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Biomedical subjects

D D Breimer

Publications and source records attributed to D D Breimer.

At least 109 records · Page 6Linked to original sources
PubMed1992

Intraindividual variability in nifedipine pharmacokinetics and effects in healthy subjects.

The intraindividual variability in pharmacokinetics and effects of oral nifedipine (10 mg), administered with 1 week intervals, was investigated in twelve young healthy subjects. The population estimate of the coefficient of intraindividual variability (CVw) in AUC of nifedipine (13%) was much smaller than the pure between-subject variability (CVb 54%). The long-term (1 1/2 year) intraindividual variability was much larger than the short-term variability. Maximum changes from baseline-values of mean blood pressure (SBP -5%, DBP -4%) and mean heart rate (HR +21%) were small. Individual maximum changes in systolic blood pressure, diastolic blood pressure, and heart rate (SBP, DBP, and HR) and areas under effect curves were highly variable (CVw 34-250%, CVb 8-88%). For most subjects a significant positive linear relation was observed between nifedipine plasma concentration and the change in HR (mean r = 0.63). The CVw in slope (106%) and intercept (685%) were even larger than the high CVb in these parameters (38% and 252%). Changes in blood pressure were not significantly related to nifedipine plasma concentrations within these healthy subjects. The small intraindividual variability in nifedipine pharmacokinetics allows crossover studies to detect pharmacokinetic relationships between nifedipine and other dihydropyridine calcium entry blockers.

Administration, Oral↗
PubMed1992

Influence of single- and multiple-dose omeprazole treatment on nifedipine pharmacokinetics and effects in healthy subjects.

The effects of single dose (20 mg) and short-term (20 mg/day for 8 days) oral treatment with omeprazole on the pharmacokinetics and effects of oral nifedipine (10 mg capsule) and on gastric pH have been investigated in a randomized, double-blind, placebo-controlled cross-over study in 10 non-smoking healthy male subjects. The single dose of omeprazole had no significant effect on any pharmacokinetic parameter of nifedipine, nor on gastric pH, or blood pressure or heart rate. Short-term omeprazole treatment increased the AUC of nifedipine by 26% (95% confidence interval 9-46%), but all other pharmacokinetic parameters of nifedipine, including elimination half-life, Cmax, tmax, and recovery of the main urinary metabolite, were not significantly changed. The median gastric pH during the absorption phase of nifedipine was increased by short-term omeprazole (pH 4.2) compared to placebo treatment (pH 1.4). Blood pressure and heart rate did not differ between treatments. The interaction between nifedipine and omeprazole is not likely to be of major clinical relevance.

Adult↗
PubMed1992

Stereoselective pharmacokinetics of oral nitrendipine in elderly hypertensive patients with normal and impaired renal function.

The pharmacokinetics of the enantiomers of nitrendipine has been studied in seven elderly patients with chronic renal failure (CRF) and in six control subjects (mean creatinine clearance 30 and 97 ml.min-1 respectively). Racemic nitrendipine 20 mg was given once daily for seven days and the pharmacokinetics of the enantiomers over the last dosage interval were determined using a stereospecific assay. In both groups nitrendipine exhibited stereoselective pharmacokinetics (AUC, Cmax), but the half-lives of the enantiomers did not differ in individual subjects. As an index of stereoselectivity, the mean S/R ratio of AUCs in control subjects (2.07) was not significantly different from the ratio in patients with CRF (2.68). The mean AUCs of (S)- and (R)-nitrendipine during the last dosage interval were increased in CRF by 132% and 85%, respectively. The observed doubling of the half-lives and the increases in Cmax did not reach significance because of the large variability in each group. Thus, the pharmacokinetics of oral nitrendipine is altered in CRF, but there was no change in the stereoselectivity of its pharmacokinetics.

Administration, Oral↗
PubMed1992

Effects of temazepam on saccadic eye movements: concentration-effect relationships in individual volunteers.

