Biomedical subjects

R C Schoemaker

Publications and source records attributed to R C Schoemaker.

At least 19 recordsLinked to original sources

PubMed1998

A phase I double-blind, placebo-controlled, single rising dose study to determine the safety, tolerability, and pharmacokinetics of oral YM934 in healthy male volunteers.

In this phase I study a novel potassium channel opener (YM934) was administered to young healthy male volunteers to identify a dose with minimal cardiovascular effects. The study was carried out using a double-blind, placebo-controlled rising dose design with oral YM934 in single doses of 20 micrograms, 60 micrograms, and 180 micrograms. During each study day frequent blood samples were obtained for drug assay, measurements of cardiovascular parameters, and parasympathetic activity. The drug was well tolerated, with headache being the only significant adverse event. No relationship could be detected between dose or plasma concentration of YM934 and headache. No significant changes in routine laboratory and pharmacodynamic parameters occurred between placebo and active drug treatment. The pharmacokinetics of YM934 were characterized by a rapid oral absorption, an elimination half-life of 30 hours, and an oral clearance of 1.7 L/h. The obtained data allow estimation of a YM934 dose regimen with minimal cardiovascular (side) effects to be used for future efficacy studies.

Administration, Oral↗

PubMed1998

Dexamethasone concentration in vitreous and serum after oral administration.

PURPOSE: To determine the dexamethasone concentration in vitreous and serum of patients after oral administration of dexamethasone and to compare the results with the concentrations in vitreous and serum found in a previous study with peribulbar injection of 5 mg dexamethasone disodiumphosphate. METHODS: In a prospective study, 54 patients who were scheduled for vitrectomy received 7.5 mg dexamethasone orally at varied time intervals before surgery. A vitreous sample was taken from each patient and serum samples were collected at multiple time points from 32 out of 54 patients. Dexamethasone concentrations were measured by radioimmunoassay. RESULTS: Dexamethasone concentrations in serum ranged from 2.5 to 98.1 ng/ml (median, 61.6 ng/ml) between 1 and 3 hours after oral administration of 7.5 mg dexamethasone. Serum concentrations after peribulbar injection of 5 mg dexamethasone disodiumphosphate (containing 3.75 mg dexamethasone) were lower by a factor of 1.5. Concentrations in vitreous ranged from 1.7 to 23.4 ng/ml (median, 5.2 ng/ml) between 4 and 10 hours after oral administration. After peribulbar injection of 5 mg dexamethasone disodiumphosphate, the intravitreal concentrations were 3.9 times higher. CONCLUSIONS: An oral dose of 7.5 mg dexamethasone resulted in an intravitreal corticosteroid concentration with an anti-inflammatory potency that is clearly above physiological level. This concentration, however, is several times lower than is the intravitreal concentration after a peribulbar injection of 5 mg dexamethasone disodiumphosphate, although the two routes of administration resulted in nearly equal dexamethasone concentrations in serum. The higher intravitreal concentration after peribulbar injection is probably caused by diffusion from the serum and additional transscleral diffusion.

Administration, Oral↗

PubMed1998

Effects of liver blood flow on the pharmacokinetics of tissue-type plasminogen activator (alteplase) during thrombolysis in patients with acute myocardial infarction.

BACKGROUND: The removal of recombinant tissue-type plasminogen activator (rt-PA; alteplase) by the liver is so rapid that liver blood flow becomes rate determining for its clearance. In patients with myocardial infarction changes in liver blood flow may result from impaired cardiac performance or drug treatment. OBJECTIVE: To estimate the effect of variations in liver blood flow on t-PA plasma concentrations during thrombolytic therapy. METHODS: Fifteen patients with acute myocardial infarction were investigated in an open single-center study at the coronary care unit of University Hospital Leiden. Patients received thrombolytic treatment with 100 mg rt-PA over 3 hours. Liver blood flow was estimated by indocyanine green clearance and by Doppler echocardiography. Concentrations of t-PA antigen, t-PA activity, indocyanine green, alpha 2-antiplasmin, fibrinogen, and fibrin and fibrinogen degradation products were measured. RESULTS: Indocyanine green clearance and clearance of both t-PA antigen (r = 0.78; p < 0:01) and t-PA activity (r = 0.54; p < 0.05) were significantly related. Significant associations between t-PA antigen and fibrin and fibrinogen degradation products and between t-PA antigen and alpha 2-antiplasmin were also found. CONCLUSIONS: The liver blood flow of patients with myocardial infarction is inversely correlated with plasma concentrations of t-PA. In patients with severely impaired liver blood flow and heart failure, high t-PA plasma concentrations may occur if standard doses are given. This finding could contribute to optimization of the dosage of t-PA in certain patient groups.

