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1.
J Pharmacol Toxicol Methods ; 60(1): 79-87, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19427912

RESUMO

INTRODUCTION: The objective of this study was to use a newly established cardiovascular model using freely moving minipigs to document the hemodynamic and electrocardiographic effects of known pharmacological agents. The data generated are to serve as the basis of pharmacological drug safety evaluations using this new model. METHODS: 6 Göttingen minipigs were equipped with a radiotelemetry system (ITS). Following a recovery period, aortic pressure (AP), left ventricular pressure (LVP), lead II of the ECG and body temperature were continuously recorded throughout an 8 h monitoring period following oral administration of one of the test agents or vehicle. Notocord HEM 4.2 software was used for data acquisition. One known hERG blocker (moxifloxacin (30, 100 or 300 mg/kg)) and one non-selective beta-adrenoreceptor antagonist (propranolol (3, 10 or 20 mg/kg)) were tested in the model using a cross-over study design in 6 pigs. RESULTS: We obtained high signal quality and found stable hemodynamic parameters with low intrinsic heart rates in the Göttingen minipig under resting, pre-treatment conditions. After oral dosing of moxifloxacin, a substantial, dose-dependent increase in the QT-interval duration could be shown, as anticipated for this agent. After propranolol administration, a decrease in HR and left ventricular dP/dt was detected as expected for a beta-adrenoceptor blocking agent. DISCUSSION: The present data demonstrate that using this model in conscious, chronically instrumented Göttingen minipigs, a cross-over study with six animals was sensitive enough to detect a dose-dependent QT prolongation when moxifloxacin was administered in oral doses leading to clinically relevant plasma drug concentrations. Additionally, we could demonstrate the expected propranolol-induced effects on heart rate and myocardial contractility, despite the low intrinsic resting heart rates in these minipigs. These data support the use of the Göttingen minipig as a sensitive cardiovascular and electrocardiographic model for the testing of new pharmaceutical agents.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Modelos Animais , Porco Miniatura , Telemetria/instrumentação , Telemetria/métodos , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/farmacologia , Animais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacologia , Compostos Aza/efeitos adversos , Compostos Aza/farmacologia , Sistema Cardiovascular/fisiopatologia , Relação Dose-Resposta a Droga , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Feminino , Fluoroquinolonas , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Moxifloxacina , Propranolol/efeitos adversos , Propranolol/farmacologia , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Suínos
2.
J Pharmacol Toxicol Methods ; 57(3): 202-11, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18434212

RESUMO

INTRODUCTION: The objective of this study was to evaluate the normal cardiovascular and ECG parameters in freely moving minipigs and to use these data as the basis of pharmacological drug safety evaluation. METHODS: 7 Göttingen Minipigs were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), lead II of the ECG and body temperature were continuously monitored. Notocord HEM 4.2 software was used for data acquisition. Power calculations for the various parameters were done to assess appropriate sample sizes. RESULTS: We obtained excellent signal quality and found stable hemodynamic parameters with a low intrinsic heart rate in the Göttingen Minipig. After oral dosing of vehicle, the hemodynamic parameters returned quickly to baseline values indicating that the procedure was well tolerated. The heart rate dependency of the QT interval had to be corrected individually. A sufficient power could be achieved with a sample size of 4 due to the low variability of the parameters measured. DISCUSSION: These are, to our knowledge, the first data documenting the course of systemic arterial and ventricular hemodynamic parameters in the freely moving Göttingen Minipig over 24 h. As such, they may serve as a basis for future studies in which drug effects are studied in these animals.


Assuntos
Fenômenos Fisiológicos Cardiovasculares , Avaliação Pré-Clínica de Medicamentos/métodos , Eletrocardiografia , Modelos Animais , Telemetria/métodos , Animais , Feminino , Frequência Cardíaca/fisiologia , Masculino , Suínos , Porco Miniatura , Telemetria/instrumentação
3.
J Pharmacol Toxicol Methods ; 56(2): 203-11, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17583538

RESUMO

INTRODUCTION: The objective of this study was to define the normal LVdP/dt (an index of myocardial contractility)-heart rate relationship in telemetered conscious dogs, primates and mini-pigs in our laboratory and to use these data as the basis for an additional parameter useful in drug safety evaluation. METHODS: Trained dogs, Rhesus monkeys, Cynomolgus monkeys and mini-pigs (Goettinger) were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), a lead II ECG and body temperature could be continuously monitored. The contractility index LVdP/dtmax was derived from the LVP signal. Notocord HEM 4.1 software was used for data acquisition. For each species an LVdP/dt-heart rate relationship was evaluated using spontaneous heart rates (HR) throughout the observation period. A validation compound with positive inotropic effects (pimobendan) was then used to investigate the LVdP/dt-heart rate relationship. RESULTS: There was a clear LVdP/dt-HR relationship in the animals tested. The inotropic agent pimobendan demonstrated the expected shift in this relationship. DISCUSSION: Contractility of the myocardium is regulated by autonomic input activating primarily myocardial beta1-adrenoceptors, but it is also affected by the "force-frequency" relationship. Compounds can therefore either directly or indirectly affect the contractility of the heart. The chronotropic effects are routinely measured in preclinical studies; however, the inotropic effects are not routinely analysed in cardiovascular safety studies. Our experience strongly recommends including this evaluation for drug candidate selection. The evaluation of LVdP/dtmax, as an index of myocardial contractile state must, however, take into account its HR-dependency.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Telemetria/métodos , Administração Oral , Animais , Cardiotônicos/administração & dosagem , Cardiotônicos/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos/instrumentação , Avaliação Pré-Clínica de Medicamentos/métodos , Eletrocardiografia/efeitos dos fármacos , Feminino , Humanos , Macaca fascicularis , Masculino , Piridazinas/administração & dosagem , Piridazinas/farmacologia , Reprodutibilidade dos Testes , Processamento de Sinais Assistido por Computador , Especificidade da Espécie , Suínos , Porco Miniatura , Telemetria/instrumentação , Função Ventricular Esquerda/efeitos dos fármacos
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