RESUMO
OBJECTIVE: To describe the successful management of 2 dogs with septic shock and persistent tachycardia using norepinephrine and esmolol, a short-acting beta receptor antagonist. SERIES SUMMARY: Two cases are reviewed. In the first case, septic shock with ventricular tachycardia was diagnosed in a 4-year-old neutered female Great Dane that underwent jejunoileal resection and anastomosis for a partial mesenteric torsion. The patient's tachyarrhythmias failed to respond to lidocaine, and an esmolol infusion was used for heart rate control. The condition of the dog improved and she was discharged after 4 days of hospitalization. The second case was a 7-year-old neutered female Cavalier King Charles Spaniel with septic peritonitis. Following surgery for intestinal resection and anastomosis, supraventricular tachycardia developed that was not responsive to volume resuscitation and was treated with an esmolol infusion. The condition of the dog improved and she was discharged after 6 days of hospitalization. Both patients were doing well at the time of long-term follow-up. NEW OR UNIQUE INFORMATION PROVIDED: This case series highlights a novel method of managing dogs in septic shock with persistent tachycardia based on recently published data in the human literature. The use of esmolol may be considered in certain veterinary patients with septic shock to improve persistent tachycardia not related to hypovolemia.
Assuntos
Doenças do Cão/tratamento farmacológico , Choque Séptico/veterinária , Taquicardia Supraventricular/veterinária , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Animais , Procedimentos Cirúrgicos do Sistema Digestório/veterinária , Cães , Quimioterapia Combinada/veterinária , Feminino , Norepinefrina/administração & dosagem , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/veterinária , Propanolaminas/administração & dosagem , Choque Séptico/complicações , Choque Séptico/tratamento farmacológico , Taquicardia Supraventricular/complicações , Taquicardia Supraventricular/tratamento farmacológico , Vasoconstritores/administração & dosagemRESUMO
Hot-melt extrusion (HME) has gained increasing attention in the pharmaceutical industry; however, its potential in the preparation of solid self-emulsifying drug delivery systems (S-SMEDDS) is still unexplored. This study sought to prepare enteric S-SMEDDS by HME and evaluate the effects of the process and formulation variables on S-SMEDDS properties via Box-Behnken design. Liquid SMEDDS were developed, and carvedilol was used as a class II model drug. Mean size, polydispersity index (PdI) and zeta potential of the resulting microemulsions were determined. The extrudates were then obtained by blending the lipid mixture and HPMCAS using a twin-screw hot-melt extruder. SEM, optical microscopy and PXRD were used to characterize the extrudates. In vitro microemulsion reconstitution and drug release were also studied. L-SMEDDS gave rise to microemulsions with low mean size, PdI and zeta potential (140.04⯱â¯7.22â¯nm, 0.219⯱â¯0.011 and -9.77⯱â¯0.86â¯mV). S-SMEDDS were successfully prepared by HME, and an HMPCAS matrix was able to avoid microemulsion reconstitution and retain drug release in pH 1.2 (12.97%-25.54%). Conversely, microemulsion reconstitution and drug release were gradual in pH 6.8 and complete for some formulations. Extrudates prepared at the lowest drug concentration and highest temperature and recirculation time promoted a complete and rapid drug release in pH 6.8 giving rise to small and uniform microemulsion droplets.
Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos , Emulsões/química , Carbazóis/administração & dosagem , Carbazóis/farmacocinética , Carvedilol , Química Farmacêutica/instrumentação , Liberação Controlada de Fármacos , Temperatura Alta , Concentração de Íons de Hidrogênio , Lipídeos/química , Metilcelulose/análogos & derivados , Metilcelulose/química , Tamanho da Partícula , Propanolaminas/administração & dosagem , Propanolaminas/farmacocinética , SolubilidadeRESUMO
In cancers, apoptosis signaling pathways and cell survival and growth pathways responsible for resistance to conventional treatments, such as Pi3K/Akt/mTOR and mitogen-activated protein kinase (MAPK) become dysregulated. Recently, alternative treatments to promote tumor cell death have become important. The present study reports on the antitumor and cytoprotective action of gold nanoparticles (GNPs) and carvedilol in combination and in isolated application. Apoptosis was analyzed by FITC/propidium iodide staining flow cytometry; caspase-3, caspase-8, Bcl-2 and MAPK/ERK activity by immunofluorescence microscopy; gene expression of proteins related to cell death as Akt, mTOR, EGFR, MDR1, survivin, FADD and Apaf, by the real-time PCR; and western blot analysis for MAPK/ERK, Akt and mTOR. Oxidative stress evaluation was performed by reduced glutathione (GSH) and malondialdehyde (MDA) levels. Intracellular GNPs targets were identified by transmission electron microscopy. After exposure to a combination of GNPs (6.25 µg/ml) and carvedilol (3 µM), death as promoted by apoptosis was detected using flow cytometry, for expression of pro-apoptotic proteins FADD, caspase-3, caspase-8 and sub-regulation of anti-apoptotic MAPK/ERK, Akt, mTOR, EGFR and MDR1 resistance. Non-tumor cell cytoprotection with GSH elevation and MDA reduction levels was detected. GNPs were identified within the cell near to the nucleus when combined with carvedilol. The combination of GNP and carvedilol promoted downregulation of anti-apoptotic and drug resistance genes, over-regulation of pro-apoptotic proteins in tumor cells, as well as cytoprotection of non-tumor cells with reduction of apoptosis and oxidative stress.