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M Danhof

Publications and source records attributed to M Danhof.

At least 127 records · Page 7Linked to original sources
PubMed1994

Pharmacokinetics of ceftazidime in adult cystic fibrosis patients during continuous infusion and ambulatory treatment at home.

Acute exacerbations of Pseudomonas aeruginosa lung infections were treated with ceftazidime (CTZ) by continuous infusion (CI) in eight adult cystic fibrosis (CF) patients. CTZ pharmacokinetics were studied after a single dose and during CI (100 mg/kg/24 h) with a CADD-PLUS infusion pump at home for 3 weeks. Individual CTZ pharmacokinetic parameters after single-dose administration were a half-life (t1/2 beta) of 1.90 +/- 0.85 h (mean +/- SD), a volume of distribution (Vs) of 0.28 +/- 0.08 L/kg, and a total body clearance (CL) of 0.152 +/- 0.014 L/h/kg. CL during CI was 0.147 +/- 0.019 L/h/kg, equal to the CL after a single dose. CTZ clearance at the start and at the end of the treatment did not differ. The mean fraction of the dose recovered from the urine was 92.6% (range 85.6-98.5%). Renal clearance was 0.147 +/- 0.015 L/h/kg and was not influenced by the pulmonary exacerbation. The early-morning serum concentrations were significantly higher than the afternoon levels (p < 0.02). The mean CTZ serum concentration during CI was 28.7 +/- 5.0 mg/L. Clinical condition and quality of life improved significantly during and after treatment. With the pharmacokinetic population data from the single-dose study, the CTZ steady-state concentrations during CI could be predicted [precision (root mean squared prediction error) 3.1 mg/L; bias (mean prediction error) 0.4 mg/L]. This method may serve as a model in the development of CTZ continuous-infusion dosage regimens in CF home treatment.

Adult↗
PubMed1994

Pharmacokinetic-pharmacodynamic relationship of the cardiovascular effects of adenosine A1 receptor agonist N6-cyclopentyladenosine in the rat.

The purpose of the investigation was to develop a pharmacokinetic-pharmacodynamic model for the characterization of the cardiovascular effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) in individual normotensive rats. After the i.v. administration of 200 micrograms/kg (0.60 mumol/kg) of CPA, the time course of heart rate and arterial blood pressure was monitored in conjunction with serial blood sampling. Potential interference of the concentration-cardiovascular effect relationship by the development of acute tolerance or the formation of (inter)active metabolites was investigated by infusion of CPA with different rates and by determination of blood concentrations both by high-performance liquid chromatography and radioreceptor assay. In the individual rats the concentration-hemodynamic effect relationships were satisfactorily modeled according to the sigmoidal Emax pharmacodynamic model. For the negative chronotropic effect, the pharmacodynamic parameters proved to be independent of the infusion rate, indicating the absence of development of acute tolerance during the experiment. Potency (EC50) and intrinsic efficacy (Emax) were 2.7 +/- 0.5 ng/ml and -209 +/- 10 bpm, respectively (mean +/- S.E., n = 17). The concentrations of CPA as determined by the radioreceptor assay were identical to those determined by high-performance liquid chromatography, thereby excluding the formation of (inter)active metabolites. It is concluded that on the basis of this integrated pharmacokinetic-pharmacodynamic model, with the negative chronotropic effect as a pharmacodynamic endpoint, estimates of the potency and the intrinsic efficacy of adenosine A1 receptor agonists in vivo can be obtained after the administration of a single dose.

Adenosine↗
PubMed1994

Characterization of the pharmacodynamics of several antiepileptic drugs in a direct cortical stimulation model of anticonvulsant effect in the rat.