Saccadic eye movements were analyzed after single oral doses of 20 mg temazepam and placebo in a randomized, double-blind crossover study in eight healthy volunteers. For an optimal evaluation of concentration-effect relationships, 18 blood samples and 43 effect measures were obtained over 33 1/2 hours. After placebo, saccadic peak velocity decreased within the first hour, with average values remaining 6.2% to 12.1% below baseline up to 15 hours after intake. After temazepam, significant changes in peak velocity occurred for 5 hours, with maximum decreases averaging 29.2% (95% confidence interval, 10.0 to 37.2). The apparent duration of effects ranged from 3 to 9 hours in individual subjects. Linear concentration-effect relationships were demonstrated for peak velocity, with individual slopes ranging from -0.11 to -0.46 deg/sec.(ng/ml)-1 (average r = -0.82, all p < 0.01). Differences in protein binding of temazepam did not account for the approximate fourfold variability in individual sensitivities to temazepam. By increasing the frequency of measurements, the accuracy of pharmacodynamic evaluations was clearly enhanced in this study.

Adult↗
PubMed1992

Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite alpha-hydroxymidazolam in healthy volunteers.

The pharmacodynamics of midazolam and its main metabolite alpha-hydroxymidazolam were characterized in individual subjects by use of saccadic eye movement and electroencephalographic (EEG) effect measurements. Eight healthy volunteers received 0.1 mg/kg midazolam intravenously in 15 minutes, 0.15 mg/kg alpha-hydroxymidazolam intravenously in 15 minutes, 7.5 mg midazolam orally and placebo in a randomized, double-blind, four-way crossover experiment. Plasma concentrations of midazolam, alpha-hydroxymidazolam and 4-hydroxymidazolam were measured by gas chromatography. The amplitudes in the 11.5 to 30 Hz (beta) frequency band were used as EEG effect measure. The concentration-effect relationships were quantified by the sigmoid maximum effect model. The median effective concentrations of midazolam and alpha-hydroxymidazolam were (mean +/- SE) 77 +/- 15 and 98 +/- 17 ng/ml, respectively, for the EEG effect measure. For peak saccadic velocity the values were 40 +/- 7 ng/ml for midazolam and 49 +/- 10 ng/ml for alpha-hydroxymidazolam. The maximum effect values were similar for both compounds. The effects observed after oral administration of midazolam could not be predicted accurately by an additive and competitive interaction model. It seems that alpha-hydroxymidazolam is highly potent with respect to the measured effects and contributes significantly to those effects of midazolam after oral administration.

Administration, Oral↗
PubMed1992

Effects of the mucoadhesive polymer polycarbophil on the intestinal absorption of a peptide drug in the rat.

The absorption across rat intestinal tissue of the model peptide drug 9-desglycinamide, 8-arginine vasopressin from bioadhesive formulations was studied in-vitro, in a chronically isolated internal loop in-situ and after intraduodenal administration in-vivo. A controlled-release bioadhesive drug delivery system was tested, consisting of microspheres of poly(2-hydroxyethyl methacrylate) with a mucoadhesive Polycarbophil-coating, as well as fast-release formulation consisting of an aqueous solution of the peptide in a suspension of Polycarbophil particles. Using the controlled-release system, a slight improvement of peptide absorption was found in-vitro in comparison with a non-adhesive control system, but not in-situ or in-vivo. In contrast, bioavailability was significantly increased in all three models from the Polycarbophil suspension in comparison with a solution of the drug in saline. The effect appeared to be dose-dependent, indicative of intrinsic penetration-enhancing properties of the mucoadhesive polymer. A prolongation of the absorption phase in-vitro and in the chronically isolated loop in-situ suggested that the polymer was able to protect the peptide from proteolytic degradation. This could be confirmed by degradation studies in-vitro. The duration of the penetration enhancing/enzyme inhibiting effect was diminished with increasing complexity of the test model, in the same way as was previously found for the bioadhesive effect. This interrelationship suggests that the observed improvement in peptide absorption and the mucoadhesive properties of this polymer are associated. The development of a fast-release oral dosage form for peptide drugs on the basis of Polycarbophil appears to be possible.

Acrylic Resins↗
PubMed1992

Effects of acute febrile infectious diseases on the oral pharmacokinetics and effects of nitrendipine enantiomers and of bisoprolol.

