Biomedical subjects

E J Antal

Publications and source records attributed to E J Antal.

At least 19 recordsLinked to original sources

PubMed1992

The pharmacokinetics of flurbiprofen in younger and elderly patients with rheumatoid arthritis.

The pharmacokinetics of flurbiprofen (Ansaid Tablets, Upjohn Company of Canada, Don Mills, Ontario) were evaluated in both younger (40 to 60 years) and elderly (65 to 83 years) rheumatoid arthritic patients after both a 100-mg single-dose administration and at steady state during a 100-mg twice-a-day dosage regimen. Both flurbiprofen plasma concentration-time profiles and the urinary excretion of flurbiprofen and its major metabolites were evaluated. The results indicate that the pharmacokinetics of flurbiprofen are linear in both age groups based on only minor changes between single-dose and steady-state parameter determinations and the agreement between calculated and predicted accumulation values in plasma concentrations. Only minor differences in the pharmacokinetic parameters were observed between the younger and elderly patients. Only free flurbiprofen clearance was found to have a significant but variable correlation to patient age. The effect of flurbiprofen on the urinary excretion of two prostaglandins were also evaluated throughout this study. In both age groups, the maximum decrease in urinary excretion was observed after the first dose, and this effect was maintained throughout the remainder of the study. Percent decreases from baseline in urinary excretion during drug administration were similar for both age groups. Similar side-effect profiles were observed between age groups.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Pharmacokinetics and pharmacodynamics of oral diazepam: effect of dose, plasma concentration, and time.

Eleven healthy subjects received single oral doses of placebo, 2 mg diazepam, 5 mg diazepam, and 10 mg diazepam in a randomized four-way crossover study. Plasma diazepam levels, the Digit Symbol Substitution Test (DSST), and fraction of total electroencephalographic (EEG) amplitude falling in the sigma plus beta (13 to 31 Hz) frequency range were determined during the 12 hours after drug administration. Peak plasma diazepam concentration and area under the 12-hour curve were proportional to dose; time of peak was independent of dose. Baseline percentage of EEG amplitude falling in the 13 to 31 Hz range averaged 15.7% and did not differ among the four trials. The percentage of EEG amplitude falling in the 13 to 31 Hz range did not change over baseline with placebo or 2 mg diazepam but was increased 1/4 to 2 1/2 hours after 5 mg diazepam, (maximum, +7.3%) and 3/4 to 12 hours after 10 mg diazepam (maximum, +15.2%). The increase in the percentage of EEG amplitude falling in the 13 to 31 Hz range was highly correlated with plasma diazepam concentration. DSST scores for placebo and 2 mg diazepam were nearly identical. DSST decrements with 5 and 10 mg diazepam paralleled and were correlated with the changes in the percentage of EEG amplitude falling in the 13 to 31 Hz range and with plasma diazepam levels. Thus the EEG analysis provides objective quantitation of benzodiazepine central nervous system effects, in turn reflecting plasma levels and other clinical measures.

Administration, Oral↗

PubMed1991

Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine.

The pharmacokinetic and pharmacodynamic effects of concomitant administration of alprazolam and fluoxetine were studied in this double-blind parallel study in 80 healthy, male volunteers. Subjects were randomly assigned to one of four treatment groups. Drug treatments consisted of 4-day regimens of 1 mg alprazolam four times daily, 60 mg fluoxetine every morning, 1 mg alprazolam four times daily and 60 mg fluoxetine every morning, and placebo four times daily. Psychomotor performance, mood status, and degree of sedation were evaluated at designated times. Combined administration of alprazolam and fluoxetine resulted in an approximate 30% increase in plasma alprazolam concentrations relative to plasma concentrations following the administration of alprazolam alone. There were no significant differences in fluoxetine or norfluoxetine plasma concentrations between the alprazolam/fluoxetine and fluoxetine treatments. Psychomotor decrements increased when fluoxetine was administered with alprazolam relative to alprazolam administration alone. Psychomotor performance of the fluoxetine treatment group was not significantly different from that of the placebo group. No significant changes were observed in mood status, and sedation was minimal in all treatment groups. As when any two psychoactive drugs are administered together, increased patient monitoring and patient education is recommended when alprazolam and fluoxetine are prescribed concurrently.