In this investigation a newly developed direct cortical stimulation technique was evaluated for measurement of anticonvulsant efficacy in rats. The kinetics of drug action for carbamazepine, phenytoin, valproate, phenobarbital, ethosuximide and oxazepam were studied in conjunction with their pharmacokinetics. Motor cortex stimulation with a ramp-shaped pulse train allowed successive determination of a threshold for localized seizure activity (TLS) and for generalized seizure activity (TGS). For each drug the time course of effect was followed in individual animals. Differential effects on the pharmacodynamic parameters were seen. Phenytoin and carbamazepine clearly elevated the TGS. However, phenytoin did not affect TLS and carbamazepine only marginally. Valproate increased both TLS and TGS to the same extent. Phenobarbital and oxazepam elevated both thresholds, but the effect on TGS was more pronounced. Ethosuximide had little effect on both thresholds. Comparison with other animal models suggested that elevation of TLS reflects an effect on seizure initiation, whereas elevation of TGS above TLS reflects an effect on seizure propagation. All drugs exhibited a nonlinear relationship between plasma concentration and anticonvulsant efficacy, without ceiling of anticonvulsant intensity at the highest concentrations. The effective concentration range of most compounds coincided with the "therapeutic" range in humans. The direct cortical stimulation technique is useful for preclinical monitoring of anticonvulsant efficacy with most antiepileptic drugs because it allows detection of both qualitative and quantitative differences. In addition the model is particularly useful for time course studies.

Animals↗
PubMed1993

High-performance liquid chromatography of the adenosine A1 agonist N6-cyclopentyladenosine and the A1 antagonist 8-cyclopentyltheophylline and its application in a pharmacokinetic study in rats.

This report describes a rapid and sensitive analysis for the simultaneous detection of the adenosine A1 receptor ligands N6-cyclopentyladenosine (CPA) and 8-cyclopentyltheophylline (CPT) in rat blood. The method involved alkaline extraction of the compounds and internal standard N6-cyclohexyladenosine (CHA) with ethyl acetate, followed by isocratic reversed-phase high-performance liquid chromatography on a 3-microns MicroSphere C18 column with UV detection at 269 nm. The mobile phase consisted of a mixture of 10 mM acetate buffer (pH 4.0)-methanol-acetonitrile (56:40:4, v/v/v) with a flow-rate of 0.50 ml/min. The total run time was ca. 19 min. For CPA and CPT extraction yields were greater than 77 and 66% in the concentration range of 0.010-0.75 microgram/ml and 0.025-15 micrograms/ml, respectively, with intra- and inter-assay variations less than 9%. In 100 microliter blood samples the corresponding limits of detection were 3.3 and 6.2 ng/ml (signal-to-noise ratio = 3). CPA was found to be degraded in rat blood in vitro with a half-life of 24 min at 37 degrees C. The utility of the analytical method was established by analyzing blood samples from rats which had received an intravenous administration of 200 micrograms/kg CPA or 12 mg/kg CPT. Due to its rapidity and sensitivity this method is concluded to be particularly useful in pharmacokinetic studies with CPA and CPT.

Adenosine↗
PubMed1993

Drug transport across the blood-brain barrier. III. Mechanisms and methods to improve drug delivery to the central nervous system.

This is the third part of a review on the transport of drugs across the blood-brain barrier. In the first two parts, the anatomical and physiological aspects and the various techniques that can be used to study blood-brain transport have been discussed and reviewed. This third part focuses specifically on the mechanisms that are involved in drug transport across the blood-brain barrier. In addition, the opportunities to improve drug transport into the brain will be reviewed. Emphasis is on the transport of peptides.

Animals↗
PubMed1993

Increased sensitivity to the anticonvulsant effect of valproate in aging BN/BiRij rats.

The aim of the present investigations was to study the influence of increasing age on the pharmacodynamics of valproate in BN/BiRij rats, applying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy male BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relationships were determined during a continuous intravenous infusion of sodium valproate at a rate of 5.5 mg/min/kg. The infusion was terminated when the anticonvulsant effect intensity had reached the maximum attainable level or at a total infusion time of three hours. A nonlinear relationship between valproate concentration and anticonvulsant effect intensity was observed with no maximal effect in the concentration range up to 1200 mg.L-1. With increasing age a parallel shift in the concentration versus anticonvulsant effect relationships toward lower concentrations occurred. Thus increasing age appears to be associated with an increased sensitivity to the anticonvulsant effect of valproate.

Aging↗
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↗
PubMed1992

Drug transport across the blood-brain barrier. II. Experimental techniques to study drug transport.

