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Biomedical subjects

C de Mey

Publications and source records attributed to C de Mey.

67 records · Page 4Linked to original sources
PubMed1989

Pharmacokinetic and pharmacodynamic interactions between single oral doses of ibopamine and food in normal man.

The pharmacokinetic and pharmacodynamic interactions between single oral doses of 200 mg ibopamine and a standard cold 3100 kJ meal were assessed in 12 normal male subjects, who were studied on 4 occasions, receiving either ibopamine or matched placebo (double-blind) in fasting condition or at the end of a meal. Treatments were randomly allocated in a period-balanced within-subject cross-over study design. The plasma concentrations of epinine (N-methyldopamine) were extensively profiled up to 4 h after dosing. Food caused a profound reduction of both Cmax and AUC of unconjugated epinine with a prolongation of Tmax. The subjects were furthermore profiled in detail up to 4 h after dosing by transthoracic impedance cardiography. Food caused substantial and protracted effects that affected virtually all parameters profiled. Ibopamine had clear cardiac performance enhancing effects only over the first hour after dosing. These effects were furthermore subject to significant food interaction. It therefore appeared that food resulted in a profound blunting of both ibopamine's pharmacokinetic and pharmacodynamic characteristics.

Administration, Oral↗
PubMed1989

Studies with two investigational interventions: a simple model to assess their effects and interaction.

The paper presents a simple way to design and analyse studies on pharmacodynamic food-interaction and drug-interaction studies. The study design includes two distinct interventions--the drug or control against eating, or fasting, and allows an analysis of variance. It provides a model for a more analytical approach in the conduct and analysis of pharmacodynamic interaction studies and pharmacotherapeutic combination trials.

Analysis of Variance↗
PubMed1988

Pharmacokinetics and pharmacodynamics of single oral doses of ibopamine, quinidine and their combination in normal man.

The pharmacokinetics and haemodynamics (phono- and impedance cardiography) of single oral doses of 200 mg ibopamine (SK&F 100168), 400 mg quinidine sulphate, and their combination, have been assessed in 6 healthy male volunteers. No significant differences in the mean pharmacokinetic parameters of either drug were seen between the single and combined doses. Ibopamine caused an increase in mean estimated stroke volume (SV +29% for the maximum change from baseline and +15% cumulatively over the first h) with no change in mean heart rate (HR) or QTc. Quinidine administered concomitantly blunted the response of SV. A tendency to a lower mean concentration of epinine early after administration of the combination may have contributed to the difference. Quinidine alone hardly affected SV (-3% from baseline over the first h), but it did increase mean HR (+6 beats.min-1) and mean QTc (+30 ms). These changes were sustained up to 8 h after dosing, and were not affected by concurrent ibopamine.

Adult↗
PubMed1988

Postprandial haemodynamic changes: a source of bias in cardiovascular research affected by its own methodological bias.

The effects of heart rate and systolic and diastolic blood pressure of eating a 3100 kJ cold meal were assessed in eight young normal subjects studied in a randomised and balanced crossover study. Blood pressure was measured simultaneously and in the same arm by auscultation of the fossa cubitalis (Korotkoff I, IV, and V), by an automated device with a microphone over the brachial artery (equivalent to Korotkoff I and V), and by graphical analysis of these microphone signals (equivalent to Korotkoff I and IV). Eating caused a rise in mean heart rate, a small rise in systolic blood pressure, and a decrease in diastolic blood pressure, which was overestimated when Korotkoff V rather than Korotkoff IV endpoints were considered. Both the automated device and the graphical analysis yielded acceptable overall quantitative agreement with the auscultatory method. Both alternative methods allowed similar postprandial blood pressure trends to be detected, but the quantitative agreement in estimating the postprandial effects was far less optimal. Eating therefore was shown to cause changes that might distort and confuse the interpretation of cardiovascular data in studies in which subjects are allowed to eat. This source of bias itself appeared to be affected by its own methodological bias.

Adult↗
PubMed1988

Noninvasive assessment of cardiac performance by impedance cardiography: disagreement between two equations to estimate stroke volume.

