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Biomedical subjects

W A Clementi

Publications and source records attributed to W A Clementi.

At least 19 recordsLinked to original sources
PubMed1994

Single dose pharmacokinetics of (S)-atenolol administered orally as a single enantiomer formulation and as a racemic mixture (Tenormin).

The purpose of this study was to describe the pharmacokinetics of and heart rate and blood pressure responses to (S)-atenolol (SATN) and (R)-atenolol (RATN) after oral administration of (S)-atenolol and (R,S)-atenolol (Tenormin) in man. Eight male subjects were given single oral doses of 50 mg of SATN as a single enantiomer formulation (SEF) and 100 mg of Tenormin (TMN) using a randomized, double-blind, 2-period, complete crossover study design. Subjects performed exercise tolerance tests (Bruce Protocol) before and 2, 4, 6, 8, 12, and 24 h after drug administration. Plasma samples were obtained 2 min before and 30 min, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 h after dosing. Urine was collected for the first 48 h after dosing. Plasma and urine samples were analyzed for SATN and RATN by an enantioselective HPLC method. SEF and Tenormin attenuate exercise-induced increases in heart rate and systolic blood pressure. Mean changes in exercise heart rates 4 h after dosing were -38 +/- 3 bpm and -37 +/- 3 bpm for SEF and TMN, respectively, P = 0.792. Mean changes in exercise systolic blood pressure were -42 +/- 12 mm Hg and -55 +/- 14 mm Hg for SEF and TMN, respectively, P = 0.484. Mean area under the plasma level time curve (AUC0-24) and mean Cmax for SATN for SEF were significantly lower than for SATN after TMN.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Pharmacodynamics of racemic and S(-)-atenolol in humans.

The cardiovascular actions of racemic atenolol (RSATN) have been well characterized in humans, but the actions of S(-)-atenolol (SATN) when administered alone are unknown. In this study, responses of heart rate (HR) and Doppler-derived aortic blood flow profiles to upright treadmill exercise were compared after oral administration of 50 mg SATN and 100 mg RSATN in eight healthy, adult, male volunteers. After a single-blind, placebo run-in period, subjects were randomly allocated in a double-blind, crossover fashion to receive SATN and RSATN. Each study period was separated by a 7-day washout period. Multiple submaximal exercise tests were performed and data were collected over the 24 hours after each treatment. Both SATN and RSATN significantly (P < .05) blunted peak exercise HR by 38 +/- 3 and 37 +/- 3 beats/min, respectively. Aortic blood flow acceleration measured during peak exercise decreased after SATN and RSATN, by 13 +/- 4 and 13 +/- 3 m/sec2, respectively (P < .05). No difference in hemodynamic effect was observed between treatments. Pharmacodynamic parameters derived from plasma S(-)-atenolol concentration-effect (HR) curves after SATN, RSATN, and total atenolol plasma concentrations after RSATN did not differ significantly. Predicted maximum reductions in heart rate (Emax) and EC50 for S(-)-atenolol after SATN were 39.6 +/- 5.8 beats/min and 38.4 +/- 40.9 ng/ml versus 34.5 +/- 8 beats/min and 25.9 +/- 29.9 ng/ml for RSATN, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Pharmacokinetics of quinidine in male patients. A population analysis.

Quinidine pharmacokinetic behaviour was evaluated in 139 adult hospitalised men receiving oral quinidine therapy. A total of 391 serum quinidine concentrations were measured by enzyme immunoassay for routine clinical purposes. The NONMEM programme was used to examine the relationship between quinidine pharmacokinetics and several potential covariates. A 1-compartment open model with first-order absorption and elimination was assumed. The mean apparent volume of distribution (Vd) was about 230L. When measured, alpha 1-acid glycoprotein (AAG) levels were not included in the analysis. Oral quinidine clearance (CL) decreased with age, severe congestive heart failure and renal disease, and increased in patients with a history of alcohol abuse. The interpatient variability in CL and the intrapatient residual variability expressed as coefficients of variation (CV) were 28 and 31%, respectively. When AAG values were incorporated into the analysis, the only important covariates of CL were the AAG measurements and the presence of renal dysfunction as indicated by a calculated creatinine clearance of less than 50 ml/min (3 L/h). The interpatient variability in CL and the residual intrapatient CVs decreased to approximately 24 and 26%, respectively. Improvement of the CL model by inclusion of measured AAG strongly suggests that quinidine elimination is dependent on the free concentration of drug in plasma and supports the use of free serum quinidine concentrations when evaluating and monitoring quinidine therapy.

