Search PubMed⌕ Search

Biomedical subjects

A J Sedman

Publications and source records attributed to A J Sedman.

At least 19 recordsLinked to original sources
PubMed1992

Clinical pharmacokinetics of procaterol: dose proportionality after administration of single oral doses.

Procaterol is a potent, orally active beta 2-agonist bronchodilator useful in the treatment of reversible bronchospastic disease. It is effective when administered as single or multiple (Q8H) 50 and 75 micrograms doses. As part of the clinical development of procaterol, the pharmacokinetics and dose proportionality of single 25, 50, 75, and 100 micrograms doses were investigated in 14 healthy subjects. Serial blood samples were collected for 16 h and urine was quantitatively collected for 48 h following administration of each dose. Procaterol concentrations in plasma and urine were determined using sensitive and specific radioimmunoassay methods. Mean values for tmax, the apparent elimination rate constant, Cl/F, renal clearance, and per cent of dose excreted unchanged in urine were similar for all doses. Dose-normalized AUC, Cmax, and amount excreted unchanged in urine (Ae) were also similar across dosage levels. Thus, the pharmacokinetics of procaterol appear to be proportional to dose over the range of doses studied.

Administration, Oral↗
PubMed1992

Effect of cimetidine administration on the pharmacokinetics of pirmenol.

The potential for a drug-drug interaction between pirmenol, an extensively metabolized antiarrhythmic agent, and cimetidine, an inhibitor of hepatic drug-metabolizing enzymes, was evaluated in eight healthy adults. A single 150-mg oral dose of pirmenol was administered on study days 1 and 8 and oral cimetidine, 300-mg QID, was administered on study days 4 through 11. Plasma and urine samples were collected after each pirmenol dose for determination of pirmenol concentration. Mean pirmenol concentration-time curves and pharmacokinetic parameters, including elimination rate constant, were not significantly altered by concomitant administration of cimetidine.

Administration, Oral↗
PubMed1992

Creep fracture in bones with different stiffnesses.

Creep fracture experiments were used to examine the differences in time to fracture of bones with very different Young's moduli (bovine bone and red deer antler) and the implications of these differences for the 'cumulative-damage' model of Caler and Carter [J. Biomechanics 22, 625-635 (1989)] for bone fracture. Using normalised stress as the explanatory variable, the slopes of the distributions agreed quite well with that of Caler and Carter for human bone. However, antler took far longer to fracture at any given normalised stress than did bovine bone. Using stress alone as the explanatory variable, the relationships within each bone type almost disappeared. Within any bone type strain is the important determinant of time to fracture, but less mineralised bone takes much longer to fracture at any given strain, or normalised stress, which seems not to be in accord with the cumulative-damage model. The rate of damage accumulation in lightly mineralised bone at high strains (greater than 1%) is much less than that occurring in more heavily mineralised bone.

Animals↗
PubMed1992

Effect of gastric acidity on enoxacin absorption.

The effect of gastric acidity on the oral absorption of the quinolone antibiotic enoxacin was evaluated in 12 healthy volunteers. In a randomized, crossover design, single 400 mg oral enoxacin doses were administered on four occasions: alone, after 50 mg intravenous ranitidine, after 2 micrograms/kg subcutaneous pentagastrin, and after combined ranitidine and pentagastrin treatment. Gastric pH was monitored by radiotelemetry capsule for 4 hours after enoxacin administration. Ranitidine pretreatment reduced enoxacin oral bioavailability by an average of 26%. This effect was abolished when pentagastrin was used to maintain low gastric pH. Thus the ranitidine-induced decrease in enoxacin oral bioavailability probably results from a decrease in gastric acidity rather than from an interaction with ranitidine itself.

Administration, Oral↗
PubMed1991

ACE inhibitors in the elderly.

As the population with hypertension becomes older, it is important to determine the properties of angiotensin-converting enzyme (ACE) inhibitors in the elderly. The pharmacokinetics and efficacy of captopril, enalapril, and a new once-daily ACE inhibitor, quinapril for the treatment of hypertension in young and elderly patients are reviewed, and the safety profiles of these agents in young and elderly patients are discussed. Although the safely profile of all three drugs is very favorable, quinapril tended to be better tolerated by patients of all ages in comparative clinical trials.

