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Introducción: La segmentectomía lateral izquierda es el procedimiento más empleado para la cirugía del donante en trasplante hepático con donante vivo adulto-pediátrico (THDVA-P), y ha demostrado ser seguro y reproducible. Sin embargo, la información aún es escasa respecto al abordaje laparoscópico. Objetivo: El objetivo de este artículo es dar a conocer los resultados posoperatorios de la segmentectomía lateral izquierda laparoscópica (SLI-L) para THDVA-P. Materiales y Método: Realizamos un estudio retrospectivo, observacional, de un solo centro, Hospital del Salvador; con vasta experiencia en trasplante hepático y en resecciones hepáticas laparoscópicas. Se ofreció realizar el procedimiento de SLI-L para la cirugía del donante vivo. Se describe la técnica quirúrgica y los resultados posoperatorios de los donantes. Resultados: Entre abril de 2015 y enero de 2021, 36 pacientes, 25 de ellos hombres, fueron sometidos a SLI-L. El 86% eran madre o padre del receptor, con una mediana de 30 años (19-45). Mediana de tiempo operatorio de 360 min (240-480). Hubo conversión en un caso debido a sangrado venoso de difícil manejo y en dos oportunidades se utilizó técnica mano asistida por la misma causa. Morbilidad Clavien-Dindo III en un paciente debido a fuga biliar precoz, manejada con prótesis vía colangiopancreatografía retrógrada endoscópica exitosamente. La mediana de hospitalización fue de 4 días (3-12) y no hubo mortalidad. Conclusión: La SLI-L ha evolucionado, desde un procedimiento innovador hasta convertirse en el actual procedimiento estándar para THDVA-P. Los buenos resultados en términos de morbimortalidad sugieren que podría ser una técnica segura y reproducible en contextos similares al del centro.
Introduction: Living donor left lateral sectionectomy is a well-established alternative in cadaveric donor pediatric liver transplantation. This procedure has proven to be safe and reproducible. However, laparoscopic approach is still under development and evidence of its feasibility is limited. Aim: The aim of this article is to present the surgical technique and postoperative outcomes of the cases of laparoscopic left lateral sectionectomy performed in this center. Materials and Method: A retrospective, observational, single center study was conducted in Hospital del Salvador. From 04/2015 - 01/2021 laparoscopic left lateral sectionectomy was offered for donor surgery. We present the surgical technique, perioperative care, and early postoperative outcomes in donors. Results: This series includes 36 patients, 25 (69%) of them were males. A total of 31 (86%) donors were mother or father of the recipient. Median age of donors was 30 years (19-45), median operative time was 360 min (240-480). All the patients underwent laparoscopic left lateral sectionectomy. Conversion was necessary in one case due to difficult management of a venous bleeding. Clavien-Dindo Morbidity III, in one patient who required endoscopic retrograde cholangiopancreatography due to an early bile leak. Median hospitalization was 4 days (3-14). There was no mortality. Conclusion: Laparoscopic left lateral sectionectomy has proven to be safe and reproducible. This technique has evolved from an innovative procedure to become the current standard of practice in our center, with excellent results in terms of morbidity and mortality.
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Mastectomia Segmentar/métodos , Transplante de Fígado/métodos , Laparoscopia/métodos , Período Pós-Operatório , Resultado do Tratamento , Doadores VivosRESUMO
Resumen El trasplante hepático con donante vivo (THDV) es un procedimiento complejo y desafiante para el cirujano, ya que exige garantizar tanto la máxima seguridad para el donante, así como también, la mejor calidad del injerto para el receptor. Debido a lo anterior, la implementación de la cirugía mini-invasiva ha sido lenta en esta área. Sin embargo, en los últimos 10 años, gracias a los avances que ha experimentado la cirugía hepática laparoscópica, ha aumentado el interés de algunos grupos altamente especializados por incorporar la cirugía mini-invasiva a la cirugía del donante, principalmente en trasplante hepático donante vivo adulto-pediátrico (THDVA-P). Los favorables resultados obtenidos en esta área incluso han llevado a los expertos en el tema, a categorizar el abordaje laparoscópico para la cirugía del donante como el procedimiento estándar en THDVA-P. Contrario a lo anterior, la implementación de la laparoscopía para trasplante hepático donante vivo adulto-adulto (THDVA-A), es más compleja y requiere en su mayoría, una hepatectomía de lóbulo derecho o izquierdo para cumplir con las necesidades volumétricas del receptor. Esta cirugía es de mayor dificultad y riesgo para el donante, por lo que su indicación por vía mini-invasiva está limitada a centros de alto volumen y preparación, tanto en laparoscopía, como en trasplante hepático. En este trabajo, se busca dar a conocer la técnica quirúrgica y nuestra experiencia inicial con la primera hepatectomía derecha totalmente laparoscópica (HDTL) para THDVA-A realizada en Chile.
