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Biomedical subjects

E L Pritchett

Publications and source records attributed to E L Pritchett.

At least 73 records · Page 4Linked to original sources
PubMed1984

Influence of cimetidine on verapamil kinetics and dynamics.

The kinetics and dynamics of single doses of verapamil (10 mg iv and 120 mg by mouth) were followed in eight subjects on oral cimetidine (300 mg every 6 hr) and placebo. Cimetidine had no effect on intravenous verapamil kinetics but induced a significant rise in oral verapamil bioavailability. Other kinetic parameters of verapamil were not altered by cimetidine. Verapamil induced a significant slowing of atrioventricular conduction (39.8 msec intravenous; 24.5 msec oral). Although there was a significant increase in oral verapamil bioavailability, after cimetidine, there was no change in PR interval prolongation with either oral or intravenous verapamil. Our data demonstrate the importance of correlating measurable drug effects with kinetic studies when drug interactions are studied and their clinical significance is assessed.

Administration, Oral↗
PubMed1984

The spontaneous occurrence of paroxysmal supraventricular tachycardia.

The seemingly unpredictable occurrence of paroxysmal supraventricular tachycardia has impeded understanding of its clinical course. We documented recurring tachycardia by telephone transmission of the electrocardiogram in 14 patients and measured the "tachycardia-free periods" between the start of therapy and the first recurrence of tachycardia and between successive recurrences. We showed that attacks of tachycardia were clinically independent by calculating the autocorrelation function for 12 to 14 consecutive tachycardia-free periods. We also found that the periods between attacks closely fit an exponential probability distribution, indicating that the occurrence of tachycardia in time was a type of random event called a Poisson process. Furthermore, occurrence of tachycardia was uniformly distributed throughout a dosing interval; there was no predilection for tachycardia to occur late in a dosing interval when plasma drug levels were presumed to be lowest. Measuring the tachycardia-free period is a simple and useful method for objectively studying paroxysmal supraventricular tachycardia and may be applied to the study of other paroxysmal arrhythmias.

Adult↗
PubMed1983

Life-table methods for evaluating antiarrhythmic drug efficacy in patients with paroxysmal atrial tachycardia.

Spontaneous variability in the occurrence of paroxysmal arrhythmias has made it difficult to apply objective and quantitative methods to describe their clinical course. In this study of paroxysmal atrial tachycardia, the "tachycardia-free interval" was used as a quantitative measure of drug efficacy during treatment with oral verapamil. The tachycardia-free interval is the time a patient remains free from an episode of tachycardia after drug treatment is begun. We documented recurrent tachycardia by telephone transmission of the electrocardiogram. Improvement caused by increasing the drug dose (360 versus 480 mg/day) or by comparing verapamil with placebo treatment was demonstrated by upward shifts in the cumulative tachycardia-free interval curves. The tachycardia-free interval is an easily measured clinical variable that has substantial promise in the study of paroxysmal arrhythmias.

Actuarial Analysis↗
PubMed1983

Pharmacokinetic and pharmacodynamic effects of diltiazem.

The pharmacokinetic and pharmacodynamic effects of diltiazem were studied in 8 patients after a short intravenous infusion (20 mg over 10 minutes), a single oral dose (60 or 90 mg), and repeated oral administration (60 or 90 mg every 6 hours for 16 doses). Diltiazem levels decreased in a triexponential manner after intravenous infusion. Terminal half-lives after intravenous, single oral, and repeated oral administration were not significantly different (4.5 +/- 1.3, 3.7 +/- 0.6, and 4.9 +/- 0.4 hours, respectively). The kinetic effects of oral diltiazem were nonlinear. With repeated oral administration, there was accumulation of both diltiazem and its metabolite, deacetyldiltiazem. The diltiazem area under the time versus concentration curve increased by a factor of 2.39 +/- 0.42 (p = 0.00002). Most patients showed a double peaked time versus concentration curve after oral administration, indicating possible enterohepatic recirculation. After intravenous administration, there was a substantial increase in the P-R interval (14.3 +/- 5.4%). Although only small changes in P-R interval were seen with a single oral dose, with chronic administration there was persistent P-R interval prolongation, peaking at 17.3 +/- 5.6% over control. Counterclockwise hysteresis was present in the P-R interval versus plasma diltiazem concentration curve after intravenous administration. Only small changes were seen in heart rate and blood pressure.

Administration, Oral↗
PubMed1983

High-performance liquid chromatographic analysis of diltiazem and its metabolite in plasma.

A rapid, selective and reproducible high-performance liquid chromatographic method for the analysis in plasma of the calcium channel blocking agent, diltiazem, and one of its metabolites, deacetyldiltiazem is described. The method involves extraction with the methyl tert.-butyl ether of the drugs and the internal standard (verapamil), back-extraction into sulphuric acid and reversed-phase chromatography with UV detection. Over a concentration range of 10-1000 ng/ml the average coefficient of variation for diltiazem was 5.4% and for deacetyldiltiazem was 8.3%.