In 2 longitudinal studies with 10 patients each, the stereoselective pharmacokinetics of nitrendipine and the pharmacokinetics of racemic (rac) bisoprolol (both 20mg orally) were investigated during acute febrile infectious diseases and at least 6 weeks later in the healthy state. The area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of rac-nitrendipine were increased in the infectious state by 89% [95% confidence interval (CI): 24 to 187%] and 95% (95% CI: 22 to 209%), respectively. Similar increases were observed for both S- and R-nitrendipine. Nitrendipine exhibited stereoselective pharmacokinetics in both the healthy state and the infectious state, but the mean ratios of S:R AUC values [healthy: 1.79 (95% CI: 1.36 to 2.11); infectious: 1.87 (95% CI: 1.62 to 2.11)] were not different. The elimination half-life, protein binding and haemodynamic effects of nitrendipine also did not differ between the infectious and the healthy state. The mechanism for the disease effects may be related to suppression of hepatic cytochrome P450 activity by mediators of inflammatory reactions. On the other hand, none of the pharmacokinetic parameters, including nonrenal clearance, of rac-bisoprolol was changed during febrile infectious disease, indicating specificity in the effects of acute febrile disease on oxidative drug metabolism.

Acute Disease↗
PubMed1992

Cerebrospinal fluid transport and disposition of the quinolones ciprofloxacin and pefloxacin in rats.

The disposition of ciprofloxacin and pefloxacin in the rat cerebrospinal fluid (CSF) was investigated after i.v. and i.c.v. administration. After injection into the lateral ventricle, the terminal half-life of pefloxacin was shorter than that of ciprofloxacin. After i.v. infusions, the relative CSF exposure, expressed as CSF: area under the plasma concentration time curve ratio, were found to be 10.4 +/- 2.8% for ciprofloxacin and 42.4 +/- 3.0% for pefloxacin. The unit impulse response methodology was applied in order to assess the CSF transport profile. The plasma-CSF transport clearance of pefloxacin and the total amount of drug transported into the CSF were significantly higher compared with ciprofloxacin. Although pefloxacin exhibited a linear CSF transport profile, the plasma-CSF transport clearance of ciprofloxacin was found to be nonlinear at the dose level studied. Pefloxacin was converted in the brain to the active metabolite norfloxacin (N-desmethyl pefloxacin). The difference in CSF exposure of both quinolones and the presence of active metabolites of N-methylated quinolones in the CSF may be of clinical relevance in the treatment of CNS infections, but differences in antimicrobial activity have to be taken into account as well.

Animals↗
PubMed1991

Interaction study between Org 10172, a low molecular weight heparinoid, and acetylsalicylic acid in healthy male volunteers.

Potential interactions between Org 10172 (Lomoparan, i.v. bolus injection of 3,250 anti-Xa units followed by 750 units twice daily s.c. for 8 days) and acetylsalicylic acid (ASA) (500 mg orally 14 and 2 h before i.v. Org 10172 administration) were studied in eight healthy male volunteers using an open, randomised three-way cross-over design. Except for moderate bruising at venepuncture and s.c. injection sites which were equally distributed over all three treatments (Org 10172 alone, ASA alone, Org 10172 and ASA combined), no side effects were observed. The effects of the separate drugs on several haemostatic parameters were as expected, although the prolongations in bleeding time after ASA were highly variable and tended to be somewhat more pronounced after the combination (p greater than 0.05). Org 10172 did not influence the inhibiting effects of ASA on platelet function nor the functional recovery afterwards, as evaluated by thromboxane A2 (TXA2) generation and collagen-induced platelet aggregation. Furthermore, no important interactions were observed with regard to the coagulation tests and plasma anti-Xa activity. Although this study did not entirely exclude small interactions between Org 10172 and ASA in this relatively small group of subjects, these effects are probably without clinical significance.

Adult↗
PubMed1991

High-performance liquid chromatographic determination of the polar metabolites of nifedipine in plasma, blood and urine.

A relatively simple reversed-phase high-performance liquid chromatographic method for the determination of the polar metabolites of nifedipine in biological fluids is described. After conversion of 2-hydroxymethyl-6-methyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylic acid 5-methyl ester (IV) into 5,7-dihydro-2-methyl-4-(2-nitrophenyl)-5-oxofuro[3,4-b] pyridine-3-carboxylic acid methyl ester (V) by heating under acidic conditions, V was extracted with n-pentane-dichloromethane (7:3) and analysed on a C18 column with ultraviolet detection. Subsequently, 2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid monomethyl ester (III) was extracted with chloroform and analysed on the same system. Limits of determination in blood were 0.1 microgram/ml for III and 0.05 microgram/ml for IV and V; these limits were two to ten times higher for urine. This inter-assay variability was always less than 7.5%.