Living donor liver transplantation is a complex and challenging procedure. The surgeon needs to guarantee maximum safety for the donor, as well as the best quality of the graft for the recipient. For this reason, the implementation of mini-invasive surgery has been slow in this area. However, in the last 10 years, due to the advances in laparoscopic liver surgery, the interest of some highly specialized groups has increased in incorporating mini-invasive surgery into donor surgery, mainly in pediatric living donor liver transplantation. The favorable results obtained in this field, have even led to turn this procedure, into the technique of choice for pediatric living donor liver transplantation. Nevertheless, this procedure is even more challenging for adult-to-adult living donor transplantation. To meet the volumetric criteria of an adult, a complete hepatectomy of right or left lobe is mostly required. This surgery is of greater complexity and risk for the donor, so its indication by minimally invasive approach is limited to high-volume centers with preparation, both in laparoscopy and liver transplants. In this report we seek to present our surgical technique and initial experience with the first pure laparoscopic right hepatectomy for adult-to-adult living donor liver transplantation carried out in Chile.
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Humanos , Feminino , Adulto , Laparoscopia , Doadores Vivos , Neoplasias Hepáticas/cirurgia , Tomografia Computadorizada por Raios X/métodos , Chile , Transplante de Fígado/métodos , Imageamento Tridimensional , Abdome/diagnóstico por imagem , HepatectomiaRESUMO
Benzodiazepines and "Z-drugs" (BZD/Z) are overprescribed in many countries. This study evaluates their consumption in a social security sector health insurance provider with national coverage in Argentina. With a descriptive and observational approach, outpatient dispensations of BZD/Zs were analyzed for people over 18 years old from April 2020 to March 2021, disaggregated by sex, age, active ingredient, and half-life. An annual prevalence of use of 11.6% was found among the 431,445 adult affiliates, with higher rates in women and in those over age 60. Overall consumption of BZD/Zs was 77.6 defined daily doses (DDD) per 1000 enrollee-days. The average user received 5.1 annual dispensations and the equivalent of 1.4 DDD for each day of the year. BZD/Zs with long half-life were the most used. We found high levels of BZD/Z consumption and for longer periods than recommended. It is necessary to improve the quality of consumption and reduce the negative impact of inappropriate use of these drugs among treated individuals.
Las benzodiazepinas y los "fármacos Z" (BZD-Z) se prescriben en exceso en muchos países. Este estudio evaluó su consumo en una organización de la seguridad social (obra social) de Argentina de alcance nacional. A partir de un diseño observacional descriptivo se analizó la dispensa ambulatoria de BZD-Z, entre abril 2020 y marzo 2021, a mayores de 18 años; desagregada por sexo, edad, principio activo y vida media. Se encontró una prevalencia anual de uso del 11,6% entre los 431.445 afiliados adultos, con valores más elevados en las mujeres y mayores de 60 años. El consumo global de BZD-Z fue de 77,6 dosis diarias definidas (DDD) cada 1.000 afiliados-día. El usuario promedio recibió 5,1 dispensas anuales y el equivalente a 1,4 DDD por cada día del año. Las BZD-Z más usadas fueron las de vida media larga. El consumo de BZD-Z resultó elevado y más prolongado que lo recomendado. Es necesario mejorar la calidad en el consumo y reducir el impacto negativo del uso inapropiado de estos fármacos entre los individuos tratados.
