G. Dennis Clifton

Effect of heart rate on left ventricular diastolic transmitral flow velocity patterns assessed by Doppler echocardiography in normal subjects

Although a number of factors, including age and ventricular loading, are known to influence the pattern of left ventricular (LV) filling as depicted by Doppler echocardiographic transmitral flow velocities, few and conflicting data are available regarding the influence of heart rate (HR). Therefore, 20 volunteers (mean age 30 years) were evaluated with pulsed-wave Doppler echocardiography, performed with the sample volume placed at the mitral anulus level in the apical 4-chamber projection. Transmitral flow measurements comprised peak and integrated early passive (E) and late atrial (A) filling velocities and the slope of velocity decline from peak E filling. Measurements were recorded during baseline (sinus rhythm, mean 70 beats/min) and during transesophageal atrial pacing (mean 88 beats/min). LV end-diastolic dimension, mean arterial pressure and PR interval (corrected for pacing-induced delay in interatrial conduction time) were unchanged during pacing versus baseline measurements. Peak and integrated E filling velocities averaged 0.59 +/- 0.09 m/s and 6 +/- 1 cm, respectively, at baseline and were not significantly greater at the higher HR. In contrast, baseline peak and integrated A velocities averaged 0.37 +/- 0.06 m/s and 2.3 +/- 0.7 cm, respectively, but were significantly greater at the higher HR (0.5 +/- 0.07 m/s and 3.2 +/- 1.1 cm, respectively [p less than 0.003 vs baseline for each]). Further analysis of a subgroup of 9 subjects for whom Doppler measurements were available at 3 HRs (sinus 70; pacing 80 and 90) yielded strong evidence for a linear relation between HR and peak A velocity (A = 0.008 HR - 0.21, with p less than 0.0001 for significance of the linear trend).(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of oral isradipine in normal volunteers

The pharmacokinetics and relative bioavailability of oral isradipine, a dihydropyridine calcium channel blocking agent, were determined in 42 normal male volunteers participating in two separate studies. Eighteen of the subjects received 2.5‐, 5‐, and 10‐mg oral doses of isradipine solution (Study 1). The remaining 24 subjects received four 2.5‐mg capsules, one 10‐mg capsule, and 10 mg of isradipine as an oral solution (Study 2). Venous blood samples were obtained prior to and at frequent intervals after administration of each dose form. Plasma isradipine concentrations were measured by radioimmunoassay. No significant dose effect occurred with respect to any pharmacokinetic parameter except AUC and Cmax in Study 1. In Study 2, Cmax, tmax, and MRT were significantly different after the solution compared with the capsular formulations. The respective pharmacokinetic parameters (mean ± SD) for the 10‐mg solution and 10‐mg capsule in Study 2 were time to maximum concentration, 0.40 ± .28 and 1.57 ± 0.44 hours; oral clearance, 284.9 ± 105.3 and 317.0 ± 138.4 L/hr; elimination half‐life, 5.36 ± 1.8 and 6.63 ± 2.4 hrs, respectively. Headache, dizziness, and tachycardia were the most frequent adverse effects in both studies.

Effect of Blood Pressure and Afterload on Doppler Echocardiographic Measurements of Left Ventricular Systolic Function in Normal Subjects

Doppler echocardiographic measurements of blood flow velocity and acceleration in the ascending aorta have been shown to be useful descriptors of left ventricular (LV) systolic function. Few data exist, however, regarding the influence of loading conditions, particularly afterload, on these Doppler measurements in human subjects. Therefore, 14 normal volunteers (mean age 28 years) were studied using continuous wave Doppler echocardiography performed from the suprasternal notch both at baseline and during a controlled infusion of methoxamine. LV peak systolic (delta pk) and end-systolic (delta ES) wall stresses were calculated noninvasively using blood pressure and echocardiographic dimensions. Heart rate was kept constant by transesophageal atrial pacing. Methoxamine resulted in significant increases in mean systolic (163 +/- 8 vs 129 +/- 10 mm Hg) and diastolic (93 +/- 7 vs 71 +/- 12 mm Hg) blood pressure, as well as delta pk (277 +/- 25 vs 222 +/- 40 g/cm2 x 10(3] and delta ES (97 +/- 26 vs 77 +/- 19 g/cm2 x 10(3] (p less than or equal to 0.0004 for all). Conversely, peak velocity decreased from 0.91 +/- 0.18 m/s at baseline to 0.8 +/- 0.18 m/s (p less than or equal to 0.002) and peak acceleration decreased from 22 +/- 5 m/s2 at baseline to 19 +/- 5 m/s2 (p less than or equal to 0.006) during methoxamine infusion. Flow velocity integral and LV end-diastolic dimension remained unchanged. Thus, aortic flow velocity and peak acceleration are inversely related to afterload. This relation should be considered when using serial determinations of these Doppler parameters for patients in whom changing levels of afterload might occur.

