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Biomedical subjects

J A Pieper

Publications and source records attributed to J A Pieper.

At least 37 records · Page 2Linked to original sources
PubMed1988

Effects of chronic phenobarbital on verapamil disposition in humans.

Very little is known about the effects of hepatic enzyme induction with phenobarbital on the disposition of high clearance drugs in humans. Our study was undertaken to investigate the effect of phenobarbital on both alpha-1 acid glycoprotein concentrations and total and free verapamil and its metabolites. Single oral, single i.v., and multiple oral verapamil administrations were evaluated before and after 21 days of phenobarbital treatment in healthy caucasian male volunteers. Significant changes in the pharmacokinetics of total and free verapamil and its metabolites occurred in a predictable manner. Mean total apparent oral clearance after a single dose of verapamil was increased after phenobarbital treatment (75.1 +/- 49.2 vs. 376.2 +/- 221.8 ml/min/kg, P less than .05). Clearance of free drug increased to a similar magnitude. Mean total verapamil systemic clearance was increased (9.95 +/- 1.3 vs. 18.9 +/- 8.7 ml/min/kg, P less than .05); however free drug clearance was not altered. After multiple oral administration, total verapamil apparent oral clearance was increased after phenobarbital pretreatment (21.2 +/- 9.8 vs. 91.2 +/- 28.5 ml/min/kg, P less than .05). Free drug clearance was increased similarly. Finally, the pharmacokinetic theories derived for hepatic extraction of drugs subject to a high metabolic clearance can be successfully applied to men after liver enzyme induction with phenobarbital.

Adult↗
PubMed1987

Nonlinear pharmacokinetics of unbound propranolol after oral administration.

After multiple oral doses, propranolol has been reported to accumulate to a greater degree than expected based on its terminal elimination rate constant and dosage interval. To determine whether the decrease in presystemic elimination can be attributed solely to a decrease in unbound intrinsic clearance or possibly a decrease in unbound fraction, we studied the pharmacokinetics of unbound propranolol in nine healthy subjects who were given 160 mg of regular or sustained-release propranolol orally as single doses, and once daily for 7 d. Unbound propranolol concentrations were calculated by HPLC and equilibrium dialysis on each serum sample. With regular propranolol, the mean unbound oral clearance (CLoral) decreased 29%, from 503 +/- 281 after a single dose to 359 +/- 143 mL/min/kg at steady state (p less than 0.05). Similarly, CLoral decreased 33% with sustained-release propranolol from 1077 +/- 514 to 721 +/- 385 mL/min/kg (NS). The corresponding accumulation ratios for regular and sustained-release propranolol were 1.39 +/- 0.49 and 1.61 +/- 0.81, respectively (NS). Therefore, the mean bioavailability of sustained-release relative to that of regular propranolol was 0.52 +/- 0.23 and 0.54 +/- 0.17 for single doses and at steady-state, respectively. The percent unbound of propranolol ranged from 6.8 to 14.0 with an average of 10.1. Neither the percent unbound nor alpha 1-acid glycoprotein (AAG) serum concentrations were statistically different between single and multiple doses. The binding ratio was significantly correlated to AAG concentration (r = 0.776, p less than 0.05). The data support a decrease in unbound intrinsic clearance of propranolol with no change in unbound fraction, leading to an increase in bioavailability at steady state.

Administration, Oral↗
PubMed1987

Lidocaine protein binding in preeclampsia.

The effect of preeclampsia on the binding of lidocaine to serum proteins was studied in 25 term parturients with severe preeclampsia and in 21 normal parturients serving as controls. There were no statistically significant differences in mean lidocaine free fraction, binding ratio, or serum AAG levels in the control vs preeclamptic patients, respectively. Binding ratio was strongly correlated with AAG concentration for the control (r = 0.91) and preeclamptic (r = 0.85) patients. A statistically significant difference was observed in the slopes of the lines relating binding ratio to AAG. Preeclampsia had little affect on serum AAG concentrations and lidocaine binding ratio. Preeclampsia may alter the interaction of lidocaine with binding sites on AAG without a significant change in lidocaine free fraction.

Blood Proteins↗
PubMed1987

Acute effects of short-term subcutaneous terbutaline on theophylline disposition.

Theophylline and subcutaneous terbutaline are frequently used concurrently in the management of acute asthma. Recent evidence demonstrating a reduction in theophylline serum concentrations during concomitant oral terbutaline therapy prompted our evaluation of subcutaneous terbutaline's effect on theophylline pharmacokinetics. Using a randomized, placebo controlled, crossover design, the disposition of a single oral theophylline dose (7 mg/kg) was studied in eight healthy, adult males before and after repeated subcutaneous administration of terbutaline (0.25 mg). Two-way analysis of variance revealed no significant difference in elimination rate constant (ke), area under the concentration-time curve (AUC), or apparent oral clearance (CL/F) of theophylline following terbutaline administration. These results indicate that subcutaneous administration of terbutaline does not alter the pharmacokinetics of single, oral doses of theophylline in adults.