Aged↗
PubMed1988

Absolute bioavailability and dose proportionality of betaxolol in normal healthy subjects.

The absolute bioavailability and dose proportionality of betaxolol [(+/-)-1-(p-[2-cyclopropylmethoxy)ethyl]phenoxy]-3- (isopropylamino)-2-propanol hydrochloride], a cardioselective beta-adrenergic antagonist effective in the treatment of angina and hypertension, was studied in 12 healthy male subjects using a four-way crossover Latin Square design. Each subject received a 10-mg iv dose administered by constant-rate infusion over a period of 30 min and three oral doses (10, 20, and 40 mg). Blood and urine were collected over a 48-h period and analyzed for betaxolol using gas-liquid chromatography with electron capture detection. Maximum concentrations occurred 3-4 h after the dose. The maximum mean (+/- SD) blood concentrations normalized to the 10-mg oral dose were 21.6 +/- 3.7, 21.1 +/- 3.7, and 22.5 +/- 4.0 micrograms/L following the 10-, 20-, and 40-mg doses, respectively. A significant lag time of 10-80 min was observed after oral doses but was not related to dose size. The terminal slope (ts), absolute bioavailability (F), and renal clearance (CLr) were likewise not affected to an important degree by dose (ts: 0.043 +/- 0.006, 0.044 +/- 0.005, 0.046 +/- 0.006 h-1; F: 0.88 +/- 0.08, 0.82 +/- 0.06, 0.84 +/- 0.07; CLr: 0.68 +/- 0.22, 0.69 +/- 0.19, 0.65 +/- 0.22 mL/min kg). Unlike many beta-adrenergic antagonists, betaxolol has a long half-life (13-20 h) and high and consistent bioavailability (70-90%), and its disposition is independent of the size of the administered dose.

Adrenergic beta-Antagonists↗
PubMed1988

Clinical assessment of a two-compartment Bayesian forecasting method for lidocaine.

The predictive performance of a two-compartment Bayesian forecasting method for lidocaine (L) was evaluated concurrently with lidocaine therapy in 46 hospitalized patients; 14 of these patients presented with congestive heart failure (CHF). Using an HP-85 microcomputer, demographic and dose-concentration information obtained during continuous lidocaine therapy was used to forecast subsequent lidocaine concentrations. One lidocaine concentration was obtained within each of the three intervals following initiation of lidocaine infusions: I1 (1-6 h), I2 (6-12 h), and I3 (greater than 12 h). Patients were categorized into 4 groups: (a) short-term infusions (less than 24 h) without CHF, (b) short-term infusions with CHF, (c) long-term infusions (greater than 24 h) without CHF, and (d) long-term infusions with CHF. The mean prediction errors (range -0.60-0.27) included zero (95% confidence limits) in all groups and suggested no bias. Forecasts of the I3 lidocaine concentrations were consistently more precise [lower mean absolute errors (MAE) and root mean squared errors] using the lidocaine concentration obtained during the 6-12-h interval (I2) than when the lidocaine concentration obtained at the earlier interval (I1) was used. The MAE was reduced by 20-40% when a single lidocaine concentration obtained during I2 was used as compared to I1. Precision was only slightly improved with the use of two lidocaine concentrations. We conclude that this Bayesian algorithm is unbiased and delivers acceptable precision in forecasting lidocaine concentrations.

Adult↗
PubMed1987

Evaluation of a Bayesian regression-analysis computer program using non-steady-state phenytoin concentrations.