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carbazóis/farmacologia , Ouro/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Propanolaminas/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/administração & dosagem , Carvedilol , Receptores ErbB/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estresse Oxidativo/efeitos dos fármacos , Propanolaminas/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Carvedilol, a drug available as a racemic mixture, is metabolised into hydroxyphenylcarvedilol (OHC) by CYP2D6 and O-desmethylcarvedilol (DMC) by CYP2C9 followed by conjugation to glucuronides. In contrast to other ß-adrenergic receptor antagonists, carvedilol does not induce insulin resistance or worsen glycaemic control in diabetic hypertensive patients. This study aims to investigate the implications of type 2 diabetes (T2DM) on the pharmacokinetics of carvedilol enantiomers using an integrated population pharmacokinetic modelling approach. In total, 14 T2DM patients with good glycaemic control receiving standard doses of metformin and glibenclamide were evaluated along with a control group of 13 healthy subjects. Serial blood samples were collected up to 24h after administration of a single 25mg dose of racemic carvedilol. A multicompartmental population pharmacokinetic model describing the enantioselective disposition of the parent compound, OHC and DMC was developed in NONMEM v7.2. Even though data are limited, it appears that despite inhibition of CYP2C9 due to long-term glibenclamide administration to T2DM patients, overall no differences are observed in the total clearance of carvedilol when compared to healthy subjects (43.1 vs. 45.9L/h for (S)-(-)-carvedilol and 29.0 vs. 33.1L/h for (R)-(+)-carvedilol). These results provide evidence of a compensatory mechanism for the inhibition of CYP2C9, with higher contribution of CYP2D6 activity to the elimination of carvedilol. Consequently, no dose adjustment is recommended for carvedilol in T2DM patients receiving glibenclamide and metformin.
Assuntos
Antagonistas Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacocinética , Carbazóis/metabolismo , Carbazóis/farmacocinética , Diabetes Mellitus Tipo 2/metabolismo , Propanolaminas/metabolismo , Propanolaminas/farmacocinética , Antagonistas Adrenérgicos beta/administração & dosagem , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Carbazóis/administração & dosagem , Carvedilol , Citocromo P-450 CYP2C9/metabolismo , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Citocromo P-450 CYP2D6/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Glibureto/administração & dosagem , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Propanolaminas/administração & dosagem , EstereoisomerismoRESUMO
Carvedilol is a drug used to treat heart failure, hypertension, and coronary artery diseases . However, it has low oral bioavailability (25-35%) due to its high first-pass hepatic metabolism. The objective of this study was to develop carvedilol-loaded mucoadhesive nanocapsules as delivery systems for the sublingual administration of the drug. Nanocapsules were prepared using poly(ε-caprolactone) (CAR-LNC) and Eudragit® RS 100 (CAR-NC) as polymeric wall. In vitro interaction of formulations with mucin was performed to predict their mucoadhesion capacity. The permeability and washability profiles of carvedilol were evaluated using porcine sublingual mucosa. The mean diameter of particles in formulations was in the nanometric range, and particles had low polydispersity and slightly acidic pH. Zeta potential values were positive for CAR-NC and negative for CAR-LNC. Encapsulation efficiency was higher than 87% and 99% for CAR-NC and CAR-LNC, respectively. Both formulations presented controlled drug release profiles and mucoadhesive properties. Carvedilol was able to permeate through the sublingual mucosa. Nanoencapsulation improved retention time on the mucosa and permeation in presence of simulated salivary flux. This study highlighted the suitability of using CAR-loaded nanocapsules in the development of innovative sublingual dosage forms.
Assuntos
Carbazóis/administração & dosagem , Carbazóis/farmacocinética , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/farmacocinética , Propanolaminas/administração & dosagem , Propanolaminas/farmacocinética , Resinas Acrílicas , Administração Sublingual , Animais , Carvedilol , Preparações de Ação Retardada , Composição de Medicamentos , Excipientes , Técnicas In Vitro , Mucosa Bucal/metabolismo , Nanocápsulas , Permeabilidade , Poliésteres , Ácidos Polimetacrílicos , Suínos , Adesivos TeciduaisRESUMO
INTRODUCTION: Dysmenorrhea is caused by the discharge of prostaglandins into the uterine tissue; therefore, non-steroidal anti-inflammatory drugs (NSAIDs) are the established initial therapy for dysmenorrhea. Dysmenorrhea therapy may include the administration of drug monotherapy or combination therapy. However, clinical scientific evidence on the efficacy of medications with two or three drugs combined is scarce or nonexistent. OBJECTIVE: To evaluate and compare the efficacy and safety of two oral fixed-dose combinations for the relief of the symptoms of primary dysmenorrhea among Mexican women. One of the combinations is widely used in Mexico (paracetamol, pyrilamine and pamabrom) and the selected comparison was a medication with naproxen sodium, paracetamol and pamabrom based on the pathophysiology of primary dysmenorrhea. METHODS: This was a single-centre, double blind, experimental, parallel group, randomized trial. Female patients with primary dysmenorrhea, older than 17 years and with pain intensity greater than 45 mm on a visual analogue scale, were included. The patients were then randomized to receive tablets with naproxen sodium, paracetamol and pamabrom or tablets with paracetamol, pyrilamine and pamabrom for one menstrual cycle. Patient evaluations of symptomatology and pain intensity were recorded throughout one menstrual period. Descriptive and inferential statistical analyses were utilized. RESULTS: An intention-to-treat population of 91 women, with a mean age of 21.3 ± 3.2 years, received paracetamol, pyrilamine and pamabrom tablets, and 98 participants, with a mean age of 21.0 ± 3.2 years, received naproxen sodium, paracetamol and pamabrom tablets. The participants assessments of pain on the Visual Analogue Scale during the menstrual cycle demonstrated a significant reduction in both treatment groups (p<0.05). There is no significant difference in efficacy between both groups (p>0.05). CONCLUSIONS: The results showed that both drug combinations were not different in reducing dysmenorrheic pain. Likewise, both treatments were well tolerated. Therefore, both treatments may be used for the treatment of primary dysmenorrhea.