Benzazepines↗
PubMed1983

Efficacy, safety, and pharmacokinetics of a concentration-maintaining regimen of intravenous pirmenol.

A 3-stage, concentration-maintaining intravenous infusion regimen of pirmenol, a new antiarrhythmic agent, was tested for efficacy and safety in 8 subjects with chronic, stable premature ventricular beats. The regimen, which consisted of (1) a priming bolus of 50 mg over 2 minutes, followed by (2) a rapid loading infusion of 2.5 mg/min for 1 hour, and (3) a maintenance infusion of 0.25 mg/min, rapidly achieved and maintained stable plasma pirmenol levels from 0.94 to 2.75 micrograms/ml, during infusions lasting up to 48 hours. Therapeutic efficacy was evaluated during 4-hour infusions in 5 patients utilizing a randomized, double-blind, placebo-controlled study design. Pirmenol suppressed average premature ventricular beat frequency 93 +/- 6% compared with control values (p = 0.03). Pirmenol infusions were unassociated with toxicity. There were slight but significant increases in diastolic blood pressure, QRS duration, and corrected Q-T interval. No significant changes occurred in systolic blood pressure, heart rate, P-R interval, or laboratory variables. Pirmenol is a promising therapeutic agent that warrants further evaluation. The 3-stage infusion satisfactorily achieves and maintains therapeutic plasma pirmenol levels.

Adult↗
PubMed1983

A system for the analysis of long-term electrocardiographic studies in clinical research and training.

A computer system has been developed for the analysis of data from long-term electrocardiographic studies in the context of an institution committed to clinical research and training. The major characteristics required of such a system are intelligence, flexibility, friendliness, and maintainability. These attributes are achieved by a user interface which consists of menus and interactive graphics, and by the use of highly modular software developed in a high-level programming language. The system has been used in studies of the effects of drugs on cardiac arrhythmias and has been easy to learn and convenient to use.

Academies and Institutes↗
PubMed1983

Verapamil plasma binding: relationship to alpha 1-acid glycoprotein and drug efficacy.

The relationship between alpha 1-acid glycoprotein (AAG) plasma concentration and plasma verapamil binding was examined in samples obtained 15 minutes after 10 mg IV verapamil to 15 subjects. There was a good correlation (r = 0.83) between the binding ratio and AAG concentration, suggesting that AAG could bind verapamil. This was confirmed in vitro by the addition of AAG to an albumin solution, which resulted in a strong correlation between binding ratio (r = 0.99) and AAG concentration. The relationship between both free and total plasma concentrations and the effects of verapamil on the PR interval was also examined several times after 10 mg IV verapamil in seven of the subjects. While there was a correlation between log of both concentrations and the percent prolongation in PR interval (P less than 0.001), the correlation was stronger with free drug concentration (r2 = 0.58) than with total plasma concentration (r2 = 0.36). The range of free concentrations associated with a given effect (220%) was also narrower than that for total concentration (300%). While these data indicate that AAG is responsible for most of the variability in plasma verapamil binding, which in turn contributes somewhat to variation in effectiveness of a given total plasma concentration, neither of these causes of individual variations is likely to have a major clinical impact in patients who, apart from arrhythmia, are otherwise healthy.

Chromatography, High Pressure Liquid↗
PubMed1982

Pharmacokinetics of verapamil: experience with a sustained intravenous infusion regimen.

Disappearance kinetic characteristics of verapamil were determined in 9 patients after a single intravenous dose. From the pharmacokinetic variables determined, we designed an intravenous regimen to maintain a plasma verapamil concentration of 150 ng/ml consisting of (1) a loading bolus (10 mg over 2 minutes), followed by (2) a rapid loading infusion (0.375 mg/min) for 30 minutes, and finally (3) a maintenance infusion (0.125 mg/min). We tested this regimen in 7 patients for 2 to 12 hours, and found it to be safe and to produce stable prolongation of the P-R interval. Verapamil concentration was highest immediately after the bolus administration and was prevented from falling below 67 ng/ml by the rapid infusion. Maintenance concentration remained between 77 and 156 ng/ml for all patients, and averaged 122 ng/ml. Transient and slight decreases in brachial blood pressure and sinus cycle length occurred coincident with the maximum verapamil concentration. Maximum P-R prolongation lagged behind peak plasma concentration but was sustained for the duration of the infusion. Prolongation of the P-R interval was not significantly different at the end of the infusion from that 90 minutes after the start of the regimen. No patient demonstrated significant side effects, arrhythmia, or clinically important hypotension. Although the specified regimen produced a final concentration averaging 125 ng/ml, it is predicted that infusion regimens producing other plasma concentrations can be similarly devised by changing the bolus, rapid loading infusion, and maintenance infusion doses in proportion to the desired final plasma concentration.