Adult↗
PubMed1987

Propranolol pharmacokinetics and pharmacodynamics after single doses and at steady-state.

The duration and extent of cardiac beta-blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steady-state for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0-24 h/AUC single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SR, there was no difference in the area under the effect-time curve at steady-state.

Administration, Oral↗
PubMed1987

Gallopamil binding to human serum proteins.

We have determined the extent and variability in the binding of gallopamil to human serum proteins. Binding was determined by equilibrium dialysis in healthy volunteer serum, human serum albumin (45 g.l-1), and alpha-1 acid glycoprotein (AAG) (600 mg.l-1) at a pH of 7.4. Nonlinear regression analysis of gallopamil binding over a wide range of concentrations (10(-9) to 10(-4) M) in healthy volunteer serum suggested two classes of binding sites (kass.1 = 4.7 x 10(5)M-1, kass.2 = 4.1 x 10(4)M-1). These values were in close agreement with those obtained from binding to AAG and human serum albumin. Gallopamil free fraction over the concentration range of 10 to 100 ng.ml-1 was independent of concentration. The free fraction in 20 volunteers was 0.075 at a concentration of 10 ng.ml-1. Gallopamil free fractions were also determined in human serum albumin, to which various concentrations of AAG were added. Bound/free ratios correlated with AAG. As we changed the pH of the serum from 7.0 to 8.0, the free fraction changed from 0.1 to 0.05. Verapamil, lignocaine, procainamide, propranolol, 40 H-propranolol, MEGX, and NAPA all caused an increase in the free fraction of gallopamil in serum. However, tocanide, quinidine, diltiazem, GX, norverapamil, D620, D617, and desacetyl diltiazem had no effect on gallopamil binding. Therefore, the data strongly suggest AAG as the high affinity, low capacity binding site and albumin as the low affinity, high capacity binding site for gallopamil, variability in gallopamil binding can be explained by alterations in AAG concentrations, pH, and the presence of other drugs and their metabolites.

Blood Proteins↗
PubMed1987

Propranolol pharmacodynamic modeling using unbound and total concentrations in healthy volunteers.

In an attempt to evaluate the propranolol (P) concentration-effect relationship, percentage reduction in exercise heart rate was modeled as a function of unbound and total P concentrations using the linear, Emax, and sigmoid Emax models. Nine volunteers underwent repeated treadmill exercise tests over 48 hr during a control period, after receiving 160 mg of P orally and again after receiving 160 mg once daily for 7 days. Beta blockade was assessed as the percentage reduction in exercise heart rate compared to control. Total serum P concentrations were determined by HPLC and unbound fractions by equilibrium dialysis. Using nonlinear least-squares regression, the Emax model was best in describing the concentration-effect relationship in each subject. Mean parameters for combined single dose and steady state were Emax 33.6 +/- 4.5% and EC50 18.2 +/- 15.6 ng/ml for total P and Emax 33.5 +/- 4.3% and EC50 1.66 +/- 1.56 for unbound P. Model fits were not significantly better for unbound versus total P and EC50 values showed similar intersubject variability. The observed unbound EC50 values are consistent with reported receptor dissociation constants. Therefore the large intersubject variability in EC50 could not be accounted for by variability in P protein binding.

Adult↗
PubMed1987

Hepatic drug clearance in children with leukemia: changes in clearance of model substrates during remission-induction therapy.

We administered a "cocktail" of three model substrates for hepatic processes: antipyrine for oxidation, lorazepam for glucuronidation, and indocyanine green for hepatic blood flow, to children with acute lymphocytic leukemia (ALL). The plasma clearance of these substrates was determined before and after remission-induction therapy in 14 children with ALL. We found an improvement in clearance of antipyrine (0.65 to 0.95 ml/min/kg; P less than 0.01) and lorazepam (0.93 to 1.20 ml/min/kg; P less than 0.05) in 12 of 14 patients, with a mean increase of 67% and 52%, respectively, from before to after remission. There was no significant difference in mean indocyanine green clearance from before to after induction (14.8 vs. 14.4 ml/min/kg). There were no significant differences in liver function test results (SGOT, prothrombin time, or serum bilirubin) from before to after induction. Plasma concentrations of albumin, alpha 1-acid glycoprotein, and apolipoprotein A changed by a mean of +11.1%, -38.2%, and +68.6%, respectively, from before to after remission. However, these changes did not account for the changes in total plasma clearance of lorazepam, because lorazepam free fraction did not change and lorazepam free clearance increased by a mean of 83%. Our hypothesis is that eradication of hepatic leukemic infiltration by ALL remission therapy resulted in an improvement in microsomal metabolism of antipyrine and lorazepam.