INTRODUCCIÓN: La dismenorrea primaria es causada por la descarga de las prostaglandinas en el tejido uterino. Por lo tanto, los fármacos antiinflamatorios no esteroideos son la terapia inicial para la dismenorrea. El tratamiento para la dismenorrea puede incluir la administración de monoterapia o la combinación de fármacos. Sin embargo, la evidencia clínica científica sobre la eficacia de los medicamentos con dos o tres fármacos combinados es escasa o ausente. OBJETIVO: Evaluar y comparar la eficacia y seguridad de dos combinaciones, en dosis fija y oral para el alivio de los síntomas de la dismenorrea primaria en mujeres mexicanas. Basados en la fisiopatología de la dismenorrea primaria, se utilizó una combinación comercializada en México de paracetamol, pirilamina y pamabrom. El comparador seleccionado fue un medicamento que contiene naproxeno sódico, paracetamol y pamabrom. MÉTODOS: Se realizó un estudio en un solo centro, a doble ciego, experimental, paralelo y aleatorizado. Las pacientes con dismenorrea primaria que se incluyeron fueron mayores de 17 años de edad y con una intensidad del dolor mayor a 45 milímetros en una escala visual analógica. Las pacientes fueron aleatorizadas para recibir tabletas con naproxeno sódico, paracetamol y pamabrom o tabletas con paracetamol, pirilamina y pamabrom para un ciclo menstrual. Se evaluó la intensidad de la sintomatología y el dolor de las pacientes a lo largo de un período menstrual. Se utilizó análisis estadístico descriptivo e inferencial. RESULTADOS: Se incluyó una población con intención de tratar de 91 mujeres, con una edad media de 21,3 ± 3,2 años la cual recibió tabletas de paracetamol, pirilamina y pamabrom. Otras 98 participantes, con una edad media de 21,0 ± 3,2 años, recibieron tabletas de naproxeno sódico, paracetamol y pamabrom. Las evaluaciones de dolor de las participantes con la escala visual analógica durante el ciclo menstrual demostraron una reducción significativa en ambos grupos de tratamiento (p<0,05). No hubo diferencia significativa en la eficacia entre los dos grupos (p>0,05). CONCLUSIONES: Los resultados mostraron que ambas combinaciones de fármacos no fueron diferentes en reducir el dolor dismenorreico. Del mismo modo, ambos tratamientos fueron bien tolerados. Por lo tanto, ambos tratamientos se pueden utilizar para el tratamiento de la dismenorrea primaria.
Assuntos
Acetaminofen/administração & dosagem , Dismenorreia/tratamento farmacológico , Naproxeno/administração & dosagem , Propanolaminas/administração & dosagem , Pirilamina/administração & dosagem , Teofilina/análogos & derivados , Acetaminofen/efeitos adversos , Adolescente , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/efeitos adversos , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Dismenorreia/fisiopatologia , Feminino , Humanos , México , Naproxeno/efeitos adversos , Medição da Dor , Propanolaminas/efeitos adversos , Pirilamina/efeitos adversos , Comprimidos , Teofilina/administração & dosagem , Teofilina/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
ABSTRACT OBJECTIVE: We compared the effects of lidocaine and esmolol infusions on intraoperative hemodynamic changes, intraoperative and postoperative analgesic requirements, and recovery in laparoscopic cholecystectomy surgery. METHODS: The first group (n = 30) received IV lidocaine infusions at a rate of 1.5 mg/kg/min and the second group (n = 30) received IV esmolol infusions at a rate of 1 mg/kg/min. Hemodynamic changes, intraoperative and postoperative analgesic requirements, and recovery characteristics were evaluated. RESULTS: In the lidocaine group, systolic arterial blood pressures values were lower after the induction of anesthesia and at 20 min following surgical incision (p < 0.05). Awakening time was shorter in the esmolol group (p < 0.001); Ramsay Sedation Scale scores at 10 min after extubation were lower in the esmolol group (p < 0.05). The modified Aldrete scores at all measurement time points during the recovery period were relatively lower in the lidocaine group (p < 0.05). The time to attain a modified Aldrete score of ≥9 points was prolonged in the lidocaine group (p < 0.01). Postoperative resting and dynamic VAS scores were higher in the lidocaine group at 10 and 20 min after extubation (p < 0.05, p < 0.01, respectively). Analgesic supplements were less frequently required in the lidocaine group (p < 0.01). CONCLUSION: In laparoscopic cholecystectomies, lidocaine infusion had superiorities over esmolol infusions regarding the suppression of responses to tracheal extubation and postoperative need for additional analgesic agents in the long run, while esmolol was more advantageous with respect to rapid recovery from anesthesia, attenuation of early postoperative pain, and modified Aldrete recovery (MAR) scores and time to reach MAR score of 9 points.