Impedance cardiography, phonocardiography, and ECG were registered prior to, during, and after 10 min of gradual passive upright tilt in 35 normal male subjects. Stroke volume (SV) was estimated according to both the standard equation of Kubicek et al. and a newly introduced equation by Sramek et al. Sramek's equation estimated larger SV values throughout. It furthermore estimated a larger SV response to upright tilt: a bias of -17 ml (95% Cl: -20 to -13) was identified for Sramek's minus Kubicek's approach. Corresponding disagreement was identified for cardiac output and systemic vascular resistance derived from SV. A far better agreement was identified when the data were expressed as percent of the supine base line prior to tilt. Under such transformation, Sramek's approach estimated slightly smaller SV responses to tilt: a bias of 4.2% (95% Cl: 3.6 to 4.7) was identified for the percent response of SV to upright tilt for Sramek's minus Kubicek's equation. Data generated by these two equations are, nevertheless, not readily interchangeable nor comparable. As Sramek's equation estimated consistently larger SV values than Kubicek's equation, it is unlikely that Sramek's equation could solve the issue of the quantitative inaccuracy which remains intrinsic to the usage of Kubicek's equation in impedance cardiography.

Adult↗
PubMed1988

Variant responses impair the usefulness of passive upright tilt in drug research.

Thirty-five male normal subjects underwent gradual passive upright tilt (1 minute at 15 degree, 2 minutes at 45 degree and 7 minutes at 85 degree) on a total of 256 occasions, in drug-free condition or after administration of placebo. Although a cardio-acceleratory and vasopressor response prevailed, seven subjects experienced imminent syncope on 9 occasions, after 2 to 7 minutes erect standing. These reactions were hypotensive in nature, and preceded by (5 instances) or concurrent with (3 instances) a sudden drop of the initially adequately rising heart rate. These reactions are likely to be of vagal origin. All reactions occurred suddenly and unexpectedly and improved rapidly when the subject was tilted back to supine position. Imminent syncopes on passive upright tilt appeared to be incidental phenomena occurring in subjects who uneventfully underwent previous or subsequent tilting, either on the same day or on another day. The potential severity of these reactions, their unpredictability and their lack of reproducibility restrict the usefulness of passive upright tilt as a test procedure in drug research. In the event that such reactions would appear after exposure to an investigational drug, it cannot be proven beyond reasonable doubt that the reaction is caused by the drug, is a variant response intrinsic to the test procedure, or a drug-related enhancement of the onset and/or severity of such a variant response.

Adult↗
PubMed1987

Postprandial changes in supine and erect heart rate, systemic blood pressure and plasma noradrenaline and renin activity in normal subjects.

The haemodynamic effects of a standard meal were assessed in a balanced cross-over study in eight normal fasting subjects, investigated under conditions applicable to many drug tests. Both the supine and erect diastolic blood pressure were reduced on average by 10 mmHg over the 4 h following the meal. The supine systolic pressure was increased on average by 2 mmHg, a difference of no biological relevance. Erect systolic blood pressure was not affected by eating. Supine heart rate was slightly but significantly increased, but the erect heart rate did not change. Postprandial plasma renin activity was increased. Venous plasma noradrenaline levels in the supine position were not affected by eating and after standing erect, and immobile for 5 min they were only slightly and not-significantly increased. A food-induced vasodepressor response combined with baroreceptor resetting is considered to have occurred in this population. The changes had a gradual onset, reaching their maximum about 2 h after eating and they were still evident after 3 h. Eating should be considered as an important potential source of bias in cardiovascular studies.

Adult↗
PubMed1986

High sensitivity assay for the alpha 2 antagonist 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and its desmethyl metabolite in plasma using gas chromatography mass spectrometry with ammonia/CCl4 chemical ionization.

A rapid and highly sensitive assay for quantifying the alpha 2-adrenoceptor antagonist SK&F 86466 and a desmethyl metabolite has been developed, using capillary column gas chromatography/chemical ionization mass spectrometry. This assay uses deuterium-labeled analogs of the analytes as internal standards, and has a lower limit of quantification of 100 pg ml-1. A novel reagent gas, consisting of carbon tetrachloride in anhydrous ammonia, was used to achieve maximal sensitivity.

Adrenergic alpha-Antagonists↗
PubMed1986

Assessment of the hemodynamic response to single passive head up tilt by non-invasive methods in normotensive subjects.