Adolescent↗
PubMed1987

Liquid chromatography and fluorescence polarization immunoassay methods compared for measuring flecainide acetate in serum.

We analyzed 99 patients' serum samples for concentrations of a new antiarrhythmic agent, flecainide acetate, by fluorescence polarization immunoassay (FPIA) and "high-performance" liquid chromatography (HPLC). Within-day and between-day coefficients of variation at concentrations in the low and high ends of the therapeutic range were less than 7% for HPLC and less than 9% for FPIA. There was no statistical difference in the mean (+/- SD) concentrations of the clinical serum samples measured by the two methods (607 +/- 334 micrograms/L by HPLC, 602 +/- 344 micrograms/L by FPIA), but results by each differed by a mean of 0.13%. FPIA and HPLC measurements correlated significantly (r = 0.98, P less than 0.05), and were linearly related (slope = 0.970, intercept = 13 micrograms/L) as assessed by orthogonal regression. Both assay methods produced similar concentration measurements and were sufficiently accurate and precise to be used in therapeutic drug monitoring.

Anti-Arrhythmia Agents↗
PubMed1986

The effect of ranitidine and cimetidine on imipramine disposition.

The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t 1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 micrograms X h X ml-1) or ranitidine (1.14 micrograms X h X ml-1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.

Administration, Oral↗
PubMed1985

Systemic, left ventricular and coronary hemodynamic effects of intravenous diltiazem in coronary artery disease.

Systemic and coronary hemodynamic effects of intravenous diltiazem, administered as a bolus of 250 micrograms/kg followed by an infusion of 1.4 micrograms/kg/min, were examined in 14 patients with effort angina. There was no change in heart rate despite significant decreases in systolic, diastolic and mean systemic pressures (13%, 10% and 11%, respectively, all p less than 0.01). The blood pressure decrease was closely correlated with the initial blood pressure (r = 0.81, p less than 0.05). Neither left ventricular end-diastolic pressure nor peak dP/dt changed significantly, but peripheral vascular resistance decreased 16% (p less than 0.001) and stroke volume index increased 10% (p less than 0.05). The pressure-rate product decreased 15% (p less than 0.005), but coronary blood flow was maintained as coronary resistance decreased 14% (p less than 0.025). Diltiazem increased regional coronary flow in some patients. Thus, intravenous diltiazem dilates coronary and systemic resistance vessels, without an increase in heart rate, favorably altering indexes of myocardial oxygen supply and demand.

Adult↗
PubMed1984

Influence of age on serum protein binding of propranolol.

The extent of propranolol protein binding was determined in three different age groups of healthy drug-free caucasian males. Volunteers selected for study were 6-15 years old, 25-36 years old and 68-76 years old. Ten milliliters of blood were obtained via venipuncture and collected in glass tubes from the subjects after an overnight fast. Binding determinations were performed by equilibrium dialysis using radiolabelled propranolol. Serum albumin and alpha 1-acid glycoprotein concentrations were determined in all subjects by radial immunodiffusion. The results obtained showed wide intersubject variability in the binding ratio of propranolol and serum concentrations of alpha 1-acid glycoprotein. Mean albumin serum concentration was found to be significantly lower in the elderly group as compared to the adult and pediatric groups (p less than 0.02). A positive correlation was found between the binding ratio of propranolol and the serum concentration of alpha 1-acid glycoprotein in all the subjects (r = + 0.66, p less than 0.005). No significant correlation was found between the binding ratio of propranolol and the serum concentration of albumin (r = -0.03, p less than 0.88). These data suggest that the extent of propranolol binding is influenced primarily by serum concentrations of alpha 1-acid glycoprotein and not by differences in age.

Adolescent↗
PubMed1984

Effects of diltiazem, dipyridamole, and their combination on hemostasis.

