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Biomedical subjects

A F Cohen

Publications and source records attributed to A F Cohen.

At least 145 records · Page 8Linked to original sources
PubMed1993

Interaction study between nifedipine and recombinant tissue-type plasminogen activator in healthy subjects.

1. In a previous study it was demonstrated that a decrease in liver blood flow produced a decrease in clearance of recombinant human tissue-type plasminogen activator (rt-PA). 2. The purpose of this randomized, double-blind, placebo-controlled, three-way, cross-over investigation was to determine the effect of nifedipine (20 mg orally), a compound that increases liver blood flow, on plasma concentrations of steady state endogenous and recombinant tissue-type plasminogen activator (t-PA and rt-PA) (35 mg of rt-PA over 2 h) in nine healthy male volunteers. 3. Nifedipine increased liver blood flow by 95% (42-167%) (mean (95% confidence interval)) as assessed by indocyanine green (ICG, 0.5 mg kg-1 i.v. bolus injection) clearance. 4. Nifedipine did not influence the plasma concentrations of total rt-PA antigen and activity as evaluated by the areas under the rt-PA curves from 30 min (time at which nifedipine was ingested) to 90 min during the rt-PA infusion (P > 0.05) and by analysis of a possible treatment x time interaction (P > 0.05). In addition, the plasma concentrations of endogenous t-PA remained unchanged when nifedipine was given alone. 5. In conclusion, by using nifedipine as a model compound it was demonstrated that the combination of rt-PA and a compound which increases liver blood flow probably does not lead to substantial changes in plasma concentrations of rt-PA.

Adult↗
PubMed1993

A comparison of the concentration-effect relationships of midazolam for EEG-derived parameters and saccadic peak velocity.

1. Concentration-effect relationships of midazolam were assessed in an open study in six healthy volunteers. Saccadic eye movements and EEG parameters derived by fast Fourier transform (FFT) and aperiodic analysis (AP) were used to quantify drug effects. 2. Midazolam was infused at a rate of 0.6 mg kg-1 h-1 for a maximum of 15 min. Hypnotic effects were avoided by terminating infusions when subjects could no longer perform the eye movement test properly. 3. Wake-sleep transitions could be recognized through frequent observation of eye movements. The dose needed to reach maximum conscious sedation averaged 0.10 mg kg-1, ranging from 0.06 to 0.13 mg kg-1. 4. Sigmoidal concentration-effect relationships were found for EEG beta-amplitudes in five of six subjects, with average EC50 values (+/- s.d.) of 120 +/- 54 ng ml-1 for FFT and 104 +/- 40 ng ml-1 for AP. For the 'total number of waves' in the beta frequency range (AP) an average (n = 6) EC50 of 63 +/- 37 ng ml-1 was found. Changes in EEG alpha-amplitudes were found in three subjects, resulting in an average EC50 value of 55 +/- 32 ng ml-1. 5. For saccadic peak velocity (PV) concentration-effect relationships were linear in five subjects and sigmoidal in one. The maximal measured decrease in PV averaged -44 +/- 9%. 6. The differences in concentration-effect relationships for various effect parameters call for further studies with emphasis on the external validity and reproducibility of data. In such studies the dose needed to reach wake-sleep transition may be used as a relevant clinical end-point.

Adult↗
PubMed1993

CNS-related performance and haemodynamics of metoprolol-Oros and propranolol after single and 3 days dosing in healthy volunteers.

1. The effects of metoprolol-Oros 14/190 once daily, propranolol 80 mg twice daily and temazepam 10 mg once daily on central nervous system (CNS) related performance and haemodynamic variables were evaluated in a double-blind, randomized, placebo controlled, crossover study in 12 healthy volunteers. Drugs were administered for 3 consecutive days except for temazepam, which was administered on days 1 and 3 only. Treatment effects were evaluated at 0, 2, 5 and 8 h on days 1 and 3. 2. Neither beta-adrenoceptor blocker had significant effects in a battery of tests after single or 3 days dosing. Temazepam caused a decrease in saccadic peak velocity of 37.4 degrees s-1 (95% CI: 6.0, 68.9) at 2 h and an increase of auditory reaction times of 11.5 ms (0.2, 22.8) at 8 h on day 1. No significant effects of temazepam were detected on day 3. 3. Both beta-adrenoceptor blockers reduced exercise heart rate. Peak effects were measured at 2 h 40 min after propranolol but not metoprolol-Oros (difference, day 1:20 (11, 29) beats min-1, day 3:13 (8, 19) beats min-1). Both beta-adrenoceptor blockers significantly reduced baseline exercise heart rate on day 3. Compared with day 1, metoprolol-Oros caused larger reductions of exercise heart rate at all times on day 3. 4. Metoprolol-Oros and propranolol caused similar reductions of systolic- and diastolic blood pressure on days 1 and 3. Temazepam caused a small reduction in diastolic blood pressure at 5 h 40 min on day 1 but was otherwise devoid of haemodynamic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The bioavailability of digoxin from three oral formulations measured by a specific h.p.l.c. assay.

