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Biomedical subjects

I Meineke

Publications and source records attributed to I Meineke.

At least 37 records · Page 2Linked to original sources
PubMed1996

Concentration-effect relationship of the positive chronotropic and hypokalaemic effects of fenoterol in healthy women of childbearing age.

OBJECTIVE: To analyse fenoterol-induced tachycardia and hypokalaemia, the most important and most frequent adverse effects of tocolytic therapy with beta 2-adrenoceptor agonists in females of childbearing age. METHODS: The study was performed as a double blind, randomised, placebo controlled, cross over trial. Seven healthy women aged 22-38 y, received intravenous infusions of fenoterol at 3 different rates within the therapeutic range for tocolysis (0.5,1.0, and 2.0 micrograms.min-1) and placebo. The time courses of the plasma concentrations of fenoterol and potassium, and the heart rate were analysed with mixed effects pharmacokinetic-pharmacodynamic (PKPD) modeling using NONMEM. RESULTS: The plasma concentration-time course followed a linear two compartment model. Fenoterol-induced tachycardia was described by a linear concentration-effect model with baseline. The estimated baseline and slope parameters were 78 beats.min-1 and 0.032 beats.min-1.microgram-1.1, respectively. Fenoterol-induced hypokalaemia could be described by a physiological indirect response model including feedback; the Estimated basal plasma potassium concentration was 3.93 mmol.1-1 and the slope factor for the fenoterol-induced relative increase in the efflux of potassium from the extracellular space was 6.22*10(-4) ng.1(-1). CONCLUSION: The estimated population parameters permitted calculation of the expected time course of tachycardia and hypokalaemia in women after the initiation of tocolysis with fenoterol over the clinically relevant concentration range, and prediction of its variability. Based on simulation, our model predicted that a continuous infusion of 2.0 micrograms.min-1 (highest rate examined) would increase heart rate to 113 beats.min-1 at steady state and lower the plasma potassium concentration to 2.77 mmol.1(-1) 1.5 h after beginning the infusion. Thereafter, the plasma potassium concentration would slowly return to normal.

Adrenergic beta-Agonists↗
PubMed1996

Pantoprazole lacks interaction with antipyrine in man, either by inhibition or induction.

Substituted benzimidazole inhibitors of the gastric H+/K(+)-ATPase may interact with the cytochrome P450 enzyme system and alter the pharmacokinetics of coadministered drugs, as known for omeprazole. The primary aim of the present studies was to determine whether pantoprazole, a new, selective proton pump inhibitor, modifies the plasma concentrations of orally-administered antipyrine, a commonly used marker for mixed hepatic oxidase enzyme activity. In the acute study, 12 healthy male volunteers were given a) a single 30 mg i.v. doses of pantoprazole, b) a single 5 mg/kg oral dose of antipyrine, or c) coadministered pantoprazole and antipyrine according to a randomized three-period change-over design. In the chronic study, another 12 volunteers received 40 mg once-daily oral doses of pantoprazole on day 3 and on days 5-12, and a single oral 5 mg/kg dose of antipyrine on days 1, 12 and 14. Antipyrine plasma concentrations were measured without pantoprazole (day 1), on the last day of chronic dosing with pantoprazole (day 12) and 48 hours after the last dose of pantoprazole (day 14) to differentiate between inhibition and induction, respectively. Both drugs were well tolerated and no adverse events or clinically relevant alterations in vital signs or laboratory parameters were observed during treatment. The point estimates of the respective AUC-and Cmax-ratios for antipyrine with and without pantoprazole were 0.99 and 0.98 in the acute study, and 1.01 and 0.93 on day 12, and 1.04 and 0.99 on day 14 of the chronic study. The corresponding 90%-confidence intervals were all within the equivalence range of 0.8-1.25 so that lack of interaction either by inhibition or induction can be concluded.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

An inexpensive and sensitive method for the determination of quinidine in plasma by high-performance liquid chromatography with ultraviolet detection.

A sensitive, specific, and rapid high-performance liquid chromatographic method with ultraviolet detection for therapeutic drug monitoring of the cardioactive compound quinidine is described. The method uses only 50 microliters of serum, which is extracted into methyl-t-butylether at an alkaline pH and consequently reextracted into dilute hydrochloric acid. Quinidine is separated from quinine, the internal standard, and dihydroquinidine on a reversed phase C18 column. The minimum detectable amount is 1 ng injected on column. The method is both precise and accurate, as shown by the validation data presented, and can also be of use in pharmacokinetic investigations.

Animals↗
PubMed1994

Pantoprazole lacks interaction with antipyrine in man, either by inhibition or induction.

Substituted benzimidazole inhibitors of the gastric H+/K(+)-ATPase may interact with the cytochrome P450 enzyme system and alter the pharmacokinetics of coadministered drugs, as known for omeprazole. The primary aim of the present studies was to determine whether pantoprazole, a new, selective proton pump inhibitor, modifies the plasma concentrations of orally-administered antipyrine, a commonly used marker for mixed hepatic oxidase enzyme activity. In the acute study, 12 healthy male volunteers were given a) a single 30 mg i.v. doses of pantoprazole, b) a single 5 mg/kg oral dose of antipyrine, or c) coadministered pantoprazole and antipyrine according to a randomized three-period change-over design. In the chronic study, another 12 volunteers received 40 mg once-daily oral doses of pantoprazole on day 3 and on days 5-12, and a single oral 5 mg/kg dose of antipyrine on days 1, 12 and 14. Antipyrine plasma concentrations were measured without pantoprazole (day 1), on the last day of chronic dosing with pantoprazole (day 12) and 48 hours after the last dose of pantoprazole (day 14) to differentiate between inhibition and induction, respectively. Both drugs were well tolerated and no adverse events or clinically relevant alterations in vital signs or laboratory parameters were observed during treatment. The point estimates of the respective AUC- and Cmax-ratios for antipyrine with and without pantoprazole were 0.99 and 0.98 in the acute study, and 1.01 and 0.93 on day 12, and 1.04 and 0.99 on day 14 of the chronic study.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1993

Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects.

