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British Journal of Pharmacology Nov 19981. In this study we used cortical stimulation to assess the effects of phenytoin (PHT), sodium valproate (VPA), and their interaction on total motor seizure and on the...
1. In this study we used cortical stimulation to assess the effects 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(-1)) 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 effect. 3. Analysis of ictal components (eyes closure, jerk, gasp, forelimb, clonus, and hindlimb tonus) and their durations revealed both qualitative and quantitative differences in drug effects. 4. The anticonvulsant effect is represented by the increase in the duration of the stimulation required to reach a given seizure threshold. PHT significantly 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 specific 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.
Topics: Analysis of Variance; Animals; Anticonvulsants; Drug Interactions; Male; Phenytoin; Rats; Rats, Wistar; Seizures; Valproic Acid
PubMed: 9846637
DOI: 10.1038/sj.bjp.0702155 -
British Journal of Pharmacology Feb 2014Voltage-activated Na(+) channels contain one distinct α-subunit. In the brain NaV 1.1, NaV 1.2, NaV 1.3 and NaV 1.6 are the four most abundantly expressed α-subunits....
BACKGROUND AND PURPOSE
Voltage-activated Na(+) channels contain one distinct α-subunit. In the brain NaV 1.1, NaV 1.2, NaV 1.3 and NaV 1.6 are the four most abundantly expressed α-subunits. The antiepileptic drugs (AEDs) carbamazepine, phenytoin and lamotrigine have voltage-gated Na(+) channels as their primary therapeutic targets. This study provides a systematic comparison of the biophysical properties of these four α-subunits and characterizes their interaction with carbamazepine, phenytoin and lamotrigine.
EXPERIMENTAL APPROACH
Na(+) currents were recorded in voltage-clamp mode in HEK293 cells stably expressing one of the four α-subunits.
KEY RESULTS
NaV 1.2 and NaV 1.3 subunits have a relatively slow recovery from inactivation, compared with the other subunits and NaV 1.1 subunits generate the largest window current. Lamotrigine evokes a larger maximal shift of the steady-state inactivation relationship than carbamazepine or phenytoin. Carbamazepine shows the highest binding rate to the α-subunits. Lamotrigine binding to NaV 1.1 subunits is faster than to the other α-subunits. Lamotrigine unbinding from the α-subunits is slower than that of carbamazepine and phenytoin.
CONCLUSIONS AND IMPLICATIONS
The four Na(+) channel α-subunits show subtle differences in their biophysical properties, which, in combination with their (sub)cellular expression patterns in the brain, could contribute to differences in neuronal excitability. We also observed differences in the parameters that characterize AED binding to the Na(+) channel subunits. Particularly, lamotrigine binding to the four α-subunits suggests a subunit-specific response. Such differences will have consequences for the clinical efficacy of AEDs. Knowledge of the biophysical and binding parameters could be employed to optimize therapeutic strategies and drug development.
Topics: Anticonvulsants; Brain; Carbamazepine; HEK293 Cells; Humans; Lamotrigine; Phenytoin; Protein Subunits; Sodium Channels; Triazines; Voltage-Gated Sodium Channel Blockers
PubMed: 24283699
DOI: 10.1111/bph.12534 -
The Cochrane Database of Systematic... Feb 2017This is an updated version of the original Cochrane Review published in Issue 2, 2002 and its subsequent updates in 2010 and 2015.Epilepsy is a common neurological... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane Review published in Issue 2, 2002 and its subsequent updates in 2010 and 2015.Epilepsy is a common neurological condition in which recurrent, unprovoked seizures are caused by abnormal electrical discharges from the brain. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenytoin are commonly-used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first-line treatment for partial onset seizures in the USA and Europe. Phenytoin is no longer considered a first-line treatment due to concerns over adverse events associated with its use, but the drug is still commonly used in low- to middle-income countries because of its low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin in individual trials, although the confidence intervals generated by these studies are wide. Differences in efficacy may therefore be shown by synthesising the data of the individual trials.
OBJECTIVES
To review the time to withdrawal, six- and 12-month remission, and first seizure with carbamazepine compared to phenytoin, used as monotherapy in people with partial onset seizures (simple partial, complex partial, or secondarily generalised tonic-clonic seizures), or generalised tonic-clonic seizures, with or without other generalised seizure types.
SEARCH METHODS
For the latest update we searched the Cochrane Epilepsy Group's Specialised Register (1st November 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 1st November 2016), MEDLINE (Ovid, 1946 to 1 November 2016), ClinicalTrials.gov (1 November 2016), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP, 1st November 2016). Previously we also searched SCOPUS (1823 to 16th September 2014) as an alternative to Embase, but this is no longer necessary, because randomised and quasi-randomised controlled trials in Embase are now included in CENTRAL. We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.