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Benzodiazepinas , Preparações Farmacêuticas , Adolescente , Adulto , Argentina , Benzodiazepinas/efeitos adversos , Feminino , Humanos , Renda , Pessoa de Meia-Idade , Previdência SocialRESUMO
ß-Adrenergic blockers are no longer recommended as first-line therapy due to the reduced cardioprotection of traditional ß-blockers compared with other antihypertensive drugs. It is unknown whether third-generation ß-blockers share the limitations of traditional ß-blockers. The aim of the present study was to compare the effects of nebivolol or atenolol on central and peripheral systolic blood pressure (SBP) and its variability and target organ damage (TOD) in N-nitro-L-arginine methyl ester (L-NAME) hypertensive rats. Male Wistar rats were treated with L-NAME for 8 weeks together with oral administration of nebivolol 30 mg/kg (n = 8), atenolol 90 mg/kg (n = 8), or vehicle (n = 8). The control group was composed of vehicle-treated Wistar rats. SBP and its variability, as well as echocardiographic parameters, were assessed during the last 2 weeks of treatment. Tissue levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor ß (TGF-ß), and histopathological parameters were evaluated in the left ventricle and aorta. Nebivolol had a greater ability than atenolol to decrease central SBP and mid-term and short-term blood pressure variability (BPV) in L-NAME rats. Echocardiographic analysis showed that nebivolol was more effective than atenolol on E/A wave ratio normalization. Compared with atenolol treatment, nebivolol had a greater protective effect on different TOD markers, inducing a decrease in collagen deposition and a reduction in the proinflammatory cytokines IL-6 and TNF-α in the left ventricle and aorta. Our findings suggest that the adverse hemodynamic profile and the reduced cardiovascular protection reported with traditional ß-blockers must not be carried forward to third-generation ß-blockers.
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Atenolol , Hipertensão , Nebivolol , Animais , Anti-Hipertensivos/farmacologia , Atenolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Hipertensão/tratamento farmacológico , Masculino , Nebivolol/farmacologia , Ratos , Ratos Wistar , Resultado do TratamentoAssuntos
Procedimentos Cirúrgicos Cardíacos , Infecções por Coronavirus/prevenção & controle , Controle de Infecções/métodos , Pandemias , Pneumonia Viral/prevenção & controle , Betacoronavirus , COVID-19 , Procedimentos Cirúrgicos Cardíacos/métodos , Coronavirus , Infecções por Coronavirus/epidemiologia , Humanos , Pandemias/prevenção & controle , Segurança do Paciente , Pneumonia Viral/epidemiologia , SARS-CoV-2 , Gestão da Segurança , CirurgiõesRESUMO
Adenosine is involved in classic preconditioning in most species and acts especially through adenosine A1 and A3 receptors. The aim of the present study was to evaluate whether remote ischemic preconditioning (rIPC) activates adenosine A1 receptors and improves mitochondrial function, thereby reducing myocardial infarct size. Isolated rat hearts were subjected to 30 min of global ischemia and 60 min of reperfusion [ischemia-reperfusion (I/R)]. In a second group, before isolation of the heart, a rIPC protocol (3 cycles of hindlimb I/R) was performed. Infarct size was measured with tetrazolium staining, and Akt/endothelial nitric oxide (NO) synthase (eNOS) expression/phosphorylation and mitochondrial function were evaluated after ischemia at 10 and 60 min of reperfusion. As expected, rIPC significantly decreased infarct size. This beneficial effect was abolished only when 8-cyclopentyl-1,3-dipropylxanthine (adenosine A1 receptor blocker) and NG-nitro-l-arginine methyl ester (NO synthesis inhibitor) were administered during the reperfusion phase. At the early reperfusion phase, rIPC induced significant Akt and eNOS phosphorylation, which was abolished by the perfusion with an adenosine A1 receptor blocker. I/R led to impaired mitochondrial function, which was attenuated by rIPC and mediated by adenosine A1 receptors. In conclusion, we demonstrated that rIPC limits myocardial infarct by activation of adenosine A1 receptors at early reperfusion in the isolated rat heart. Interestingly, rIPC appears to reduce myocardial infarct size by the Akt/eNOS pathway and improves mitochondrial function during myocardial reperfusion. NEW & NOTEWORTHY Adenosine is involved in classic preconditioning and acts especially through adenosine A1 and A3 receptors. However, its role in the mechanism of remote ischemic preconditioning is controversial. In this study, we demonstrated that remote ischemic preconditioning activates adenosine A1 receptors during early reperfusion, inducing Akt/endothelial nitric oxide synthase phosphorylation and improving mitochondrial function, thereby reducing myocardial infarct size.