The plasma pharmacokinetics of pantoprazole have been investigated following single intravenous infusion and single oral administration at a dose of 40 mg to 12 healthy male subjects in a randomised cross-over study. Both treatments were generally well tolerated and no relevant compound-related adverse events were noted. The plasma pharmacokinetics of pantoprazole following intravenous infusion in this group of subjects were characterised by a total plasma clearance of 0.13 l.h-1 x kg-1 and apparent terminal elimination half-life 1.9 h. The apparent volume of distribution estimated at steady state (0.17 l.kg-1) was compatible with the localization of a major fraction of the compound in extracellular water. Following oral administration as an enteric-coated tablet formulation, a variable onset of absorption was followed by rapid attainment of maximum plasma concentrations of pantoprazole. Pantoprazole was well absorbed following oral administration; the absolute systemic bioavailability of the compound was estimated as 77% (95% CI, 67 to 89%).

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1993

Cardiovascular effects of eating, atenolol and their interaction: beta1-adrenergic modulation does not play a predominant role in the genesis of postprandial effects.

1. Eight healthy subjects were investigated on four occasions at least 1 week apart when they either ate a standard 3100 kJ cold meal or fasted. One hour earlier, either 50 mg atenolol or placebo was administered. 2. Eating was followed by prominent changes of systolic cardiovascular function: a rise of heart rate (+7, 95% CI: 4 to 9 beats min(-1)), systolic BP (+5, CI: 1 to 8 mmHg), a drop of diastolic BP (-6, CI:-9 to -3 mmHg), shortening of the pre-ejection period PEP (-11, CI: -13 to -9 ms) and electromechanical systole QS2c (-13, CI: -17 to -8 ms), a rise of the estimated cardiac output CO (+1.3, CI: 1.0 to 1.6 1 min(-1)) and a reduction of the calculated total peripheral resistance TPR (-306, CI: -389 to -222 dyn s cm(-5)). 3. Eating was also followed by an increase of the non-renal clearance of sorbitol (as a measure of hepatic blood flow) and this change was larger than proportional to the increase of CO. The plasma renin activity rose after the meal but the venous plasma noradrenaline and adrenaline concentrations were not affected. 4. The postprandial effects peaked over the first 1-2 h after the meal but remained well detectable up to 4 h after eating. 5. The administration of 50 mg atenolol before the meal reduced the postprandial effects to the same extent as the atenolol effects in the fasting state. This lack of interaction (or mere arithmetic additivity) indicates that the efferent beta1-adrenergic tone does not play a predominant role in the modulation of postprandial cardiovascular changes.

Adrenergic beta-Antagonists↗
PubMed1993

Evaluation of the 13CO2 kinetics in humans after oral application of sodium bicarbonate as a model for breath testing.

The kinetics of 13CO2 have been investigated following oral administration at five doses between 12.5 and 100 mg of 13C labelled sodium bicarbonate to 10 healthy subjects in a randomized study. Sodium bicarbonate in this study served as a model compound for carbon dioxide/bicarbonate generated in breath tests. Exhalation of 13CO2 into breath was monitored by stable isotope ratio mass spectrometry. The kinetics of 13CO2 were characterized by an apparent terminal elimination half-life of 1 h and a mean recovery of 0.630 of the dose administered. The kinetics were not dose-dependent. These results were in agreement with the findings reported previously after i.v. application of sodium bicarbonate.

Administration, Oral↗
PubMed1992

Prandial and diurnal effects on the absorption of orally administered enteric coated 5-aminosalicylic acid (5-ASA).

Plasma and urine concentrations of 5-ASA and its N-acetyl metabolite 5-AcASA were measured over 48 h in 12 young healthy male subjects, who received three doses of three times enteric coated 500 mg 5-ASA tablets at 7 h interval, on two occasions 14 days apart. On one occasion the doses were given after standard meals; on the other occasion, they were given 1 h before meals. Administration of the tablets after meals delayed systemic drug absorption but did not affect the extent of absorption. There was a sharp rise in the plasma concentrations of 5-ASA and 5-AcASA in the early morning (i.e. circa 24 h after administration of the 1st dose) independent of when the tablets were taken with respect to the meals. This suggests that tablets or tablet fragments remained in the stomach until the later part of the night. Thus, diurnal effects may be more important than prandial effects in the evaluation of the kinetics of 5-ASA and its metabolites after peroral administration of enteric coated tablets.

Administration, Oral↗
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↗
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

Routine measurement of plasma catecholamines in clinical pharmacology by high-performance liquid chromatography with electrochemical detection.

A method for the simultaneous determination of epinephrine, norepinephrine and dopamine in human plasma is described, which combines the advantages of liquid-liquid extraction sample preparation, high-performance liquid chromatography on weak cation-exchange stationary phases and dual-electrode coulometric detection. The limits of quantification are less than 5 pg/ml (at a signal-to-noise ratio greater than 5) for each analyte. The influence of various experimental parameters (e.g., composition of the mobile phase, pretreatment of the assay buffer, components of the re-extraction system) on the performance of the assay is reported in detail. A number of applications are presented, which demonstrate the quality of the data obtained in terms of sensitivity, reproducibility and significance.

Catecholamines↗
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↗