Adult↗

PubMed1991

Pharmacokinetics and pharmacodynamics of glyburide in young and elderly nondiabetic adults.

The pharmacokinetics and pharmacodynamics of glyburide were studied in elderly and young nondiabetic adults. Healthy nondiabetic men and women 18-40 years of age (young subjects) and 60-85 years of age (elderly subjects) were recruited. After an overnight fast, the subjects were given a baseline glucose tolerance test (GTT). The next day, again after a fast, each subject was given a 5-mg oral tablet of glyburide, and the GTT was performed one hour later. Serum glucose, serum insulin, and plasma glyburide concentrations were determined. Twenty elderly (mean +/- S.D. age, 65.7 +/- 5.3 years) male (n = 10) and female (n = 10) volunteers and 15 young (22.3 +/- 4.5 years) male volunteers were enrolled. Compared with the young subjects, the elderly subjects had slower glyburide absorption, as determined from a lower peak plasma concentration and smaller area under the plasma concentration-time curve from zero to four hours (AUC0-4). The elderly subjects also had a lower glyburide elimination rate constant and higher volume of distribution and a 52% higher free fraction. There was no difference in the glyburide AUC0-24 or AUC0-infinity or in oral clearance between the groups. The elderly group had greater increases in serum glucose and insulin concentrations after the baseline GTT. After glyburide administration, the elderly group had a smaller fractional decrease in the glucose AUC0-3 from the baseline GTT result than the young subjects. Linear regression analysis of the relationship between the fractional change in glucose concentration and the glyburide AUC0-4 showed significantly different slopes between the two groups. The aging process appears to affect the pharmacokinetics and pharmacodynamics of glyburide.

Adolescent↗

PubMed1990

An evaluation of the therapeutic effects and dosage equivalence of glyburide and glipizide.

Nineteen noninsulin-dependent diabetic patients [ten women, nine men, aged 36-80 years (mean +/- SE 56.8 +/- 2.7 years)] were randomized to receive either glyburide or glipizide for 16 weeks, in a double-blind crossover fashion. A 2-week washout period preceded each treatment period. The patients measured blood glucose concentrations 16 times weekly using Chemstrip-bG. The medication dosages were titrated to achieve fasting blood glucose concentrations of less than or equal to 6.2 mM and preprandial and postprandial concentrations of less than or equal to 9.0 mM, or to a total daily dose of 20 mg for glyburide and 40 mg for glipizide. Glyburide therapy resulted in a significant decline in fasting, preprandial, postprandial and bedtime blood glucose levels, while glipizide treatment led to a significant lowering of postprandial and bedtime blood glucose. Furthermore, fasting, preprandial and postprandial blood glucose concentrations were significantly lower during glyburide as compared to glipizide treatment phase. Glycosylated hemoglobin levels were decreased only with glyburide. Serum C-peptide and insulin concentrations were not altered over the entire study. The mean final daily dose of glyburide (15.4 +/- 1.6 mg) was markedly lower than that of glipizide (29.7 +/- 3.1 mg). Thus, in this patient population, glyburide was twice as potent on a weight basis than glipizide.

Adult↗

PubMed1990

Unaltered drug metabolizing enzyme systems in type II diabetes mellitus before and during glyburide therapy.