Animals↗
PubMed1991

Physical exercise induces enhancement of urokinase-type plasminogen activator (u-PA) levels in plasma.

The enhancement of the blood fibrinolytic potential by physical exercise is generally attributed to the release of tissue-type plasminogen activator (t-PA) from the vessel wall. In this study we have investigated the possible contribution of urokinase-type plasminogen activator (u-PA). Six healthy male volunteers (age 21-25 years) were screened for their ability to perform maximal exercise for their age-group for 12 min on a bicycle ergometer. Subsequently, on one occasion they were required to remain supine for 2 h (from 8.30 a.m. onwards) an on another they performed maximal exercise (from 9.00 a.m. onwards). During exercise an increase in u-PA antigen and plasmin-activatable pro-urokinase (proUK) activity, concurrent with t-PA antigen and euglobulin t-PA activity, was observed in all six volunteers, while at rest these parameters remained unaffected. Mean u-PA- and t-PA antigen increased, respectively, from 4.2 +/- 1.0 ng/ml and 5.8 +/- 2.1 ng/ml before exercise to 9.8 +/- 3.0 ng/ml and 18.3 +/- 3.8 ng/ml (peak). Mean plasmin-activatable proUK activity and t-PA activity increased, respectively, from 2.1 +/- 0.4 ng/ml and 0.3 +/- 0.2 ng/ml before exercise to 4.3 +/- 1.7 ng/ml and 7.2 +/- 4.0 ng/ml (peak). The increases were statistically significant throughout (paired t-test, pre vs post, antigen P less than 0.005 and activity P less than 0.02). After cessation of exercise u-PA and t-PA declined concurrently to normal values with a 50% decay in about 5 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Influence of chlorthalidone on the pharmacokinetics and pharmacodynamics of Org 10172 (Lomoparan), a low molecular weight heparinoid, in healthy volunteers.

The influence of chlorthalidone (100 mg PO) on the pharmacokinetics and pharmacodynamics of Org 10172 (IV bolus injection of 3250 anti-Xa units), a low molecular weight heparinoid, was studied in six healthy male volunteers using an open randomized two-way crossover design. Chlorthalidone produced a slight decrease in clearance of anti-Xa activity from 7.1 +/- 1.0 to 6.6 +/- 0.8 mL/min and a decrease of the volume of distribution from 0.20 +/- 0.05 to 0.16 +/- 0.04 L/kg, whereas the volume of distribution of antithrombin activity increased from 0.14 +/- 0.05 to 0.26 +/- 0.10 L/kg (all differences P less than .05). During the entire study period no adverse events occurred. In summary, chlorthalidone showed separate effects on different fractions of Org 10172. The clinical implication of the slight change observed in plasma anti-Xa activity is likely to be limited, whereas the 80% increase in distribution volume of plasma antithrombin activity can not be defined as yet in terms of clinical relevance.

Adult↗
PubMed1991

Development of specific antisera against 9-desglycinamide-8-arginine vasopressin by site-specific immunization.

Four specific and sensitive antisera against 9-desglycinamide-8-arginine vasopressin (DGAVP) were obtained by means of site-specific immunization in rabbits, using a Keyhole Limpet haemocyanin-DGAVP conjugate synthesized by a specific reaction of a thiol function with a maleimide group. Compared with conventionally raised antisera, the cross-reactivity with endogenous arginine vasopressin (AVP) and vasopressin-derived fragments was substantially lower. Interassay variability was 18.1% at maximum. Possible applicability of the new antisera in pharmacokinetic studies of DGAVP with respect to blood-brain barrier transport was tested by means of a pilot study in the rat.

Amino Acid Sequence↗
PubMed1991

Interaction of ORG 10172, a low molecular weight heparinoid, and digoxin in healthy volunteers.