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Precondicionamento Isquêmico Miocárdico , Mitocôndrias Cardíacas , Receptor A1 de Adenosina , Antagonistas do Receptor A1 de Adenosina/uso terapêutico , Trifosfato de Adenosina/biossíntese , Animais , Inibidores Enzimáticos/uso terapêutico , Masculino , Potencial da Membrana Mitocondrial , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Nitroarginina/uso terapêutico , Consumo de Oxigênio , Ratos , Ratos Sprague-Dawley , Xantinas/uso terapêuticoRESUMO
INTRODUCTION: Although main antihypertensive drugs are able to efficiently reduce blood pressure, only a third of treated hypertensive patients achieve optimal blood pressure control. Extensive interpatient variability on drug metabolism and oral disposition of blood pressure lowering drugs can contribute to this failure in hypertension management. Areas covered: The aim of the present review is to update the knowledge on the features of hepatic metabolism of the main antihypertensive agents, including ß-blockers, calcium channel blockers, angiotensin receptor blockers, and angiotensin converting enzyme inhibitors. The factors that contribute to the large interindividual variability of main antihypertensive drugs are also covered. Expert opinion: The variability of plasma concentration of antihypertensive drugs due to the involvement of hepatic metabolism can contribute to the inadequate control of blood pressure in the daily clinical practice. Genotype screening of specific hepatic drug-metabolizing enzymes may contribute to optimize dose selection and to increase the rate of blood pressure control in patients treated with specific ß-blockers, calcium channel blockers, and angiotensin receptor blockers.
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Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacocinética , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacocinética , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacocinética , Relação Dose-Resposta a Droga , Genótipo , HumanosRESUMO
Methyl gallate is a gallotannin widely distributed in nature. Previous studies have demonstrated its antioxidant, anti-inflammatory, antimicrobial and anti-tumor activities. In the present study, the activity of methyl gallate on experimental models of inflammatory bowel disease has been investigated. Experimental colitis was induced in Sprague-Dawley rats through the intracolonic instillation of an acetic acid solution (2 mL, 4% v/v). Methyl gallate (100 and 300 mg/kg, p.o.) and the reference drug mesalazine (100 mg/kg, p.o.) were tested. Methyl gallate induced a significant reduction in the colon weight/length ratio and macroscopic lesion score. Besides, the malondialdehyde content and the GSSG/GSH ratio were remarkably decreased. Furthermore, the administration of methyl gallate reduced the expression of COX2, IL-6, TNFα and the severity of microscopic tissue damage induced by acetic acid, while the mean goblet cell density was significantly higher in both the group treated with methyl gallate and the one treated with mesalazine, in comparison with untreated animals. The Na+K+ATPase pump activity was recovered in treated groups (control: 827.2 ± 59.6, colitis: 311.6 ± 54.8, methyl gallate 100 mg/kg: 642.2 ± 175.0, methyl gallate 300 mg/kg: 809.7 ± 100.6, mesalazine: 525.3 ± 81.7). Methyl gallate was also found to induce a significant reduction in the castor oil-induced intestinal motility in Swiss mice, decreasing the peristalsis by 74.5 and 58.82% at 100 and 300 mg/kg p.o., respectively. This compound also antagonized the jejunum contractions induced by Ach and CaCl2. This study demonstrates that methyl gallate exerts beneficial effects in a preclinical model of intestinal disorders.
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Colite/induzido quimicamente , Colite/tratamento farmacológico , Ácido Gálico/análogos & derivados , Extratos Vegetais/uso terapêutico , Ácido Acético/toxicidade , Animais , Colite/patologia , Relação Dose-Resposta a Droga , Feminino , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Camundongos , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Resultado do TratamentoRESUMO
OBJECTIVE: This review covers the pharmacokinetics and pharmacodynamic of ß-blockers, the rationale for their use, some recent controversies in its use for managing hypertension, as well as, the beneficial properties of the third-generation ß-blockers beyond hypertension. BACKGROUND: The efficacy and safety of ß-blockers in the treatment of hypertension and other cardiovascular diseases have been established during more than 50 years of clinical experience. Recent updates of clinical guidelines have downgraded the use of ß-blockers for the treatment of uncomplicated hypertension to second and third line therapy. It is a well-known fact that ß-blockers exhibit heterogeneous pharmacokinetic and pharmacodynamic properties that clearly influence their clinical efficacy and tolerability in the management of essential hypertension. Conventional nonvasodilating ß-blockers (atenolol and metoprolol) are inferior to first-line antihypertensive agents in terms of cardioprotection due to lower ability to reduce central blood pressure and its variability and the adverse effects on glycemic and lipid metabolism. CONCLUSION: New vasodilating ß-blockers, mainly carvedilol and nebivolol, show enhanced hemodynamic and metabolic properties, which probably result in a higher prevention of major cardiovascular events in hypertensive patients. Despite head-to-head clinical trials comparing the effects of vasodilating vs nonvasodilating ß-blockers on hard clinical endpoints are lacking, the current evidence suggests that third-generation ß-blockers are superior to conventional ß-blockers for the prevention of cardiovascular events in patients with essential hypertension. Moreover, beyond their antihypertensive properties, third-generation ß-blockers also have pleiotropic, antioxidant and antiinflammatory effects that warrant a "promissory new era" of this newly group.