Aged↗

PubMed1998

The influence of cisapride and clarithromycin on QT intervals in healthy volunteers.

OBJECTIVE: Recently a few cases of long QT syndrome were reported during treatment with cisapride. In most of these cases, risk factors for cardiac arrhythmias or pharmacologic interactions might have been involved, and the role of cisapride remained unclear. Macrolides such as clarithromycin potentially interact with the metabolic elimination of cisapride and have overlapping indication areas. We therefore studied whether combined treatment with clarithromycin and cisapride leads to pharmacokinetic changes and increased QT intervals. METHODS: The study was an open, randomized, 2-way crossover study with washout periods of 1 week. Twelve healthy volunteers were recruited. Treatments were cisapride (10 mg 4 times a day) for 10 days with concomitant clarithromycin (500 mg twice a day) from days 6 through 10, or clarithromycin (500 mg twice a day) for 10 days combined with cisapride (10 mg 4 times a day) from days 6 through 10. Frequent ECG recordings were performed for 24 hours before drug treatment (baseline). After 5 days of monotherapy and combination therapy, frequent ECG recordings and assessments of plasma drug levels were performed for 24 hours. RESULTS: Clarithromycin alone was associated with a minimal increase in QTc intervals. Monotherapy with 10 mg cisapride 4 times a day led to a concentration-dependent QTc elevation, amounting to 6 ms during steady state. Combination of cisapride and clarithromycin caused an average QTc increase of 25 ms above pretreatment values and 3-fold increases in cisapride concentrations. CONCLUSIONS: QTc elevations after cisapride or clarithromycin alone remained within the normal range of diurnal variation. Coadministration of cisapride and clarithromycin produced a substantial QT prolongation. The data support the recently purported interaction between cisapride and clarithromycin and thus the filed contraindication to combine these drugs.

Adult↗

PubMed1998

The influence of nifedipine and captopril on liver blood flow in healthy subjects.

AIMS: Application of single methods to assess liver blood flow (LBF) yielded conflicting results on the magnitude and duration of effect on LBF of oral nifedipine and captopril. The aim of this study was to investigate the influence of these drugs on LBF by simultaneous use of ICG infusion and echo-Doppler. METHODS: The study was performed according to a double-blind, placebo-controlled, randomized, cross-over design in nine healthy male volunteers. After an overnight fast and an equilibration period, subjects received a continuous i.v. indocyanine green (ICG) infusion for 4 h. At presumed ICG steady state (t=45 min), subjects were dosed with oral nifedipine (20 mg), captopril (50 mg) or placebo. During the experiment, blood sampling for ICG assay and measurement of portal venous blood flow (echo-Doppler) took place regularly. Treatments were compared using analysis of variance. Differences are reported with 95% confidence intervals (CI). RESULTS: The area under the curves (AUC) for ICG over 1 h and over 3 h after nifedipine were 15% (difference in AUC: + 0.6, + 7.0 mg l(-1) min) and 22% (+ 7.0, + 28.4 mg l(-1) min) lower compared with placebo. After captopril, the AUC values were 8-10% lower compared with placebo but the 95% CIs included zero. Portal venous flow was 15% (+ 5, + 86 ml min(-1)) higher compared to placebo after nifedipine but not after captopril (-3%; -49, +33 ml min(-1)). The duration of effect on liver blood flow lasted approximately 2 h but was variable (range: 40-160 min). The time to maximal blood flow increase and the duration of effect after nifedipine were very similar for both measures of LBF. Changes in ICG concentrations could be reasonably well predicted from the changes in portal blood flow. CONCLUSIONS: Nifedipine increases LBF for a substantial period of time but the effect is variable between subjects. This effect could be detected by both the ICG method and echo-Doppler and the findings of both methods were in agreement. In this respect it is likely that captopril does not influence LBF in healthy volunteers as no effect was detected with either method.

Administration, Oral↗

PubMed1998

Assessment of hepatic blood flow using continuous infusion of high clearance drugs.