This is part II of a review on the transport of drugs across the blood-brain barrier. In this part, the emphasis is on the various experimental techniques that can be used to characterize the blood-brain barrier transport of drugs. Generally speaking, three approaches can be distinguished: in vitro techniques using isolated brain capillaries, cerebrovascular endothelial cells in primary culture or endothelium-derived cell lines; in vivo techniques (both single-passage and multi-passage techniques) and in situ perfusion techniques. Each of these techniques has specific advantages and disadvantages associated with it. Therefore, in many instances, a combination of different approaches is needed to study the fundamental aspects of drug transport across the blood-brain barrier.

Animals↗
PubMed1992

Drug transport across the blood--brain barrier. I. Anatomical and physiological aspects.

This review describes various aspects of the transport of drugs across the blood-brain barrier and comprises three parts. In this first part, the anatomical and physiological aspects of blood-brain transport are discussed. It appears that the blood-brain barrier has an anatomical basis at the endothelium of the capillary wall. This endothelium is characterized by the presence of very tight junctions. As a result, the transport by passive diffusion of drugs with a low lipophilicity, is restricted. For certain classes of closely related relatively hydrophilic compounds, however, the presence of specialized carrier systems has been demonstrated which may facilitate transport. Also evidence is presently available, that the permeability of the blood-brain barrier may be under active regulatory control. It is expected that improved knowledge of the anatomical and physiological aspects of the blood-brain barrier and its regulation will provide a scientific basis for the development of strategies to improve the transport of drugs into the central nervous system.

Animals↗
PubMed1992

Influence of single- and multiple-dose omeprazole treatment on nifedipine pharmacokinetics and effects in healthy subjects.

The effects of single dose (20 mg) and short-term (20 mg/day for 8 days) oral treatment with omeprazole on the pharmacokinetics and effects of oral nifedipine (10 mg capsule) and on gastric pH have been investigated in a randomized, double-blind, placebo-controlled cross-over study in 10 non-smoking healthy male subjects. The single dose of omeprazole had no significant effect on any pharmacokinetic parameter of nifedipine, nor on gastric pH, or blood pressure or heart rate. Short-term omeprazole treatment increased the AUC of nifedipine by 26% (95% confidence interval 9-46%), but all other pharmacokinetic parameters of nifedipine, including elimination half-life, Cmax, tmax, and recovery of the main urinary metabolite, were not significantly changed. The median gastric pH during the absorption phase of nifedipine was increased by short-term omeprazole (pH 4.2) compared to placebo treatment (pH 1.4). Blood pressure and heart rate did not differ between treatments. The interaction between nifedipine and omeprazole is not likely to be of major clinical relevance.

Adult↗
PubMed1992

Properties of the convulsive threshold determined by direct cortical stimulation in rats.

The threshold for convulsions in rats can be determined by applying ramp-shaped pulse trains directly to the cerebral cortex in rats, which provides a convenient model for investigating anticonvulsant drug effects. This study was undertaken to extend a previous study on the properties of this model. Analysis of the cortical EEG, recorded from two motor areas and one somatosensory area, showed that the start of clonic forepaw movement, marking the convulsive threshold, is preceded by the appearance of sharp negative spikes at the electrodes in the two motor areas. There was a strong linear relation between the clinically determined threshold and the EEG derived threshold (r = 0.93, slope 0.99, SD 0.04), confirming the validity of the clonic movement threshold as an objective and accurate measure. Examination of the seizure patterns seen with various degrees of suprathreshold stimulation led to the distinction between a threshold for localized and for generalized seizure activity (TLS and TGS respectively). Carbamazepine selectively and strongly increased the TGS, whereas it only slightly affected the TLS, indicating that cortical stimulation can be used to select drugs that specifically prevent seizure spread, for which carbamazepine is a prototype. It was found that the TLS was not affected by testing at intervals as short as 1 min, provided that no self-sustained seizures were induced. However, if the TGS was passed, the TLS was increased substantially for at least 10 min, while complete recovery could take several hours. The intensity of stimulation, rather than seizure duration, appeared to be the determinant for the TLS increase. There was no seasonal influence or effect of stimulation electrode depth. There may be a minor effect of experience in using the test. It was concluded that the observed variability was mainly an intrinsic property of the individual animal.