SELECTION CRITERIA
Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures, comparing carbamazepine monotherapy versus phenytoin monotherapy.
DATA COLLECTION AND ANALYSIS
This is an individual participant data (IPD) review. Our primary outcome was time to withdrawal of allocated treatment, and our secondary outcomes were time to six-month remission, time to 12-month remission, and time to first seizure post-randomisation. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) and the generic inverse variance method to obtain the overall pooled HR and 95% CI.
MAIN RESULTS
IPD were available for 595 participants out of 1192 eligible individuals, from four out of 12 trials (i.e. 50% of the potential data). For remission outcomes, HR greater than 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes, HR greater than 1 indicates an advantage for carbamazepine. The methodological quality of the four studies providing IPD was generally good and we rated it at low risk of bias overall in the analyses.The main overall results (pooled HR adjusted for seizure type) were time to withdrawal of allocated treatment: 1.04 (95% CI 0.78 to 1.39; three trials, 546 participants); time to 12-month remission: 1.01 (95% CI 0.78 to 1.31; three trials, 551 participants); time to six-month remission: 1.11 (95% CI 0.89 to 1.37; three trials, 551 participants); and time to first seizure: 0.85 (95% CI 0.70 to 1.04; four trials, 582 participants). The results suggest no overall statistically significant difference between the drugs for these outcomes. There is some evidence of an advantage for phenytoin for individuals with generalised onset seizures for our primary outcome (time to withdrawal of allocated treatment): pooled HR 0.42 (95% CI 0.18 to 0.96; two trials, 118 participants); and a statistical interaction between treatment effect and epilepsy type (partial versus generalised) for this outcome (P = 0.02). However, misclassification of seizure type for up to 48 individuals (32% of those with generalised epilepsy) may have confounded the results of this review. Despite concerns over side effects leading to the withdrawal of phenytoin as a first-line treatment in the USA and Europe, we found no evidence that phenytoin is more likely to be associated with serious side effects than carbamazepine; 26 individuals withdrew from 290 randomised (9%) to carbamazepine due to adverse effects, compared to 12 out of 299 (4%) randomised to phenytoin from four studies conducted in the USA and Europe (risk ratio (RR) 1.42, 95% CI 1.13 to 1.80, P = 0.014). We rated the quality of the evidence as low to moderate according to GRADE criteria, due to imprecision and potential misclassification of seizure type.
AUTHORS' CONCLUSIONS
We have not found evidence for a statistically significant difference between carbamazepine and phenytoin for the efficacy outcomes examined in this review, but CIs are wide and we cannot exclude the possibility of important differences. There is no evidence in this review that phenytoin is more strongly associated with serious adverse events than carbamazepine. There is some evidence that people with generalised seizures may be less likely to withdraw early from phenytoin than from carbamazepine, but misclassification of seizure type may have impacted upon our results. We recommend caution when interpreting the results of this review, and do not recommend that our results alone should be used in choosing between carbamazepine and phenytoin. We recommend that future trials should be designed to the highest quality possible, with considerations of allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.
Topics: Adult; Anticonvulsants; Carbamazepine; Child; Epilepsies, Partial; Epilepsy, Generalized; Humans; Induction Chemotherapy; Phenytoin; Randomized Controlled Trials as Topic; Time Factors; Withholding Treatment
PubMed: 28240353
DOI: 10.1002/14651858.CD001911.pub3 -
Biochimica Et Biophysica Acta Oct 2016GFAP is the major intermediate filament protein in mature astrocytes. Its increased expression and aggregation was firstly associated to Alexander's disease, and...
BACKGROUND
GFAP is the major intermediate filament protein in mature astrocytes. Its increased expression and aggregation was firstly associated to Alexander's disease, and successively in different neurological diseases including scrapie, Alzheimer's and Creutzfeld-Jacob diseases. Recently, ceftriaxone a multi-potent β-lactam antibiotic able to overcome the blood-brain barrier, successfully eliminated the cellular toxic effects of misfolded mutated GFAP, similarly to phenytoin sodium, in a cellular model of Alexander's disease and inhibited α-synuclein aggregation protecting PC12 cells from the exposure to 6-hydroxydopamine.
METHODS
In this study, synchrotron radiation circular dichroism spectroscopy has been used to obtain structural information about the GFAP-ceftriaxone (phenytoin) interactions, while computational methods allowed the identification of the relevant putative binding site of either ceftriaxone or phenytoin on the dimer structure of GFAP, permitting to rationalize the spectroscopic experimental results.