Effect of heart rate on Doppler indexes of systolic function in humans

Recent investigations have shown Doppler echocardiography to be useful in the noninvasive assessment of left ventricular systolic function. No data exist, however, regarding the influence of heart rate on Doppler measurements of aortic blood flow velocity and acceleration in humans. Thus, 12 normal volunteers underwent continuous wave Doppler ultrasound recording from the suprasternal notch at baseline and during progressive transesophageal atrial pacing at intervals of 10 beats/min between 90 and 140 beats/min while 100% atrial capture and 1:1 atrioventricular conduction were maintained. Subjects were studied both upright (n = 12) and supine (n = 10). With the subject upright at baseline (mean heart rate 77.8 +/- 10.6 beats/min), peak acceleration averaged to 16.8 +/- 3.4 m/s2, and peak modal velocity and flow velocity integral averaged 0.72 +/- 0.14 m/s and 8.4 +/- 2.1 cm, respectively. With pacing at 90 beats/min, peak acceleration decreased to 15.6 +/- 3.6 m/s2, a significant decline from baseline values (p less than 0.005). Similar declines were seen during pacing at 90 beats/min for peak modal velocity and flow velocity integral (0.64 +/- 0.16 m/s and 7.1 +/- 1.9 cm, respectively; both p less than 0.005 versus baseline values). At the peak pacing rate of 140 beats/min, average peak acceleration decreased to 12.8 +/- 3.1 m/s2, and peak modal velocity and flow velocity integral decreased to 0.52 +/- 0.11 m/s and 5.02 +/- 1.25 cm, respectively. A significant linear correlation (r greater than or equal to 0.97, p less than 0.0001) was obtained for the relation between heart rate and peak acceleration, peak modal velocity and flow velocity integral.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of long-term oral carvedilol on the steady-state pharmacokinetics of oral digoxin in patients with mild to moderate hypertension

The effect of multiple oral doses of carvedilol on steady‐state plasma digoxin pharmacokinetics was evaluated in 12 patients with mild to moderate hypertension. Area under the curve (AUC), mean maximum plasma concentration (Cmax), mean time to maximum concentration (Tmax), concentration at 24 hours after the dose (C24), creatinine clearance, renal digoxin clearance, and urinary digoxin excretion were determined after patients took oral digoxin 0.25 mg once/day for 2 weeks. Carvedilol was added to the regimen, and digoxin pharmacokinetics were assessed after 2 weeks of concurrent treatment. The AUC and Cmax for digoxin increased by 14% and 32%, respectively (p<0.05), with no change in Tmax. The 24‐hour urinary digoxin excretion and 24‐hour renal digoxin clearance increased by 45% and 26%, respectively (p<0.05), with no change in creatinine clearance. Carvedilol appears to increase digoxins oral bioavailability as well as renal elimination. The absolute change in digoxin pharmacokinetics was small and not clinically significant. The significance of the interaction in other patient populations remains to be studied.

Multiple dose pharmacokinetics of four different doses of nisoldipine in hypertensive patients.

This randomized double‐blind parallel group study characterized the pharmacokinetics of the calcium channel antagonist, nisoidipine (core‐coat tablets), administered once daily for 7 days in doses of 5 mg (n = 12), 10 mg (n = 13), 20 mg (n = 12), and 30 mg (n = 11) to patients with mild to moderate hypertension. Serial blood samples were obtained from 0 to 24 hours and from 0 to 48 hours after nisoidipine administration on days 1 and 7, respectively. Nisoldipine plasma concentrations were determined by gas chromatography with electron capture detection. No statistically significant difference was found in dose‐normalized area under the curve between the four groups. Area under the curve (standardized to body weight) correlated to dose (r = .74, P < .05). No significant difference existed in oral clearance (L/h/kg) when analyzed for equivalence across the four doses: 8.21 ± 3.47 (5 mg), 11.84 ± 13.85 (10 mg), 11.48 ± 7.49 (20 mg), and 10.36 ± 5.49 (30 mg). The present investigation characterizes the pharmacokinetics of nisoidipine core‐coat tablets in hypertensive patients and demonstrates the dose proportionality or linearity of nisoidipine plasma concentrations and area under the curve, measured over a dose range of 5 to 30 mg.