Animals↗
PubMed1992

Age and the pharmacokinetic-pharmacodynamic relationship of phenobarbital in rats: "pseudo"-longitudinal vs cross-sectional study design.

In a previous study, an apparent age-related increase in brain sensitivity to the anesthetic effect of phenobarbital was observed in BN/BiRij rats. However, since this study was conducted according to a cross-sectional design, the observed change could, in principle, also have been the result of a cohort effect. The purpose of the present investigation was to exclude the role of such a cohort effect by adopting a "pseudo"-longitudinal study design. In this design 45 animals out of one cohort were reserved, and one subgroup was investigated at five ages (7, 14, 21, 29, and 34 months). A decrease in the anesthetic threshold dose of phenobarbital was found during aging, which appeared to be due mainly to an increase in the brain sensitivity. It is concluded that the previously observed increase in brain sensitivity is indeed the result of the aging process rather than a cohort effect.

Aging↗
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

Differences in intrinsic efficacy of benzodiazepines are reflected in their concentration-EEG effect relationship.

1. The relevance of EEG effect parameters as a measure of the central nervous system effects of benzodiazepines was evaluated. The concentration-EEG effect relationships of the benzodiazepine agonist midazolam, partial agonist bretazenil, antagonist flumazenil and inverse agonist Ro 19-4603 were quantified and compared with the intrinsic efficacy and affinity of these compounds at the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. 2. The pharmacokinetics and pharmacodynamics of the compounds were determined after a single intravenous bolus administration of 5 mg kg-1 midazolam, 2.5 mg kg-1 bretazenil, 10 mg kg-1 flumazenil or 2.5 mg kg-1 Ro 19-4603 to male Wistar derived rats. In a separate experiment the distribution between blood, cerebrospinal fluid and brain concentrations of these compounds was determined. A sensitive assay was developed to measure bretazenil and Ro 19-4603 concentrations in small samples of biological fluids. 3. The benzodiazepine-induced changes in amplitudes in the 11.5-30 Hz frequency band, as determined by aperiodic analysis, was used as EEG effect measure. Concentration-EEG effect relationships were derived by a pharmacokinetic-pharmacodynamic modelling procedure and in the case of midazolam, bretazenil and Ro 19-4603 successfully quantified by the sigmoidal Emax model. Large differences in maximal effect of midazolam (Emax = 73 +/- 2 microVs-1), bretazenil (Emax = 19 +/- 1 microVs-1) and Ro 19-4603 (Emax = -6.5 +/- 0.4 microVs-1) were observed, reflecting their differences in intrinsic efficacy. A close correlation was found between the EC50 values based on free drug concentration and receptor affinity as determined by displacement of [3H]-flumazenil in a washed brain homogenate at 37 degrees C. In the concentration range of receptor saturation flumazenil did not produce any changes in the EEG effect measure.4. The study demonstrated that the change in amplitudes in the 11.5-30 Hz frequency band of the EEG is a relevant measure of the pharmacological effect intensity of benzodiazepines, because it seems to reflect their affinity and intrinsic efficacy at the central GABA-benzodiazepine receptor complex.

Animals↗
PubMed1992

Pharmacodynamics of the anticonvulsant effect of oxazepam in aging BN/BiRij rats.