AIMS: To provide methods for the translation of the concentration-time profile of highly cleared marker compounds into the underlying clearance and hepatic blood flow profile. METHODS: Continuous infusion of indocyanine green or sorbitol was used to assess the effect of the hepatic blood flow modifiers exercise, somatostatin and octreotide. Three distinct methods are described for the translation of concentration into flow: 1. assuming successive phases of constant clearance 2. point to point estimation of clearance using estimates of concentration change 3. using a parametric description of the flow profile in combination with the differential equations describing the change in marker concentrations. RESULTS: The marker compound concentration profiles are adequately described using the different methods. Exercise results in a decrease in hepatic blood flow of about 80%. Somatostatin and octreotide elicit an indistinguishable hepatic blood flow decrease from 1.49 to 1.07 l min(-1). Return to baseline takes much longer for octreotide (half-life 126+/-104 min) than for somatostatin (half-life 4.29+/-3.55 min). CONCLUSIONS: Translation of concentration profiles into clearance profiles is possible making continuous assessment of hepatic blood flow feasible.

Coloring Agents↗

PubMed1998

Pharmacokinetic and pharmacodynamic profile of oral and intravenous meta-chlorophenylpiperazine in healthy volunteers.

meta-Chlorophenylpiperazine (mCPP) is a compound that is frequently used in challenge tests of the serotonergic system. Its human pharmacology is largely unexplored. The objective of this study was to investigate the pharmacokinetic and pharmacodynamic profile of mCPP. Eight female and six male healthy volunteers were included in a randomized, double-blind, double-dummy, three-way crossover design of single-dose intravenous (0.1 mg/kg), oral (0.5 mg/kg), and placebo treatment, with 24-hour follow-up. mCPP showed a large variability in clearance (11-92 mL/hr) and bioavailability (14-108%). Two female subjects dropped out because of headache and dysphoria. During the 27 occasions in which mCPP was administered, autonomic physical symptoms were observed in 23 subjects and disturbances of mood in 6 subjects. Oral and intravenous mCPP caused sudden increases in cortisol levels, prolactin levels, and total scores of the Body Sensation Questionnaire. Administration of mCPP also led to concentration-dependent increases of saccadic peak velocity and adaptive tracking performance and to a decrease of electroencephalographic occipital theta activity. No clinically relevant effects on electrocardiogram, temperature, and blood pressure were found. In conclusion, it is doubtful whether mCPP is a useful compound for challenge tests in view of the large pharmacokinetic variability after intravenous and oral administration. The effects of mCPP are consistent with disinhibition of the central nervous system.

Administration, Oral↗

PubMed1998

Circadian rhythm of plasma leptin levels in upper and lower body obese women: influence of body fat distribution and weight loss.

Plasma leptin concentrations were measured every 20 min for 24 h in eight normal weight women and in eight upper body and eight lower body obese women matched for body mass index. The circadian rhythm of leptin, which could mathematically be described by a cosine, was characterized by an acrophase just after midnight in all subjects. The amplitude of a cosine fit as well as the average 24-h leptin concentration were increased by 280% and 420%, respectively, in obese compared to normal weight women. All characteristics of leptin concentration profiles were similar in upper body and lower body obese women, except for a significantly higher amplitude in the lower body obese group. Visceral and sc body fat depots were measured using magnetic resonance imaging in all three groups. Average 24-h leptin concentrations were strongly correlated with sc fat (r = 0.84), whereas visceral fat was not an independent predictor of the plasma leptin level. A loss of 50% of the overweight was associated with a 55% decrease in the average 24-h leptin concentrations in obese women (95% confidence interval, 12.3, 26.6), whereas the characteristics of the circadian rhythm of leptin remained unchanged. Finally, it was observed that a fasting plasma leptin concentration is not an acceptable indicator of the average leptin concentration over 24 h.

Adipose Tissue↗

PubMed1997

Peribulbar corticosteroid injection: vitreal and serum concentrations after dexamethasone disodium phosphate injection.