1. We have studied the absolute bioavailability of three oral formulations of digoxin, 1.0 mg, in 12 young healthy volunteers in a four way randomised cross-over study using an intravenous control. 2. Digoxin tablets (250 micrograms), liquid filled digoxin capsules (100 micrograms) and an experimental enteric-coated capsule (100 micrograms) were evaluated. In vitro dissolution at pH 1 demonstrated extensive hydrolytic breakdown of digoxin from the tablets and capsules but not from the enteric-coated capsules. 3. Serum 'digoxin' concentrations were measured by fluorescence polarization immunoassay (FPI). The systemic availability (+/- s.d.) of the capsules was 70.5 +/- 11.3%, and that of the tablets 71.5 +/- 8.6%. Drug was less available from the enteric-coated capsules (62.1 +/- 10.3%) measured with FPI. These results were reflected in the urinary drug recoveries measured by FPI. 4. By contrast, there were no differences in urinary recovery of unchanged digoxin between any of the oral treatments, when this was measured by h.p.l.c. The cross-reactivity of immunoassays for metabolites of digoxin may produce artefactual results and the optimal pharmaceutical formulation for digoxin remains to be determined.

Administration, Oral↗
PubMed1993

A cross-over comparison of the anti-clotting effects of three low molecular weight heparins and glycosaminoglycuronan.

1. The anti-clotting effects after intravenous administration of three low molecular weight (LMW) heparins, Fragmin (KABI 2165), Fraxiparine (CY 216), Clexane (PK 10169) and the LMW mixture of glycosaminoglycuronans Orgaran (Org 10172) were compared in a randomized cross-over study in 12 healthy male volunteers. 2. The time courses of the anti-Xa activity of Fragmin, Fraxiparine and Clexane (five subjects) were best fitted by a monoexponential function and had comparable half-lives of 1.9 h, 2.3 h and 2.8 h, respectively. The time courses of the anti-Xa activity of Orgaran and Clexane (four subjects) were described by a biexponential function with terminal half-lives of 56.8h and 27.7 h, respectively. They were longer than those of Fraxiparine and Fragmin. Orgaran injection was associated with a significantly smaller 'clearance' (0.8 +/- 0.2 l h-1) of the plasma anti-Xa activity compared with Fragmin (2.0 +/- 0.5), Fraxiparine (1.7 +/- 0.5) and Clexane (1.6 +/- 0.5). 3. In comparison with the three LMW heparins, the terminal half-life of plasma anti-IIa activity after Orgaran was longer and the 'clearance' of Orgaran was lower than that after Clexane. The area under the curve of the plasma anti-IIa activity after administration of Orgaran was negligible compared with that obtained after injection of the LMW heparins. 4. Orgaran caused the smallest and Fragmin the greatest prolongation of the activated partial thromboplastin time (Orgaran 5.8 +/- 1.2 s vs Fragmin 18.5 +/- 5.2 s) and the thrombin clotting time (Orgaran 2.9 +/- 1.7 s vs Fragmin 47.8 +/- 0.9 s).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Evidence for brain serotonin-mediated control of carbohydrate consumption in normal weight and obese humans.

A plasma insulin and amino acid-mediated mechanism is thought to modulate brain serotonin concentration, thereby regulating carbohydrate consumption on a meal to meal basis. It has been suggested that obesity is associated with a defect in the appetite control system. Furthermore, post-absorptive plasma levels of several amino acids are increased in obese subjects, which is ascribed to obesity-associated insulin resistance and/or hyperinsulinemia. We studied breakfast-induced changes in plasma ratios of tryptophan to other large neutral amino acids and associated differences in macro-nutrient composition of lunch food in normal weight and obese human subjects. The study was randomized, double blind and cross-over with a 2 x 2 factorial design with drug/placebo and type of breakfast as factors. Nineteen healthy, non-obese (body mass index (BMI) 22.5 +/- 1.9 kg/m2, mean +/- s.d.) and 19 obese (BMI 34.7 +/- 6.2 kg/m2) female volunteers were treated with either 60 mg fluoxetine (FXT), a serotonin re-uptake blocker specifically acting in the brain, or placebo for four days with a wash-out period between treatments of four weeks. The subjects received either a carbohydrate (CHO) breakfast (80 g maltodextrin, 300 kcal) or a protein-rich (PROT) breakfast (60% milk protein and 40% CHO, 300 kcal) on two consecutive days (days 4 and 5 of each treatment period). Plasma glucose, insulin and amino acids were measured at several time points after breakfast. Three hours after breakfast, subjects were able to choose from 29 different food items. Total energy content and weight of lunch food and energy percentage of each macronutrient were calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

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↗
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

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

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↗
PubMed1992

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↗
PubMed1991

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↗