RESULTS
We found that GFAP exhibited enhanced stability upon the addition of two equivalents of each ligands with ceftriaxone imparting a more spontaneous interactions and a more ordered complex system than phenytoin.
CONCLUSIONS
SRCD data and MD models indicate a stronger protective effect of ceftriaxone in neurological disorders characterized by an increased production and polymerization of GFAP.
GENERAL SIGNIFICANCE
This result, in addition to our previous works in which we documented that ceftriaxone interacts with α-synuclein inhibiting its pathological aggregation and that a cyclical treatment with this molecule in a patient with adult-onset Alexander's disease halted, and partly reversed, the progression of neurodegeneration, suggests the possibility of a chaperone-like effect of ceftriaxone on protein involved in specific neurodegenerative diseases.
Topics: Alexander Disease; Animals; Astrocytes; Binding Sites; Ceftriaxone; Glial Fibrillary Acidic Protein; Humans; Intermediate Filament Proteins; Molecular Docking Simulation; Molecular Dynamics Simulation; Nerve Degeneration; PC12 Cells; Phenytoin; Protein Aggregation, Pathological; Rats; alpha-Synuclein
PubMed: 27133445
DOI: 10.1016/j.bbagen.2016.04.021 -
British Medical Journal Apr 1979
Topics: Adolescent; Drug Administration Schedule; Epilepsy, Tonic-Clonic; Humans; Male; Phenytoin
PubMed: 107994
DOI: 10.1136/bmj.1.6169.1000 -
British Journal of Pharmacology Dec 1998Treatment of epilepsy with a combination of antiepileptic drugs remains the therapeutic choice when monotherapy fails. In this study, we apply...
Treatment of epilepsy with a combination of antiepileptic drugs remains the therapeutic choice when monotherapy fails. In this study, we apply pharmacokinetic-pharmacodynamic modelling to characterize the interaction between phenytoin (PHT) and sodium valproate (VPA). Male Wistar rats received a 40 mg kg(-1) intravenous dose of PHT over 5 min either alone or in combination with an infusion of VPA resulting in a steady-state concentration of 115.5+/-4.9 microg ml(-1). A control group received only the infusion of VPA. The increase in the threshold for generalized seizure activity (ATGS) was used as measure of the anticonvulsant effect. PHT pharmacokinetics was described by a pharmacokinetic model with Michaelis-Menten elimination. The concentration-time course and plasma protein binding of PHT were not altered by VPA. The pharmacokinetic parameters Vmax and Km were, respectively, 294+/-63 microg min(-1) and 7.8+/-2.4 microg ml(-1) in the absence of VPA and 562+/-40 microg min(-1) and 15.6+/-0.9 microg ml(-1) upon administration in combination with VPA. A delay of the onset of the effect relative to plasma concentrations of PHT was observed. The assessment of PHT concentrations at the effect site was based on the effect-compartment model, yielding mean ke0 values of 0.128 and 0.107 min(-1) in the presence and absence of VPA, respectively. A nonlinear relationship between effect-site concentration and the increase in the TGS was observed. The concentration that causes an increase of 50% in the baseline TGS (EC50%TGS) was used to compare drug potency. A shift of EC50%TGS from 13.27+3.55 to 4.32+/-0.52 microg ml(-1) was observed upon combination with VPA (P<0.01). It is concluded that there is a synergistic pharmacodynamic interaction between PHT and VPA in vivo.
Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Male; Phenytoin; Rats; Rats, Wistar; Valproic Acid
PubMed: 9884091
DOI: 10.1038/sj.bjp.0702235 -
European Journal of Clinical... Mar 2013We performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic...
PURPOSE
We performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range.
METHODS
We used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10-20 μg/mL.
RESULTS
We used a linear two-compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg.
CONCLUSIONS
The pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration.
Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticonvulsants; Biotransformation; Child; Child, Preschool; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Computer Simulation; Drug Dosage Calculations; Female; Humans; Infusions, Intravenous; Japan; Linear Models; Male; Middle Aged; Models, Biological; Phenytoin; Prodrugs; Randomized Controlled Trials as Topic; Retrospective Studies; Software; Young Adult
PubMed: 22918614
DOI: 10.1007/s00228-012-1373-8 -
Neurology India Jun 2006It is now agreed that the prognosis of seizure disorder due to solitary cysticercus granuloma (SCG) is generally good. However, the choice antiepileptic drugs (AEDs)... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
It is now agreed that the prognosis of seizure disorder due to solitary cysticercus granuloma (SCG) is generally good. However, the choice antiepileptic drugs (AEDs) remain empirical, with no comparative trials of different AEDs being available.
