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P M Edelbroek

Publications and source records attributed to P M Edelbroek.

At least 19 recordsLinked to original sources
PubMed2004

Simultaneous high-performance liquid chromatographic analysis of pregabalin, gabapentin and vigabatrin in human serum by precolumn derivatization with o-phtaldialdehyde and fluorescence detection.

A rapid, simple and robust method is presented for the simultaneous determination of the gamma-amino-n-butyric acid (GABA) derivatives pregabalin (PGB), gabapentin (GBP) and vigabatrin (VGB) in human serum by high-performance liquid chromatography (HPLC). Serum is deproteinized with trichloroacetic acid and aliquots of the supernatant are precolumn derivatized with o-phtaldialdehyde (OPA) and 3-mercaptopropionic acid. Separation is achieved on a Alltima 3C18 column using isocratic elution; the drugs are monitored using fluorescence detection. Norvaline is used as an internal standard. Within-day precision (COV; n = 10) is 1.2% for PGB (serum concentration 10.0 mg/l), 1.1% for GBP (serum concentration 15.8 mg/l) and 0.3% for VGB (serum concentration 15.5 mg/l). The method is linear up to at least 63 mg/l for PGB, 40 mg/l for GBP and 62 mg/l for VGB. Lower limits of quantitation (LOQ) are 0.13 mg/l for PGB, 0.53 mg/l for GBP and 0.06 mg/l for VGB. No interferences were found from commonly coadministered antiepileptic drugs (AEDs) and from endogenous amino acids. Experimental design in combination with statistical evaluation (ANOVA) was used to study the robustness of chromatography and sample preparation. The method is very suitable for routine therapeutic drug monitoring and for pharmacokinetic studies.

Amines↗
PubMed2002

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers.

AIMS: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. METHODS: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. RESULTS: Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. CONCLUSIONS: In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.

Administration, Intranasal↗
PubMed2001

Visual field loss associated with vigabatrin: quantification and relation to dosage.

PURPOSE: To describe the correlation between visual field loss and the duration, dosage, and total amount of vigabatrin (VGB) medication in a group of patients with epilepsy. Co-medication of antiepileptic drugs (AEDs) and compliance were also studied. METHODS: Ninety-two patients (53 male and 39 female) taking VGB medication in the past or the present, attending the Outpatient Epilepsy Clinic in Utrecht, were examined with the Goldmann perimeter. The amount of visual field loss was calculated by the Esterman grid method and by a new method, with which the percentage surface loss of the visual field is measured. A complete drug history was compiled, specifying the amount and duration of VGB medication. Concomitant AED medication was noted. Serum levels of AEDs were determined. RESULTS: Linear regression showed the total amount of VGB as the most significant parameter to predict visual field loss (p < 0.001). Further, men were more affected than women (p = 0.026). Compliance was good, and other AEDs did not influence the results. CONCLUSIONS: Because prolonged use of VGB medication is correlated with the amount of visual field loss, VGB should be prescribed only when there are no alternatives. In such cases, we recommend an examination of the peripheral visual field before starting therapy and a repeated examination every 6 months.

Adult↗
PubMed2000

Pharmacokinetic-pharmacodynamic correlation of lamotrigine, flunarizine, loreclezole, CGP40116 and CGP39551 in the cortical stimulation model.

The purpose of this study was to assess the concentration-anti-convulsant effect relationships of a number of anti-convulsant drugs in the direct cortical stimulation model, to obtain more insight in the properties and predictive value of this model. The time course of the effect of lamotrigine, loreclezole, flunarizine, CGP40116 and CGP39551 was determined after iv. administration in conjunction with their pharmacokinetics. Convulsive activity was induced by stimulation of the motor cortex with a ramp-shaped pulse train. This technique allows consecutive measurements of the treshold for localized (TLS) and for generalized (TGS) seizure activity. Increase in threshold was used as measure of the anti-convulsant effect. After administration of lamotrigine, pronounced elevation of the TGS, with little change in the TLS, was observed. Flunarizine caused a similar effect, but much less intense. Loreclezole strongly elevated the TGS and to a lesser extent the TLS, also. The concentration-anti-convulsant effect relationship of the three compounds could be fitted by an exponential model. The NMDA antagonists, CGP40116 and CGP39551, induced minor changes in the TLS and a slight increase in the TGS. The onset of this effect was marked by a delay relative to blood concentrations. The biophase equilibration kinetics was estimated and a linear model was applied to describe the concentration-effect relationship of both NMDA antagonists. The present results show that the cortical stimulation model is a suitable technique for integrated pharmacokinetic-pharmacodynamic modelling and for assessing anti-convulsant efficacy. The results show that the model is rather insensitive to calcium channel blockers and NMDA antagonists.