Diabetes mellitus is associated with alterations in hepatic drug metabolizing enzyme activities in experimental animals. To determine whether Type II diabetes or glyburide affect hepatic drug metabolism, the authors used 13C-labeled aminopyrine and caffeine breath tests as in vivo probes of the hepatic cytochrome P450 and P(1)450 enzyme activities respectively in six subjects with Type II diabetes (4 women, 2 men). These subjects had been treated previously with diet, had an age range of 41-63 years, had a body mass index range of 24.1-43.3 kg/m2 and had a mean fasting plasma glucose of 14.6 +/- 1.2 mM and a mean hemoglobin A1c of 12.2 +/- 0.7%. These subjects did not drink alcohol or take drugs known to affect hepatic drug metabolism. The caffeine and aminopyrine breath tests (CBT, ABT) were performed sequentially while fasting before the start of glyburide treatment (5 mg daily) and at weekly intervals for 4 weeks. ABT and CBT values are expressed as cumulative percentage of dose exhaled through 2 hours. Before beginning glyburide, the mean ABT and CBT results were 10.2 +/- 0.7% and 4.2 +/- 0.7% respectively, well within the normal ranges for these tests (ABT 6.5-15%; CBT 2.5-10%). The ABT and CBT values remained unaltered during 4 weeks of glyburide therapy. However, FBS decreased to 10.2 +/- 1.1 mM and HbA1C to 10.1 +/- 0.8% by the end of drug treatment. Type II diabetes that is poorly controlled by diet alone is not associated with alterations of the hepatic drug metabolizing enzymes as judged by the caffeine and aminopyrine breath tests. Furthermore, glyburide does not induce or inhibit the drug metabolizing enzyme systems in the liver, thereby precluding drug-drug interactions of this type.

Adult↗

PubMed1990

The relationship of alprazolam dose to steady-state plasma concentrations.

Alprazolam is a widely used antianxiety agent, yet relatively little is known about the relationship between chronic oral doses and steady-state plasma levels. This study examines the relationship over a wide range of therapeutic doses. We conducted a parallel, double-blind, placebo-controlled study in 36 patients with agoraphobia with panic attacks, or panic disorder with limited phobic avoidance based on DSM-III criteria. Patients received alprazolam (N = 25) or placebo (N = 11) beginning at 1 mg/day and increased weekly until either a maximum tolerated dose or 10 mg/day was achieved. Dosages were then gradually tapered according to a predetermined schedule. The entire study period lasted 14 weeks. Laboratory and clinical assessments were conducted weekly. Doses up to 6 mg/day were tolerated by 80% of patients on alprazolam and doses of 10 mg/day were tolerated by 40% of patients. Twenty-seven percent of the placebo patients reached 10 tablets/day. In the alprazolam group, the principal cause of intolerance was sedation. Throughout the study no significant changes in vital signs or laboratory parameters were observed. Steady state alprazolam, 4-hydroxy alprazolam, and alpha-hydroxy alprazolam plasma levels were linearly related to dose. A 1 mg dosage increment produced, on the average, a corresponding 10 ng/ml increase in steady state level of the parent drug. Significant response was observed in subjects who achieved concentrations greater than 20 ng/ml, with a maximum of 81% of the samples classified as responders within the 60 ng/ml and above group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Disposition of guanadrel in subjects with normal and impaired renal function.

The disposition of a single 25 mg oral dose of guanadrel was evaluated in 22 subjects with various degrees of renal function. The terminal elimination half-life was significantly prolonged in subjects with a creatinine clearance (ClCr) less than 30 mL/min/1.73 m2 (19.2 +/- 16.8 h) compared to 3.7 +/- 1.9 h in subjects with a ClCr greater than 80 mL/min/1.73 m2. Apparent total body clearance (Clp/F) was also progressively lower in the patients with decreased renal function and the decline was significantly correlated with ClCr (Clp/F = 0.0294 + 0.0236 Clcr, r = 0.74, P = 0.002). Renal clearance and apparent nonrenal clearance also declined as creatinine clearance decreased, and both were significantly correlated with the observed ClCr. Apparent volume of distribution averaged 11.5 +/- 8.9 L/kg and did not differ in patients with decreased renal function compared to those with normal renal function. Thus, the disposition of guanadrel is significantly altered in the presence of renal insufficiency and dosage adjustments may be necessary, especially in patients with ClCr less than 50 ml/min.

Adult↗

PubMed1989

An evaluation of population pharmacokinetics in therapeutic trials. Part III. Prospective data collection versus retrospective data assembly.