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Antagonistas Adrenérgicos beta/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipertensão Essencial/tratamento farmacológico , Antagonistas Adrenérgicos beta/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Índice Glicêmico/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacosRESUMO
The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects.
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Fator Natriurético Atrial/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Dopamina/metabolismo , Sódio/metabolismo , Animais , Transporte Biológico , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Diurese/efeitos dos fármacos , Dopamina/urina , Rim/metabolismo , Túbulos Renais/metabolismo , Masculino , Natriurese/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
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NEW FINDINGS: What is the central question of this study? Ischaemia-reperfusion of peripheral tissues protects the heart from subsequent myocardial ischaemia-reperfusion injury, a phenomenon referred to as remote ischaemic preconditioning (rIPC). This study evaluated the possible myocardial triggers of rIPC. What is the main finding and its importance? Remote ischaemic preconditioning reduces infarct size through a vagal pathway and a mechanism involving phosphorylation of Akt and endothelial nitric oxide synthase, opening of mitochondrial ATP-dependent K(+) channels and an increase in mitochondrial H2 O2 production. All these phenomena occur before the myocardial ischaemia; hence, they could act as 'triggers' of rIPC. It has been proposed that remote ischaemic preconditioning (rIPC) activates a parasympathetic neural pathway. However, the myocardial intracellular mechanism of rIPC remains unclear. Here, we characterized some of the intracellular signals participating as rIPC triggers. Isolated rat hearts were subjected to 30 min of global ischaemia and 120 min of reperfusion (Non-rIPC group). In a second group, before the isolation of the heart, an rIPC protocol (three cycles of hindlimb ischaemia-reperfusion) was performed. The infarct size was measured with tetrazolium staining. Expression/phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) and mitochondrial H2 O2 production were evaluated at the end of the rIPC protocol, before myocardial ischaemia-reperfusion. The rIPC significantly decreased the infarct size and induced Akt and eNOS phosphorylation. The protective effect on infarct size was abolished by cervical vagal section, l-NAME (an NO synthesis inhibitor) and 5-hydroxydecanoate (a mitochondrial ATP-dependent K(+) channel blocker). Mitochondrial production of H2 O2 was increased by rIPC, whereas it was abolished by cervical vagal section, l-NAME and 5-hydroxydecanoate. We conclude that rIPC activates a parasympathetic vagal pathway and a mechanism involving the phosphorylation of Akt and eNOS, the opening of mitochondrial ATP-dependent K(+) channels and the release of H2 O2 by the mitochondria. All these phenomena occur before myocardial ischaemia and could act as triggers of rIPC.
Assuntos
Infarto do Miocárdio/metabolismo , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Ácidos Decanoicos/farmacologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/metabolismo , Peróxido de Hidrogênio/metabolismo , Hidroxiácidos/farmacologia , Precondicionamento Isquêmico Miocárdico/métodos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Reperfusão Miocárdica/métodos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Sistema Nervoso Parassimpático/efeitos dos fármacos , Sistema Nervoso Parassimpático/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Canais de Potássio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Nervo Vago/efeitos dos fármacos , Nervo Vago/metabolismoRESUMO
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.