Potential pharmacokinetic and pharmacodynamic interactions between a new low molecular weight heparinoid Org 10172 (bolus injection of 3250 anti-Xa units) and digoxin (0.25 mg once daily for 8 days) were studied in 6 healthy male volunteers using an open, randomised three-way cross-over design. Digoxin produced a slight increase in clearance of anti-Xa activity from 4.3 to 4.8 ml.min-1, while plasma antithrombin and thrombin generation inhibiting (TG1) activity remained unchanged. Digoxin did not affect the actions of Org 10172 on the clotting tests. In the presence of Org 10172 there was a reduction in the AUC of digoxin during one dosing interval after the seventh digoxin tablet from 20 to 17 ng.ml-1.h, and a significant reduction in the average serum digoxin concentration. Since renal digoxin clearance was not significantly changed this probably might be due to a change in the non-renal clearance of digoxin. Atrio-ventricular node conduction, as measured by PR-time intervals, remained unchanged during all three treatments. In conclusion, although the pharmacokinetics of Org 10172 and digoxin were slightly changed by the combination, it is probably safe to administer Org 10172 and digoxin simultaneously. The clinical relevance of the slight decrease in plasma anti-Xa activity levels cannot yet be defined.

Administration, Oral↗
PubMed1991

Analysis of nifedipine and its pyridine metabolite dehydronifedipine in blood and plasma: review and improved high-performance liquid chromatographic methodology.

A reversed-phase HPLC method is described for the simultaneous determination of nifedipine and its primary pyridine metabolite dehydronifedipine in blood and plasma, that involves UV detection and neutral (blood) or alkaline (plasma) extraction. The limit of reliable determination is found to be 3 ng ml-1 with an inter-assay RSD of below 11%. In the presence of haemoglobin, nifedipine is unstable at pH greater than 10, necessitating neutral extraction for the measurement of nifedipine in haemolysed blood. Published methods for analysis of nifedipine are reviewed, emphasizing the lack of specificity and sensitivity which render many of them unsuitable for the investigation of nifedipine disposition in man.

Chromatography, High Pressure Liquid↗
PubMed1991

Stereoselective transport of baclofen across the blood-brain barrier in rats as determined by the unit impulse response methodology.

The blood-brain barrier transport characteristics of racemic baclofen and the separate R- and S-enantiomers have been determined in vivo in rats by using the unit impulse response methodology. Transport rate was determined as blood-brain barrier clearance, the volume of plasma per unit time cleared of baclofen by transport across the blood-brain barrier. Plasma elimination kinetics and CSF elimination kinetics did not differ among racemic baclofen and the R- and S-enantiomers. Transport of each compound could be described by a linear V(t) curve, suggesting the absence of saturable transport processes in the concentration range studied. However, for R-baclofen the blood-brain barrier clearance (4.7 +/- 1.0 microliters/min, mean +/- SE; n = 6) and cumulative transported amount (0.085 +/- 0.007%; n = 6) were significantly higher than these values for the S-enantiomer (1.1 +/- 0.3 microliters/min, 0.031 +/- 0.005%; n = 6) and racemic baclofen (1.0 +/- 0.1 microliters/min, 0.036 +/- 0.003%; n = 6). These findings indicate that there is stereoselective transport of baclofen across the blood-brain barrier.

Animals↗
PubMed1991

A comparison of the sensitivities of adaptive tracking, eye movement analysis and visual analog lines to the effects of incremental doses of temazepam in healthy volunteers.

The effects of single oral doses of 5, 10, and 20 mg temazepam were evaluated with the adaptive tracking test, analysis of smooth-pursuit and saccadic eye movements, and visual analog lines in a placebo-controlled, double-blind, crossover experiment with 12 healthy volunteers. Pharmacodynamic testing was performed until 10 hours and pharmacokinetics were evaluated until 24 hours. Temazepam, 20 mg, caused effects in all tests, with peak effects occurring at 30 minutes. The 10 mg dose caused effects on saccadic eye movements and subjective scores of alertness, whereas 5 mg temazepam was detected only by analysis of saccadic eye movements. Linear relationships between plasma concentrations and effects were found in nine subjects for saccadic peak velocity and eight subjects for subjective scores of alertness. The results of this study demonstrate manifest differences in the sensitivities of performance tests and stress the importance of validation of methods when effects of drugs on human performance are studied.

Adult↗