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Biomedical subjects

C de Mey

Publications and source records attributed to C de Mey.

At least 55 records · Page 3Linked to original sources
PubMed1992

Agreement and reproducibility of the estimates of cardiovascular function by impedance cardiography and M-mode echocardiography in healthy subjects.

The reproducibility and agreement of the estimates of stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) by transthoracic impedance cardiography (ZCG) and M-mode echocardiography (ECHO) were analyzed before and after the placebo-controlled administration of ascending doses of isosorbide dinitrate and nicorandil in 12 healthy subjects. There was no biostatistical agreement between the two methods in estimating cardiovascular function either before or after dosing (ZCG estimated substantially larger SV, CO and lower TPR). But, ZCG and ECHO estimated about similar overall treatment related changes (across treatments and periods) and reached substantially better agreement when the values were expressed as ratio of the baseline before dosing. Such improvement did not occur when the data were expressed as arithmetic difference from baseline. In spite of the improvement of agreement by expressing the data as ratio of baseline, the coefficients of reproducibility between the two methods (circa 25% of baseline) remained too large to judge the methods interchangeable.

Adult↗
PubMed1991

Noninvasive assessment of the inodilator action of amrinone in healthy man.

The effects of a single dose of 2 mg/kg amrinone (60 min constant rate IV infusion) have been assessed in a double-blind, placebo-controlled, within-subject cross-over study in six healthy volunteers. Combined impedance cardiography, phonocardiography and electrocardiography revealed a protracted drop in mean ventricular ejection time and electromechanical systole together, with a protracted rise in the "contractility" indices dZ/dtmax and the Heather index HI. The profile is compatible with combined venous vasodilation and positive inotropic action. In spite of the methodological constraints, endpoints were reached that were both detectable and relevant. The profiling permitted a better distinction to be made between the possible levels of action than systolic time intervals alone could have done. Therefore, these methods may be of value in the early development of "inodilator" drugs.

Adult↗
PubMed1991

The assessment of bioequivalence in a two-period cross-over design: development of a simple BASIC program.

The complete algorithms needed in the calculation of confidence intervals on the basis of observations from a two-way cross-over bioequivalence trial are described. They do not contain assumptions as to the expected sampling distribution or possible period effects. The algorithms were used in a BASIC program, which was developed subsequently. Its validity is demonstrated here with a set of literature data. The program is available from the authors upon request.

Algorithms↗
PubMed1991

Interactions between domperidone and ropinirole, a novel dopamine D2-receptor agonist.

1. Ropinirole, SK&F 101468 has been characterized preclinically as a specific dopamine D2-receptor agonist. Nine male healthy subjects were investigated for the effects on supine and erect heart rate and blood pressure, catecholamines and prolactin, of a single dose of 800 micrograms ropinirole preceded by a single dose of 20 mg domperidone or domperidone-placebo, and those of a single dose of domperidone followed by ropinirole-placebo. 2. Single doses of 800 micrograms ropinirole did not cause clinically significant changes in supine resting heart rate and blood pressure. However, they caused postural faintness on 3 min immobile upright standing on 10/26 occasions. 3. Pretreatment with 20 mg domperidone 1 h before administration of ropinirole prevented the postural symptoms in all but one subject. It did not alter ropinirole's plasma pharmacokinetics. 4. Ropinirole did not alter supine or standing catecholamine concentrations. 5. Domperidone increased the plasma concentrations of prolactin whereas ropinirole administered alone reduced them. A single dose of 800 micrograms ropinirole did not attenuate the prolactin increase induced by a single dose of 20 mg domperidone administered 1 h earlier.

Adult↗
PubMed1991

[Evaluation of pharmacodynamic equivalence of glycerol trinitrate-containing sprays for oral administration with or without chlorofluorocarbons ].