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In a previous research, we described that vagal stimulation increases the infarct size by sympathetic co-activation. The aim of this study was to determine if hemodynamic changes secondary to the vagal stimulation are able to activate sympathetic compensatory neural reflexes, responsible for increasing the infarct size. A second goal was to determine if intermittent vagal stimulation avoids sympathetic activation and reduces infarct size by muscarinic activation of the Akt/glycogen synthase kinase 3 ß (GSK-3ß) pathway. Rabbits were subjected to 30 min of regional myocardial ischemia and 3 h of reperfusion without vagal stimulation, or the following protocols of right vagus nerve stimulation for 10 min before ischemia: (a) continuous vagal stimulation and (b) intermittent vagal stimulation (cycles of 10 s ON/50 s OFF). Continuous vagal stimulation increased the infarct size (70.7 ± 4.3 %), even after right vagal section (68.6 ± 4.1 %) compared with control group (52.0 ± 3.7 %, p < 0.05). Bilateral vagotomy, pacing, and esmolol abolished the deleterious effect, reaching an infarct size of 43.3 ± 5.1, 43.5 ± 2.1, and 46.0 ± 4.6 % (p < 0.05), respectively. Intermittent stimulation reduced the infarct size to 29.8 ± 3.0 % (p < 0.05 vs I/R). This effect was blocked with atropine (50.2 ± 3.6 %, p < 0.05). Continuous vagal stimulation induced bradycardia and increased the loading conditions and wall stretching of the atria. These changes provoked the co-activation reflex of the sympathetic nervous system, observed by the rise in plasmatic catecholamine levels, which increased the infarct size. Sympathetic co-activation was abolished by continuous vagal stimulation with constant heart rate or parasympathetic deafferentation. Intermittent vagal stimulation attenuated the sympathetic tone and reduced the infarct size by the muscarinic activation of the Akt pathway and GSK-3ß inhibition. Continuous stimulation only phosphorylated Akt and GSK-3ß when esmolol was administered.
Assuntos
Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Sistema Nervoso Simpático/fisiologia , Nervo Vago/fisiologia , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Animais , Antiarrítmicos/farmacologia , Atropina/farmacologia , Catecolaminas/sangue , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Hemodinâmica , Masculino , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Propanolaminas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Coelhos , Reflexo , Transdução de Sinais , Sistema Nervoso Simpático/efeitos dos fármacos , Nervo Vago/efeitos dos fármacosRESUMO
The cardiovascular effects and pharmacokinetics of nebivolol were assessed in N(G)-nitro-l-arginine methyl ester (L-NAME) hypertensive and normotensive control rats. Male Wistar rats were randomly divided to drink tap water (control) or L-NAME solution for 2 weeks. The effects of nebivolol (3 or 10 mg kg(-1) i.v.) on blood pressure (BP), heart rate and BP variability (BPV) were recorded in awake L-NAME and control rats. Short-term and beat-to-beat BPV was assessed by the s.d. and spectral analysis of the BP recordings. Nebivolol pharmacokinetics was studied by means of traditional blood sampling. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; the clearance and the volume of distribution of l-nebivolol were significantly greater than those of the d-enantiomer. The hypotensive response to nebivolol was significantly enhanced in L-NAME rats (Δmean arterial pressure (MAP): -16.1±1.1%, P<0.05 vs. control rats) compared with normotensive animals (ΔMAP: -1.4±2.1%). An analysis of the beat-to-beat BPV showed a greater reduction in VLF BPV in the L-NAME compare with the control rats. Nebivolol significantly reduced the low-frequency/high-frequency ratio in hypertensive L-NAME animals compared with normotensive rats. Short-term BPV was markedly reduced by nebivolol in both experimental groups, although the attenuation of the s.d. of BP recording was greater in L-NAME rats. In conclusion, the hypotensive efficacy of nebivolol is significantly enhanced in L-NAME rats compared with normotensive animals, which is most likely due to a greater reduction in vascular sympathetic activity. Nebivolol markedly attenuated short-term BPV in both experimental groups, suggesting that ß-blockers with additional pharmacological actions provide beneficial cardiovascular effects by controlling high BP and its short-term variability.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacocinética , Benzopiranos/farmacologia , Benzopiranos/farmacocinética , Inibidores Enzimáticos , Etanolaminas/farmacologia , Etanolaminas/farmacocinética , Hemodinâmica/efeitos dos fármacos , Hipertensão/induzido quimicamente , NG-Nitroarginina Metil Éster , Antagonistas Adrenérgicos beta/química , Animais , Área Sob a Curva , Benzopiranos/química , Pressão Sanguínea/efeitos dos fármacos , Química Farmacêutica , Relação Dose-Resposta a Droga , Etanolaminas/química , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Injeções Intravenosas , Masculino , Nebivolol , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Ratos , Ratos Wistar , EstereoisomerismoRESUMO