Adult↗
PubMed1982

Hemodynamic effects of the antiarrhythmic drug pirmenol.

We examined the hemodynamic effects of pirmenol, a new antiarrhythmic drug, for the first time in man. Right and left heart pressures, Fick cardiac output, and radionuclide ejection fraction were measured before and during infusion of pirmenol in 10 patients with coronary artery disease who were undergoing routine diagnostic cardiac catheterization. Pirmenol was given as a 50-mg IV injection over 2 min followed by a constant infusion of 2.5 mg/min for up to 36 min. Plasma pirmenol levels were within or near the previously determined therapeutic range in all patients. There were no significant changes in systolic blood pressure or cardiac output. Diastolic blood pressure rose from a mean (+/- SD) 78 +/- 7 during the control period to 82 +/- 6 during the infusion, heart rate rose from 66 +/- 6 during the control period to 75 +/- 7 during infusion and ejection fraction fell from 60 +/- 8 during control to 55 +/- 12 during infusion. Although the left ventricular end-diastolic pressure rose from 6 +/- 2 during control to 8 +/- 3 during the infusion, the left ventricular stroke work index fell and the left ventricular work index per minute did not change. The fall in ejection fraction did not correlate with the control ejection fraction, plasma pirmenol levels, or the change in heart rate. The decline in ejection fraction and the failure of the left ventricular work index per minute to rise despite a small rise in left ventricular end-diastolic pressure may indicate a potential myocardial depressant effect of pirmenol.

Anti-Arrhythmia Agents↗
PubMed1982

Pirmenol kinetics and effective oral dose.

The oral form of pirmenol has not been administered to man. Pirmenol was given by mouth to eight patients with chronic, stable premature ventricular beats (PVBs) to determine effective dose and kinetics. The patients were evaluated with a dose-ranging protocol following by a double-blind, crossover, placebo-controlled study of doses that were effective during dose ranging. Oral doses of 150 to 250 mg induced at least 90% suppression of PVBs 18 of the 19 times they were administered during both protocols. During the double blind experiment, a single oral dose of pirmenol suppressed 95 +/- 8% PVBs/hr (mean +/- SD) for 3 consecutive hr, while placebo suppressed 4 +/- 42% PVBs/hr (P less than 0.01). a 90% or greater reduction in PVBs persisted for a median of 6 hr (range 1 to 8 hr). The range of plasma pirmenol concentrations associated with an at last 90% reduction in PVBs was 0.7 to 2.0 micrograms/ml. Median half-life (t1/2) was 9.3 hr (range 6.0 to 12.4) with 86.6 +/- 2.4% protein binding and 82.6 +/- 23.6% bioavailability. At peak drug level there was lengthening of the QTc interval (0.036 sec, P less than 0.05), but no change in heart rate, blood pressure, PR interval or QRS duration, or symptoms. In this single-dose study, pirmenol effectively reduced PVBs, has a relatively long t1/2, and was minimally toxic.

Administration, Oral↗
PubMed1982

Comparison of intravenous and oral verapamil dosing.

To compare the effects of intravenous and oral verapamil we examined the prolongation of the PR interval in 11 patients after (1) a single 10 mg IV bolus given over 2 min, (2) a single oral dose of 120 mg, and (3) a sustained concentration-maintaining infusion. Maximal PR interval prolongation was delayed relative to peak plasma verapamil concentration in all patients after the bolus and in seven of 11 patients after oral dosing. In all 11 patients oral verapamil was less potent than a single intravenous bolus of verapamil; the plasma verapamil concentration corresponding to a 10% prolongation of the PR was 39.5 +/- 21.7 ng/ml after the bolus and 146.3 +/- 75.1 ng/ml after the oral dose (P = 0.001). However, there was no such difference between oral verapamil and an infusion in six patients. The plasma verapamil concentration corresponding to a 10% PR prolongation was 35.7 +/- 24 ng/ml after the bolus, 132.5 +/- 80.8 ng/ml after the oral dose, and 85.2 +/- 29.9 ng/ml after the infusion. Maximum PR prolongation (drug efficacy) was comparable for the three methods of administration. There was no evidence of tachyphalaxis during prolonged infusions. We conclude that both oral doses and infusions of verapamil are less potent then bolus doses, but that drug efficacy at the concentrations reached is equivalent for the three. Plasma verapamil concentrations determined after bolus doses appear to underestimate effective plasma concentration when the drug is given by the oral or infusion methods.

Administration, Oral↗