The predictive performance of a Bayesian regression-analysis computer program that uses non-steady-state phenytoin data was evaluated. Forty patients receiving phenytoin or phenytoin sodium who had two or more non-steady-state serum concentrations were selected for study. Additional serum concentrations and dosing data were collected as they became available, but no effort was made to control the number or timing of serum concentration determinations. Patients were categorized into four groups for evaluation of the effect of potential bioavailability problems and length of dosing history (time over which serum concentration-time data were collected) on the ability to predict subsequent phenytoin concentrations. Population parameters for phenytoin maximum rate of elimination (Vmax), apparent Michaelis-Menten constant (Km), volume of distribution (V), and bioavailability (F) were obtained from the literature. Predictions based on serum phenytoin concentrations and dosing histories (information intervals) of 5 or 10 days were compared with predictions based on naive (population-based) estimates using prediction-error analysis. In each patient group, the use of either 5-day or 10-day information intervals resulted in a significant increase in precision and a significant reduction in bias compared with naive estimates. For the group of patients who initially had two or more serum concentrations within the first five days of monitoring, predictions showed a marked increase in bias and a decrease in precision as the time interval from the last measured concentration to the time of prediction increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Bayes Theorem↗
PubMed1986

Measurement of lidocaine free concentration.

Since lidocaine exhibits significant variation in serum protein binding, the availability of a practical method for measuring free lidocaine concentration could contribute to the optimization of individual lidocaine dosage regimens. Fifty serum samples from patients receiving lidocaine were partitioned by ultrafiltration and equilibrium dialysis. The lidocaine concentration in the ultrafiltrate was measured using an enzyme multiplied immunoassay (EMIT) and a gas-liquid chromatographic assay (GLC). The lidocaine concentrations in dialysates and filtered retentates were measured by EMIT. Ultrafiltrate concentrations measured by EMIT correlated well with those measured by GLC (r2 = 0.77), but the EMIT results were approximately 10-20% higher than the GLC measurements (GLC = 0.09 + 0.79 EMIT). At least a portion of this difference could be attributed to minor calibrator differences. The concentrations in dialysate and filtered retentate agreed well (r2 = 0.93; filtered retentate = -0.05 + 1.12 X dialysate). The fraction free values obtained by ultrafiltration were slightly lower than those obtained by equilibrium dialysis (0.301 +/- 0.086 vs. 0.345 +/- 0.137; p less than 0.05). It can be concluded that sample partitioning with ultrafiltration and measurement of free lidocaine concentration by EMIT yields results similar to those obtained by equilibrium dialysis or a GLC assay procedure.

Chromatography, Gas↗
PubMed1986

Captopril modifies the hemodynamic and neuroendocrine responses to sodium nitroprusside in hypertensive patients.

To determine if clinically effective doses of the antihypertensive agent captopril affected the neuronal release of norepinephrine or baroreflex sensitivity, changes in plasma norepinephrine concentration and heart rate were related to the changes in mean arterial pressure seen during the intravenous infusion of stepwise incremental doses of sodium nitroprusside before and during captopril treatment in eight hypertensive men with normal or low plasma renin activity. At all times, significant linear correlations were found between the decrease in mean arterial pressure and the dose of sodium nitroprusside, the increase in heart rate and the decrease in mean arterial pressure, and the increase in plasma norepinephrine concentration and the decrease in mean arterial pressure. When the subjects were treated with captopril (25 mg t.i.d.) for 2 to 4 weeks, supine mean arterial pressure decreased from 130 to 114 mm Hg (-12%; p less than 0.05), heart rate did not change, supine and upright plasma renin activity increased, while supine plasma norepinephrine and epinephrine concentration decreased slightly. Therapy with captopril (25 mg t.i.d.) increased baroreflex sensitivity, as assessed by the slope of the regression line relating the increase in heart rate to the decrease in mean arterial pressure, and increased the responsiveness of the sympathetic nervous system, as assessed by the slope of the regression line relating the increase in plasma norepinephrine concentration to the decrease in mean arterial pressure. These increases were accompanied by a decrease in the slope of the regression line relating the decrease in mean arterial pressure to the dose of sodium nitroprusside and thus were associated with a decreased sensitivity to the vasodepressor effects of sodium nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1986

Experience with intrainstitutional clinical evaluations of newly marketed preparations as a basis for drug-product selection to hospital formularies.

