Tsunetaro Sakurai

Acute hemodynamic effects of a new inotropic agent, OPC-8212, on severe congestive heart failure.

SummaryThe hemodynamic and clinical effects of OPC-8212, a newly synthesized, orally effective inotropic agent, were assessed for the first time in ten patients with severe congestive heart failure by means of right heart catheterization with a Swan-Ganz catheter. Cardiac output was determined by the thermodilution technique. Patients received a single oral dose of 6 mg/kg. To determine the magnitude and time-course of the effects of OPC-8212, measurements were made during an observation period before and 2, 4, 8, and 12 h after administration. Blood was also taken at these times for measurement of the concentration of plasma OPC-8212. No large meals were allowed during the first 4 h. After the single oral dose of OPC-8212, plasma concentrations increased rapidly, reaching an effective level after 8 h and peaking at 12 h. Hemodynamic performance improved as the mean OPC-8212 plasma level increased, with the maximum effect being observed between 8 and 12 h after acute administration of the drug. At 8 h, the cardiac index was increased from the baseline value of 2.4±0.2 (SEM) to 2.8±0.3 l/min/m2 (P<0.01). The stroke work index rose from 26.2±5.1 to 31.7±60 g · m/m2. The excessive pulmonary artery diastolic pressure fell from 22±2 to 17±3 mmHg at 8 h (P<0.001) and to 16±2 mmHg (P<0.001) at 12 h. The incidence of ventricular premature beats was not increased and no other side effects were observed. These changes were not associated with significant changes in heart rate or systolic blood pressure. Thus, this drug appears to be very promising for the long-term treatment of congestive heart failure.

Quinidine-induced rise in ajmaline plasma concentration.

A high‐performance liquid chromatographic method is described for the simultaneous determination of ajmaline and quinidine in human plasma. With 0·5 ml plasma samples of ajmaline and quinidine, concentrations as low as 0·001 and 0·01 μg ml−1, respectively, could be detected and the technique could be used to investigate the effect of quinidine on the pharmacokinetics of ajmaline. Four healthy subjects were given oral ajmaline (50 mg) alone or in combination with quinidine sulphate (200 mg) on separate occasions. When ajmaline was administered alone, its plasma concentrations were less than 0·03 μg ml−1. Quinidine induced a marked increase to give a mean peak concentration of ajmaline which increased from 0·018 μg ml−1 after a single administration to 0·141 μg ml−1 in combination with quinidine. The area under the ajmaline concentration‐time curves was increased 10 to 30‐fold by the concurrent administration of quinidine. According to the one compartment open model, the absorption rate constant of ajmaline did not change appreciably, but the elimination rate constant was reduced to approximately 50% of the value in the absence of quinidine. The results indicate the existence of a significant interaction between oral ajmaline and quinidine.

Myocardial relaxation in atrial fibrillation

Although myocardial contractility has been known to vary from beat to beat in atrial fibrillation, myocardial relaxation in this arrhythmia has not been investigated. In this study, left ventricular relaxation was examined in seven patients with atrial fibrillation (four with mitral valve disease, one with aortic regurgitation, one with secundum type atrial septal defect and one with apical left ventricular hypertrophy). The left ventricular pressure was measured with a micromanometer-tipped catheter and the time constant of isovolumic left ventricular pressure decline (the relaxation time constant) was calculated by means of exponential curve fitting from more than 20 consecutive beats in each patient. The maximal rate of rise of left ventricular pressure (dP/dt) and the relaxation time constant were examined in relation to the preceding RR interval (RR2) and to the ratio of the RR2 interval to the pre-preceding RR interval (RR2/RR1), and the correlation coefficients were obtained. The dP/dt correlated better with RR2/RR1 than with the RR2 interval (0.82 +/- 0.05 versus 0.48 +/- 0.2), but the relaxation time constant did not show any correlation with RR2/RR1 or the RR2 interval (0.03 +/- 0.21 and 0.06 +/- 0.21, respectively). The relaxation time constant was fairly constant in each patient even when the RR2 interval and RR2/RR1 varied greatly. Thus, relaxation in atrial fibrillation is independent of changes in contractility as seen in the relation between postextrasystolic relaxation and postextrasystolic potentiation of contractility.

A multicenter study of a new inotropic agent, piperanometozine (opc-8212) in congestive heart failure: Clinical improvement during short-term treatment