The ability to estimate population pharmacokinetic parameters of alprazolam from fragmentary clinical data collected during clinical efficacy trials was evaluated in this series of studies. In the first study modifications to the protocol and case report forms were employed to allow for the prospective collection of accurate dosing and blood sampling time data. In the second study only total daily dose and measured drug concentration data were recorded. Dosage and blood sampling time data were assembled retrospectively by assuming strict adherence to protocol guidelines. Comparisons of the results of these analyses demonstrate the marked impact of prospective data collection efforts on data quality and the ability to determine subsequent pharmacokinetic parameters. Analysis of the prospectively collected data yielded pharmacokinetic estimates for alprazolam that were nearly identical to previously reported values obtained according to traditional methods, whereas the analysis of retrospectively collected data yielded biased estimates of the mean pharmacokinetic parameters and markedly upward biased estimates of both interindividual and residual variability. These analyses demonstrate the ability to estimate population pharmacokinetic parameters from data collected during clinical efficacy trials, provided that critical issues pertaining to the design and use of data collection forms to enhance data quality and the education of patients and staff are satisfactorily addressed.

Adult↗

PubMed1989

Differential effects of flurbiprofen and aspirin on acetazolamide disposition in humans.

The plasma concentration-time profile of acetazolamide (AZ) following an intravenous bolus dose (5 mg kg-1) was determined during control, aspirin and flurbiprofen (FLU) treatment periods. The unbound fraction of AZ in plasma increased three-fold in the presence of salicylate (SA) while, in contrast, FLU produced consistent, but statistically insignificant, increases in binding. SA caused a two-fold decrease in both unbound AZ renal clearance and apparent volume of distribution at steady-state, while FLU produced a small, but significant, increase only in the latter. The area under the concentration-time curve for AZ in erythrocytes was increased by about 40% during SA treatment while FLU had no effect. Our results suggest that on a pharmacokinetic basis FLU may be a safer nonsteroidal anti-inflammatory drug (NSAID) to co-administer with AZ.

Acetazolamide↗

PubMed1988

A system approach to pharmacodynamics. II: Glyburide pharmacodynamics and estimation of optimal drug delivery.

A system approach to the analysis of pharmacodynamic systems is applied to the relationship between the glyburide serum concentration (Cd) and a resulting pharmacologic effect response, that is, the C-peptide serum concentration (Cc) in patients with non-insulin dependent diabetes mellitus (NIDDM). Glyburide, glucose, and C-peptide serum concentrations were measured in eight patients with NIDDM following each of five treatments: Treatment A: one glyburide 5-mg tablet (formulation 1); Treatment B: one glyburide 5-mg tablet (formulation 2); Treatment C: glyburide solution as an intragastric infusion (4.67 mg over 12 h); Treatment D: glyburide solution as an intragastric infusion (9.33 mg over 12 h); and Treatment E: no glyburide. The overall relationship between the C-peptide (Cc), glyburide (Cd), and glucose (Cg) serum concentrations is successfully described by operator equations of the form, Cc(t) = t-infinity psi p(t-u)phi t(Cd(u), Cg(u)) du or Cc(t) = t-infinity psi p(t-u)phi t(Cd(u), Cg(u),u) du. The forms of the individual functions are selected empirically based on the results of the present study and those of previous investigations, and are estimated by conventional curve-fitting procedures. The resulting operator equations are used to describe glyburide pharmacodynamics in NIDDM patients and to estimate the optimal glyburide systemic concentration and delivery rate profiles for such patients based on pharmacodynamic response.

Blood Glucose↗

PubMed1988

Clinical outcome and adverse effect profile associated with concurrent administration of alprazolam and imipramine.