Animals↗
PubMed1999

Application of a combined "effect compartment/indirect response model" to the central nervous system effects of tiagabine in the rat.

Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic-pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5-30 Hz frequency band (beta), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg-1 of tiagabine or vehicle over 10 min. The EEG was continuously recorded in conjunction with frequent arterial blood sampling. The pharmacokinetics of tiagabine could be described by a biexponential equation. The pharmacokinetics of tiagabine were not dose dependent, and the pooled values for clearance, volume of distribution at steady state and terminal half-life were (mean +/- SE, n 23) 96 +/- 9 ml min-1 kg-1, 1.5 +/- 0.1 L kg-1 and 20 +/- 0.2 min. A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo = 0.030 min-1 and kout = 81 min-1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates (mean +/- SE) were E0 = 155 +/- 6 microV, Emax = 100 +/- 5 microV, EC50 = 287 +/- 7 ng ml-1, Hill factor = 1.8 +/- 0.2 and keo = 0.030 +/- 0.002 min-1. The results of this analysis show that for tiagabine the combined "effect compartment-indirect response" model can be simplified to the classical "effect compartment" model.

Animals↗
PubMed1999

Stereoselective central nervous system effects of the R- and S-isomers of the GABA uptake blocker N-(4, 4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid in the rat.

1. The 'effect compartment' model was applied to characterize the pharmacodynamics of the R- and S-isomers of tiagabine in conscious rats in vivo using increase in the beta activity of the EEG as a pharmacodynamic endpoint. 2. No pharmacokinetic differences in plasma were observed between R- and S-tiagabine. The values for clearance and volume of distribution at steady-state were 103+/-10 versus 90+/-6 ml min(-1) kg(-1) and 1.8+/-0.2 versus 1.6+/-0.2 l kg(-1) for the R- and S-isomer, respectively. In contrast, plasma protein binding showed a statistically significant difference with values of the free fraction of 5.7+/-0.5 and 11.4+/-0.6%. In addition the rate constant for transport to the effect compartment was also different with values of 0.027 versus 0.067 min(-1). 3. For both isomers the relationship between concentration and EEG effect was non-linear and successfully characterized on basis of the Hill equation. A statistically significant difference in the value of EC(50) of 328+/-11 versus 604+/-18 ng ml(-1) was observed for R- and S-tiagabine respectively. The values of the other pharmacodynamic parameters were identical. 4. It is concluded that the differences in in vivo pharmacodynamics of R- and S-tiagabine can be explained by stereoselective differences in both the affinity to the GABA-uptake transporter and the degree of non-specific protein binding in plasma and at the effect site.

Animals↗
PubMed1998

High-performance liquid chromatographic analysis of vigabatrin enantiomers in human serum by precolumn derivatization with o-phthaldialdehyde-N-acetyl-L-cysteine and fluorescence detection.

A rapid and simple method is presented for the determination of vigabatrin enantiomers in human serum by high-performance liquid chromatography. Serum is deproteinized with trichloroacetic acid and aliquots of the supernatant are precolumn derivatized with o-phthaldialdehyde and N-acetyl-L-cysteine, resulting in the formation of diastereomeric isoindoles. Separation was achieved on a Spherisorb 3ODS2 column using a gradient solvent program and the column eluent is monitored using fluorescence detection. L-Homoarginine was used as an internal standard. Within-day precisions (C.V.; n=8) were 2.8 and 1.1%, respectively, for the (R)-(-)- and (S)-(+)-enantiomer in serum containing 15.4 mg/l (RS)-vigabatrin. The method was linear in the 0-45 mg/l range for both enantiomers and the minimum quantitation limit was 0.20 mg/l for (R)-(-)-vigabatrin and 0.14 mg/l for (S)-(+)-vigabatrin. No interferences were found from commonly co-administered antiepileptic drugs and from endogenous amino acids. The method is suitable for routine therapeutic drug monitoring and for pharmacokinetic studies.

