilidad de la presión arterial a corto plazo.The cardiovascular and pharmacokinetic effects of nebivolol were evaluated in hypertensive fructose-fed and control rats, analyzing the effect of intravenously administered nebivolol 3 or 10 mg/kg on blood pressure, heart rate, and short-term and beat-to-beat blood pressure variability. The enantioselective pharmacokinetic profile of d- and l-nebivolol enantiomers was evaluated. Short-term and beat-to-beat blood pressure variability was assessed using standard deviation and blood pressure spectral analysis, respectively. The hypertensive state altered the pharmacokinetics of nebivolol, evidenced by reduction of nebivolol clearance in the fructose group compared to the control group after administration of the highest dose. The antihypertensive effect of nebivolol was similar in both groups, while the bradycardic effect was greater in control rats. Although no significant differences were found in beat-to-beat blood pressure variability, short-term blood pressure variability showed greater reduction after nebivolol administration in fructose-fed rats compared to control normotensive animals (-57.9%±11.8% vs.-19.6%±9.2%; p<0.05). In conclusion, although nebivolol reduces blood pressure and blood pressure variability in both groups, no significant differences were found in the pharmacokinetics and cardiovascular effects of fructose-fed rats, except for lower bradycardic efficacy and greater reduction in short-term blood pressure variability.Fil: Santander Plantamura, Yanina Alejandra. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Bertera, Facundo Martin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina. Universidad de Buenos Aires. Instituto de Investigaciones en Fisiopatología y Bioquímica Clínica; ArgentinaFil: del Mauro, Julieta Sofía. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Carranza, Maria Andrea. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina. Universidad de Buenos Aires. Instituto de Investigaciones en Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Universidad de Buenos Aires. Instituto de Investigaciones en Fisiopatología y Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Hötch, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina. Universidad de Buenos Aires. Instituto de Investigaciones en Fisiopatología y Bioquímica Clínica; Argentin

Tempol-nebivolol therapy potentiates hypotensive effect increasing NO bioavailability and signaling pathway

Nebivolol is a third generation beta blocker with endothelial nitric oxide synthase (eNOS) agonist properties. Considering the role of reactive oxygen species (ROS) in the uncoupling of eNOS, we hypothesized that the preadministration of an antioxidant as tempol, could improve the hypotensive response of nebivolol in normotensive animals increasing the nitric oxide (NO) bioavailability by a reduction of superoxide (O2•−) basal level production in the vascular tissue. Male Sprague Dawley rats were given tap water to drink (control group) or tempol (an antioxidant scavenger of superoxide) for 1 week. After 1 week, Nebivolol, at a dose of 3 mg/kg, was injected intravenously to the control group or to the tempol-treated group. Mean arterial pressure, heart rate, and blood pressure variability were evaluated in the control, tempol, nebivolol, and tempol nebivolol groups, as well as, the effect of different inhibitor as Nβ-nitro-l-arginine methyl ester (L-NAME, a Nitric oxide synthase blocker) or glybenclamide, a KATP channel inhibitor. Also, the expression of α,β soluble guanylate cyclase (sGC), phospho-eNOS, and phospho-vasodilator-stimulated phosphoprotein (P-VASP) were evaluated by Western Blot and cyclic guanosine monophosphate (cGMP) levels by an enzyme-linked immunosorbent assay (ELISA) commercial kit assay. We showed that pretreatment with tempol in normotensive rats produces a hypotensive response after nebivolol administration through an increase in the NO bioavailability and sGC, improving the NO/cGMP/protein kinase G (PKG) pathway compared to that of the nebivolol group. We demonstrated that tempol preadministration beneficiates the response of a third-generation beta blocker with eNOS stimulation properties, decreasing the basal uncoupling of eNOS, and improving NO bioavailability. Our results clearly open a possible new strategy therapeutic for treating hypertension.Fil: Bertera, Facundo Martin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Santa Cruz, Diego Mario. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Balestrasse, Karina Beatriz. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gorzalczany, Susana Beatriz. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; ArgentinaFil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Polizio, Ariel Héctor. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Catecolaminas síntesis metabolismo: receptores adrenérgicos y dopaminérgicos

El sistema nervioso autónomo representa uno de los principales mecanismos del organismo en la regulación a corto plazo de la presión arterial. El cambio, en el tono simpático y parasimpático inducido por diferentes estímulos detectados por las aferencias simpáticas barorreceptores arteriales, receptores de baja presión, quimiorreceptores periféricos, entre otros permite la regulación de la hemodinamia en el corto plazo a través de la modificación de la actividad neuronal simpática que inerva el corazón, el riñón o el músculo liso arterial y venoso y del sistema nervioso parasimpático cardíaco.Fil: Taira, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Carranza, Andrea del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Bertera, Facundo Martin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; 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

ALMA 26 Arcmin2^{2} Survey of GOODS-S at One-millimeter (ASAGAO): Average Morphology of High-zz Dusty Star-Forming Galaxies is an Exponential-Disk (n≃1n \simeq 1)

We present morphological properties of dusty star-forming galaxies at z=1-3 determined with high-resolution (FWHM~0"19) Atacama Large Milllimeter/submilimeter Array (ALMA) 1-mm band maps of our ASAGAO survey covering a 26-arcmin^2 area in GOODS-S. In conjunction with the ALMA archival data, the present sample consists of 42 ALMA sources with a wide rest-frame far-infrared (FIR) luminosity L_FIR range of ~10^11-10^13 Lo. To obtain an average rest-frame FIR profile, we perform individual measurements and careful stacking of the ALMA sources using the uv-visibility method that includes positional-uncertainty and smoothing-effect evaluations through Monte-Carlo simulations. We find that the dusty star-forming galaxies have the average FIR-wavelength Sersic index and effective radius of n_FIR=1.2+/-0.2 and R_e,FIR=1.0-1.3 kpc, respectively, additionally with a point source at the center, indicative of the existence of AGN. The average FIR profile agrees with a morphology of an exponential-disk clearly distinguished from a spheroidal profile (Sersic index of 4). We also examine the rest-frame optical Sersic index n_opt and effective radius R_e,opt with the deep Hubble Space Telescope (HST) images. Interestingly, we obtain n_opt=0.9+/-0.3 (~n_FIR) and R_e,opt=3.2+/-0.6 kpc (>R_e,FIR), suggesting that the FIR-emitting disk is embedded within a larger stellar disk. The rest-frame UV and FIR data of HST and ALMA provide us a radial surface density profile of the total star-formation rate (SFR), where the FIR SFR dominates over the UV SFR at the center. Under the simple assumption of a constant SFR, a compact stellar distribution found in z~1-2 compact quiescent galaxies (cQGs) is well reproduced, while a spheroidal stellar morphology of cQGs (n_opt=4) cannot, suggestive of other important mechanisms such as dynamical dissipation.Comment: 13 pages, 6 figures, ApJ in pres

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

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo