RESUMO
PURPOSE: To use cardiovascular data from computerized tomographic (CT) pulmonary angiography for facilitating the identification of pulmonary hypertension (PH) in patients without acute pulmonary embolism. MATERIALS AND METHODS: The institutional human research committee approved this retrospective study; informed consent was waived. Patients without pulmonary embolism who underwent CT pulmonary angiography and echocardiography within 24 hours of each other between December 2008 and October 2012 were retrospectively identified. The diameters of the pulmonary artery, aorta, and right and left ventricles and the severity of reflux of contrast material were assessed. The volumes of each cardiac compartment were calculated. Doppler echocardiography served as a reference standard for PH. A prediction model for PH was built by using backward logistic regression and was presented on a nomogram. The prediction model was evaluated with 10-fold cross-validation, and a test group of patients was studied between November 2012 and June 2014. RESULTS: The final study group included 182 patients, of whom 98 (54%) were given a diagnosis of PH on the basis echocardiographic results. Age of 67 years or older (odds ratio [OR] = 4.46), reflux grade of 3 or higher (OR = 2.63), right atrial volume of greater than or equal to 106 cm(3) (OR = 3.59), pulmonary artery diameter greater than or equal to 28 mm (OR = 2.52) and pulmonary artery diameter to aorta diameter ratio of greater than or equal to 0.86 (OR = 2.17) were independently associated with PH. The logistic model showed good discrimination ability (area under the curve = 0.844, discrimination slope = 0.359). Tenfold cross-validation showed 85.7% sensitivity, 60.7% specificity, 71.3% positive predictive value, and 76.1% negative predictive value for identification of PH, while the test group showed similar results (84.1%, 60.5%, 71.2%, and 76.7%, respectively). CONCLUSION: Cardiovascular data derived from CT pulmonary angiography are associated with PH, and a nomogram can be created that may facilitate identification of PH after exclusion of acute pulmonary embolism.
Assuntos
Hipertensão Pulmonar/diagnóstico por imagem , Nomogramas , Artéria Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Embolia Pulmonar , Estudos RetrospectivosRESUMO
A series of 2-aminoalkylethers prepared as potential antiarrhythmic agents is described. The present compounds are mixed sodium and potassium ion channel blockers and exhibit antiarrhythmic activity in a rat model of ischemia-induced arrhythmias. Structure-activity studies led to the identification of three compounds 5, 18, and 26, which were selected based on their particular in vivo electrophysiological properties, for studies in two canine atrial fibrillation (AF) models. The three compounds converted AF in both models, but only compound 26 was shown to be orally bioavailable. Resolution of the racemate 26 into its corresponding enantiomers 40 and 41 and subsequent biological testing of these enantiomers led to the selection of (1S,2S)-1-(1-naphthalenethoxy)-2-(3-ketopyrrolidinyl)cyclohexane monohydrochloride (41) as a potential atrial selective antiarrhythmic candidate for further development.
Assuntos
Antiarrítmicos/síntese química , Fibrilação Atrial/tratamento farmacológico , Cicloexanos/síntese química , Éteres/síntese química , Pirrolidinonas/síntese química , Administração Oral , Animais , Antiarrítmicos/farmacocinética , Antiarrítmicos/farmacologia , Fibrilação Atrial/etiologia , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Cicloexanos/farmacocinética , Cicloexanos/farmacologia , Cães , Estimulação Elétrica , Éteres/química , Éteres/farmacologia , Feminino , Humanos , Masculino , Camundongos , Estrutura Molecular , Isquemia Miocárdica/complicações , Técnicas de Patch-Clamp , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Pirrolidinonas/farmacocinética , Pirrolidinonas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/fisiologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Obstructive sleep apnea (OSA) shares many cardiovascular risk factors with metabolic syndrome, including obesity, hypertension, insulin resistance, and pro-inflammatory state. This study aimed to examine the possible association of OSA severity with insulin resistance, inflammation and the metabolic syndrome. Ninety eight patients suspected for OSA (54.9+/-13.1 years) were studied. Overnight polysomnography and blood sampling was taken for glucose, insulin, high-density lipoprotein(HDL)-cholesterol, triglycerides, high-sensitivity C-reactive protein (Hs-CRP), and serum amyloid A (S-AA). Insulin resistance was estimated by the homeostatic model assessment (HOMA). Each patient was assigned a metabolic score according to the number of discrete components of metabolic syndrome identified, and categorized by OSA severity. Nine patients had primary snoring, nine had mild, 27 moderate and 53 severe OSA. Metabolic score increased from 1.56+/-1.01 to 2.92+/-1.20 with OSA severity (p=0.004), and was correlated independently with apnea hypopnea index (AHI; r=0.432, p=0.001) and with body mass index (BMI; r=0.518 p=0.001). Hs-CRP increased from 3.44+/-4.25 to 5.87+/-4.76mg/dL with OSA severity (p=0.066) and correlated with AHI (r=0.348; p=0.002). Insulin resistance, correlated significantly with AHI (r=0.390 p=0.021). Inflammation, insulin resistance and metabolic syndrome increase with OSA severity. The number of cardinal features of metabolic syndrome increases with an increase in OSA severity, regardless of the BMI.