PURPOSE: To study the dexamethasone level reached in human vitreous after a peribulbar injection of 5 mg of dexamethasone disodium phosphate and to assess its systemic uptake. METHODS: In a prospective study, 61 eyes of 61 patients scheduled for vitrectomy received a single peribulbar injection of 5 mg of dexamethasone disodium phosphate at varied intervals before surgery. At the start of vitrectomy, an undiluted vitreous sample was taken. In 22 patients, multiple serum samples were collected. Dexamethasone concentrations were measured by radioimmunoassay. The physiologic cortisol concentration was determined in the vitreous of 12 eyes of 12 patients who did not receive dexamethasone. RESULTS: An average dexamethasone peak concentration of approximately 13 ng/ml was reached in vitreous 6 to 7 hours after peribulbar injection. In serum the average peak concentration was approximately 60 ng/ml 20 to 30 minutes after peribulbar injection. The average physiologic cortisol concentration in vitreous was 5.1 ng/ml. CONCLUSIONS: After a peribulbar injection of 5 mg of dexamethasone disodium phosphate, an average intravitreal dexamethasone concentration is reached with a 75 times greater anti-inflammatory potency than physiologically present cortisol. Dexamethasone concentration in serum, however, is several times higher. Peribulbar injection is not just a local treatment but results in serum levels comparable to those achieved by a high oral dose.

Adult↗

PubMed1997

Tobramycin population pharmacokinetics in neonates.

OBJECTIVE: To establish a tobramycin dosing schedule for neonates of various gestational ages. METHODS: This was a retrospective study with prospective validation. A retrospective study in 470 neonates, with suspected septicemia in the first week of life, was performed. All patients received tobramycin according to the following scheme: neonates with a gestational age of less than 28 weeks received 3.5 mg/kg every 24 hours, neonates from 28 to 36 weeks received 2.5 mg/kg every 18 hours, neonates older than 36 weeks received 2.5 mg/kg every 12 hours. Trough and peak tobramycin serum levels were determined before drug administration and 30 minutes after the fourth dose. Tobramycin data were analyzed according to a one-compartment open model with use of NONMEM population pharmacokinetic software. Individual empirical Bayes estimates were generated on the basis of the population estimates and used to calculate predicted peak and trough levels for different doses and dosing intervals. To establish an optimal dosing regimen, target trough levels were set at below 2 mg/L and target peak levels were set above 5 to 10 mg/L. The dosing regimen was prospectively evaluated in 23 patients. RESULTS: Of the 470 patients, 19.1% of measured peak and 32.8% of measured trough tobramycin serum levels were outside the desired therapeutic range, and 48.8% of neonates with a gestational age of less than 28 weeks had an aberrant trough level. With use of population estimates, the following dosing regimen was recommended: gestational age below 32 weeks, 4 mg/kg every 48 hours; gestational age between 32 and 37 weeks, 4 mg/kg every 36 hours, gestational age above 37 weeks, 4 mg/kg every 24 hours. With this dosing schedule, predicted peak levels were higher than 5 mg/L in 95.1% of the neonates. Predicted trough levels were higher than 2 mg/L in 1.9% of the neonates and higher than 1 mg/L in 7.6%. Prospectively measured peak levels were higher than 5 mg/L in all but one infant. Measured trough levels were higher than 2 mg/L in three patients and marginally higher than 1 mg/L in four patients. CONCLUSIONS: With the use of this proposed schedule, taking into account differences in gestational ages, predicted peak levels will be therapeutic, whereas predicted trough levels will minimize toxicity.

Anti-Bacterial Agents↗

PubMed1997

Pharmacodynamics of temazepam in primary insomnia: assessment of the value of quantitative electroencephalography and saccadic eye movements in predicting improvement of sleep.

BACKGROUND AND OBJECTIVE: Quantitative electroencephalographic parameters and saccadic eye movements are frequently used as pharmacodynamic measures of benzodiazepine effect. We investigated the relationship between these measures and the hypnotic effect. METHODS: The correlation between the pharmacodynamic measures and sleep quality was determined in 21 patients with primary insomnia. The pharmacokinetic-pharmacodynamic relationships were characterized after administration of 20 mg oral temazepam. The hypnotic effect was determined on the basis of polysomnographic sleep recordings and a subjective sleep evaluation questionnaire. Correlations between pharmacodynamic measures and the improvement of sleep were investigated. RESULTS: The pharmacokinetic-pharmacodynamic relationships for the parameters derived from electroencephalography and saccadic eye movements showed considerable interindividual variability. Administration of temazepam led to a significant improvement in the objective parameters sleep period efficiency, wake time after sleep onset, and sleep efficiency and in the subjective assessment of sleep quality. No significant correlations were observed between the pharmacokinetic-pharmacodynamic-derived parameters and the improvement in objective or subjective sleep parameters. CONCLUSION: In subjects with primary insomnia the administration of 20 mg oral temazepam results in changes in both the pharmacodynamic measures and in quality of sleep. No individual correlations between the pharmacodynamic measures and quality of sleep were observed. We concluded that the investigated pharmacodynamic measures are of value in the first assessment of clinical efficacy and for the selection of the dose(s) to be investigated in subsequent trials that aim at showing clinical efficacy. However, the conclusive quantification of clinical efficacy should be performed only on the basis of the clinical end point itself.

