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1 The elimination and anticoagulant activity of a single intravenous dose of warfarin (1.0‐1.2 mg/kg) without and with concomitant cholestyramine treatment (about 4 g three times daily) was studied in five healthy male subjects. 2 Cholestyramine treatment decreased the biological half‐life of plasma warfarin (from a mean value of 2 days − 1.3 days) and increased the total clearance of this drug (from a mean value of 37 ml kg‐1 day‐1–53 ml kg‐1 day‐1). 3 The total anticoagulant effect per dose of warfarin, as measured by the area under the effect v time curve, was also reduced by cholestyramine (average reduction of about 25%). 4 Warfarin possibly undergoes enterohepatic recycling in man which can be interrupted by cholestyramine.

Hemodynamic response to graded immersion was studied in healthy male subjects in a thermoneutral bath in the sitting position. Pressures in the right heart and cardiac output were determined by means of a semifloating catheter with a thermistor probe. Pressures in the right atrium, pulmonary artery and in pulmonary wedge position increased with increasing depth of immersion, cardiac output was likewise augmented. Heart rate decreased from rest to hip immersion but remained constant from hip to head out water immersion. Plasma norepinephrine concentration remained constant throughout the experiment. The reported changes depend on the blood shift from capacitance vessels into the thoracic cavity. From this, preload increased and cardiac performance was improved. However, in patients with disturbed left ventricular function, immersion to the neck may be potentially hazardous due to augmented left ventricular filling pressure.

In a cross-over study, the cardiovascular effects of dobutamine were assessed in 11 patients who had undergone operation for replacement of the mitral or aortic valve approximately four hours earlier. In 9 of these the effects of isoprenaline were assessed for comparison. Dose-resporse curves were obtained using four dose levels of dobutamine in the range 1-25-10 Vg/kg per min and of isoprenaline in the range of 0 005-0 04 [tg/kg per min. Both drugs produced similar dose-dependent increases in heart rate and cardiac output and a dosedependent decrease in peripheral resistance. Mean arterial pressure was only slightly increased by either drug. The positive inotropic effect of dobutamine was confirmed, but the chronotropic effect was not significantly different from that of isoprenaline. This contrasts with the findings of previous studies, and possible reasons for this are discussed.One of the most serious sequels of cardiac surgery is naline were compared in 9 patients, the other 2 cardiovascular failure associated with low cardiac receiving dobutamine alone. Only those patients output (Dietzman et al., 1969). Isoprenaline is of in sinus rhythm and free of other postoperative benefit in this situation (Harrison, Kerber, and complications requiring continuous intensive treatAlderman, 1970) but its use is often limited by the ment were included in the study. Patients in atrial development of excessive tachycardia or of ven-fibrillation were excluded because dobutamine is tricular arrhythmias (Beregovich et al., 1971). The known to shorten atrioventricular conduction time results of animal (McRitchie et al., 1973; Tuttle, (Sinno et al., 1973). All were receiving intermittent 1974; Tuttle and Mills, 1975) and clinical studies positive-pressure respiration via endotracheal tube in man (Jewitt et al., 1974) suggests that dobuta-and had been sedated intravenously with diazepam mine, a novel sympathomimetic amine, has a lesser and papaveretum (2-5 to 5*0 mg of each). No other chronotropic effect than isoprenaline at doses drugs had been given after operation. The study equipotent in inotropic effect.took place approximately four hours after the end The purpose of the present clinical study was to of the operation and other intravenous infusions compare the effects of dobutamine and isoprenaline were interrupted during administration of dobutaon heart rate, cardiac output, and arterial pressure mine or isoprenaline.during the early postoperative period after heart Heart rate was determined by auscultation for one valve replacement. minute. Cardiac output was measured by the indicator dilution technique. Indocyanine green Patients and methods (5 mg dissolved in 1 ml saline) was injected through a pulmonary artery catheter inserted at the time of Eleven patients (5 male, 6 female) aged 16 to 63 operation. Blood from a cannulated radial artery years (mean 4041) were studied. All had undergone was pumped through a Gilford cuvette densitometer single valve replacement (6 aortic, 5 mitral) with using a Harvard pump. Post-stud...

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Cardiovascular effects of 1-butyl-3(1-(6,7-dimethoxyquinazolin-4-yl) piperidin 4 yl urea) (BDPU) were studied in 16 anesthetized dogs and in 7 healthy male volunteers. In animal experiments intravenous doses of 100, 250, and 500 mug/kg/min produced dose-related, significant increases in cardiac output and peak left ventricular dp/dt. No changes in heart rate and blood pressure occurred at 100 mug/kg/min, whereas higher doses caused falls in both systolic and diastolic blood pressures, accompanied by significant rises in heart rate. Inotropic effects could also be demonstrated in man. Changes of the systolic time intervals were dose-related and began at 64 mug/kg/min. At 250 mug/kg/min, the highest dose administered, the pre-ejection period decreased by 14.8 +/- 4.42 msec and its ratio with left ventricular ejection time by 0.049 +/- 0.017 against their respective control values (p less than 0.01). In contrast to animal experiments, no hypotension or tachycardia was observed in any subject. Pharmacokinetic studies showed a plasma elimination half-life of 76 +/- 3 min (mean +/- SE). There were no subjective side effects and standard laboratory tests were not altered, but there was a slight but significant rise in the urinary enzymes, lactic dehydrogenase (LDH) and glutamic oxaloacetic transaminase (GOT), which persisted up to 7 days.

The cardiovascular effects of dobutamine, a derivative of dopamine have been investigated in seven patients with chronic left ventricular dysfunction. The patients were either suffering from coronary heart disease or from cardiomyopathy.Dobutamine was administered at doses of 2.5-5.0-7.5-10.0 and 15.0 gg/kg/min. The following parameters were measured: aortic pressure, left ventricular pressure (LVEDP, LVdp/dt ..... ) by using a Millar tip manometer, pulmonary artery pressure and cardiac output (dy-dilution technique).The positive chronotropic effect of dobutamine was small in the lower dosage range and reached significance only with the highest dose of 15.0 tig/kg/ min. Systolic aortic pressure was increased moderately over the whole dosage range (p < 0.05). However the increment of mean aortic pressure ( + 11 mm Hg), of stroke volume ( + 22%) and of stroke work ( + 49%) was already maximum (p < 0.05) at a dose of 5.0 gg/ kg/min.The positive inotropic action of dobutamine caused a dose related increase of cardiac index and of LVdp/dtm~, of + 53% and of + 193% respectively. This effect was accompanied by a continuous and significant decrease of LVEDP and of peripheral resistance. Dobutamine induced arrhythmias have not been observed. 15 rain after infusion stop, no dobutamine effect could be detected. These findings demonstrate that the actions of dobutamine are not merely cardioselective. However, in the dose range between 2.5 and 15.0 lag/kg/min a positive inotropic effect is predQminant. Further clinical trials with dobutamine on patients with severe myocardial dysfunction and low output syndrome may yield promising results.Sonderdruckanfragen an: Prof. Dr. P. Limbourg (Adresse s. n. Lit.) Key words: Dobutamine -Contractility -Low output cardiac failure -Low output state.