Aged↗
PubMed1990

Pharmacokinetics of quinapril and its active metabolite, quinaprilat, in patients on chronic hemodialysis.

The pharmacokinetics of quinapril and its active metabolite, quinaprilat, were evaluated in 12 patients with end-stage renal disease (ESRD) on chronic hemodialysis. Each subject received a single 20-mg oral dose of quinapril 4 hours before a 4-hour hemodialysis treatment. Serial dialysate and blood samples were obtained over 4 and 96 hours, respectively. Samples were analyzed for quinapril and quinaprilat concentrations by gas chromatography. Mean tmax and Cmax values for quinapril were 1.2 hours and 129 ng/mL, respectively. Only one patient had detectable quinapril dialysate concentrations which accounted for 2.8% of the quinapril dose. Mean apparent plasma clearance for quinapril was 1275 mL/min with a mean half-life of 1.7 hours. Quinapril was extensively de-esterified to its diacid metabolite, quinaprilat. Mean tmax and Cmax for quinaprilat were 4.5 hours and 671 ng/mL, respectively. Mean apparent plasma clearance for quinaprilat was 24.0 mL/min with a mean half-life of 17.5 hours. As with quinapril, quinaprilat was not readily dialyzable. Only 5.4% of the administered quinapril dose was recovered as quinaprilat during a single hemodialysis treatment. In view of these results, supplemental quinapril doses need not be routinely given to patients following hemodialysis. Overall, quinapril and quinaprilat pharmacokinetics in patients with ESRD on chronic hemodialysis were not markedly different from those previously observed in patients with moderate to severe renal dysfunction (CLcr less than 29 mL/min) not yet requiring hemodialysis (RDND).

Adult↗
PubMed1990

Overview of quinapril, a new ACE inhibitor.

Quinapril has been extensively studied for efficacy and safety in patients with hypertension or congestive heart failure (CHF) in the United States and Europe. Thirty-nine clinical pharmacology studies involving 383 patients have been completed. Moreover, 12 controlled, multicenter clinical studies and 3 single-center studies involving 1,793 patients have been conducted in hypertension. Three hemodynamic trials, two of which included both acute and long-term phases, and one placebo-controlled, dose-response study have been conducted in 333 patients with CHF. An additional 519 patients who completed studies on comparative agents were started on quinapril at the initiation of six long-term, open-label trials, which extended for up to 3 years. Twelve of 15 hypertension trials evaluated quinapril as first-line monotherapy in 1,452 patients with hypertension. Comparative agents included placebo in five trials (524 patients), enalapril in three trials (339 patients), captopril in four trials (335 patients), and chlorthalidone in one trial (74 patients). A total of 510 patients received quinapril in addition to a diuretic in double-blind trials: 341 patients with moderate to severe hypertension participated in three trials, and 169 patients with CHF participated in one trial. Quinapril administered once daily (o.d.) was evaluated in four placebo-controlled studies and in two studies of o.d. vs. twice-daily doses. The safety of quinapril has been evaluated in almost 2,700 patients in controlled, double-blind studies or in open-label extensions, for a total of more than 1,600 patient-years of exposure to quinapril. More than one-half of all patients participated in long-term trials: 980 patients were studied for 1 year and 315 patients were studied for 2 years at the time of data analysis. Safety data are available for 451 older patients (aged greater than or equal to 65 years), and comparative safety data from other compounds in the controlled studies are available for 1,058 patients. Quinapril's efficacy is comparable to that of other angiotensin-converting enzyme (ACE) inhibitors, and it has a lower incidence of adverse events or withdrawals due to adverse events than has been associated with captopril or enalapril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Theophylline dosage adjustment during enoxacin coadministration.

