P165 PK/PD modelling of the anticonvulsant and EEG effects of phenytoin

Paschoa, O.E. Della; Mandema, J.W.; Voskuyl, Rob A.; Danhof, Meindert

doi:10.1016/0928-0987(94)90338-7

Cited by 2 publications

(3 citation statements)

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“…The plasma concentrations and TGS measurements obtained up to 5 h after drug administration were used for this purpose. The pharmacokinetics could be fitted to a Michaelis‐Menten elimination model with a biophase equilibration delay, as previously reported (Della Paschoa et al , 1998). The use of a pharmacokinetic model with biophase equilibration supplies information about drug concentration at the effect‐site and explains why plasma concentrations do not correlate directly with the pharmaco‐dynamics.…”

Section: Resultsmentioning

confidence: 99%

“…The aim of this investigation was to use ictal components to assess the pharmacological effects of phenytoin (PHT) and sodium Valproate (VPA) on seizure activity and their interaction when administered in combination. PHT is a well‐studied anti‐epileptic drug with nonlinear pharmacokinetics (Della Paschoa et al , 1998), which is still prescribed in general clinical practice (Brodie & Dichter, 1997; Pimentel, 1997). VPA is often combined either with carbamazepine or with PHT in the management of severe or refractory epileptic seizures (Davis et al , 1994; Miller, 1994; Schmidt, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacodynamic interaction between phenytoin and sodium valproate changes seizure thresholds and pattern

Paschoa

Kruk

Hamstra

et al. 1998

British J Pharmacology

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1 In this study we used cortical stimulation to assess the e ects of phenytoin (PHT), sodium valproate (VPA), and their interaction on total motor seizure and on the constituent elements of the seizure. 2 PHT (40 mg kg 71 ) was administered as an intravenous bolus infusion to animals receiving either a continuous infusion of VPA or saline. VPA plasma concentration was maintained at levels that produced no detectable anticonvulsant e ect. 3 Analysis of ictal components (eyes closure, jerk, gasp, forelimb, clonus, and hindlimb tonus) and their durations revealed both qualitative and quantitative di erences in drug e ects. 4 The anticonvulsant e ect is represented by the increase in the duration of the stimulation required to reach a given seizure threshold. PHT signi®cantly increased the duration of the stimulation and of the motor seizure. This increase was greatly enhanced by VPA. In addition, ictal component analysis revealed that the combination of PHT and VPA causes the reduction of a speci®c seizure component (JERK). 5 Neither the free fraction of PHT nor the biophase equilibration kinetics changes in the presence of VPA. It is concluded that the synergism may be due to a pharmacodynamic rather than a pharmacokinetic interaction.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacodynamic interaction between phenytoin and sodium valproate changes seizure thresholds and pattern

Paschoa

Kruk

Hamstra

et al. 1998

British J Pharmacology

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“…However, considerable inter‐ and intra‐subject variability in EEG activity was observed (Figure 3). The data were described by a reduced form of the sigmoid E max equation, which is useful in cases where the maximum response cannot be estimated from the data [18]. When b n is made equal to E max /E C 50 n , the sigmoid E max equation appears under the condition that c≪E C 50 , where E C 50 is the concentration at half maximal effect.…”

Section: Discussionmentioning

confidence: 99%

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

Knoester

Jonker

Hoeven

et al. 2002

Brit J Clinical Pharma

135

113

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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. b-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 (ts.d.) peak plasma concentration of midazolam of 71 (t25 ng ml x1 ) was reached after 14 (t5 min). Mean bioavailability following intranasal administration was 0.83t0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11t0.25 l kg x1 , mean systemic clearance 16.1t4.1 ml min x1 kg x1 and harmonic mean initial and terminal half lives 8.4t2.4and 79t30 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.

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P165 PK/PD modelling of the anticonvulsant and EEG effects of phenytoin

Cited by 2 publications

References 0 publications

Pharmacodynamic interaction between phenytoin and sodium valproate changes seizure thresholds and pattern

Pharmacodynamic interaction between phenytoin and sodium valproate changes seizure thresholds and pattern

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

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