Adult↗

PubMed1997

Variability of splanchnic blood flow measurements using MR velocity mapping under fasting and post-prandial conditions--comparison with echo-Doppler.

BACKGROUND/AIMS: The aim was to study the reproducibility of magnetic resonance velocity mapping, when measuring portal vein and superior mesenteric artery blood flow, under fasting and post-prandial conditions. Magnetic resonance flow measurements for the portal vein were compared with echo-Doppler measurements in the right portal vein. METHODS: Eight healthy volunteers were studied on two occasions, separated by 1 week. Blood flow in the portal vein and superior mesenteric artery was measured repeatedly under basal fasting conditions. On one occasion measurements were also made after a meal. Every magnetic resonance measurement was followed by an echo-Doppler measurement in the right portal vein. Correlations between flow values were calculated using Pearson's r. Variability components were assessed using ANOVA. RESULTS: Intra-individual variability was approximately 7% for portal vein flow measurements using magnetic resonance velocity mapping. This variability did not increase after 1 h, 1 week and after a meal. Values of flow measured in the portal vein and superior mesenteric artery using magnetic resonance velocity mapping correlated well (r = 0.80, p < 0.001). Fasting portal flow as measured with magnetic resonance velocity mapping was 1.2 l/min (range 0.96-1.6 l/min). Variability in echo-Doppler measurements was comparable to the variability of magnetic resonance velocity mapping, and flow measurements obtained with the two techniques correlated well (r = 0.74; p < 0.001). CONCLUSIONS: Magnetic resonance velocity mapping accurately measures blood flow in the portal vein with low variability and should be preferred when absolute flow values are necessary. Echo-Doppler measurement of the right portal vein has a low variability and can be used to study changes in flow.

Adult↗

PubMed1997

A study of the effects of long-term use on individual sensitivity to temazepam and lorazepam in a clinical population.

AIMS: The central effects of benzodiazepines may be attenuated after chronic use by changes in pharmacokinetics, pharmacodynamics or both. This attenuation may be influenced by the dosing pattern and the characteristics of the user population. The objectives of this study were to evaluate drug sensitivity in long-term users of temazepam and lorazepam in a clinical population. METHODS: The sensitivity to benzodiazepine effects in chronic users (1-20 years) of lorazepam (n = 14) or temazepam (n = 13) was evaluated in comparison with age and sex matched controls. Drug sensitivity was evaluated by plasma concentration in relation to saccadic eye movement parameters, postural stability and visual analogue scales. RESULTS: Pharmacokinetics of lorazepam and temazepam did not differ between patients and control subjects. Chronic users of lorazepam showed clear evidence of reduced sensitivity, indicated by lack of any pharmacodynamic difference between patients and controls at baseline, when drug concentrations were similar to the peak values attained in the control subjects after administration of 1-2.5 mg of lorazepam. In addition, there was a two- to four fold reduction in the slopes of concentration-effect plots for measures of saccadic eye movements and body sway (all; P < or = 0.01). By contrast, sensitivity in chronic users of temazepam was not different from controls. The difference between the temazepam and the lorazepam group appears to be associated with a more continuous drug exposure in the latter, due to the longer half-life and a more frequent intake of lorazepam. This pattern of use may be partly related to the more anxious personality traits that were observed in the chronic users of lorazepam. CONCLUSIONS: Chronic users of lorazepam show evidence of tolerance to sedative effects in comparison with healthy controls. Tolerance does not occur in chronic users of temazepam. The difference may be related to pharmacological properties, in addition to different patterns of use, associated with psychological factors.