Assuntos
Resistência à Insulina , Síndrome Metabólica/etiologia , Apneia Obstrutiva do Sono/complicações , Adulto , Idoso , Glicemia/análise , Humanos , Insulina/sangue , Lipídeos/sangue , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Polissonografia , Fatores de Risco , Apneia Obstrutiva do Sono/sangueRESUMO
These studies examined the opioid and non-opioid in vivo and in vitro actions of PD117,302 (((±)-trans-N-methyl-N-[2-(l-pyrrolidinyl)-cyclohexyl]benzo[b]thiophene-4-acetamide), a kappa (κ)-opioid receptor agonist. PD117,302 selectively labeled the κ-opioid receptor in guinea pig cerebellar membranes and in mice the ED50 for analgesia was 2.3µmol/kg. A non opioid cardiovascular assessment of PD117,302 showed that it dose-dependently increased left-ventricular peak systolic pressure in rat isolated perfused hearts but reduced heart rate and blood pressure in anaesthetized rats. Over the concentration range 0.3-30µM in vitro, and dose-range 0.25-4µmol/kg in vivo, PD117,302 dose-dependently prolonged the P-R interval, QRS width and Q-T interval of the rat heart ECG. Naloxone (either 1µM or 8µmol/kg) did not antagonize the observed ECG effects of PD117,302. Cardiac electrical stimulation studies in anesthetized rats showed that threshold currents for capture and fibrillation were increased and effective refractory period (ERP) prolonged. In rats subject to coronary artery occlusion PD117,302 reduced arrhythmia incidence. Intracellular cardiac action potential studies qualified the ECG changes produced by PD117,302 such that there was a dose-dependent reduction in the maximum rate of depolarization of phase 0 (dV/dtmax) and prolongation of the action potential duration (APD). In isolated cardiac myocytes PD117,302 dose-dependently (1-100µM) reduced peak Na(+) current and produced a hyperpolarizing shift in the inactivation curve. Transient outward and sustained outward K(+) currents were blocked by PD117,302. Thus, the ECG changes and antiarrhythmic effects observed in vivo result from direct blockade of multiple cardiac ion channels.
Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/prevenção & controle , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Pirróis/farmacologia , Receptores Opioides kappa/efeitos dos fármacos , Tiofenos/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Potenciais de Ação , Animais , Antiarrítmicos/metabolismo , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Ligação Competitiva , Estimulação Cardíaca Artificial , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Oclusão Coronária/complicações , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletrocardiografia , Cobaias , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Ventrículos do Coração/metabolismo , Preparação de Coração Isolado , Ligantes , Masculino , Camundongos Endogâmicos BALB C , Contração Miocárdica/efeitos dos fármacos , Dor/metabolismo , Dor/prevenção & controle , Limiar da Dor/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Ligação Proteica , Pirróis/metabolismo , Ensaio Radioligante , Ratos Sprague-Dawley , Receptores Opioides kappa/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/metabolismo , Tiofenos/metabolismo , Pressão Ventricular/efeitos dos fármacosRESUMO
The extrapolation from animal data to therapeutic effects in humans, a basic pharmacological issue, is especially critical in studies aimed to estimate the protective efficacy of drugs against nerve agent poisoning. Such efficacy can only be predicted by extrapolation of data from animal studies to humans. In pretreatment therapy against nerve agents, careful dose determination is even more crucial than in antidotal therapy, since excessive doses may lead to adverse effects or performance decrements. The common method of comparing dose per body weight, still used in some studies, may lead to erroneous extrapolation. A different approach is based on the comparison of plasma concentrations at steady state required to obtain a given pharmacodynamic endpoint. In the present study, this approach was applied to predict the prophylactic efficacy of the anticholinergic drug caramiphen in combination with pyridostigmine in man based on animal data. In two species of large animals, dogs and monkeys, similar plasma concentrations of caramiphen (in the range of 60-100 ng/ml) conferred adequate protection against exposure to a lethal-dose of sarin (1.6-1.8 LD(50)). Pharmacokinetic studies at steady state were required to achieve the correlation between caramiphen plasma concentrations and therapeutic effects. Evaluation of total plasma clearance values was instrumental in establishing desirable plasma concentrations and minimizing the number of animals used in the study. Previous data in the literature for plasma levels of caramiphen that do not lead to overt side effects in humans (70-100 ng/ml) enabled extrapolation to expected human protection. The method can be applied to other drugs and other clinical situations, in which human studies are impossible due to ethical considerations. When similar dose response curves are obtained in at least two animal models, the extrapolation to expected therapeutic effects in humans might be considered more reliable.