SummaryPiperanometozine (OPC-8212) is a new, orally effective inotropic agent. To evaluate the efficacy of this agent on systemic hemodynamics and clinical symptoms in patients with congestive heart failure, a multicenter study was performed. Thirty four patients with New York Heart Association (NYHA) functional classes II to IV and initially treated with digitalis were enrolled from ten centers. After a washout period of one or two weeks (placebo period), digitalis was replaced by piperanometozine (30 or 60 mg/day) for four weeks, while other drugs were continued. Clinical symptoms, routine physical findings, electrocardiogram, chest roentgenogram, echocardiogram, exercise tolerance time, and routine laboratory data were obtained in 34 patients. Four patients were withdrawn from the study before completion. After the withdrawal of digitalis, heart rate was increased and ejection fraction was decreased. Exercise tolerance time was increased while other parameters were unchanged. At the end of the treatment period with piperanometozine, ejection fraction significantly (p<0.05) increased with a decrease in LV end-systolic volume (p<0.05), whereas heart rate and blood pressure remained unchanged. Systolic blood pressure/LV end-systolic volume (P/V index) tended to decrease after the withdrawal of digitalis and increase during piperanometozine therapy. Exercise tolerance time was further increased (p<0.01) and NYHA functional class was improved in 11 patients, whereas it worsened in only one patient. No major adverse effects were observed. These results indicate that a short-term therapy of oral piperanometozine restored the depressed cardiac performance of the heart and improved clinical symptoms in patients with congestive heart failure. Thus, this promising agent deserves further clinical study in long-term trials.

Kinetics of ajmaline disposition and pharrnacologic response in beagle dogs

Pharmacokinetics and pharmacodynamics of ajmaline were studied in four healthy dogs after intravenous administration of the drug at the infusion rate of 1.0 mg/min for 45 min. Ajmaline exhibited a saturable binding to plasma protein. One kind of binding site was found in the range of observed drug concentrations and its binding capacity showed nearly threefold interindividual difference. The time course of ajmaline concentration in whole blood Cbcould be described by the two-compartment open model and the unbound concentration of ajmaline in plasma Pf wasestimated from Cbby using the hematocrit value and the parameters of plasma protein binding and erythrocyte partitioning. The pharmacologic responses to ajmaline were assessed by recording ECG, and the changes in PQ and QRS interval were studied in relation to ajmaline disposition. When ECG changes were related to the ajmaline concentration, a significant degree of hysteresis was observed. The relationship between the unbound drug concentration and the pharmacologic effect was analyzed by a combined pharmacokinetic-pharmacodynamic model, where the hypothetical effect compartment is connected to the Pfin the central compartment by a first-order process. This model allows estimation of the changes in PQ and QRS intervals after intravenous administration of ajmaline. By comparing the drug effect on PQ and QRS intervals, it was suggested that ajmaline distributes to the atrial and the ventricular tissue in a similar degree and causes a reduction in the conduction rate in both sites with similar activity.

Improved evaluation of hypertrophic cardiomyopathy by biventriculography with axial projection.

To delineate the precise anatomic abnormalities of the interventricular septum (IVS), mitral valve (MV), and left ventricular posterior wall (LVPW) in patients with hypertrophic cardiomyopathy (HCM), we used axial biventriculography (BVG) (hepato-clavicular projection: angled BVG) to examine 17 patients with HCM and four with concentric hypertrophy due to systemic hypertension. We also examined 9 of these 21 patients with conventional left anterior oblique (LAO) BVG (non-angled BVG). The IVS and along axis of the LV cavity when measured by angled BVG were significantly longer than when measured by non-angled BVG. The IVS, MV, and LVPW were better seen in profile in angled than in non-angled BVG. In two patients with HCM with obstruction (HOCM), systolic anterior motion of the anterior leaflet of the MV was readily identifiable with angled BVG, which is usually not the case with non-angled BVG. Thus, angled BVG is superior to conventional LAO BVG in the angiographic assessment of patients with HCM.

Transient intraventricular conduction disturbances in hypertrophic obstructive cardiomyopathy.

ventricular septum, a 2.0 to 2.5 cm defect was demonstrated consistently in the left ventricular side of the septum (Fig. 1) and entered a large, irregularly defined space (aneurysm) communicating witb the right ventricular apex through an 0.5 cm defect in the right ventricular side of the septum (Fig. 2). The aneurysm showed maximal bulging into the right ventricle toward the end of ventricular diastole and became progressively smaller in ventricular systole. The changes resulted from the hypermobility of the thin right side of the septum. The left side of the septum was virtually immobile and no change occurred in the area of septal disruption. -mode echocardiograpby was confusing and nondiagnostic. The echocardiographic findings were confirmed at, surgery, at which time the aneurysm was plicated and the septal rupture into the right ventricle was repaired. The postoperative echocardiogram demonstrated no septal discontinuity and linear echo densities consistent with metallic sutures used to bnttress Teflon pledgets (Fig. 3). Recognition of a dissecting ventricular septal aneurysm following acute myocardial infarction is new and represents an extension of the capabilities of real-time ZDE. The potential now exists for early echocardiographic diagnosis of ventricular septai aneurysm prior to rupture which results in hemodynamic deterioration from ventricular shunting. Wood A: Perforation of the interventricular septum due to cardiac infarction. Br Heart J 6:191, 1944. Peel A: Dissecting aneurysm of the interventricular septum. Br Heart J 10:239, 1948. Scanlon d, Seward J, Tajik A: Visualization of ventricular septal rupture utilizing wide-angle two-dimensional echocardiography. Mayo Clin Proc 54:381, 1979. Farcot J, Boisante L, Rigaud M, Bardet J, Bourdarias J: Two-dimensional echocardiographic visualization of ventricular septal rupture after acute myocardial infarction. Am J Cardiol 45:370, 1980.