The decision to admit a new drug-product formulation (NDPF) to a hospital pharmacy formulary is a difficult task, particularly when minimal pharmacokinetic or clinical efficacy data are available. To provide objective information to the Pharmacy and Therapeutics (P&T) Committee, we implemented a procedure to evaluate these NDPFs at our institution. This procedure, termed clinical evaluation, was initiated at our institution in 1981. The clinical evaluations of two NDPFs were performed. The two NDPFs studied were a transdermal nitroglycerin preparation and a sustained-release procainamide preparation. The clinical assessment of the therapeutic and the pharmacokinetic performance of each preparation was made by clinical pharmacists. Following completion of the clinical evaluation, the data were presented at a regular meeting of the P&T committee. The presentation of clinical data derived from our patient population facilitated objective assessment by the P&T committee regarding formulary status. We conclude that the clinical evaluation represents a novel approach to acquire data necessary for objective decisions on NDPFs by the P&T committee.

Administration, Topical↗
PubMed1984

Comparative assessment of in vitro inactivation of gentamicin in the presence of carbenicillin by three different gentamicin assay methods.

Inactivation of gentamicin (G) is known to occur secondarily to the formation of complexes with certain beta-lactam antibiotics. However, aminoglycosides in the presence of aminoglycoside-beta-lactam complexes may not be recognized uniformly by all assay methods. We tested this hypothesis by using mixtures of G plus carbenicillin (C), with and without the addition of penicillinase, in pooled sera under several in vitro conditions: at 25 and 35 degrees C and at low and high C concentrations. Samples were assayed for G with the EMIT and TDx systems, and a microbiological assay was performed with a strain of Klebsiella pneumoniae resistant to C. In the presence of C (500 micrograms/ml) at 35 degrees C, the initial G concentration of 5 micrograms/ml decreased markedly over 48 h as assessed by all three assay methods. However, significantly greater degradation was noted when samples were measured by microbiological assay and TDx than by EMIT. Differences between assays were less marked when mixtures were studied at a lower temperature and with a lower G to C ratio (5 micrograms of G plus 100 micrograms of C per ml). The addition of penicillinase to the antibiotic mixtures prevented the degradation of G over time when measured by all three assay systems. We concluded (i) that EMIT measures higher serum concentrations of G than do TDx or microbiological assays when complexes of G and C are present and (ii) that the addition of penicillinase to serum samples containing C and G would be effective in preventing G degradation during prolonged (greater than 24-h) periods between the time of sampling and assay.

Carbenicillin↗
PubMed1983

Decrease in theophylline clearance after the administration of erythromycin to a patient with obstructive lung disease.

It has been demonstrated previously that erythromycin can inhibit the total body clearance of theophylline, resulting in elevated serum theophylline concentrations. The overall incidence of this interaction and the population at risk have not been elucidated fully. Recent investigations have suggested that such an interaction is doubtful and that patients in whom this occurrence was suspect developed alterations in theophylline disposition secondary to worsening pulmonary function, not from erythromycin therapy alone. This case report shows that the interaction between theophylline and erythromycin can be clinically significant, producing as much as a 50-percent reduction in the total body clearance of the bronchodilator. The magnitude and time course of this interaction in patients with congestive heart failure and chronic obstructive pulmonary disease may differ considerably from that reported in healthy volunteers.

Aged↗
PubMed1982

Endogenous generation of hydralazine from labile hydralazine hydrazones.