Evaluation of Pharmacodynamic Equivalence of Glyceryl Trinitrate Sprays for Oral Application with or without Fluorochlorohydrocarbons. The pharmacodynamic equivalence of a fluorochlorohydrocarbons(FCH)-free vs a FCH-containing glyceryl trinitrate (NTG, CAS 55-63-0) spray was investigated. Three oral sprays were administered at 24 h intervals to 9 male and 6 female healthy subjects in a double-blind placebo-controlled period-balanced 3-way cross-over study design: treatment NT (FCH-free, NTG-containing spray, dose of 0.8 mg NTG), treatment NR (FCH- and NTG-containing spray, dose of 0.8 mg NTG) and treatment PL (placebo: FCH- and NTG-free spray, dose of 2 puffs). The treatments were administered after suitable preparation and under strict standardisation. Subsequently digital plethysmography (systolic a-wave, dicrotic b-wave and the c-incisura) was monitored for 2 h. After administration of the NTG-containing sprays (NR and NT) the median a-wave increased rapidly, the median c-incisura deepened and the median b-wave rose slightly. The time courses of these changes and those of the resulting b/a- and c/a-ratios were superimposable and clearly distinct from those after PL. On the basis of the analysis of variance of the response variables (Rmin: maximum drop, and A(0-60): the area under the time course during the first hour after dosing) of the c/a-ratio as change from the predosing baseline, the following point estimates and 90% confidence intervals (CI) were calculated for the true ratio of treatments NT/NR: 104.4%, CI: 88.3 to 120.5% for Rmin, and 101.4%, CI: 79.3 to 123.5% for A(0-60).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1990

The role of DA1- and DA2-receptors in the control of blood pressure.

1. Endogenous dopamine, acting through specific receptors on blood vessels, renal tubules and adrenal cortical cells, may play a role in the development and maintenance of the hypertensive state. 2. In hypertensive patients, activation of the DA1-receptor with intravenous fenoldopam produces a rapid and sustained reduction in blood pressure, in contrast to the tachyphylaxis seen in some rat models. 3. Activation of the DA2-receptor also represents a viable antihypertensive approach, based on the chronic efficacy of hydergine. However, none of the recently developed selective DA2-receptor agonists has been shown to reduce blood pressure in man. 4. Since animal experiments suggest qualitatively different antihypertensive profiles for quinpirole and SK&F 101468, both presumed to be selective agonists at the DA2-receptor, it may be possible to design new DA2-receptor agonists more effective as antihypertensive drugs. 5. Dopamine receptors at different sites, even if of the same subtype, can be differentially regulated; this may be a consequence of activation of multiple second messenger systems by receptor occupation.

Animals↗
PubMed1990

Effects of the novel D2-dopaminergic agonist ropinirol on supine resting and stimulated circulatory and neuroendocrine variables in healthy volunteers.

Ropinirol (SK&F 101468) is a novel drug characterized preclinically as a potent and selective D2-dopaminergic agonist. In the present study the effects of acute doses of 0.4, 0.8 and 1 mg were profiled in eight healthy male volunteers, using a placebo-controlled cross-over study design with incremental dosing. The drug was found to cause mild nausea and postural faintness at the highest dose in one subject. There were no further relevant clinical events, and the postural responses at 200 and 360 min after dosing remained in general well maintained, with the exception of a slight reduction of standing systolic blood pressure. The drug furthermore was found to reduce serum prolactin levels; the magnitude and duration of this effect were dose-related. The drug tended to reduce the noradrenaline responses to 5 min isometric handgrip testing (30% of maximal strength) at 165 min after dosing, and the noradrenaline responses to 3 min immobile standing at 200 min after dosing. The drug also tended to blunt the venous plasma dopamine responses to 3 min cold pressor test (90 min after dosing) and to standing at 200 min after dosing. These changes are concluded to be compatible with the assumed peripheral D2-dopaminergic actions of the drug.

Adult↗
PubMed1990

Pressor tests in clinical pharmacology: response morphology heterogeneity.