Acetylcysteine↗
PubMed1997

High-performance liquid chromatographic determination of carbamazepine and metabolites in human hair.

To study the use of hair analysis in monitoring drug compliance and historical changes in pharmacokinetics we developed a method for the quantitative determination of the anti-epileptic drug carbamazepine (CBZ) and trans-10,11-dihydro-10,11-dihydroxy-carbamazepine (CBZ-diol) in hair from carbamazepine users. Digestion by 1 M NaOH was found to be the best method for isolating CBZ and CBZ-diol from hair, followed by solid-phase extraction and reversed-phase HPLC with UV detection. Recoveries from spiked hair samples were 76-86%. Within-day precision (C.V.; n = 10) for CBZ and CBZ-diol in hair of a CBZ user containing 10.9 microg/g CBZ and 3.2 microg/g CBZ-diol were 1.7 and 5.0%, respectively. Sectional hair analysis of a patient on a constant dosage of CBZ demonstrates an exponential decrease in hair concentrations of CBZ and CBZ-diol with increasing distance from the root, probably caused by shampooing. No CBZ-10,11-epoxide (CBZ-epox) could be detected. However, one component in the chromatogram is probably CBZ-beta-hydroxythioether, an adduct of CBZ-epox with cysteine, or acridinethioacetal, its rearrangement product. The concentration of this component does not decrease with increasing distance from the root.

Adult↗
PubMed1997

Antiepileptic drug treatment in the nineties in The Netherlands.

In this review the 'state of the art' of treating patients with epilepsy in the nineties in the Netherlands is presented. It describes general strategies for treatment with antiepileptic drugs and the history of development of the classical anticonvulsant drugs. Eight new drugs, including vigabatrin, lamotrigine, felbamate, oxcarbazepine, gabapentin, tiagabine, levetiracetam and topiramate are discussed. A review of their pharmacological and clinical properties is presented. Dutch experience with these drugs is included.

Animals↗
PubMed1996

Photosensitive epilepsy: a model to study the effects of antiepileptic drugs. Evaluation of the piracetam analogue, levetiracetam.

The experimental antiepileptic drug, levetiracetam (UCB L059), a piracetam analogue has been investigated in photosensitive patients in the "photosensitivity model", an early phase II study. A total of 12 patients (10 females, 2 males) with a mean age of 21.5 years (range 13-38) were investigated during a 3 day period in 3 centres (France, The Netherlands, Germany), using the same standardised method. The subjects were either treated with a single oral dose of 250 mg, 500 mg, 750 mg or 1,000 mg. In addition, 4 patients took 250 mg b.i.d. for 3-5 days, after which they were re-examined. In 9 of 12 photosensitive patients (75%) a clear suppression (3 patients) or abolishment (6 patients) of IPS evoked photoparoxysmal EEG responses was found. This effect appeared to be dose-dependent, the higher the dose the greater the effect; complete abolishment was only seen at dosages of 750 mg and 1,000 mg, occurring at peak plasma levels and lasting between 6 and 30 h. There was no indication of pharmacokinetic interaction with concomitant antiepileptic drugs such as valproic acid, ethosuximide or phenobarbitone. No serious side-effects were seen and some patients reported enhancement of their mood. Two patients with myoclonic jerks noticed a clear reduction of their myoclonus, although this was not one of the objectives of the study. In conclusion, levetiracetam showed a clear antiepileptic effect in the photosensitivity model.

Administration, Oral↗
PubMed1994

High-performance liquid chromatographic and megabore gas-liquid chromatographic determination of levetiracetam (ucb L059) in human serum after solid-phase extraction.

For monitoring drug levels of the new potential anticonvulsant drug levetiracetam (ucb L059) in human serum, two assay methods were developed and compared. A solid-phase extraction procedure was followed by either reversed-phase HPLC separation and UV-detection or GLC separation using cold on-column injection on a megabore column and nitrogen-phosphorous detection. Absolute recovery of the drug exceeded 97%. Precision and accuracy values for the 16.0 micrograms/ml quality control sample were 2.4% and 101 +/- 5% (n = 10), respectively, for the GLC method. Precision and accuracy values for the 12.1 micrograms/ml quality control sample were 1.0% and 100 +/- 1% (n = 7), respectively, for the HPLC method. Agreement between both methods was excellent (r = 0.993). Both methods are suitable for pharmacokinetic studies and therapeutic drug monitoring as well. Serum level data for levetiracetam in a patient on chronic antiepileptic medication are presented.