RESUMO OBJETIVO: Comparar os efeitos de infusões de lidocaína e esmolol sobre as alterações hemodinâmicas no período intraoperatório, a necessidade de analgésicos intra- e pós-operatoriamente e a recuperação após colecistectomia laparoscópica. MÉTODOS: O primeiro grupo (n = 30) recebeu infusões IV de lidocaína a uma taxa de 1,5 mg/kg/min e o segundo grupo (n = 30) recebeu infusões IV de esmolol a uma taxa de 1 mg kg/min. Alterações hemodinâmicas, necessidade de analgésicos no intra- e pós-operatório e características da recuperação foram avaliadas. RESULTADOS: No grupo lidocaína, os valores da pressão arterial sistólica foram menores após a indução da anestesia e 20 minutos após a incisão cirúrgica (p < 0,05). O tempo até o despertar foi menor no grupo esmolol (p < 0,001), os escores na escala de Sedação de Ramsay 10 minutos após a extubação foram menores no grupo esmolol (p < 0,05). Os escores de Aldrete modificados em todos os tempos mensurados durante o período de recuperação foram relativamente baixos no grupo lidocaína (p < 0,05). O tempo necessário para atingir um escore de Aldrete ≥ 9 pontos foi prolongado no grupo lidocaína (p < 0,01). Os escores Eva em repouso e em movimento no pós-operatório foram maiores no grupo lidocaína nos minutos 10 e 20 após a extubação (p < 0,05,p < 0,01, respectivamente). Analgésicos suplementares foram necessários com menos frequência no grupo lidocaína (p < 0,01). CONCLUSÃO: Em colecistectomia laparoscópica, a infusão de lidocaína foi superior às infusões de esmolol quanto a suprimir as respostas à extubação traqueal e necessidade de analgésicos adicionais no pós-operatório, enquanto esmolol foi mais vantajoso quanto à rápida recuperação da anestesia, à atenuação da dor no pós-operatório imediato e aos escores de recuperação de Aldrete modificado (RAM) e o tempo até atingir o escore RAM de 9 pontos.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Idoso , Adulto Jovem , Propanolaminas/administração & dosagem , Colecistectomia Laparoscópica/métodos , Analgésicos/administração & dosagem , Lidocaína/administração & dosagem , Dor Pós-Operatória/tratamento farmacológico , Fatores de Tempo , Pressão Sanguínea/efeitos dos fármacos , Infusões Intravenosas , Período de Recuperação da Anestesia , Método Duplo-Cego , Hemodinâmica/efeitos dos fármacos , Anestésicos Locais/administração & dosagem , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: We compared the effects of lidocaine and esmolol infusions on intraoperative hemodynamic changes, intraoperative and postoperative analgesic requirements, and recovery in laparoscopic cholecystectomy surgery. METHODS: The first group (n=30) received IV lidocaine infusions at a rate of 1.5mg/kg/min and the second group (n=30) received IV esmolol infusions at a rate of 1mg/kg/min. Hemodynamic changes, intraoperative and postoperative analgesic requirements, and recovery characteristics were evaluated. RESULTS: In the lidocaine group, systolic arterial blood pressures values were lower after the induction of anesthesia and at 20min following surgical incision (p<0.05). Awakening time was shorter in the esmolol group (p<0.001); Ramsay Sedation Scale scores at 10min after extubation were lower in the esmolol group (p<0.05). The modified Aldrete scores at all measurement time points during the recovery period were relatively lower in the lidocaine group (p<0.05). The time to attain a modified Aldrete score of ≥9 points was prolonged in the lidocaine group (p<0.01). Postoperative resting and dynamic VAS scores were higher in the lidocaine group at 10 and 20min after extubation (p<0.05, p<0.01, respectively). Analgesic supplements were less frequently required in the lidocaine group (p<0.01). CONCLUSION: In laparoscopic cholecystectomies, lidocaine infusion had superiorities over esmolol infusions regarding the suppression of responses to tracheal extubation and postoperative need for additional analgesic agents in the long run, while esmolol was more advantageous with respect to rapid recovery from anesthesia, attenuation of early postoperative pain, and modified Aldrete recovery (MAR) scores and time to reach MAR score of 9 points.
Assuntos
Analgésicos/administração & dosagem , Colecistectomia Laparoscópica/métodos , Lidocaína/administração & dosagem , Propanolaminas/administração & dosagem , Adolescente , Adulto , Idoso , Período de Recuperação da Anestesia , Anestésicos Locais/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Fatores de Tempo , Adulto JovemRESUMO
Oxidative imbalance, alterations in brain-derived neurotrophic factor (BDNF), and mitochondrial dysfunction are implicated in bipolar disorder (BD) pathophysiology and comorbidities, for example, cardiovascular conditions. Carvedilol (CVD), a nonselective beta-blocker widely used for the treatment of hypertension, presents antioxidant and mitochondrial stabilizing properties. Thus, we hypothesized that CVD would prevent and/or reverse mania-like behavioral and neurochemical alterations induced by lisdexamfetamine dimesylate (LDX). To do this, male Wistar rats were submitted to two different protocols, namely, prevention and reversal. In the prevention treatment the rats received daily oral administration (mg/kg) of CVD (2.5, 5 or 7.5), saline, valproate (VAL200), or the combination of CVD5 + VAL100 for 7 days. From the 8th to 14th day LDX was added. In the reversal protocol LDX was administered for 7 days with the drugs being added from the 8th to 14th day of treatment. Two hours after the last administration the behavioral (open field and social interaction) and neurochemical (reduced glutathione, lipid peroxidation, and BDNF) determinations were performed. The results showed that CVD prevented and reversed the behavioral and neurochemical alterations induced by LDX. The administration of CVD5 + VAL100 potentiated the effect of VAL200 alone. Taken together these results demonstrate a possible antimanic effect of CVD in this preclinical model.
Assuntos
Antimaníacos/administração & dosagem , Transtorno Bipolar/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carbazóis/administração & dosagem , Propanolaminas/administração & dosagem , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Antimaníacos/uso terapêutico , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carbazóis/uso terapêutico , Carvedilol , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Dimesilato de Lisdexanfetamina , Masculino , Malondialdeído/metabolismo , Atividade Motora/efeitos dos fármacos , Propanolaminas/uso terapêutico , Ratos , Ratos Wistar , Isolamento Social , Ácido Valproico/administração & dosagem , Ácido Valproico/uso terapêuticoAssuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Carbazóis/administração & dosagem , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacocinética , Digoxina/administração & dosagem , Digoxina/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Propanolaminas/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antagonistas Adrenérgicos beta/sangue , Adulto , Idoso , Disponibilidade Biológica , Carbazóis/sangue , Cardiotônicos/efeitos adversos , Carvedilol , Ensaios Clínicos como Assunto , Estudos Cross-Over , Digoxina/efeitos adversos , Interações Medicamentosas , Insuficiência Cardíaca/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Propanolaminas/sangueRESUMO
BACKGROUND AND OBJECTIVE: The aim of this randomized, prospective and double blinded study is to investigate effects of different esmolol use on hemodynamic response of laryngoscopy, endotracheal intubation and sternotomy in coronary artery bypass graft surgery. METHODS: After approval of local ethics committee and patients' written informed consent, 45 patients were randomized into three groups equally. In Infusion Group; from 10 min before intubation up to 5th minute after sternotomy, 0.5mg/kg/min esmolol infusion, in Bolus Group; 2 min before intubation and sternotomy 1.5mg/kg esmolol IV bolus and in Control Group; %0.9 NaCl was administered. All demographic parameters were recorded. Heart rate and blood pressure were recorded before infusion up to anesthesia induction in every minute, during endotracheal intubation, every minute for 10 minutes after endotracheal intubation and before, during and after sternotomy at first and fifth minutes. RESULTS: While area under curve (AUC) (SAP×time) was being found more in Group B and C than Group I, AUC (SAP×Tint and Tst) and AUC (SAP×T2) was found more in Group B and C than Group I (p<0.05). Moreover AUC (HR×Tst) was found less in Group B than Group C but no significant difference was found between Group B and Group I. CONCLUSION: This study highlights that esmolol infusion is more effective than esmolol bolus administration on controlling systolic arterial pressure during endotracheal intubation and sternotomy in CABG surgery.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Ponte de Artéria Coronária/métodos , Laringoscopia/métodos , Propanolaminas/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Idoso , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Infusões Intravenosas , Injeções Intravenosas , Intubação Intratraqueal/métodos , Masculino , Pessoa de Meia-Idade , Propanolaminas/farmacologia , Estudos Prospectivos , Esternotomia/métodosRESUMO
BACKGROUND AND OBJECTIVE: The aim of this randomized, prospective and double blinded study is to investigate effects of different esmolol use on hemodynamic response of laryngoscopy, endotracheal intubation and sternotomy in coronary artery bypass graft surgery. METHODS: After approval of local ethics committee and patients' written informed consent, 45 patients were randomized into three groups equally. In Infusion Group; from 10 min before intubation up to 5th minute after sternotomy, 0.5 mg/kg/min esmolol infusion, in Bolus Group; 2 min before intubation and sternotomy 1.5 mg/kg esmolol IV bolus and in Control Group; %0.9 NaCl was administered. All demographic parameters were recorded. Heart rate and blood pressure were recorded before infusion up to anesthesia induction in every minute, during endotracheal intubation, every minute for 10 minutes after endotracheal intubation and before, during and after sternotomy at first and fifth minutes. RESULTS: While area under curve (AUC) (SAP × time) was being found more in Group B and C than Group I, AUC (SAP × T int and T st) and AUC (SAP × T2) was found more in Group B and C than Group I (p < 0.05). Moreover AUC (HR × T st) was found less in Group B than Group C but no significant difference was found between Group B and Group I. CONCLUSION: This study highlights that esmolol infusion is more effective than esmolol bolus administration on controlling systolic arterial pressure during endotracheal intubation and sternotomy in CABG surgery. .
JUSTIFICATIVA E OBJETIVO: o objetivo deste estudo prospectivo, randômico e duplo-cego foi investigar os efeitos do uso diferente de esmolol na resposta hemodinâmica à laringoscopia, intubação orotraqueal e esternotomia em cirurgia de revascularização coronária. MÉTODOS: após obter a aprovação do Comitê de Ética local e consentimento informado assinado pelos pacientes, 45 pacientes foram randomicamente divididos em três grupos. O Grupo I (infusão) recebeu 0,5 mg/kg/min de esmolol em infusão a partir de 10 min antes da intubação até 5 minutos após a esternotomia; o Brupo B (bolus) recebeu 1,5 mg/kg de esmolol em bolus IV a partir de 2 min antes da intubação e esternotomia; o grupo C (controle) recebeu NaCl a 0,9%. Todos os parâmetros demográficos foram registados. Os valores de frequência cardíaca e pressão arterial foram registrados desde antes da infusão até a indução da anestesia a cada minuto, durante a intubação endotraqueal, a cada minuto durante 10 min após a intubação endotraqueal e antes, durante e após a esternotomia no primeiro e quinto minutos. RESULTADOS: enquanto a área sob a curva (ASC) (SAP × tempo) foi maior nos grupos B e C que no Grupo I, a ASC (SAP × T int e T st) e ASC (SAP × T2) foram maiores nos grupos B e C que no Grupo I (p < 0,05). Além disso, a ASC (FC × T st)) foi menor no Grupo B que no Grupo C, mas não houve diferença significante entre os grupos B e I. CONCLUSÃO: este estudo destaca que a administração de esmolol em infusão é mais eficaz que em bolus para controlar a pressão arterial sistólica durante a intubação endotraqueal e esternotomia em CRC. .