1. The purpose of this investigation was to examine the influence of increasing age on the pharmacokinetics and the time course of the anticonvulsant response of oxazepam in BN/BiRij rats as an animal model of aging. 2. Oxazepam was administered intravenously in a dose of 12 mg kg-1 body weight and the anticonvulsant effect intensity was measured as elevation above baseline of a threshold for induction of localized seizure activity (TLS). Direct cortical stimulation with ramp shaped electrical pulse trains of increasing intensity was used to determine this threshold. 3. The pharmacological effect vs. time profile showed in young rats an anticonvulsant component followed by proconvulsant component which is suggestive for the occurrence of acute tolerance and/or withdrawal syndrome. With increasing age the proconvulsant component disappeared, resulting in a monophasic effect profile (anticonvulsant effect only) at the age of 35 months with significantly higher anticonvulsant effect intensity immediately following drug administration. No age-related changes in the pharmacokinetic parameters of oxazepam were observed. 4. In five animals of each age group, benzodiazepine receptor binding characteristics were determined in vitro with [3H]-flunitrazepam as a ligand. Both receptor density and affinity did not show age-related changes. Available literature data on post-receptor events do not indicate conclusive age-related changes. 5. It is concluded, that the observed change in the pharmacodynamics of anticonvulsant effect of oxazepam can be explained by the disappearance of the tolerance/withdrawal phenomenon. This is compatible with a decreased efficiency of homeostatic control mechanisms in the elderly.

Aging↗
PubMed1992

Pharmacokinetic-EEG effect relationship of midazolam in aging BN/BiRij rats.

1. The purpose of the present investigations was to determine the influence of increasing age on the pharmacokinetics and pharmacodynamics of midazolam in male BN/BiRij rats as an animal model of aging. 2. Midazolam was administered intravenously at a dose of 2.5 mg kg-1 and its pharmacokinetics were determined on the basis of plasma concentrations as measured by high performance liquid chromatography (h.p.l.c.). Pharmacodynamics were studied using the midazolam-induced changes in the electro-encephalogram (EEG) as a measure of the pharmacological effect. Results were evaluated on the basis of simultaneous pharmacokinetic-pharmacodynamic modelling. In an attempt to differentiate between the effects of aging and of concurrent disease, an extensive clinical biochemical/pathological examination was conducted in individual rats by an independent pathologist. 3. The pharmacokinetics of midazolam were best characterized on the basis of a two exponential model. In the 4-month-old rats the values of the clearance, volume of distribution and elimination half-life were 104 +/- 13 ml min-1 kg-1 (mean +/- s.e. mean), 3.4 +/- 0.7 l kg-1 and 30 +/- 3 min, respectively. With increasing age, no changes in the pharmacokinetics of midazolam were observed. 4. The pharmacodynamics of midazolam were determined on the basis of the sigmoidal Emax model. In the 4-month-old rats the values of the parameters relative maximum effect, midazolam concentration at half maximum effect and Hill factor were 106 +/- 10%, 50 +/- 6 micrograms l-1 and 1.6 +/- 0.3, respectively. In the group as a whole no significant changes in the pharmacodynamic parameters of midazolam were observed.4. The pharmacodynamics of midazolam were determined on the basis of the sigmoidal Emax model. In the 4-month-old rats the values of the parameters relative maximum effect, midazolam concentration at half maximum effect and Hill factor were 106 +/- 10%, 50 +/-6 lg 1' and 1.6 +/- 0.3, respectively. In the group as a whole no significant changes in the pharmacodynamic parameters of midazolam were observed. However, when diseased animals were excluded from the evaluation, a tendency towards a decrease in the midazolam concentration at half maximum effect to 25 +/- 14 pg 1-1 was observed in the 36-month-old rats.5. These findings suggest, that increasing age is associated with a tendency towards an increased brain sensitivity to midazolam, which is reflected in a parallel shift of the concentration vs. EEG effect relationship towards lower concentrations. However, it appears that factors other than age also contribute to interindividual variability in pharmacodynamics, considering the substantial interindividual variability within certain age groups.

Aging↗
PubMed1992

Disposition of heptabarbitone in the rat: identification of a new metabolite by tandem mass spectrometry.

The purpose of this study was to elucidate the structure of a metabolite of heptabarbitone, the occurrence of which was reported previously in a number of pharmacokinetic and pharmacodynamic modelling studies. By application of thermospray liquid chromatography (tandem) mass spectrometry, the identity of the metabolite was proposed to be 5-ethyl-5-(1',[3' or 6']-cycloheptadienyl)-barbituric acid. By measuring the ratios between the areas under the concentration time curves of the metabolite and heptabarbitone after administration of three different intravenous dosages of heptabarbitone, it was shown that the exposure to the metabolite is directly correlated with the exposure of heptabarbitone.

Animals↗