Clearance of plasminogen activator--a major determinant of plasma concentration: therapeutic and diagnostic implications.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
A F Cohen
Publications and source records attributed to A F Cohen.
Influence of heparin and a low molecular weight heparinoid on specific endogenous and exogenous fibrinolytic factors during rest and exercise.
The effects of heparin (5,000 IU i.v.) and the low molecular weight heparinoid Org 10172 (Orgaran) (3,250 anti-Xa units i.v.) on components of the fibrinolytic system were studied in two double-blind, randomised, placebo-controlled, cross-over trials using healthy subjects. In study A (n = 6) the effects were studied during rest and standardized exercise and in study B (n = 6) during a low dose infusion of recombinant tissue-type plasminogen activator (rt-PA; 80 micrograms over 16 min). At rest, heparin and Org 10172 did not influence the plasma concentrations of endogenous t-PA antigen and activity, urokinase-type PA (u-PA) antigen, plasmin activatable pro-urokinase (scu-PA), active urokinase (tcu-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen. Recombinant t-PA antigen and activity during rt-PA infusion were also not affected. During exercise, neither heparin nor Org 10172 influenced the area under the curve (AUC) of t-PA and u-PA antigen and t-PA activity when compared with placebo. Unexpectedly, after heparin the AUC of t-PA activity was 49% larger (range +19 to +245%) than after Org 10172 (p < 0.05). The last difference was considered spurious, scu-PA, tcu-PA and PAI-1 antigen levels at 2 min after termination of exercise were unaffected by both compounds (p > 0.05). Sulphated polysaccharides do not increase fibrinolytic activity of the plasma by changing the concentrations of the components of the fibrinolytic system.
Adult↗
Pronounced effects of the combination of a new thromboxane antagonist (GR32191) and heparin on bleeding time in man.
Potential pharmacokinetic and pharmacodynamic interactions between two oral doses of GR32191 (40 and 80 mg), a new thromboxane antagonist, and heparin (5,000 IU bolus + 1,000 IU/h for 3 h) were studied in eighteen healthy male volunteers using two separate double-blind, randomised, placebo-controlled, cross-over studies. Mean (range) bleeding time values were 8.4 min (7.5-9.7) during heparin/placebo, 12.1 min (9.2-18.6) (GR32191/placebo) and 16.3 min (11.5-21.4) (GR32191/heparin) in the 40 mg study, while these values were 8.7 min (5.5-15.5), 16.0 min (9.3 - greater than 36.0) and 23.8 min (10.7 - greater than 36.0), respectively in the 80 mg study. Compared to screening values, the combination of 80 mg of GR32191 and heparin had a greater effect on the bleeding time than the sum of the prolongations after the separate treatments (p = 0.05). In the 40 mg study this was not the case. Pharmacokinetics of heparin (as assessed by plasma anti-Xa and antithrombin activity) and GR32191 were unaltered during co-administration of the two drugs. GR32191 did not influence the effects of heparin on APTT. Heparin slightly diminished the inhibition of collagen induced platelet aggregation by 80 mg of GR32191 and the U-46619 (thromboxane A2-mimetic) induced platelet aggregation remained unchanged. Overall fibrinolytic activity (as evaluated by the fibrin plate test) was similar during all three treatments in the study with 80 mg. The combination of 80 mg of GR32191 and heparin caused a prolongation of the bleeding time which was more than expected on the basis of their individual effects.
Biphenyl Compounds↗
Diurnal rhythm in anticoagulant effect of heparin during a low dose constant rate infusion. A study in healthy volunteers.
The objective of the study was to investigate possible diurnal rhythms in coagulation tests during a continuous intravenous infusion of unfractionated heparin. Six volunteers participated in the study, which was divided in a treatment (500 U heparin/h for 30 h) and a control experiment. Under basal conditions, no rhythm was found in coagulation tests. During heparin treatment, APTT, thrombin clotting time and anti-Xa activity showed a greater anticoagulant effect at night, with a striking decrease in the morning. In a search for the explanation of this phenomenon we looked for diurnal variations in the urinary excretion of heparin, in the plasma concentrations of antithrombin III and platelet factor 4, and in the effect of heparin added to the plasma samples in vitro. None of these studies provided the explanation.
Adult↗
Serious intercurrent disease in healthy volunteers in clinical pharmacological research.
Explore the source record for details and available documents.
Adult↗
Liver blood flow as a major determinant of the clearance of recombinant human tissue-type plasminogen activator.