Introducción: Accidente Cerebrovascular (ACV) es una injuria cerebral que deja como secuela post-ictus, crisis epiléptica (CE) en 2-14%. En Chile es un importante problema de salud pues ACV es el factor de riesgo más común de CE en personas mayores. Objetivos: Revisar prevalencia de casos en Hospital de Chillán, identificar factores predictivos y evaluar crisis. Hipótesis: A mayor cantidad de factores predictores, mayor posibilidad de CE post-ACV. Pacientes y Método: Estudio descriptivo, de serie de casos. Se selecciona pacientes con ACV entre enero 2013-agosto 2014. Se escoge aquellos que al egreso presentaron CE como secuela, 6 de 539. Se revisa fichas clínicas y compara se con literatura. Resultados: De 6 pacientes, se pierde seguimiento de 1. De los restantes, 60% hombres, 40% mujeres, con edad media de 64,8 años. En 100% ACV isquémico con crisis tónico-clónica generalizada, 80% y parcial simple, 20%. Todos presentaron primera crisis durante hospitalización. El 100% tiene morbilidad cardiovascular. Discusión: La incidencia local es inferior a realidad nacional e internacional y la edad de manifestación es similar al promedio reportado en literatura; 66,5 años. Todos los pacientes tienen criterios predictores para desarrollar CE post-ACV: presentación en paciente joven, coagulopatías, alto puntaje NIHSS. Conclusión: La gravedad no difirió entre pacientes y en quien se perdió seguimiento, por lo que se considera poco probable que influya en nuestros resultados. Además, aceptamos que pueden existir factores predictores ante cualquier ACV que permitan evitar complicaciones de CE. El envejecimiento poblacional, hace crucial encontrar métodos para prevenir crisis, por su impacto psicosocial.
Introduction: cerebrovascular accident (CVA) is a brain injury that can result in epileptic seizures (ES) as a sequel in 2-14% of patients. For Chile is an important health care problem because CVA is the greatest risk factor of ES in the elderly. Objective: Review the incidence of these cases at Chillán Hospital, find predictive factors, and evaluate crisis. Hypothesis:As the risk factors increase, there is a higher chance of getting ES after CVA. Patients and method: Descriptive study of case series. Patients with CVA between January 2013 and August 2014 were chosen. From this group, patients that presented ES as a sequel on discharge were 6 from 539. Medical records are reviewed and compared with literature. Results:from six pacient one is loss. From the remaining 60% are males, and 40% female, with an mean age of 64.8 years. In 100% CVA with 80% presenting generalized tonic-clonic and 20% simple partial seizures during and hospitalization. 100% presented their first ES during hospitalization. 100% has cardiovascular morbidity. Discussion: Local incidence is lower than both national and international incidence, mean age is similar to that reported in literature; 66.5. The 100% had predictive factors to develop ES after CVA: young patient, coagulopathy, high NIHSS. Conclusion: it is unlikely that the missing patient would influence the results. There may be predictive factors for CVA that can help prevent complications such as the ES. It is crucial to find methods to prevent these sequels as mean age of the population is increasing.
RESUMO
An increase in blood pressure variability (BPV) contributes to the development of target organ damage associated with hypertension. Treatment with conventional ß-blockers, such as atenolol, has been associated with an increase in BPV; however, the extrapolation of these results to third generation ß-blockers with pleiotropic effects seems to be inappropriate. The cardiovascular effects of third generation ß-blockers, carvedilol and nebivolol, were assessed in sinoaortic-denervated rats (SAD) and compared with the second generation ß-blocker atenolol and the calcium channel blocker verapamil, with a special focus on short-term BPV. Male SAD rats were acutely treated with carvedilol, nebivolol, atenolol or verapamil at two different doses, and the effects on blood pressure and BPV were recorded. Short-term BPV was assessed by the s.d. of BP recordings. Beat-to-beat BPV was studied using spectral analysis to assess the vascular sympatholytic activity of carvedilol and nebivolol by estimating the effects of these drugs on the ratio of low frequency (LF) to high frequency (HF) BPV (LF/HF ratio). Nebivolol, carvedilol and the calcium channel blocker verapamil significantly attenuated short-term BPV at both doses in SAD animals, and there were no differences between the drugs. Conversely, atenolol did not modify baseline s.d. values at either dose. Carvedilol and nebivolol significantly reduced the LF/HF ratio in SAD rats compared with the effects of atenolol and verapamil, suggesting the ability of the third generation ß-blockers to reduce vascular sympathetic activity. In conclusion, third generation ß-blockers induce a marked reduction in short-term BPV in SAD rats compared to atenolol. Moreover, the ability of carvedilol and nebivolol to reduce short-term BPV in SAD rats is equivalent to that of verapamil, suggesting that these ß-blockers may have an additional beneficial effect through their control of short-term variability to a similar extent to calcium channel blockers.