Based on the results of a previous study which demonstrated a 50% reduction in theophylline clearance during coadministration of 400 mg of enoxacin twice a day (b.i.d.), a sequential-design study was completed with seven nonsmoking, healthy adult female human volunteers. The subjects were given 200 mg of theophylline (Theo-Dur) orally every 12 h for 4 days. On day 5, the subjects began receiving 400 mg of enoxacin with each theophylline dose, and the dosage of theophylline was reduced to 100 mg b.i.d. This regimen was continued through day 8, after which enoxacin was discontinued. The theophylline dosage was increased to 200 mg b.i.d. on day 9, and theophylline monotherapy continued through day 12. The mean apparent theophylline clearance decreased by approximately 50% during enoxacin coadministration. No significant differences in mean theophylline maximum concentration in serum, time to maximum concentration in serum, lowest concentration observed, or area under the concentration-time curve during the steady-state dosing were observed before, during, or after enoxacin coadministration when the theophylline dosage was reduced to 100 mg b.i.d. Reduction of the theophylline dose by 50% at the onset of enoxacin dosing maintained constant theophylline concentrations in plasma. A return to the original theophylline dose immediately upon cessation of enoxacin therapy resulted in a transient 35% increase in theophylline concentrations in plasma which lasted 24 to 48 h before returning to preenoxacin values. Although a 50% reduction in the theophylline dose maintained constant mean theophylline concentrations when enoxacin was administered concomitantly, it appears that larger dose reductions (up to 75%) could be required in patients with high theophylline clearances. In addition, larger transient increases in the theophylline concentration in plasma may be observed in these patients upon cessation of enoxacin therapy if the theophylline dose is immediately returned to normal. Thus, it is recommended that theophylline concentrations in plasma be monitored when concurrent enoxacin therapy is required.

Adult↗
PubMed1990

Steady-state pharmacokinetics of tacrine in patients with Alzheimer's disease.

Neurochemical studies of Alzheimer's disease (AD) suggest deficiencies in the cholinergic system. We evaluated the steady-state pharmacokinetics of tacrine (Cognex), an oral cholinesterase inhibitor, in 12 patients with AD. Patients sequentially received nine doses of 10 mg, 20 mg, and 30 mg of tacrine every 6 hours. Blood samples were collected until 24 hours after the final dose. Plasma tacrine concentrations were measured using a validated high-performance liquid chromatographic method. Mean maximum plasma concentrations (Cmax) were 5.1 ng/ml, 20.7 ng/ml, and 33.9 ng/ml following administration of 10 mg, 20 mg, and 30 mg doses, respectively. Corresponding mean values for steady-state area under the curve (AUC) were 19.7 ng/ml, 82.9 ng/ml, and 139 ng/ml.hr. Dose-normalized Cmax and AUC values after administration of the 20 mg and 30 mg doses of tacrine were comparable to each other but were significantly greater (p less than .05) than those after the 10 mg doses. The apparent elimination half-life was approximately 3.4 hours for all dosing regimens. Dose-dependent increases in Cmax and AUC values in patients with AD were similar to those previously reported in normal volunteers. The mechanism of the nonlinearity in tacrine pharmacokinetics is unknown.

Aged↗
PubMed1989

Effect of a high-fat meal on the bioavailability of a polymer-coated erythromycin particle tablet formulation.

The effect of food on the relative bioavailability of an erythromycin particles-in-tablet formulation was studied in 27 healthy volunteers, using a four-way, crossover study design with the following treatments: one or two erythromycin capsules USP (Eryc, Parke-Davis), or one polymer-coated erythromycin particles-in-tablet (PCE, Abbott) administered fasting or with a high-fat meal. Under fasting conditions the erythromycin particles-in-tablet and erythromycin capsule formulations are bioequivalent based on similar tmax and dose-normalized Cmax and AUC values. The rate and extent of absorption from the particles-in-tablet formulation, however, are dramatically reduced following administration with a meal. Mean Cmax and AUC values decreased by 73% and 72%, respectively, and seven subjects had no detectable erythromycin plasma concentrations for 16 hours following administration of the particles-in-tablet formulation with the high-fat meal. Greater than 40% of the subjects had nonfasting Cmax and AUC values that were less than 10% of those values following administration of the dose fasting. Cmax and AUC values in nonfasting subjects were within 75% to 125% of fasting values in only two and one of 27 subjects, respectively. The erythromycin particles-in-tablet formulation therefore should not be administered with meals.