The influence of changes in liver blood flow on the clearance of rt-PA was studied both in healthy subjects and in a perfused rat liver model. Liver blood flow in healthy subjects was documented indirectly by the clearance of indocyanine green (ICG). Exercise reduced liver blood flow on average by 57% with a 95% confidence interval (95% CI) ranging from 51% to 62% (n = 5) and increased plasma levels of rt-PA activity (after an i.v. infusion of 18 mg of rt-PA over 120 min) by 119% (95% CI, 58%-203%) and rt-PA antigen by 91% (95% CI, 30%-140%). In the perfused rat liver model it was shown that halving or doubling of the physiological flow rate of a perfusate, containing rt-PA caused a proportional change in the clearance of rt-PA, while the extraction of rt-PA by the liver remained similar. In conclusion, liver blood flow is a major determinant of the clearance of rt-PA. This may have important implications for dosage of rt-PA in patients with myocardial infarction.
Adult↗
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↗
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↗
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↗
Self-selection for personality variables among healthy volunteers.
1. Healthy student volunteers (n = 103) participating in ongoing clinical pharmacological research completed the Dutch Personality Inventory (DPI), the Dutch version of the Spielberger State-Trait Anxiety Inventory (STAI-DY) and the Dutch version of the Sensation Seeking Scale (SSS). 2. The volunteers were more extrovert (P less than 0.001), more flexible (P less than 0.001), more tolerant or less impulsive (P less than 0.001), had more self-confidence and initiative (P less than 0.001), and were more satisfied and optimistic (P less than 0.01) when compared with the general norm. When compared with a student norm, volunteers had lower levels of state (P less than 0.001) and trait (P less than 0.05) anxiety. The general sensation seeking tendency of volunteers was higher than in the student norm group (P less than 0.001). The volunteers had a greater tendency to thrill-and-adventure-seeking (P less than 0.001) and to disinhibition (P less than 0.01). 3. Hence, volunteers were a selected sample of the total population of students. This may influence the interpretation of pharmacokinetic and pharmacodynamic parameters. 4. Personality screening should be added to the screening procedures for volunteers.
Adult↗
Highly variable anticoagulant response after subcutaneous administration of high-dose (12,500 IU) heparin in patients with myocardial infarction and healthy volunteers.
BACKGROUND: In this study, the anticoagulant response of 12,500 IU heparin s.c. was investigated in patients with myocardial infarction and healthy volunteers to determine variabilities in response and modifying factors. METHODS AND RESULTS: On the fourth day after thrombolytic therapy, blood samples were taken before and at frequent intervals until 10 hours after the injection of 12,500 IU heparin s.c. Plasma anti-Xa activity, anti-IIa activity, and the activated partial thromboplastin time (APTT) were measured in addition to body weight and thickness of the abdominal subcutaneous fat layer. Contrary to expectations, the increase of anti-Xa activity, anti-IIa activity, and APTT compared with baseline (predrug) levels was very small, with an average maximal APTT of 42.6 seconds (SD, 12.4 seconds; range, 30.4-70.7 seconds). Subsequently, the influence of the length of the injection needle on the anticoagulant effect of 12,500 IU heparin s.c. was studied in 10 healthy volunteers to find a factor that could be responsible for the poor response in the patients. The length of the injection needle did not influence the anticoagulant effect of heparin. Large interindividual and intraindividual variabilities were seen in the volunteers. The majority of volunteers had minimal prolongation of the APTT, but very strong prolongation was also seen (maximal APTT, 163 seconds). There was no correlation between the abdominal skinfold thickness and anti-Xa activity, anti-IIa activity, or APTT (p > 0.05), but in the patient study, there was a correlation between weight and anti-Xa activity and anti-IIa activity (p < 0.05), and in the volunteer study, there was a correlation between weight and anti-Xa activity and APTT (p < 0.05). CONCLUSIONS: Subcutaneous administration of heparin in a fixed dose for prophylactic and therapeutic purposes may be inadequate because of the large interindividual and intraindividual variations in anticoagulant effect.
Adult↗
Influence of gastric acidity on the bioavailability of digoxin.
OBJECTIVE: To study how changes in gastric acidity induced by omeprazole and pentagastrin affect the absorption of unchanged digoxin and its hydrolytic breakdown products. DESIGN: Double-blind, double-dummy, randomized, crossover study. SETTING: Academic department of clinical pharmacology. SUBJECTS: Six healthy male volunteers. INTERVENTIONS: Subjects received digoxin, 1 mg orally, on three separate occasions: first, after pretreatment with omeprazole; second, after pretreatment with pentagastrin; and third, after "pretreatment" with placebo. MEASUREMENTS: The in-vitro decomposition of digoxin wa studied using a standard dissolution test. The urinary excretion of digoxin over a 120-hour period was measured using selective high-pressure liquid chromatography (HPLC) and a polarization enzyme immunoassay (EIA). Plasma concentrations were measured at 2 hours with the EIA. MAIN RESULTS: Digoxin was rapidly released from the tablets in the in-vitro test. At acid pH, decomposition (as measured with HPLC) was rapid. Pentagastrin reduced the urinary excretion of unchanged digoxin, as measured by HPLC, from 34% to 21.4% of the dose (difference, -12.6%; 95% Cl, -23.5 to -1.8; P less than 0.05), whereas omeprazole increased urinary excretion to 47.4% (difference, 13.4%; 95 Cl, 2.5% to 24.4%; P less than 0.05). However, such differences were not found with the nonselective polarization EIA. CONCLUSIONS: Our data suggest that gastric acidity causes the breakdown of digoxin to products that cross-react in the assay (EIA) that is commonly used clinically. In patients with reduced gastric acidity, increased plasma concentrations of unchanged digoxin may not be detected because of limitations of the EIA, which may invalidate the quantitative use of the plasma digoxin concentration as a predictor of digoxin toxicity. Omeprazole, and presumably other gastric-acid inhibitors, may increase the bioavailability of unchanged digoxin.