Adult↗

PubMed1997

Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

AIMS: This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48-6791, compared with midazolam, in healthy subjects during first administration to man studies. METHODS: The study was double-blind and five-way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48-6791 was administered as a slow i.v. infusion in doses of 0.1-0.3-1 mg in the first group, and 1-2-3 mg in the second. Midazolam was infused at 0.1 mg kg(-1). The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min(-1)) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two-compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (beta-power). These parameters were used for pharmacokinetic/pharmacodynamic modelling. RESULTS: Ro 48-6791 and midazolam were both well tolerated. Most clinical events were dose-dependent central depressant effects. The volume of distribution (V(SS)) and plasma clearance of Ro 48-6791 were on average markedly larger than those of midazolam (171 +/- 65 vs 41 +/- 10 l and 2.2 +/- 0.9 vs 0.42 +/- 0.11 l min(-1), respectively). The doses of Ro 48-6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48-6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action for saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in beta-power than Ro 48-6791 at the highest administered dose. Ro 48-6792, a metabolite of Ro 48-6791, showed a considerably longer half-life than the parent compound. Although there were no indications of a discernable effect of Ro 48-6792 in the present study, the effects of possible accumulation during prolonged administration should be investigated further. CONCLUSIONS: This first study with Ro 48-6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.

Adjuvants, Anesthesia↗

PubMed1997

Integrated pharmacokinetics and pharmacodynamics of Ro 48-8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

AIMS: This study aimed to investigate the pharmacodynamics and pharmacokinetics of ascending doses of Ro 48-8684, compared with midazolam, in healthy subjects during first administration to man. METHODS: The study was double-blind and five-way crossover (three ascending doses, placebo, fixed midazolam dose), performed in two groups of five males. Ro 48-8684 was infused in doses of 0.1-0.3-1 mg in the first group, and 1-3-10 mg in the second, with different infusion rates (expressed as mg min(-1)) among doses. Midazolam was infused at 0.1 mg(-1) kg. Infusions were stopped after 20 min or if sedation became too strong for proper performance of saccadic eye movements. Pharmacokinetics and pharmacodynamics and their relationships were evaluated as described in the companion article. RESULTS: Ro 48-8684 caused dose-dependent sedation. No serious adverse events occurred. The volume of distribution and clearance of Ro 48-8684 were larger than of midazolam (337+/-114 vs 50+/-121 and 2.4+/-0.5 vs 0.47+/-0.11 l min(-1), resp). The recovery of saccadic eye movements from equal levels of sedation was on average almost half an hour faster for Ro 48-8684 than for midazolam, with considerable interindividual differences (range 2, 55 min). The doses of Ro 48-8684 leading to the same clinical endpoint as midazolam were comparable, but the corresponding predicted effect compartment concentrations of Ro 48-8684 were on average 2.6 times lower (range 1.5, 4.9 times). The slope of the linear concentration-effect-relationship for saccadic peak velocity was on average 2.2 times steeper for 10 mg Ro 48-8684 than for midazolam (range 1.3, 3.3). The slope decreased on average 4.4-fold (range 1.6, 7.3 times), with doses of Ro 48-8684 increasing from 1 to 10 mg. The metabolite Ro 61-2466 had a longer half-life than the parent compound Ro 48-8684. The influence of this metabolite during prolonged administration should be further investigated. CONCLUSIONS: These results show that Ro 48-8684 has a considerably shorter duration of action than midazolam. There may be a reduction of sensitivity to Ro 48-8684 with repeated administration of rising doses due to as yet undetermined factors.

Adult↗

PubMed1997

Effect of changes in liver blood flow on the pharmacokinetics of saruplase in patients with acute myocardial infarction.

BACKGROUND: The recombinant unglycosylated single chain urokinase-type plasminogen activator saruplase is cleared for a large part by the liver. A large interindividual variation in saruplase concentration is found in acute myocardial infarction (AMI) patients. The variable cardiac performance after an infarct may induce differences in liver blood flow that could explain the concentration diversity. This study was performed to investigate the relation between hepatic blood flow and the pharmacokinetic and pharmacodynamic properties of saruplase. METHODS AND RESULTS: Thirteen AMI patients were enrolled in this open label study. Patients received a bolus injection of 20 mg saruplase followed by a one-hour infusion of 60 mg saruplase. Concurrently 36 mg intravenous indocyanine green (ICG) was given over 1 h to measure hepatic blood flow. Blood samples were taken at regular time intervals to measure plasma levels of urokinase-type plasminogen activator (u-PA) antigen and activity, the two-chain form (tcu-PA) activity, indocyanine green, fibrinogen, fibrin and fibrin degradation products, alpha2-antiplasmin and thrombin antithrombin III complex. A correlation was seen between the clearance of ICG and both those of u-PA antigen (r = 0.62; p <0.05) and u-PA activity (r = 0.57; p <0.05). A negative correlation was seen between the area under the curve of tcu-PA activity and the areas under the effect curves of both fibrinogen and alpha2-antiplasmin (r = -0.84; p <0.01 and r = -0.65; p <0.05). CONCLUSIONS: Liver blood flow is an important determinant of the clearance of u-PA antigen and activity and reduction of flow in patients with heart failure will lead to an increase in plasma concentrations. High plasma concentrations of tcu-PA activity lead to increased systemic fibrinogenolysis. These results may be used to optimize saruplase treatment in patients with impaired cardiac function or after co-medication with drugs that affect liver blood flow.