Adult↗
PubMed1989

The theophylline-enoxacin interaction: II. Changes in the disposition of theophylline and its metabolites during intermittent administration of enoxacin.

The pharmacokinetics of theophylline and its three major metabolites, 3-methylxanthine, 1-methylurate, and 1,3-dimethylurate, were studied during intermittent administration of enoxacin. The addition of enoxacin (400 mg, twice daily) to a theophylline dosing regimen (150 mg, twice daily) resulted in an immediate fall in plasma theophylline metabolite concentrations. Mean steady-state theophylline concentration in plasma during the dosing interval increased from 3.17 to 8.23 micrograms/ml. The mean 12-hour recovery of total theophylline metabolite decrease from 76.3 to 38.6 mg. After the discontinuation of enoxacin, but not theophylline, the plasma theophylline metabolite levels immediately increased to near or above the concentrations observed before enoxacin coadministration. Concurrently, theophylline concentrations decreased to levels equivalent to those observed before enoxacin coadministration. In general, the changes in plasma theophylline concentrations observed after the addition of discontinuation of enoxacin were complete within 3 days.

Adult↗
PubMed1989

Inhibition of enoxacin absorption by antacids or ranitidine.

Ten normal volunteers participated in a randomized, five-way crossover study to determine the effect of concurrent enoxacin and antacid or ranitidine administration on enoxacin absorption. The bioavailability of a single oral 400-mg enoxacin dose was significantly decreased, by 73 and 49%, when Maalox TC was administered 0.5 and 2 h before enoxacin, respectively. Enoxacin bioavailability was not significantly altered when the antacid was given 8 h before or 2 h after enoxacin administration. Ranitidine, administered intravenously 2 h before enoxacin, also significantly decreased enoxacin bioavailability, by 40%. The correlation between the proximity of antacid administration and the magnitude of the decrease in enoxacin bioavailability supports complexation as the mechanism of the antacid-enoxacin interaction. However, reduction of enoxacin bioavailability by ranitidine suggests that elevated gastric pH may also play a role in the antacid-enoxacin drug-drug interaction.

Adolescent↗
PubMed1989

The clinical pharmacokinetics of quinapril.

Quinapril (Q) and quinaprilat (QT) pharmacokinetics are dose proportional following single oral 2.5- to 80-mg Q doses. Q absorption and hydrolysis to QT is rapid with peak Q and QT concentrations occurring one and two hours postdose, respectively. Peak plasma QT concentrations were approximately fourfold higher than those of Q (923 vs 207 ng/mL following 40-mg Q). Dose-proportional QT area under the curve and dose-independent percent of dose excreted in urine as QT demonstrate that the extent of Q conversion to QT is constant over the dose range studied. Q and QT were eliminated from plasma with apparent half-lives of 0.8 and 1.9 hours and apparent plasma clearances of 1,850 and 220 mL/min, respectively, over the 2.5- to 80-mg dose range. Following oral 14C-Q, 61% and 37% of radiolabel was recovered in urine and feces, respectively. Q plus QT accounted for 46% of radioactivity circulating in plasma and 56% of that excreted in urine. Metabolism to compounds other than QT is not extensive. Two diketopiperazine metabolites of Q have been identified in plasma and urine, with approximately 6% of an administered dose excreted in urine as each of these metabolites. Peak plasma concentrations of these metabolites are similar to that of Q, and each is eliminated rapidly with a half-life of approximately one hour. Urinary excretion profiles indicate the presence of other minor metabolites. In summary, the absorption of Q and conversion to QT is rapid and dose-proportional, subsequent clearance of both Q and QT is independent of dose, and metabolism to compounds other than QT is not extensive.

Absorption↗
PubMed1989

Clinical pharmacology of quinapril in healthy volunteers and in patients with hypertension and congestive heart failure.