Clinical outcome and adverse effects associated with concurrent alprazolam and imipramine administration were studied in 29 patients with major depressive disorder who completed a 6-week trial in which they served as their own controls. Alprazolam was added on Day 8 in gradually escalating, then gradually tapering dosages while imipramine dosages remained unchanged. Significant decreases were observed in scores on the Hamilton Rating Scales for Depression and Anxiety at all later evaluation days with Day 8 as baseline. The mean total Symptom and Side Effects score decreased significantly from Day 8 to Day 22 when alprazolam doses were 1 mg q.i.d. For most side effects, total number of reports remained constant or decreased from Day 1 to later evaluation days. Standing diastolic blood pressures were significantly lower on Day 22 than on Day 1. No significant relationship was found between any rating scale score and plasma concentration data.

Adult↗

PubMed1988

Clindamycin pharmacokinetics and tissue penetration after head and neck surgery.

Penetration of clindamycin into surgical wounds was studied in 10 patients undergoing radical head and neck surgery. Patients received one preoperative and three postoperative intravenous doses of clindamycin 600 mg. During surgery, samples of plasma and sternocleidomastoid muscle were obtained. Additional plasma samples were collected just before the fourth dose of clindamycin, just after that dose was infused, and 1, 2, 4, 6, 8, and 12 hours after dosing. Samples of wound exudate were collected at 2, 4, 6, 8, and 12 hours after the fourth dose. The muscle, plasma, and wound exudate samples were assayed for clindamycin base by a gas-liquid chromatographic method. Plasma and wound exudate samples obtained during surgery and one and eight hours after the fourth dose were assayed by a radial immunodiffusion technique for content of alpha 1-acid glycoprotein (AAG), the major binding protein for clindamycin. Pharmacokinetic values for plasma and wound drainage were calculated and compared. Concentrations of clindamycin in muscle (three to six hours after the first dose) ranged from 0.6 to 5.1 micrograms/g; the ratio of tissue to plasma concentrations ranged from 0.24 to 0.82. The highest mean clindamycin concentration in wound drainage was 4.9 micrograms/mL after the fourth dose, approximately 90% of simultaneous plasma concentrations. Concentrations in wound exudate exceeded those measured in plasma four hours after the dose, and elimination from the wound was slower than from plasma. AAG concentrations in plasma increased from a mean of 89 mg/dL intraoperatively to 134 mg/dL postoperatively. AAG was present in wound exudate in concentrations that were approximately 53% of those observed in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1987

An evaluation of population pharmacokinetics in therapeutic trials. Part II. Detection of a drug-drug interaction.

The use of observational data, collected during the routine clinical care of patients, has been advocated as a means to obtain clinically relevant information regarding the pharmacokinetic parameters of drugs. However, the validity of this approach and its proper role in new drug development is unclear. This study was performed to evaluate the ability of three approaches to estimate population pharmacokinetic parameters: the traditional approach, mixed-effect modeling, and a simple pharmacokinetic screen. The evaluation was performed with data collected during a multicenter, open-label study evaluating the efficacy, safety, and pharmacokinetics of imipramine and alprazolam in combination. The traditional pharmacokinetic study demonstrated a 20% decrease in the clearance of imipramine in the presence of 4 mg/day alprazolam. Mixed-effect modeling extends these findings by suggesting that the interaction is dependent on the simultaneous concentration of alprazolam, a finding that was not possible under the study design typically used for traditional pharmacokinetic studies. Although the simple screen suggests the presence of the drug-drug interaction, limited information regarding pharmacokinetic parameters is available and those parameters that can be estimated are biased.

Adult↗

PubMed1987

The paradoxical effect of cimetidine and ranitidine on glibenclamide pharmacokinetics and pharmacodynamics.