Home Monitoring of Theophylline Levels: A Novel Therapeutic Approach

This pilot clinical investigation was conducted to compare a home therapeutic drug‐monitoring (TDM) method for theophylline blood levels and a traditional TDM method with respect to various patient outcome factors. Outpatients with chronic obstructive pulmonary disease (COPD) or asthma who were receiving long‐term theophylline therapy were randomized to one of two groups: home TDM or traditional TDM (controls). Patients in the former group monitored their serum theophylline levels at home over 6 months. Patients in both groups completed survey instruments, including questionnaires, visual analog scales, and other psychosocial measures, at designated times throughout the study period. Pulmonary function tests and dyspnea index scores were evaluated at each clinic visit. Results indicated a significantly lower (p < 0.05) number of changes in concomitant drug therapy in the home TDM group compared with controls. Other indicators that showed a trend toward more favorable outcomes in the home TDM group included symptomology, percentage of levels within the therapeutic range, patient attitudes regarding participation in health care management, and pulmonary function test results. Home monitoring prevented unnecessary clinic visits in several instances when theophylline dosage adjustments were based on telephone reports from patients. The utility of a home TDM method for theophylline has not been reported previously despite potential for broad applications. Findings from this preliminary study may support the use and feasibility of state‐of‐the‐art methodologies in carefully selected subpopulations outside the confines of the hospital or clinic setting.

Influence of beta-adrenergic blockade upon hemodynamic response to exercise assessed by Doppler echocardiography☆

Peak aortic blood flow acceleration and velocity measured by Doppler echocardiography have been documented to be accurate descriptors of left ventricular systolic function. Both acceleration and velocity are reduced in the presence of beta-blockade at rest and during exercise. Whether and to what extent the simultaneous alterations in heart rate (HR) due to beta-blockade affect these parameters has received little study. In order to determine the influence of alterations in HR on Doppler measurements of velocity and acceleration, 10 healthy men were studied during upright exercise under control conditions, following propranolol administration, and following propranolol plus transesophageal atrial pacing. In addition, we assessed the response of stroke volume (measured as flow velocity integral) during beta-blocked and control exercise. Propranolol significantly reduced acceleration and velocity during all stages of exercise compared with control values (p less than 0.05). Increasing the HR during exercise via pacing had no effect on acceleration or velocity compared with propranolol administration alone, thus demonstrating that during upright exercise, changes in acceleration and velocity are independent of alterations in HR. At low levels of exercise, propranolol significantly reduced flow velocity integral (FVI) compared with control (-1.14 cm, p less than 0.05.). At high levels of exertion, however, FVI exceeded values obtained during control conditions (1.2 cm at stage 4). Pacing during beta-blockade reduced FVI at high levels of exercise but had no effect at lower levels. Our results suggest that during low levels of exercise stroke volume is increased as a consequence of both increased contractility and augmented left ventricular filling.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary Function in the Elderly: Response to Theophylline Bronchodilation

This clinical investigation was designed to characterize the pharmacologic response to theophylline in elderly individuals. Incremental theophylline plasma concentrations (0, 5, 10, 15, and 20 mcg/mL), achieved through dose escalation of intravenous aminophylline, were correlated with pulmonary airway responses in ten young and ten elderly male asthmatic volunteers. The older group had lower baseline pulmonary function values, suggestive of a greater degree of baseline airways obstruction. Despite wide intersubject variability, the elderly subjects demonstrated a lower absolute change in bronchodilator response to equal concentrations of theophylline than did their younger counterparts (P <.05). A progressive increase in heart rate was noted with increasing theophylline concentrations, but no significant difference in heart rate change between groups was detected (P > .05). Whether the difference in theophylline induced bronchodilator response observed in the young and elderly groups is due to a difference in age or in severity of airway obstruction is yet unknown.

Hemodynamic effects of calcium channel and β-receptor antagonists: Evaluation by Doppler echocardiography

To evaluate the ability of Doppler echocardiography to identify hemodynamic changes due to cardiac medications, 10 volunteers underwent Doppler examination at rest and immediately following vigorous treadmill exercise. Upon completion of the control test, each subject received moderate oral doses of propranolol, verapamil, pindolol, or nifedipine, and the same exercise protocol was repeated. During four control tests, values for peak acceleration and flow velocity integral were similar for each subject at rest and exercise. Following propranolol and pindolol, resting acceleration fell by 4.5 and 2 m/sec2, respectively p less than 0.05. Resting acceleration was unchanged by verapamil and increased following nifedipine by 1.7 m/sec2 (p less than 0.0001), but neither verapamil nor nifedipine altered either Doppler parameter. Flow velocity integral was increased by nifedipine at rest and by each of the beta-blockers during exercise (p less than 0.05). We conclude that (1) rest and exercise Doppler measurements are stable and reproducible, given stable cardiovascular status; (2) pindolol produced less hemodynamic depression as measured by Doppler echocardiography at rest relative to propranolol, but showed similar potency at maximal exertion; (3) nifedipine enhanced global cardiac performance at rest, but neither calcium antagonist affected Doppler measurements during exercise; and (4) Doppler echocardiography is a useful, noninvasive technique for evaluating hemodynamic effects of medication at rest and during vigorous exercise.