The hemodynamic response to passive upright tilt in thirty-five normal subjects was assessed by combined electrocardiography, differentiated electrical impedance cardiography, phonocardiography and non-invasive blood pressure measurement. The increase in transthoracic impedance and decrease in estimated stroke volume were accompanied by a cardio-acceleratory and vasopressor response. The increase in heart rate did not compensate for the decrease in estimated stroke volume and the estimated cardiac output decreased. Diastolic and mean blood pressure, however, increased. The relative systolic time interval was largely increased. Most of these changes returned to base-line on resuming the supine position. This test procedure and the non-invasive methods used offered a suitable setting for the within-subject assessment of postural changes in cardiovascular function. Certain methodological aspects were found to affect the interpretation of the impedance cardiographic data. Pre-systolic low amplitude-high velocity changes in transthoracic impedance, especially when occurring in conditions where strict respiratory control cannot be sustained, can complicate the delineation of the systolic time intervals and the correction of respiration-related fluctuations in the signal's base-line. One further subject is presented with imminent syncope on tilting, in order to highlight this intrinsic but unpredictable morbidity as a limiting factor in the application of this study procedure.

Adult↗
PubMed1983

Epoprostenol (prostacyclin, PGI2) binding and activation of adenylate cyclase in platelets of diabetic and control subjects.

1 The binding of epoprostenol (prostacyclin, PGI2) to isolated fractured human platelets has been studied using tritiated PGI2. 2 High and low affinity binding sites for PGI2 have been identified (Kd values = 16 and 382 nM). 3 Analysis of the prostacyclin-dependent activation of adenylate cyclase suggests that enzyme activation is mediated by the high affinity binding site. 4 Platelet PGI2 receptor binding and adenylate cyclase activation by PGI2 are unchanged in diabetic and normal human platelets. 5 This work suggests that hyperaggregability of diabetic platelets is not due to any alteration of platelet prostacyclin receptor numbers or their activation.

Adenylyl Cyclases↗
PubMedDate not supplied

Temelastine, a novel histamine H1-receptor antagonist, does not induce oxidative hepatic enzyme activity in man.

Temelastine (SK&F 93944) is a novel histamine H1-receptor antagonist with a high degree of protein binding and predominant hepatic elimination. The pharmacokinetics of antipyrine were assessed in eight male normal subjects after single oral doses of 10 mg/kg antipyrine, administered prior to chronic dosing with temelastine 100 mg twice daily for 2 weeks, and 48 hours after the last dose of temelastine. After the first dose of antipyrine the mean maximum plasma concentration (Cmax) was 78.3 mumol/l (range: 60.3 to 95.8), the mean AUC (0-infinity) was 1330 mumol.h/l (range: 1030 to 2074), the mean apparent terminal disposition rate constant K was 0.0656 h-1 (range: 0.0428 to 0.0769) and the mean residence time (MRT) was 16.7 h on average (range: 14.4 to 24.1). After the second dose the mean Cmax, AUC (0-infinity) and MRT had slightly increased by on average 11, 5 and 7% respectively whereas the mean K had decreased by 9%. None of the differences between the means of the log-transformed parameters for second-first dose reached statistical significance. Temelastine therefore did not appear to induce hepatic oxidative enzyme activity in man, as judged by antipyrine as a model substance.

Aged↗
PubMedDate not supplied

Influence of the dopamine agonist alpha-dihydroergocryptine on the pharmacokinetics of levodopa in patients with Parkinson's disease.

This study investigated whether chronic coadministration of alpha-dihydroergocryptine (DHEC) altered the plasma pharmacokinetics of individualized treatments with levodopa in 12 patients with Parkinson's disease. Steady-state pharmacokinetics of plasma levodopa (L-Dopa) under combined treatment were compared with those under treatment with L-Dopa alone. There was no evidence of increased exposure to L-Dopa caused by concomitant treatment with DHEC. In contrast, additional treatment with DHEC reduced the overall exposure to L-Dopa (17.5% reduction in area under the curve; 95% CI: 23%-6%). This effect was small but statistically significant for the area under the plasma concentration-time curve, whereas tmax (time of maximum plasma concentration) and peak-to-trough fluctuation were not affected. Cmax (maximum plasma concentration), on average, was reduced to a similar extent (-14.5%; 95% CI: 38% to -17%), albeit not significantly. The magnitude of the interaction does not suggest changing the current clinical practice of up-titrating DHEC and subsequently adapting L-Dopa to the individual needs of patients.

Adult↗