Heart rate, blood pressure and venous plasma catecholamine responses to passive upright tilt, immobile erect standing, upright sitting, immersion of hand or foot in cold water, isometric handgrip and delayed auditory feedback were assessed in young healthy volunteers. Each of the tests was characterized by its own typical response morphology. Postural stress caused mainly a rise in heart rate and diastolic blood pressure with little change in systolic blood pressure. The cold pressor test caused a rapid rise in heart rate, systolic and diastolic blood pressure which then was attenuated on further exposure to cold. Isometric handgrip caused the largest pressor responses in linear fashion relative to time. Protracted isometric handgrip (i.e., 5 rather than 3 min) seemed to add psychological stress to the response profile. Delayed auditory feedback caused a less well structured rise in heart rate, systolic and diastolic blood pressure. The postural tests were the most powerful stimuli for venous plasma catecholamines. For all further tests, the catecholamine responses were in general quite small. Therefore, the tests should be considered as complementary and more than one test should be used in order to cover the spectrum of relevant pressor drives. All tests were affected by substantial variability. Sufficiently large samples should be used in order to assure appropriate statistical power and precision when the effects of investigational drugs on these test responses are studied.

Adult↗
PubMed1989

Effects of low-dose atenolol on postural and postprandial changes in heart rate, blood pressure, venous plasma catecholamines, and plasma renin activity.

The administration of a single dose of atenolol 50 mg 1 h before a standard 3100 kJ cold meal in fasting healthy subjects reduced the supine preprandial heart rate and systolic blood pressure, and blunted the postural and postprandial rises in mean heart rate and systolic blood pressure relative to placebo. It did not affect the preprandial supine diastolic blood pressure, nor the postural rise and postprandial drop in diastolic blood pressure. Preprandial administration of atenolol blunted the postural and postprandial rises in mean plasma renin activity, and it enhanced the rise in plasma noradrenaline during eating in the sitting position, and the postprandial concentrations of noradrenaline. The findings do not permit the conclusion that beta 1-adrenergic stimulation was the predominant cause of these atenolol-responsive changes.

Adult↗
PubMed1989

Assay of antipyrine and its main metabolites 3-hydroxymethylantipyrine, norantipyrine and 4-hydroxyantipyrine in urine.

Two assay methods for antipyrine (AP) and its main metabolites 3-hydroxymethylantipyrine (3-HMA), norantipyrine (NORA) and 4-hydroxyantipyrine (4-HA) in urine samples have been compared. Method I involved a 3 h incubation at 37 degrees C with beta-glucuronidase, whereas method II used acid hydrolysis with 3 M hydrochloric acid to convert NORA glucuronide to the aglycone and 24 h incubation at 37 degrees C with beta-glucuronidase for hydrolysis of 3-HMA and 4-HA glucuronides. The precision of both sample preparation procedures was evaluated by means of HPLC with UV detection. The relative standard deviation (RSD) for the metabolites were considerably greater than 10% with method I. Application of method II, however, led to intra-assay and inter-assay RSD of less than 10%.

Antipyrine↗
PubMed1989

Time course and nature of postprandial haemodynamic changes in normal man.

The present study describes the nature and time course of the cardiovascular and neuro-endocrine changes that followed a standard 3100 kJ cold meal in 12 supine and fasting normal men who were studied in a balanced cross-over design. Heart rate, blood pressure, systolic time intervals and estimates of cardiac performance by impedance cardiography were measured every 10 min up to 4 h after eating. Eating caused a rapid and short-lasting increase in systolic blood pressure, estimated stroke volume and maximum velocity of impedance changes. Eating also caused a rapid and more protracted decrease in diastolic and mean blood pressure, PEP-i, QS2-i and estimated systemic vascular resistance with an increase in heart rate and estimated cardiac output. In the later phase of the profiling a drop in LVET-i was also observed. The differences vs. fasting were statistically significant and judged to be biologically relevant. Venous plasma noradrenaline rose during eating as a consequence of the postural change, but eating itself did not alter venous plasma noradrenaline, and plasma adrenaline even tended to decrease. This reflects both the roughness of venous catecholamines in estimating adrenergic changes and the complexity of the underlying mechanisms and related reflexes.

Adult↗
PubMed1989

SK&F 86466, a novel alpha-adrenolytic drug: effects on heart rate, blood pressure, and neuroendocrine function in supine resting position and in response to postural and cold stimulation in normal humans.