The hypothesis that the pharmacologically active hydralazine hydrazones (HH) are endogenously hydrolyzed to parent hydralazine (H) was tested in a series of in vitro and in vivo systems. The stable hydrazones H alpha-ketoglutaric acid hydrazone and H pyruvic acid hydrazone did not hydrolyze to H in vitro (buffer or plasma), were inactive in vivo and did not generate urinary metabolites of parent H. By contrast, the labile HH, H acetaldehyde hydrazone and acetone hydrazone (HAH) generated H in vitro. H acetaldehyde hydrazone produced in vitro effects that were equipotent to the H concentration measured in the dose solutions. When administered to conscious rats and rabbits, the labile hydrazones reduced blood pressure. This effect was more gradual in onset than that of H. The hypotensive effects of HH were significantly greater than predicted by the amount of H contained in the dose solutions. Metabolic studies were conducted with the labile HH, HAH. After administration of HAH to rabbits, the proportional excretion of the urinary H metabolite, H pyruric acid hydrazone, was equal to that observed after the administration of H. We conclude that HH are inactive, except when hydrolyzed to H. The hydrolysis of certain HH, including HAH and H acetaldehyde hydrazone, in vivo may be nearly complete. Differences in the pharmacodynamic properties between labile HH and H may be related to the time course of generation of H, sequestration of hydrolysis in physiologically inactive sites or other unrecognized mechanisms.

Animals↗
PubMed1980

Quantitative analysis of hydralazine pyruvic acid hydrazone, the major plasma metabolite of hydralazine.

A specific, high-performance liquid chromatographic technique for the measurement of hydralazine pyruvic acid hydrazone is described. This method utilized reversed-phase chromatography for the separation of this hydrophilic metabolite of hydralazine from other fluid constituents present in serum, plasma, or urine of human volunteers and rabbits receiving hydralazine. Detection of the compound of interest is accomplished spectrophotometrically at 250 nm.

Animals↗
PubMed1980

Route and rate of hydrallazine administration as determinants to its hypotensive effect in rabbits.

1. The cardiovascular responses to varying doses of hydrallazine were studied in renal hypertensive rabbits. 2. The depressor effect of hydrallazine was independent of the rate of its i.v. administration (bolus v. a 15 min constant infusion). 3. Intraperitoneally administered hydrallazine was significantly less active than equimolar i.v. doses, and the relative potency (i.p. v. i.v.) did not increase with increasing doses. 4. In spite of inferential evidence to the contrary, we did not find any pharmacodynamic support for non-linear processes being involved in metabolism of hydrallazine.

Animals↗
PubMed1979

Phenytoin cumulation kinetics.

Four male subjects were given phenytoin orally in single or twice-daily doses. Subjects were on 2 or 3 different dosing rates from 260 to 600 mg phenytoin sodium daily. Predose blood samples were obtained almost daily. The resulting serum levels, measured by gas-liquid chromatography, ranged from 1 to 18 micrograms/ml. Serum phenytoin concentration-time data were fit to a 1-compartment open model with zero-order input and Michaelis-Menten elimination. The resulting computer-generated parameter estimates (Vmax, 5.28 to 8.41 mg/kg/day; Km, 0.83 to 4.18 mg/1; Vd, 0.74 to 0.97 1/kg) are in agreement with the ranges of values in the literature. The time course of phenytoin cumulation is compatible with the presence of a major elimination pathway exhibiting Michaelis-Menten kinetic behavior.

Administration, Oral↗
PubMed1979

Pharmacokinetics and cardiovascular effects in rabbits of a major hydralazine metabolite, the hydralazine pyruvic-acid hydrazone.

The hydrazone of hydralazine and pyruvic acid (HPH) has been recognized as a quantitatively important metabolite of hydralazine in human plasma. We evaluated the disposition of [14C] HPH after its i.v. administration to normal, anephric and probenecid-pretreated rabbits. Renal clearance of HPH in normal rabbits exceeded the glomerular filtration rate by a factor of 3 to 4 and accounted for 80 to 90% of the total body clearance. Active tubular secretion was established by the effect of probenecid pretreatment to reduce the renal clearance of HPH by 80%. Total body clearance of HPH in anephric rabbits was 10% of that of normal animals, emphasizing the minor importance of metabolic conversion for the overall disposition of HPH. HPH in a maximum dose of 50 mumol/kg i.v. had no hypotensive effect in renal hypertensive rabbits and did not interfere with the subsequent hypotensive response to hydralazine. This HPH dose produced plasma levels at least 50 times in excess of those reported in humans after administration of therapeutic doses of parent hydralazine. HPH is consequently of negligible clinical significance, despite the relatively high plasma concentration of this metabolite which occurs after administration of parent hydralazine.

Animals↗