Autoanalysis↗
PubMed1992

Biochemical measures in patients with a somatoform pain disorder, before, during, and after treatment with amitriptyline with or without flupentixol.

The possible relationship between a number of biochemical parameters and measures of pain and depression was studied in chronic pain patients without a major depression. In a double-blind crossover study, patients were treated with amitriptyline combined with a low dose of flupentixol or placebo. We investigated whether pretreatment biochemical values correlated with initial data on pain and/or depression, or whether they had predictive value for treatment outcome. We also studied systematically the effect of both treatment regimes on the biochemical parameters themselves and their relation to the plasma levels of amitriptyline. From our results, the possible involvement of the serotonin system in somatoform pain disorder is confirmed and no direct relation with the noradrenergic system could be inferred. The lack of involvement of a number of putative, depression-related, biochemical parameters suggests that affective disorders and pain syndromes do not share all mechanisms in common.

Adult↗
PubMed1992

Increased neurotoxicity of arsenic in methylenetetrahydrofolate reductase deficiency.

A 16-year-old girl from Surinam presented with mental deterioration and severe paraparesis with areflexia and bilateral Babinski signs. Laboratory examination showed a hyperhomocysteinemia that was caused by 5,10-methylene-tetrahydrofolate reductase (MTHFR) deficiency. In addition, urine samples contained large amounts of arsenic. An open bag with the pesticide copper acetate arsenite was found to be the source of exposure. In remethylation defects such as MTHFR deficiency, the concentration of methyldonors is severely reduced. As arsenic is detoxified by methylation, we suggest that the MTHFR deficiency in this girl might explain the fact that of all family members exposed to arsenic, only she developed severe clinical signs and symptoms of arsenic poisoning.

Adolescent↗
PubMed1992

Conventional and controlled release valproate in children with epilepsy: a cross-over study comparing plasma levels and cognitive performances.

We studied plasma levels and behavioural effects of a newly developed controlled release formulation of valproate (VPA-CR) in children with epilepsy. Valproate plasma levels and performances in attention and vigilance tasks were monitored during a 12-h period (daytime), both during monotherapy of conventional valproate (VPA) and 4 weeks after switching to a similar dosage of VPA-CR taken once daily. There was no significant difference between the two formulations with respect to mean diurnal trough and peak valproate plasma levels, and to mean fluctuation. The significantly higher Cmax/Cmin ratio during VPA-CR seems mainly due to low valproate plasma levels early in the morning. Neuropsychological assessment showed no significant differences, either between patients and controls, or within patients and controls when comparing the results obtained on the VPA and VPA-CR day. During both VPA and VPA-CR treatment, no correlation was found between cognitive performance and valproate plasma levels. The advantage of VPA-CR is that the once daily regimen may increase compliance and is more convenient for schoolchildren.

Adolescent↗
PubMed1991

Analysis of bismuth in serum and blood by electrothermal atomic absorption spectrometry using platinum as matrix modifier.

Bismuth-containing medicines have been used for years, but there is a lack of clinically applicable methods for measuring bismuth in body fluids. We describe a sensitive, accurate and precise method for analysis of bismuth in blood and serum, which is suitable both for monitoring purposes and for further investigations into the biokinetics and safety of bismuth. Bismuth was quantitated with electrothermal atomic absorption spectrometry with Zeeman background correction. In the furnace programme a cool-down step was introduced and platinum was used as a matrix modifier. Recovery for 40 micrograms/l is 93.7 +/- 4.6% (mean +/- SD) from serum and 92.8 +/- 5.4% from blood; within-day precision (n = 10) at 40 micrograms/l is 3.2% for serum and 4.2% for blood. Day-to-day precision at 40 micrograms/l (n = 10) was 4.5% for serum and 4.0% for blood. The detection limit is 0.7 microgram/l for serum and 1.0 microgram/l for blood. Blood samples have to be collected in glass tubes and stored at -20 degrees C.

Animals↗