The potential interactions between H2-receptor antagonists, cimetidine and ranitidine, and glibenclamide were studied in 15 non-smoking male volunteers. The study consisted of six treatment phases. Treatment A (3 h oral glucose tolerance test) consisted of 75 g dextrose in 300 ml carbonated water. Treatment B consisted of one 5 mg tablet of glibenclamide in addition to a glucose tolerance test. Treatment C, cimetidine 300 mg orally four times daily for 4 days and Treatment D, ranitidine 150 mg orally twice daily for 4 days were administered in a randomized, crossover fashion. On day 3 of Treatments C and D, subjects received an oral glucose tolerance test. On day 4 of Treatments C and D, subjects received 5 mg of glibenclamide in addition to cimetidine (Treatment E) or ranitidine (Treatment F) and an oral glucose tolerance test. Compared with the control treatment, cimetidine increased the glibenclamide AUC (973 vs 710 ng ml-1 h), but during ranitidine dosing glibenclamide AUC (726 ng ml-1 h) was not significantly different from the control. Apparent oral glibenclamide clearance decreased from 8.25 l h-1 under the control treatment to 6.0 l h-1 following cimetidine but was unchanged during ranitidine (7.97 l h-1). Plasma glucose concentrations were unexpectedly higher when glibenclamide was administered with cimetidine or ranitidine (glucose AUC 237 mg dl-1 h, 228 mg dl-1 h) when compared with glibenclamide administered alone (195 mg dl-1 h, P less than 0.0001). Plasma insulin concentrations were significantly elevated when H2-receptor antagonists and glibenclamide were administered concurrently.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

The influence of hemodialysis on the pharmacokinetics of ibuprofen and its major metabolites.

The pharmacokinetics of ibuprofen and its two major metabolites, the hydroxy and carboxy derivatives, were studied in seven functionally anephric subjects undergoing hemodialysis therapy. Subjects received ibuprofen 800 mg tid for 14 days. Hemodialysis was performed three times weekly during this period. Arterial and venous blood samples were collected before dialysis and along with dialysate, and during the final dosing interval and dialysis session. No accumulation of ibuprofen plasma concentrations and an absence of intact ibuprofen in dialysate indicated clearance through metabolic pathways. The metabolites did accumulate significantly (mean plasma levels, carboxy 249 micrograms/mL and hydroxy 57 mu/mL); however, both were detected in dialysate. Mean extraction efficiencies were 0.16 (hydroxy) and 0.15 (carboxy). Dialysis clearance calculated by arterial-venous difference was found to agree with actual recovery in dialysate for both metabolites. Side effects were not observed in any subject.

Adult↗

PubMed1986

An evaluation of population pharmacokinetics in therapeutic trials. Part I. Comparison of methodologies.

NONMEM, a computer program that uses the method of extended least-squares analysis, has been advocated as a means of obtaining estimates of population pharmacokinetic parameters when only fragmentary information can be obtained from subjects. To assess the performance of this program, we compared NONMEM with traditional methods for the estimation of population pharmacokinetic parameters with data collected during a phase III clinical trial of alprazolam. NONMEM estimates of the population mean clearance and its coefficient of variation were identical to the estimates obtained with traditional pharmacokinetic techniques. Moreover, NONMEM estimates of these parameters remained stable even when a few as three data points were available per subject. NONMEM estimates of the mean volume of distribution and its coefficient of variation appear to be overestimated, apparently because of the sampling scheme used to generate data for the NONMEM analysis. Suggestions for the effective use of NONMEM in clinical trials, to maximize the benefits of this approach, are provided. Our results lend further support for the use of NONMEM to estimate population pharmacokinetic parameters of a drug from data generated during phase III clinical trials.

Administration, Oral↗

PubMed1986

Pharmacokinetic disposition of 14C-glyburide in patients with varying renal function.

The pharmacokinetics of 14C-labeled glyburide were studied in 13 men with varying degrees of renal impairment. Patients received a single, 5 mg oral dose of glyburide as a solution (10 microCi/ml/mg) after a high-carbohydrate breakfast. Serial plasma and breath samples were collected for 48 hours and urine and feces were collected for 5 to 7 days. Patients with normal to moderately impaired renal function (creatinine clearance [CLCR] of 29 to 131 ml/min/1.7 m2) had glyburide plasma t1/2 values of 2.0 to 5.0 hours, with no relationship between CLCR and glyburide clearance. One subject with severe renal impairment (CLCR = 5 ml/min/1.7 m2) had decreased glyburide clearance that resulted in a t1/2 of 11 hours. The elimination of metabolites was more dependent on renal status but was only significantly affected in the patient with severe renal impairment.

Absorption↗