SK&F 86466 is a novel alpha-adrenoceptor blocking drug shown in preclinical profiling to have relative selectivity for the pre- and postjunctional alpha 2-adrenoreceptor. In the present clinical study, the effects of single oral doses of 10, 25, and 50 mg SK&F 86466 on supine and stimulated circulatory and neuroendocrine function were assessed in eight normal subjects studied in a placebo-controlled balanced cross-over design with the drugs administered in double-blind fashion. SK&F 86466 caused a dose-related increase in stimulated (postural and cold challenge) and supine plasma norepinephrine (NE) concentrations. This increase was associated with an increase in supine heart rate (HR) and plasma renin activity and orthostatically stimulated HR, with little increase in systolic blood pressure (SBP) and no increase in diastolic blood pressure (DBP). Assuming that no changes occurred in catecholamine clearance, SK&F 86466 thus appeared to have a prejunctional alpha 2-adrenoreceptor blocking effect, which was countered by a post-junctional alpha-adrenoreceptor blocking effect at the level of the resistance vessels, whereas this latter effect did not alter the pressor responses to cold and postural challenge.

Adrenergic alpha-Antagonists↗
PubMed1989

Transdermal delivery of mepindolol and propranolol in normal man. 1st communication: study design, clinical and pharmacodynamic aspects.

In the present study the beta-adrenoreceptor blocking effects of acute and repeated transdermally delivered mepindolol (20 mg/9.8 cm2 patch) and propranolol (40 mg/9.8 cm2 patch) on supine and stimulated circulatory function (isoprenaline infusion, isometric hand grip, delayed auditory feed-back) in nine healthy male volunteers were assessed. The study was conducted in a placebo-controlled double-blind cross-over fashion, with three one-week treatment courses randomly allocated in a period-balanced fashion. Treatment phases were separated by a one-week wash-out phase. The placebo and mepindolol patch were well tolerated, whereas the propranolol patch caused skin irritation and itching in most subjects, and even vesicular lesions in 3/9 subjects. Acute and repeated 24 h application of the propranolol patch caused only small and clinically not relevant changes of heart rate and blood pressure. Acute application of the mepindolol patch induced only mild blunting of the diastolic blood pressure and heart rate responses to isoprenaline i.v. infusion at 8 h. However, the isoprenaline responses were nearly abolished after one week repeated 24 h application of the mepindolol patch, in a stable and protracted fashion. The circulatory responses to isometric handgrip and delayed auditory feedback tended to be reduced, but to a smaller extent than for the isoprenaline test. Repeated application of mepindolol via the investigational device for transdermal drug delivery (BIO TSD) thus resulted in stable and protracted beta-adrenoreceptor blockade.

Administration, Cutaneous↗
PubMed1989

Transdermal delivery of mepindolol and propranolol in normal man. 2nd communication: pharmacokinetic and neuro-endocrine aspects.

The plasma and urinary pharmacokinetics of mepindolol and propranolol were assessed in nine healthy volunteers after single and 1-week daily repeated application of the drugs by a novel transdermal delivery system (BIO TSD). Qualitatively, the time courses of the plasma concentrations for both compounds were similar and indicative of effective drug input. On the first day of the treatment courses plasma levels rose slowly, reaching their observed maximum after 24 h. The latter still was in the rising phase of the curve and further input on longer application is likely. After 1 week daily repeated application apparent steady state conditions were reached. The plasma concentrations were low in comparison to the levels reported for oral dosing. Only small amounts of unchanged drug were excreted via urine. The effects of the investigational treatments on supine-resting and stimulated neuroendocrine variables were assessed also. A blunting of the adrenaline response to delayed auditory feed-back mental stress testing (DAF) was consistently observed after propranolol, but not after mepindolol. Noradrenaline responses to DAF were not altered. No consistent effects were observed in terms of the adrenaline responses to 3 min isometric handgrip testing (IHG). Noradrenaline responses to IHG were slightly blunted, relative to placebo on the first day when propranolol and mepindolol were applied. This was probably related to the usually high responses to placebo as reference. At the end of 1 week repeated application of the patches mean supine resting plasma renin activity (PRA) was significantly reduced by propranolol but not by mepindolol, and the mean PRA responses to 5 min i.v. infusion of isoprenaline was reduced by both.

Administration, Cutaneous↗