Adult↗
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↗
Influence of skinfold thickness on heparin absorption.
The absorption of high and low molecular fractions of heparin from the subcutaneous compartment was evaluated in eight healthy males. They were given an intravenous infusion of 4000 U calcium heparin in 4 hours and on another occasion a subcutaneous injection of 12,500 U calcium heparin (washout period of 1 week). Anticoagulation was monitored by anti-Xa, antithrombin activity, and activated partial thromboplastin time. To evaluate factors that might influence absorption, body weight, body fat, and abdominal skinfold thickness were recorded. There was a pronounced inter-individual variability in absorption but the absorption of the two fractions of heparin was similar. The highly variable absorption was related to the abdominal skinfold thickness, and this could have implications for therapeutic and prophylactic heparin regimens.
Abdominal Muscles↗
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↗
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↗
The pharmacokinetics of recombinant double-chain t-PA (duteplase): effects of bolus injection, infusions, and administration by weight in patients with myocardial infarction.
The current mode of administration of recombinant tissue-type plasminogen activator (rt-PA) in acute myocardial infarction is rather complex, although the rationale for the different components of this scheme is not clearly established. We compared pharmacokinetics of a continuous infusion of 38.5 MU of Burroughs Wellcome t-PA (duteplase) over 90 minutes in nine patients (phase I) with a scheme including a 0.04 MU/kg bolus, a 60-minute 0.36 MU/kg lytic infusion and a 180-minute 0.21 MU/kg maintenance infusion in 15 patients with acute myocardial infarction (Phase II). t-PA activity and antigen were fitted in a one-compartment model from which model-dependent and model-independent parameters were derived. Clearance of t-PA activity was 1020 +/- 465 (mean +/- SD) ml/min in phase I and 1359 +/- 590 ml/min in phase II. Clearance of t-PA antigen was 666 +/- 230 ml/min in phase I and 704 +/- 199 ml/min in phase II. Clearance of activity was significantly (p less than 0.01) higher than of antigen. Clearance and steady-state plasma levels showed a large interindividual variability (coefficient of variation, 56.4%), but this was significantly reduced by dosing by weight (coefficient of variation, 28.9%; p = 0.031). A 10% bolus in phase II shortened the time to reach 75% and 90% of the steady-state plasma level by 4 and 5 minutes, respectively, not significantly different from phase I. A simulation study showed that a bolus should be approximately 15% of the lytic dose to achieve a maximal level in the shortest period.
Aged↗
Grapefruit juice and cimetidine inhibit stereoselective metabolism of nitrendipine in humans.
The effects of grapefruit juice (150 ml at -15, -10, -1/4, +5, and +10 hours) and cimetidine (200 mg at the same times) on the stereoselective pharmacokinetics and effects of 20 mg oral racemic nitrendipine were investigated in a placebo-controlled crossover study in nine healthy men. In all subjects the AUC of racemic nitrendipine was increased by grapefruit juice (mean increase 106%; 95% confidence interval 64% to 158%) and cimetidine treatment (+154%; 95% confidence interval 77% to 265%). Comparable results were obtained for the peak plasma drug concentration and for both parameters of (S)- and (R)-nitrendipine. There were highly significant differences in the area under the concentration-time curve and peak plasma drug concentration between enantiomers within all treatments. Grapefruit juice had no effect on this stereoselectivity, but cimetidine increased the mean S/R ratio of areas under the curve (2.25) by 20% (95% confidence interval 12% to 29%) compared with placebo treatment (1.89). Half-lives and time to reach peak concentration of the enantiomers were not different within and between treatments. There were no consistent effects on blood pressure with all treatments, but in most subjects there was a small temporary increase in heart rate after intake of nitrendipine. Grapefruit juice and cimetidine did not affect these hemodynamic parameters and did not cause additional adverse effects.
Adult↗