I is presently under evaluation for potential utility in essential tremor and seizure disorders. The compound lacks prominent sedative-hypnotic activity usually associated with this chemical class of drugs. I is biotransformed to monomethoxymethyl-5,5-diphenylbarbituric acid (II) and to 5,5-diphenylbarbituric acid (III) in the rat, dog and man. II and III appear to be active metabolites. I has limited aqueous solubility; in an effort to enhance absorption from the gastrointestinal tract, we evaluated the influence of a high fat breakfast on gastrointestinal absorption of I in 23 healthy non-smoking male volunteers between 19 and 54 years of age. The rate and extent of absorption was assessed by measuring the plasma levels of I, II and III over the course of 5 days after an oral dose of 400 mg of I. Results: The mean ratios for Cmax (fed/fasting) for I, II and III were 6.88, 3.14 and 1.59, respectively. Mean tmax ratios (fed/fasting) for the 3 compounds were 0.65, 0.44 and 0.88 for I, II and III. Mean ratios for AUC0-t (fed/fasting) for I, II and III were 2.81, 2.74 and 1.53, respectively. Mean terminal half-lives for I, II and III ranged between 18-26, 16-27 and 39-43 hours, respectively. Conclusion: A high fat meal enhances the oral absorption of T2000 in man as indicated by higher Cmax, earlier tmax and greater AUC after a high fat breakfast than in the fasting state. As expected, terminal half-lives of all 3 compounds did not change.

We studied the physiology of pulmonary venous flow in 13 normal subjects and five patients with atrial rhythm disorders and atrioventricular conduction disturbances with pulsed Doppler and two-dimensional echocardiography. The left atrium, mitral valve, and pulmonary venous ostia were visualized through the apical four-chamber view. Mitral and pulmonary venous flows were obtained by placing the Doppler sample volume at the appropriate orifice. Pulmonary venous flow was biphasic: a rapid filling wave was observed during systole when the mitral valve was closed; a second wave was observed in diastole during the rapid ventricular filling phase of mitral flow, but was significantly delayed. In patients without atrial contraction (atrial fibrillation and sinoatrial standstill), the initial rapid filling was greatly diminished and only the second diastolic wave appeared to contribute to left atrial filling. In patients with high-grade atrioventricular block, each atrial contraction was followed by a surge in flow fromi the pulmonary veins. These results are consistent with data obtained from invasive measurements in both dogs and man, and confirm the validity of the use of pulsed Doppler echocardiography in the study of pulmonary venous flow. We suggest that pulmonary venous flow is influenced by dynamic changes in left atrial pressure created by contraction and relaxation of the atrium and ventricle. The initial peak in pulmonary venous flow occurs with atrial relaxation simultaneously with the reduction of left atrial pressure, and the second peak occurs with left ventricular relaxation and rapid transmitral filling of the ventricle. Circulation 71, No. 6, 1105-1112, 1985. THE PATTERN OF FLOW in the large extraparenchymal pulmonary veins is pulsatile in both dog and man.'-'' The pulsatile nature of pulmonary venous flow has been suggested by several investigators to result from changes in left atrial pressure occurring throughout the cardiac cycle.' 6 Others have attributed pulmonary flow to forward transmission of pressure pulses from the right ventricle through the pulmonary circulation7"'' or to a combination of the propulsive force of the right ventricle and suction created by the left heart.' I] Simultaneous invasive measurements of pulmonary vein flow and left atrial pressure in a canine preparation and in patients with aortic stenosis revealed that pulmonary vein flow velocity was maximal during the troughs and minimal during the peaks of left atrial pressure.' From the Department of Cardiology. Tel Aviv Medical Center. Tel Aviv University. Sackler School of Medicine. Address tor correspondence: Dr. S. Laniado. Department of Cardiology, Tel Aviv Medical Center. Ichilov Hospital. 6 Weizmann St.. Tel Aviv. Israel. Received Sept. 18 1984; revision accepted Feb. 28. 1985. Vol. 71, No. 6, June 1985 Using pulsed Doppler echocardiography, we stud~ ied the pattern of the pulmonary venous flow in normal subjects and in patients with atrial fibrillation, atrial standstill, and high-grade atrioventricular block to attempt to elucidate the relationship between pulmonary venous flow, atrial systole, and other events occurring during the cardiac cycle. Materials and methods Subjects. Eighteen individuals were recruited to participate in the study and data from all are reported. Eleven subjects were normal student volunteers; one was a normal baby and another a normal octagenarian. Two patients had --loneatrial fibrillation, one patient had isolated sinoatrial standstill, one patient had 2:1 atrioventricular block, and another patient had complete atrioventricular block. The latter patients had primary conduction disorders and presented for pacemaker implantation. Only patients clinically free of structural heart disease were selected for study. All patients underwent thorough clinical evaluation before the study; relevant findings are given in table 1. M mode and two-dimensional echocardiography as well as pulsed Doppler cardiographic studies of the mitral. pulmonary venous, and pulmonary arterial flows were performed. Echocardiographic studies. An Electronics for Medicine/

Warfarin is, among drugs, considered to have a narrow therapeutic index for which individual bioequivalence has been suggested. To establish the propriety of "switching," an individual bioequivalence study involving a replicate-design study and three "switchings" in healthy subjects was undertaken using the U.S.-brand warfarin sodium tablet and a generic product. A randomized, single-center, open-label, single-dose, four-way crossover replicate bioequivalence study was performed in 24 healthy male volunteers in which each subject received the same 5 mg warfarin test and reference tablets twice on different occasions under fasting conditions. Concentrations of warfarin in plasma were measured by a validated specific HPLC method. The individual pharmacokinetic parameters obtained with test and reference products were compared using pooled data and Liu's method. Bioequivalence was shown with both average and individual bioequivalence methods. The individual bioequivalence assessment did not show a subject-by-formulation interaction, nor did it add value to the bioequivalence assessment of warfarin.