Aged↗

PubMed1996

Pharmacokinetics of the conventional and microemulsion formulations of cyclosporine in pancreas-kidney transplant recipients with gastroparesis.

Cyclosporine (CsA) is an immunosuppressive drug requiring dose individualization and regular control due to its highly variable pharmacokinetics. Since gastroparesis may influence the absorption of CsA, a randomized cross-over study was performed to assess the pharmacokinetics and tolerability of a novel microemulsion CsA formulation in comparison with the standard CsA dosage form in six stable pancreas-kidney transplant recipients with scintigraphically proven gastroparesis. The absorption of CsA was investigated during three 2-hr study days during each treatment period, and a full pharmacokinetic profile was done for each formulation. No adverse events or differences in tolerability/safety parameters between the treatments were found. The average AUC (0-->2 hr) was 150% higher after the novel formulation. The coefficient of variation in AUC (0-->2 hr) for both formulations was comparable (37% after the microemulsion and 40% after the standard formulation). The median time at which blood CsA levels exceeded the preceding trough level by 20% was 30 min (range: 30 -> 718 min) after the standard formulation. With approximately the same average dose, the AUCss tau after the microemulsion was 81% higher than the standard formulation, while predose and 12-hr trough levels were similar. The average maximal CsA plasma level after the microemulsion was 396 ng/ml (95% CI: 71-722 ng/ml) higher than after the standard formulation. The median time at which the highest blood levels were observed was 90 min (range: 150 -> 718 min) after the standard formulation. The time profiles of the CsA metabolites followed those of the parent compound. The microemulsion resulted in a higher systemic exposure to CsA than the standard formulation in pancreas-kidney transplant patients with diabetic gastroparesis, but substantial variability in blood concentrations remained.

Adult↗

PubMed1996

Effects of increased liver blood flow on the kinetics and dynamics of recombinant tissue-type plasminogen activator.

OBJECTIVE: To investigate the influence of increased liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue-type plasminogen activator (rt-PA) and to study the changes in endogenous urokinase-type plasminogen activator (u-PA). METHODS: This open, randomized, crossover trial was carried out in a clinical research unit. Eight healthy, nonsmoking volunteers received linear infusions of 24 mg rt-PA and 92 mg indocyanine green over 160 minutes. Sixty minutes after the infusions were started, the subjects consumed a standardized meal to increase liver blood flow on one occasion and abstained from taking food on the other occasion. Plasma concentrations of indocyanine green, tissue-type plasminogen activator (t-PA) antigen, t-PA activity, total u-PA antigen, plasmin-activatable single-chain u-PA (scu-PA), active two-chain u-PA (tcu-PA), fibrinogen, total fibrin, and fibrinogen/fibrin degradation products (TDP), and alpha 2-antiplasmin were measured. RESULTS: After the consumption of the meal, the area under the curve (AUC) was 35% (95% confidence interval [CI]: 25%, 43%) lower for indocyanine green, 15% (CI: 6%, 24%) lower for t-PA antigen, and 11% (CI: 2%, 19%) lower for t-PA activity compared to the AUC after subjects abstained from food. No changes were observed in fibrinogen, TDP, or alpha 2-antiplasmin concentrations that were attributable to the intake of food. The infusion of rt-PA caused a fivefold increase in the concentration of active tcu-PA and a concomitant decrease in scu-PA concentrations by more than 50%. CONCLUSIONS: Increased liver blood flow results in an increase in t-PA clearance. The conversion of the inactive zymogen scu-PA to the active tcu-PA is increased by an infusion of rt-PA, but total u-PA antigen concentrations remain unchanged.

Adult↗