Quinapril is converted to quinaprilat, a long-acting angiotensin converting enzyme (ACE) inhibitor, and is currently being studied for the treatment of hypertension and congestive heart failure. In studies of healthy volunteers, single quinapril doses of 0.625 mg to 80 mg inhibited plasma ACE activity for up to forty-eight hours. Dose-related inhibition of angiotensin I pressor response occurred after administration of quinapril doses of 0.625 mg to 20 mg. In addition, plasma renin activity increased and aldosterone and angiotensin II concentrations decreased following single or multiple doses of quinapril. Subsequently, dose-ranging studies were conducted in patients with mild to moderate hypertension and congestive heart failure. Pilot studies suggested that 5 mg of quinapril given once daily had minimal antihypertensive effect. Therefore, a definitive, multiple-dose, placebo-controlled, double-blind study of 5, 10, and 20 mg once daily doses of quinapril was performed. Quinapril doses of 10 mg and 20 mg were statistically significantly superior to placebo (p less than 0.05) in lowering sitting diastolic blood pressure (DBP), whereas 5 mg of quinapril had only marginal clinical effectiveness. A twenty-four-hour blood pressure monitoring study indicated that quinapril administered once or twice daily effectively lowered DBP in patients with mild to moderate hypertension. This study suggested, however, that some patients may not achieve sustained reductions in DBP over the entire twenty-four-hour interval with quinapril administered once daily and may require twice daily therapy. In studies of patients with refractory congestive heart failure, acute favorable hemodynamic effects were demonstrated after the administration of quinapril.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Multiple-dose cimetidine administration does not influence the single-dose pharmacokinetics of quinapril and its active metabolite (CI-928).

The potential effect of cimetidine on the pharmacokinetic profiles of quinapril and its active metabolite CI-928 was evaluated in eight healthy volunteers. Each subject received a single 40-mg quinapril dose on days 1 and 12 and cimetidine 300 mg four times daily on days 8 through 13. Serial blood and urine samples were collected for assay of quinapril and CI-928 concentrations. No statistically significant differences were observed in quinapril or CI-928 Cmax, tmax, AUC(0-infinity), beta, or percent of dose excreted in urine values for quinapril administered alone and in combination with cimetidine. Therefore, multiple-dose cimetidine administration does not influence the single-dose pharmacokinetics of quinapril and its active metabolite, CI-928, in healthy volunteers.

Adult↗
PubMed1988

Enhanced pirmenol elimination by rifampin.

The potential for drug-drug interaction between pirmenol, an extensively metabolized antiarrhythmic agent, and rifampin, a potent inducer of hepatic drug-metabolizing enzymes, was evaluated in 12 healthy adults. After administration of a single 150-mg oral dose of pirmenol on day 1, pirmenol plasma and urine concentrations were determined for 72 hours postdose. On days 4 through 17, subjects received 600 mg of rifampin once daily. On day 15, subjects were given a second single 150-mg oral dose of pirmenol concomitantly with rifampin, and plasma and urine concentrations were again determined. Coadministration of rifampin with pirmenol resulted in significant (P less than .005) changes in pirmenol pharmacokinetic parameters. A sixfold decrease in pirmenol AUC and sevenfold increase in the apparent plasma clearance of pirmenol were found. Elimination half-life decreased more than twofold. Based on these findings, pirmenol dosage adjustment will be required when pirmenol is given to patients concurrently receiving rifampin. These results suggest that the administration of pirmenol with other agents that induce hepatic enzymes may result in accelerated pirmenol clearance.

Adult↗
PubMed1988

The theophylline-enoxacin interaction: I. Effect of enoxacin dose size on theophylline disposition.

Theophylline interacts pharmacokinetically with a variety of other drugs. Recently enoxacin was found to change theophylline's disposition. In a four-subject, four-way crossover study enoxacin was administered every 12 hours at four levels (0, 25, 100, and 400 mg) for 14 doses. With the ninth dose of enoxacin, 200 mg theophylline was coadministered. Blood and urine samples were assayed by sensitive and specific assays for the parent drugs and their metabolites. Significant reduction in the formation of theophylline's three major metabolites occurred on coadministration of enoxacin. At the 400 mg dose level, enoxacin caused a threefold decrease in theophylline's plasma clearance, a fourfold decrease in the urinary recovery of 3-methylxanthine and 1,3-dimethylurate, and a threefold decrease in the recovery of 1-methylurate.

Adult↗