JUSTIFICACIÓN Y OBJETIVO: el objetivo de este estudio prospectivo, aleatorizado y doble ciego fue investigar los efectos del diferente uso del esmolol en la respuesta hemodinámica a la laringoscopia, intubación orotraqueal y esternotomía en cirugía de revascularización coronaria. MÉTODOS: después de obtener la aprobación del Comité de Ética local y el consentimiento informado firmado por los pacientes, 45 de ellos fueron aleatoriamente divididos en 3 grupos. El grupo I (infusión) recibió 0,5 mg/kg/min de esmolol en infusión desde 10 min antes de la intubación hasta 5 min después de la esternotomía; el grupo B (bolo), que recibió 1,5 mg/kg de esmolol en bolo iv a partir de 2 min antes de la intubación y esternotomía; el grupo C (control) recibió NaCl al 0,9%. Todos los parámetros demográficos fueron registrados. Los valores de frecuencia cardíaca y presión arterial fueron registrados ya antes de la infusión y hasta la inducción de la anestesia cada minuto durante la intubación endotraqueal, cada minuto durante 10 min después de la intubación endotraqueal, y antes, durante y después de la esternotomía en el primer y quinto minutos. RESULTADOS: mientras que el área bajo la curva (AUC) (presión arterial sistólica [PAS] × tiempo) fue mayor en los grupos B y C que en el grupo I, el AUC (PAS ×T int y T st ) y AUC (PAS × T 2 ) fueron mayores en los grupos B y C que en el grupo I (p < 0,05). Además, el AUC (frecuencia cardíaca × T st ) fue menor en el grupo B que en el grupo C, pero no hubo diferencia significativa entre los grupos B e I. CONCLUSIÓN: este estudio destaca que la administración del esmolol en infusión es más eficaz que en bolos para controlar la PAS durante la intubación endotraqueal ...
Assuntos
Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Ponte de Artéria Coronária/métodos , Laringoscopia/métodos , Propanolaminas/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Infusões Intravenosas , Injeções Intravenosas , Intubação Intratraqueal/métodos , Estudos Prospectivos , Propanolaminas/farmacologia , Esternotomia/métodosRESUMO
Periodontal diseases are initiated primarily by Gram-negative, tooth-associated microbial biofilms that elicit a host response that causes osseous and soft tissue destruction. Carvedilol is a ß-blocker used as a multifunctional neurohormonal antagonist that has been shown to act not only as an anti-oxidant but also as an anti-inflammatory drug. This study evaluated whether Carvedilol exerted a protective role against ligature-induced periodontitis in a rat model and defined how Carvedilol affected metalloproteinases and RANKL/RANK/OPG expression in the context of bone remodeling. Rats were randomly divided into 5 groups (n = 10/group): (1) non-ligated (NL), (2) ligature-only (LO), and (3) ligature plus Carvedilol (1, 5 or 10 mg/kg daily for 10 days). Periodontal tissue was analyzed for histopathlogy and using immunohistochemical analysis characterized the expression profiles of MMP-2, MMP-9, COX-2, and RANKL/RANK/OPG and determined the presence of IL-1ß, IL-10 and TNF-α, myeloperoxidase (MPO), malonaldehyde (MDA) and, glutathione (GSH). MPO activity in the group with periodontal disease was significantly increased compared to the control group (p<0.05). Rats treated with 10 mg/kg Carvedilol presented with significantly reduced MPO and MDA concentrations (p<0.05) in addition to presenting with reduced levels of the pro-inflammatory cytokines IL-1 ß and TNF-α (p<0.05). IL-10 levels in Carvedilol-treated rats remained unaltered. Immunohistochemical analysis demonstrated reduced expression of MMP-2, MMP-9, RANK, RANKL, COX-2, and OPG in rats treated with 10 mg/kg Carvedilol. This study demonstrated that Carvedilol affected bone formation/destruction and anti-inflammatory activity in a rat model of periodontitis.
Assuntos
Carbazóis/farmacologia , Ciclo-Oxigenase 2/metabolismo , Interleucina-1beta/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Osteoprotegerina/metabolismo , Periodontite/metabolismo , Propanolaminas/farmacologia , Ligante RANK/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Carbazóis/administração & dosagem , Carvedilol , Modelos Animais de Doenças , Masculino , Estresse Oxidativo , Periodontite/genética , Periodontite/patologia , Propanolaminas/administração & dosagem , RatosRESUMO
Carvedilol is an antihypertensive drug available as a racemic mixture. (-)-(S)-carvedilol is responsible for the nonselective ß-blocker activity but both enantiomers present similar activity on α(1)-adrenergic receptor. To our knowledge, this is the first study of carvedilol enantiomers in human plasma using a chiral stationary phase column and liquid chromatography with tandem mass spectrometry. The method involves plasma extraction with diisopropyl ether using metoprolol as internal standard and direct separation of the carvedilol enantiomers on a Chirobiotic T® (Teicoplanin) column. Protonated ions [M + H](+) and their respective ion products were monitored at transitions of 407 > 100 for the carvedilol enantiomers and 268 > 116 for the internal standard. The quantification limit was 0.2 ng ml(-1) for both enantiomers in plasma. The method was applied to study enantioselectivity in the pharmacokinetics of carvedilol administered as a single dose of 25 mg to a hypertensive patient. The results showed a higher plasma concentration of (+)-(R)-carvedilol (AUC(0-∞) 205.52 vs. 82.61 (ng h) ml(-1)), with an enantiomer ratio of 2.48.