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Nó Sinoatrial/fisiologia , Animais , Pressão Arterial/efeitos dos fármacos , Atenolol/farmacologia , Benzopiranos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Carbazóis/farmacologia , Carvedilol , Denervação , Relação Dose-Resposta a Droga , Etanolaminas/farmacologia , Frequência Cardíaca/fisiologia , Masculino , Nebivolol , Propanolaminas/farmacologia , Ratos , Ratos Wistar , Verapamil/farmacologiaRESUMO
Cardiovascular effects and pharmacokinetics of nebivolol were assessed in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) animals. Male SH and WKY rats were treated with vehicle or nebivolol 0.3, 3, or 10 mg kg(-1) (i.v.) and effects on blood pressure (BP), heart rate, and blood pressure variability (BPV) were recorded. Plasma pharmacokinetics of d- and l-nebivolol was studied by traditional blood sampling. Short-term and beat-to-beat BPV was assessed by standard deviation and spectral analysis of BP recording, respectively. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; clearance of l-nebivolol was significantly greater than d-enantiomer. Clearance of nebivolol was significantly reduced in SHR with regards to WKY animals. Hypotensive response to nebivolol 3 and 10 mg kg(-1) was significantly enhanced in SHR compared with normotensive animals. Spectral analysis of beat-to-beat BPV showed a greater reduction in low frequency BPV in SHR than in WKY rats. Nebivolol 3 and 10 mg kg(-1) significantly reduced ratio low frequency/high frequency BPV only in SHR. Short-term BPV was markedly reduced by nebivolol 0.3, 3, and 10 mg kg(-1) in WKY and SHR. In conclusion, the hypertensive stage in SHR modifies nebivolol pharmacokinetic properties and enhances its hypotensive response due to a greater attenuation in vascular sympathetic activity and enhancement of endothelial-derived NO activity. Nebivolol markedly attenuates short-term BPV in both experimental groups providing beneficial cardiovascular effects by both controlling high blood pressure and its short-term variability.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Anti-Hipertensivos/farmacologia , Benzopiranos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Etanolaminas/farmacologia , Animais , Anti-Hipertensivos/farmacocinética , Área Sob a Curva , Benzopiranos/farmacocinética , Química Farmacêutica , Etanolaminas/farmacocinética , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Injeções Intravenosas , Masculino , Nebivolol , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , EstereoisomerismoRESUMO
The cardiovascular effects and pharmacokinetics of carvedilol were assessed in spontaneously hypertensive (SH) and Wistar Kyoto (WKY) animals with special focus on short-term blood pressure variability (BPV). Male SH and WKY rats were acutely treated with vehicle or carvedilol 1 or 5 mg kg(-1) (i.v.), and effects on blood pressure (BP), heart rate (HR) and BPV were recorded. Plasma pharmacokinetics of R- and S-carvedilol was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by pharmacokinetic-pharmacodynamic (PK-PD) modelling. Short-term BPV was assessed by standard deviation of BP recording. Vascular sympatholytic activity of carvedilol was studied by estimation of drug effects on ratio between low frequency (LF) and high frequency (HF) BPV (LF/HF ratio). Although pharmacokinetic properties of carvedilol remained mainly unaffected in SH rats with regard to WKY rats, hypertensive animals showed a reduction in drug clearance of R- and S-carvedilol after administration of 1 mg kg(-1) compared with WKY rats. PK-PD analysis of HR changes induced by S-carvedilol showed a greater maximal bradycardic response to carvedilol in SH rats (E (max), -27.6 ± 3.9%; p < 0.05) compared with WKY group (E (max), -13.4 ± 2.5%). SH rats showed a greater hypotensive effect of racemic carvedilol (E (max), -45.5 ± 5.0%; p < 0.05) with regard to WKY group (E (max), -17.9 ± 4.5%). Carvedilol induced a greater reduction of LF/HF ratio in SH rats compared with WKY rats. Short-term BPV was markedly reduced by carvedilol in WKY and SH rats. In conclusion, as a consequence of an enhanced bradycardic response and a greater vascular sympatholytic activity, carvedilol exerts a greater hypotensive response in SH rats compared with WKY animals and dramatically reduces short-term BPV.