Background and objectives: Carbamazepine is among those drugs that have been considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administration has approved new generic products based on standard single-dose bioequivalence studies, several state formularies, including the New Jersey Drug Utilization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting the use of some approved generic drugs in specific states. To further validate the adequacy of single-dose studies for the determination of bioequivalence of narrow therapeutic index drugs, a multiple-dose study was conducted that more closely reflected therapeutic use.Methods: A single-center, multiple-dose, randomized, open-label, 2-way crossover bioequivalence study was conducted in 32 fasting volunteers at steady state, Subjects received the test and reference products as a 200 mg carbamazepine tablet 3 times a day in a crossover fashion. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in plasma were measured by a validated specific HPLC method.Results: A total of 28 subjects completed the study, Pharmacokinetic parameters and measures of fluctuation for both products at steady state were similar, with 90% and 95% confidence intervals falling within 90% and 110%,Conclusion: The multiple-dose study provided reliable safety and bioequivalence data under rigorous statistical conditions and confirmed bioequivalence of test and reference products determined by a single-dose study.

While the three classical pharmacokinetic (PK) parameters, AUC, Cmax and tmax are adequate to assess bioequivalence of immediate release (IR) formulations, they are not designed to fully characterize the pharmacokinetic (PK) performance of controlled release (CR) formulations and provide only limited insight into the function of carbamazepine (CBZ) CR products. Thus, for reliable assessment of bioequivalence in CR formulations, there is a role for the use of additional criteria (parameters). The following are the proposed new parameters: MRT (mean residence time), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), tapical (the arithmetic mean of the times associated with POT) and Capical (the arithmetic mean of the concentrations within 25% of Cmax). The above proposed parameters, were utilized in a recent PK study of new CR products of CBZ (600 mg) designed for once daily dosing. The comparative PK analysis was conducted in a three-way crossover single dose studies of three CBZ CR formulations (Teril 600 CR tablet, CBZ 600 granulate and Timonil 600 Retard tablet). Teril 600 CR was found to be bioequivalent to Timonil 600 Retard while CBZ 600 granulate was not. This conclusion was reached utilizing both the classical and the proposed new parameters. The new parameters showed that CBZ 600 granulate has similar rate of absorption as the two 600 mg CR tablets, but its extent of absorption was lower. The new parameters examined in this paper are more attractive than the single point parameters, Cmax and tmax, for assessment of rate of absorption and the flatness of the plasma concentration versus time curve. Their potential benefit and practical utility was confirmed in this study, which demonstrated bioequivalence between a new CR and an innovator CBZ (600 mg) tablet. Absorption rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

Summary: Purpose: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled‐release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (Cmax), and time to reach Cmax (tmax), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time‐concentration curve. They include mean residence time (MRT), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), tapical, and Capical, (the arithmetic mean of the POT times and concentrations within 25% of Cmax respectively). Additional parameters for multiple‐dose studies include the percentage fluctuation and the flatness of the steady state‐concentration curve. Methods: These proposed parameters were used in two recent (single and multiple dose) two‐way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab. Results: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time‐concentration curves as assessed by visual inspection and the proposed parameters. Conclusions: The additional parameters examined may supplement the traditional single‐point parameters, Cmax and tmax for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption‐rate assessment is important in light of concentration‐related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

The pathophysiology of the syndrome of congestive heart failure (CHF) includes 2 major components that closely interact. The first one is a reduction in ventricular performance, which is manifested initially during exercise and is later present at rest. The second one involves abnormalities of the peripheral circulation and organs, which become gradually more prominent and lead ultimately to symptoms. The exercise capacity of patients with chronic CHF is limited not only by an inadequate increase in cardiac output and an excessive increase in ventricular filling pressure, but also by a fixed vasodilatory response to exercise. Although the role of increased activity of the sympathetic and renin-angiotensin-aldosterone systems in the derangements of the peripheral circulation has been extensively investigated, the structural abnormalities of the arterial wall have received little emphasis in patients with CHF. Chronic reduction of the cardiac output may lead to endothelium-dependent reduction in arterial diameter and vasomotor response, which may in turn increase systemic vascular resistance and further reduce cardiac output. Therapeutic agents should be characterized by their acute and chronic effects not only on ventricular performance, but also on the peripheral circulation. More specifically, when one is concerned with the effect of a therapeutic intervention on exercise capacity, evaluation of its direct and indirect effects on the skeletal muscle vasculature is particularly important. Accordingly, the effects of phosphodiesterase inhibition on vascular smooth muscle tone and skeletal muscle vasculature are reviewed. In addition, the potential of phosphodiesterase inhibition to reverse structural abnormalities of the arterial wall is discussed.

Digitalis is a drug widely used in modern medicine for the control of ventricular response in atrial fibrillation and the treatment of congestive heart failure (CHF). Recently, the use of digitalis for the treatment of CHF in patients in sinus rhythm has become quite controversial. The findings of several clinical studies suggest a small but definite hemodynamic or clinical improvement in patients treated with digitalis. These effects are limited by the onset of toxicity, which is at least partially mediated via the central nervous system. If the inotropic effect of the drug could be separated from the central nervous system effect, much higher doses of digitalis could be tolerated and presumably a greater therapeutic effect could be obtained.