AIMS
To determine the safety and efficacy (measured by the incidence of 'treatment failure') of clobazam in comparison to standard treatment with phenytoin-sodium for prevention of seizures in persons with solitary cysticercus granulomas (SCGs).
SETTINGS AND DESIGN
This pilot study was conducted in a neurology department of a medical college hospital in the form of a prospective, randomized, open-labeled trial.
MATERIALS AND METHODS
Forty-eight patients with seizures due to SCG were randomized in an open-labeled trial to either, clobazam (1 mg/kg oral loading followed by 0.5 mg/kg/d) (n=21) or phenytoin (15 mg/kg, oral loading in 3 divided doses over 24 h, followed by 5 mg/kg/d) (n=27). They were followed over 6 months with the primary outcome measure being treatment failure (either discontinuation or modification of AEDs) due to either adverse effects or breakthrough seizures.
RESULTS
Treatment failures were noted to be significantly less common (P =0.03) in the clobazam-treated group (n=1; 4.7%) than in phenytoin-treated group (n=9; 33.3%). These included one patient (4.7%) in the clobazam-group who had breakthrough seizures and 3 (11.1%) who had breakthrough seizures and 6 (22.2%) in the phenytoin-treated group who had adverse effects requiring treatment discontinuation.
CONCLUSIONS
Clobazam was well tolerated, safe and more effective than phenytoin in the AED treatment of patients with SCG.
Topics: Adolescent; Adult; Aged; Anticonvulsants; Benzodiazepines; Child, Preschool; Clobazam; Double-Blind Method; Female; Granuloma; Humans; Male; Middle Aged; Neurocysticercosis; Phenytoin; Prospective Studies; Seizures; Treatment Outcome
PubMed: 16804259
DOI: No ID Found -
Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.The Cochrane Database of Systematic... Jun 2017Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices.
OBJECTIVES
To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).
SEARCH METHODS
We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016.
SELECTION CRITERIA
We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types).
DATA COLLECTION AND ANALYSIS
This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to-head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events.
MAIN RESULTS
IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than both current first-line treatments carbamazepine and lamotrigine; lamotrigine performed better than all other treatments (aside from levetiracetam), and carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate- to high-quality evidence).Generally, direct evidence and network meta-analysis estimates (direct plus indirect evidence) were numerically similar and consistent with confidence intervals of effect sizes overlapping.The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders.
AUTHORS' CONCLUSIONS
Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first-line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity.
Topics: Adult; Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Fructose; Gabapentin; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Network Meta-Analysis; Oxcarbazepine; Phenobarbital; Phenytoin; Piracetam; Remission Induction; Topiramate; Triazines; Valproic Acid; Zonisamide; gamma-Aminobutyric Acid
PubMed: 28661008
DOI: 10.1002/14651858.CD011412.pub2 -
British Journal of Clinical Pharmacology 19951. The effects of tenidap sodium 120 mg day-1 at steady state and placebo on the plasma protein binding and pharmacokinetics of phenytoin were compared in this... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
1. The effects of tenidap sodium 120 mg day-1 at steady state and placebo on the plasma protein binding and pharmacokinetics of phenytoin were compared in this randomised, double-blind, placebo-controlled, parallel-group study, involving 12 healthy young men, conducted over 34 days. 2. Single oral doses of phenytoin 200 mg were given on days 1-3 and 29-31, and intravenous phenytoin, 250 mg infused over 20 min, was given on days 4 and 32. Tenidap (120 mg day-1), or matching placebo, was administered as single oral daily doses from days 8 to 34 inclusive. 3. The plasma protein binding of phenytoin was determined immediately before oral phenytoin administration on days 1 and 29. Pharmacokinetic parameters were estimated from the serum phenytoin concentration-time curves derived on days 4 and 32 following the phenytoin infusions. The differences between the pre- and post-treatment mean percentage of unbound plasma phenytoin and mean pharmacokinetic parameters were compared between treatment groups. 4. Tenidap sodium 120 mg day-1, at steady state, increased the percentage of unbound phenytoin in plasma by approximately 25%, but did not significantly affect AUC(0,48h) or Cmax. 5. Since tenidap increases the percentage of unbound phenytoin in plasma, when monitoring phenytoin plasma concentrations free concentrations of phenytoin should be considered. 6. Tenidap was well tolerated throughout the study.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Proteins; Double-Blind Method; Drug Interactions; Humans; Indoles; Male; Oxindoles; Phenytoin; Protein Binding
PubMed: 7547092
DOI: 10.1111/j.1365-2125.1995.tb04500.x