Assuntos
Anti-Hipertensivos/sangue , Anti-Hipertensivos/química , Análise Química do Sangue/métodos , Carbazóis/sangue , Carbazóis/química , Cromatografia Líquida/métodos , Propanolaminas/sangue , Propanolaminas/química , Espectrometria de Massas em Tandem/métodos , Administração Oral , Adulto , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Carbazóis/administração & dosagem , Carbazóis/farmacocinética , Carvedilol , Humanos , Hipertensão/metabolismo , Limite de Detecção , Propanolaminas/administração & dosagem , Propanolaminas/farmacocinética , Reprodutibilidade dos Testes , EstereoisomerismoRESUMO
This study examined the food intake changes evoked by intracerebroventricular (icv) injection of a selective agonist (BRL37344, 2 and 20 nmol) or antagonist (SR59230A, 10 and 50 nmol) of β3-adrenergic receptors in 24-h fasted rats (adult male Wistar rats, 200-350 g, N = 6/treatment). The animals were also pretreated with saline icv (SAL) or SR59230A (50 nmol) followed by BRL37344 (20 nmol) or SAL in order to determine the selectivity of the effects evoked by BRL37344 on food intake or the selectivity of the effects evoked by SR59230A on risk assessment (RA) behavior. The highest dose of BRL37344 (N = 7) decreased food intake 1 h after the treatment (6.4 ± 0.5 g in SAL-treated vs 4.2 ± 0.8 g in drug-treated rats). While both doses of SR59230A failed to affect food intake (5.1 ± 1.1 g for 10 nmol and 6.0 ± 1.8 g for 50 nmol), this treatment reduced the RA frequency (number/30 min) (4 ± 2 for SAL-treated vs 1 ± 1 for 10 nmol and 0.5 ± 1 for 50 nmol SR59230A-treated rats), an ethological parameter related to anxiety. While pretreatment with SR59230A (7.0 ± 0.5 g) abolished the hypophagia induced by BRL37344 (3.6 ± 0.9 g), BRL37344 suppressed the reduction in RA frequency caused by SR59230A. These results show that the hypophagia caused by BRL37344 is selectively mediated by β3-adrenergic receptors within the central nervous system. Moreover, they suggest the involvement of these receptors in the control of anxiety.
Assuntos
Animais , Masculino , Ratos , /farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Etanolaminas/farmacologia , Propanolaminas/farmacologia , Análise de Variância , /administração & dosagem , /administração & dosagem , /farmacologia , Ansiedade/metabolismo , Etanolaminas/administração & dosagem , Injeções Intraventriculares , Modelos Animais , Propanolaminas/administração & dosagem , Distribuição Aleatória , Ratos Wistar , Medição de RiscoRESUMO
This study examined the food intake changes evoked by intracerebroventricular (icv) injection of a selective agonist (BRL37344, 2 and 20 nmol) or antagonist (SR59230A, 10 and 50 nmol) of ß3-adrenergic receptors in 24-h fasted rats (adult male Wistar rats, 200-350 g, N = 6/treatment). The animals were also pretreated with saline icv (SAL) or SR59230A (50 nmol) followed by BRL37344 (20 nmol) or SAL in order to determine the selectivity of the effects evoked by BRL37344 on food intake or the selectivity of the effects evoked by SR59230A on risk assessment (RA) behavior. The highest dose of BRL37344 (N = 7) decreased food intake 1 h after the treatment (6.4 ± 0.5 g in SAL-treated vs 4.2 ± 0.8 g in drug-treated rats). While both doses of SR59230A failed to affect food intake (5.1 ± 1.1 g for 10 nmol and 6.0 ± 1.8 g for 50 nmol), this treatment reduced the RA frequency (number/30 min) (4 ± 2 for SAL-treated vs 1 ± 1 for 10 nmol and 0.5 ± 1 for 50 nmol SR59230A-treated rats), an ethological parameter related to anxiety. While pretreatment with SR59230A (7.0 ± 0.5 g) abolished the hypophagia induced by BRL37344 (3.6 ± 0.9 g), BRL37344 suppressed the reduction in RA frequency caused by SR59230A. These results show that the hypophagia caused by BRL37344 is selectively mediated by ß3-adrenergic receptors within the central nervous system. Moreover, they suggest the involvement of these receptors in the control of anxiety.
Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Etanolaminas/farmacologia , Propanolaminas/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 3/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Análise de Variância , Animais , Ansiedade/metabolismo , Etanolaminas/administração & dosagem , Injeções Intraventriculares , Masculino , Modelos Animais , Propanolaminas/administração & dosagem , Distribuição Aleatória , Ratos , Ratos Wistar , Medição de RiscoRESUMO
OBJECTIVE: Two carvedilol aqueous solutions and one carvedilol aqueous suspension for paediatric oral use (1mg/ml) were studied to determine their stability. METHOD: All samples were stored at 4, 25 and 40°C. Carvedilol content of each of the three formulations was tested using high performance liquid chromatography (HPLC). Each sample was analysed in triplicate at 0, 3, 7, 14, 28 and 56 days. RESULTS: Carvedilol stayed stable in the acidic aqueous solution at the three different temperatures during the 56 days of the study. In the alkaline solution, carvedilol was stable during 56 days at 25°C, but only 28 days at 4 and 40°C. In the aqueous suspension, carvedilol was stable during 56 days at 4 and 25°C, but only 28 days at 40°C. CONCLUSIONS: All the formulations that were tested can be stored at 25°C for at least 56 days.
Assuntos
Carbazóis/farmacologia , Propanolaminas/farmacologia , Administração Oral , Carbazóis/administração & dosagem , Carvedilol , Criança , Estabilidade de Medicamentos , Humanos , Soluções Farmacêuticas , Propanolaminas/administração & dosagem , SuspensõesRESUMO
The clinical use of cisplatin is highly limited by its nephrotoxicity, which has been associated with mitochondrial dysfunction. We investigated the protective effect of carvedilol, an antihypertensive with strong antioxidant properties, against the nephrotoxicity induced by cisplatin in rats. Carvedilol was able to counteract the renal damage by preventing the mitochondrial dysfunction induced by cisplatin. The mitochondrial eletrochemical potential, calcium uptake, respiration and the phosphorylative capacity were preserved by the co-administration of carvedilol. The mechanism of protection probably does not involve alterations in the cellular and sub-cellular distribution of cisplatin. The study suggests that carvedilol is a potential drug for the adjuvant nephroprotective therapy during cisplatin chemotherapy.
Assuntos
Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Carbazóis/farmacologia , Cisplatino/toxicidade , Nefropatias/prevenção & controle , Mitocôndrias/efeitos dos fármacos , Propanolaminas/farmacologia , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Antineoplásicos/administração & dosagem , Antioxidantes/administração & dosagem , Cálcio/metabolismo , Carbazóis/administração & dosagem , Carvedilol , Cisplatino/administração & dosagem , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/ultraestrutura , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Propanolaminas/administração & dosagem , Ratos , Ratos WistarRESUMO
We investigated the clinical response of chronic heart failure patients with beta(2)-adrenergic receptor Gln(27)-->Glu polymorphism treated for 6 months with carvedilol, a alpha/beta-antagonist with antioxidant properties. The 6-min. walk test, the left ventricular ejection fraction, heart rate, plasma norepinephrine and malondialdehyde, a stress oxidative marker, concentrations were evaluated at baseline and after treatment for 6 months with carvedilol in 33 stable chronic heart failure patients with the Gln(27)-->Glubeta(2)-adrenergic receptor polymorphism. Carvedilol significantly increased the left ventricular ejection fraction, while decreasing the heart rate and malondialdehyde plasma concentrations in chronic heart failure patients with the Glu(27)beta(2)-adrenergic receptor allele. There were however, no significant changes in patients with the Gln(27)beta(2)-adrenergic receptor variant.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Carbazóis/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Polimorfismo Genético , Propanolaminas/uso terapêutico , Receptores Adrenérgicos beta 2/genética , Antagonistas de Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacologia , Carbazóis/administração & dosagem , Carbazóis/farmacologia , Carvedilol , Doença Crônica , Regulação para Baixo , Feminino , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Farmacogenética , Propanolaminas/administração & dosagem , Propanolaminas/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
INTRODUCTION: The aim of the work was to establish the impact of urethane-chloralose anaesthesia on pharmacokinetic-pharmacodynamic (PK-PD) properties of carvedilol in control rats and L-NAME hypertensive animals. METHODS: Male Wistar Rats were randomly divided into: control (n=12) with tap water to drink and L-NAME rats (n=12) with L-NAME solution (40 mg/kg/day) to drink for 2 weeks. Effects of carvedilol (1 mg kg(-1), i.v.) on blood pressure and heart rate were recorded during 3 h in conscious and urethane (500 mg kg(-1), i.p.) - chloralose (50 mg kg(-1), i.p.) anaesthetized rats. Carvedilol plasma pharmacokinetics was studied by means of traditional blood sampling. PK-PD modeling of carvedilol was made by means of an effect compartment model. RESULTS: Neither urethane-chloralose nor L-NAME modified estimation of pharmacokinetic parameters of carvedilol. Although urethane-chloralose did not modify potency of carvedilol comparing with awake animals in control and hypertensive group, maximal negative chronotropic response was significantly greater in anaesthetized L-NAME rats in comparison to awake animals. Conversely, anaesthesia did not modify maximal chronotropic response to carvedilol in control rats. Whilst no differences were found in the estimated potency of carvedilol hypotensive response comparing control and L-NAME rats in both awake and anaesthetized conditions, maximal hypotensive effect of carvedilol was significantly greater in anaesthetized control and L-NAME animals in comparison to conscious rats. L-NAME rats showed a greater maximal hypotensive response comparing to control group. DISCUSSION: Urethane-chloralose anaesthesia is an acceptable experimental condition for the evaluation of PK-PD properties of carvedilol, considering that it does not affect the potency of carvedilol for its chronotropic and hypotensive effect. Conclusions obtained from urethane-chloralose anaesthetized animals, regarding the impact of l-NAME treatment on PK-PD properties of carvedilol, did not differ from those obtained from conscious animals. Anaesthesia did not modify pharmacokinetic behaviour of carvedilol in both normotensive and L-NAME hypertensive rats.