Calcium channel blockers and antiplatelet agents, alone and in combination, have been reported to induce bleeding in patients undergoing surgery. Since diltiazem and dipyridamole influence platelet function in vitro and in vivo, their influence on hemostasis was examined in five normal men given diltiazem, 90 mg by mouth, followed by 60 mg every 6 hr for 48 hr, or dipyridamole, 75 mg by mouth every 8 hr for 48 hr. At 24 hr, the alternate drug was added to the regimen to assess effects of the combination on hemostasis. Platelet aggregation, serum thromboxane B2 and 6-keto-PGF1 alpha concentrations (stable metabolites of thromboxane A2 and prostacyclin), bleeding time, prothrombin time, partial thromboplastin time, and serum diltiazem concentrations were measured. Diltiazem and dipyridamole alone and in combination had no significant effect on bleeding time, prothrombin time, or partial thromboplastin time. Platelet aggregation induced by threshold concentrations of adenosine diphosphate, epinephrine, and calcium ionophore A 23187 were inhibited by diltiazem and dipyridamole alone and in combination. The only change in prostaglandin concentrations was a slight increase in serum 6-keto-PGF1 alpha after diltiazem. Despite influences on platelet function, neither diltiazem nor dipyridamole alone or in combination induced clinically relevant changes in hemostasis.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Pharmacokinetics of verapamil and norverapamil during long-term oral therapy.

Serum concentrations of verapamil and its pharmacologically-active metabolite, norverapamil, were measured in six patients with angina at rest after six to fifteen months of therapy. Optimal daily doses were selected during a previous in-hospital titration period and ranged from 240 to 640 mg per day. There was no significant relationship between dose, corrected for body weight, and area under the verapamil serum concentration-time curve (AUC). The mean apparent oral clearance of verapamil was highly variable with a mean of 21.9 +/- 9.1 ml/min/kg and a range of 7.7 to 32.0 ml/min/kg. The ratio of verapamil AUC to norverapamil AUC, used to assess accumulation kinetics of parent drug and metabolite, was less than 1.0 in five of six patient (mean 0.93). However, one patient with verapamil concentrations ranging from 300 to 900 ng/ml had a ratio of 1.37 suggesting saturation of the enzymes that convert verapamil to norverapamil. When the relationship between serum concentration at the end of the dosing interval and angina frequency was studied, it was observed that patients in whom angina was completely suppressed had concentrations greater than 160 ng/ml and patients with poor control (greater than 5 anginal episodes per week) had concentrations less than 60 ng/ml. The findings suggest that the oral clearance of verapamil following long-term (greater than 6 mo.) administration may be different than after short-term therapy and that it is difficult to predict verapamil serum concentrations and antianginal effect during long-term oral therapy. Individualizing verapamil therapy to maintain serum concentrations greater than 100 ng/ml may improve therapeutic response and appears to more reliably predict response than daily dose.

Aged↗
PubMed1983

Stability of cimetidine hydrochloride in admixtures after microwave thawing.

The stability of cimetidine hydrochloride in admixtures subjected to freezing and subsequent microwave thawing was studied. Admixtures containing cimetidine 300 mg were prepared using 18 50-ml bags of 5% dextrose injection and 18 100-ml bags of 0.9% sodium chloride injection. A sample for analysis of pH and drug concentration was withdrawn from each bag, and all admixtures were frozen for 28 days. Nine admixtures of each solution were thawed at room temperature and the other nine in a microwave oven until a final solution temperature of 24 +/- 2 degrees C was reached. An additional five cimetidine admixtures in 0.9% sodium chloride injection were prepared and irradiated in the microwave oven until boiling occurred for five seconds. Samples of all admixture solutions were withdrawn within 30 minutes of thawing and again at 24 +/- 2 hours after thawing to determine pH and cimetidine concentration. Concentrations were measured by high-performance liquid chromatography. Admixtures pH after thawing did not vary substantially from baseline values. A significant difference in cimetidine concentration for each solution was observed between samples drawn at 0 and 24 hours after thawing; drug concentrations in 5% dextrose increased by 5.9% while those in 0.9% sodium chloride decreased by 1.5%. Thawing method had no significant effect on drug concentration in either admixture solution. In the solutions and drug concentrations tested, microwave thawing did not affect cimetidine stability. Increases in cimetidine concentrations in 5% dextrose solution may have been attributable to greater insensible water losses produced by heating of the small 50-ml bags.

Chromatography, High Pressure Liquid↗
PubMed1982

Lidocaine clinical pharmacokinetics.

A review of the clinical pharmacokinetics of lidocaine is presented. Available evidence suggests that antiarrhythmic effects are reasonably well correlated wih plasma concentration. Adverse effects also covary with plasma concentration, but available evidence suggests that the correlation is not strong. A simple, multiple-bolus loading schedule appears to be superior to techniques using loading infusions; most of the multiple-bolus protocols mandate that only enough drug be given to attain the desired pharmacologic effect. In contrast, the loading infusion protocols almost invariably require the administration of a fixed dose, regardless of what fraction of the dose has been given when arrhythmia suppression is achieved. Since multiple-bolus and constant-rate infusion techniques have been shown to reduce substantially the incidence of primary ventricular fibrillation, they should be considered appropriate prophylactic and treatment regimens for acute myocardial infarction patients.

Humans↗