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Pharmacotherapy May 2015To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL ) of FPHT... (Comparative Study)
Comparative Study Randomized Controlled Trial
STUDY OBJECTIVE
To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL ) of FPHT sodium injection compared with PHT sodium injection based on pharmacokinetic modeling in healthy volunteers.
DESIGN
Open-label, randomized, single-dose, two-period, two-sequence crossover study.
SETTING
University-affiliated clinical research center funded by the National Center of Research Resources.
SUBJECTS
Ten healthy adult volunteers.
INTERVENTION
Subjects were randomized to receive a single oral dose of either PHT sodium injection or FPHT sodium injection at a dose equivalent to 400 mg PHT acid. Blood samples were collected at baseline (just prior to administration) and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after dose administration. After a 7-14-day washout period, the subjects underwent the same study procedures for administration of the other agent (PHT or FPHT).
MEASUREMENTS AND MAIN RESULTS
The mean age and weight of the 10 subjects were 37 years and 72.5 kg, respectively, and the mean dose was 5.6 mg/kg based on PHT acid equivalence. The mean FREL of FPHT was 1.21 (95% confidence interval [CI] 1.07-1.35). Serum PHT concentrations were determined by fluorescence polarization immunoassay. The median (range) maximum serum concentration (Cmax ) values were significantly higher after FPHT administration compared with PHT: 10.7 (9.0-19.4) mg/L versus 5.0 (3.2-8.9) mg/L (p=0.002). The PHT concentration after oral administration of FPHT displayed faster absorption compared with PHT, with a median (range) time to reach Cmax of 1.0 (0.5-2.0) hours versus 6.0 (2.0-24.0) hours (p=0.008). All subjects completed the study without any serious adverse events reported.
CONCLUSION
FPHT sodium injection given orally was absorbed more rapidly and to a significantly greater extent than PHT sodium injection given orally to healthy volunteers. Further evaluation of oral FPHT as an alternative in patients requiring enteral feedings is warranted.
Topics: Administration, Oral; Adult; Cross-Over Studies; Female; Food-Drug Interactions; Humans; Male; Phenytoin
PubMed: 26011141
DOI: 10.1002/phar.1589 -
BMJ Clinical Evidence Jun 2010About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission. (Review)
Review
INTRODUCTION
About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of starting antiepileptic drug treatment following a single seizure? What are the effects of drug monotherapy in people with partial epilepsy? What are the effects of additional drug treatments in people with drug-resistant partial epilepsy? What is the risk of relapse in people in remission when withdrawing antiepileptic drugs? What are the effects of behavioural and psychological treatments for people with epilepsy? What are the effects of surgery in people with drug-resistant temporal lobe epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiepileptic drugs after a single seizure; monotherapy for partial epilepsy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second-line drugs for drug-resistant partial epilepsy (allopurinol, eslicarbazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, losigamone, oxcarbazepine, retigabine, tiagabine, topiramate, vigabatrin, or zonisamide); antiepileptic drug withdrawal for people with partial or generalised epilepsy who are in remission; behavioural and psychological treatments for partial or generalised epilepsy (biofeedback, cognitive behavioural therapy (CBT), educational programmes, family counselling, relaxation therapy (alone or plus behavioural modification therapy, yoga); and surgery for drug-resistant temporal lobe epilepsy ( lesionectomy, temporal lobectomy, vagus nerve stimulation as adjunctive therapy).
Topics: Anticonvulsants; Clinical Trials as Topic; Cost-Benefit Analysis; Epilepsies, Partial; Epilepsy; Humans; Phenytoin; Vigabatrin
PubMed: 21429248
DOI: No ID Found -
General Pharmacology Oct 19961. Phenytoin has been used with much clinical success against all types of epileptiform seizures, except petit mal epilepsy, for over 50 years. Its mechanism of action,... (Review)
Review
1. Phenytoin has been used with much clinical success against all types of epileptiform seizures, except petit mal epilepsy, for over 50 years. Its mechanism of action, however, is still open to interpretation. 2. Several potential targets for phenytoin action have been identified within the central nervous system. These include the Na-K-ATPase, the GABAA receptor complex, ionotropic glutamate receptors, calcium channels and sigma binding sites. 3. To date, though, the best evidence hinges on the inhibition of voltage-sensitive Na+ channels in the plasma membrane of neurons undergoing seizure activity. Quieter nerve cells are far less affected. Moreover, the fact that phenytoin also has important cardiac antiarrhythymic effects and can inhibit Na+ influx into cardiac cells supports the idea that the primary target of phenytoin is, indeed, the Na+ channel.
Topics: Animals; Anticonvulsants; Central Nervous System; Epilepsy; Humans; Neurons; Phenytoin; Sodium Channels
PubMed: 8981053
DOI: 10.1016/s0306-3623(96)00062-6 -
Turkish Neurosurgery 2011Cerebro-spinal fluid (CSF) leakage caused by defects on the dura mater after trauma or some neurosurgical interventions is an important issue. In this study, we...
AIM
Cerebro-spinal fluid (CSF) leakage caused by defects on the dura mater after trauma or some neurosurgical interventions is an important issue. In this study, we investigated the effects of local and systemic use of phenytoin sodium on dural healing.
MATERIAL AND METHODS
Thirty-six male Wistar rats were divided into control, local phenytoin and systemic phenytoin groups with 12 rats in each. For each group, a dura defect was created at thoracic segment. Subjects were sacrificed at following 1st and 6th weeks and damaged segments were isolated. The results were compared histopathologically by Hematoxylin-Eosin and Masson-Trichrome staining. Criteria for the rate of collagen, neovascularization, and granulation formation were assessed semi quantitatively according to the histological assessment scale modified by Ozisik et al.
RESULTS
Better healing was achieved in the systemic and local phenytoin groups than in the control group. The level of healing was significantly higher in the systemic group in both early and late periods than in other groups (p < 0.01). The level of healing in the late-local group was also statistically significantly higher than that in the control group.
CONCLUSION
We observed that both systemic and local uses of phenytoin sodium (especially systemic) have positive effects on dura healing.
Topics: Animals; Anticonvulsants; Cerebrospinal Fluid Leak; Cerebrospinal Fluid Rhinorrhea; Disease Models, Animal; Dura Mater; Granulation Tissue; Male; Neurosurgical Procedures; Phenytoin; Rats; Rats, Wistar; Wound Healing
PubMed: 22194102
DOI: No ID Found -
Drug Intelligence & Clinical Pharmacy Feb 1988The influence of enteral feedings (with Ensure) on the absorption of phenytoin sodium from capsules was studied. Six healthy adult volunteers were given a single dose of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The influence of enteral feedings (with Ensure) on the absorption of phenytoin sodium from capsules was studied. Six healthy adult volunteers were given a single dose of phenytoin capsules 400 mg po on two occasions. Blood specimens were collected for 48 hours after each dose. In a randomized, crossover fashion, each subject completed the following two phases: (1) phenytoin without enteral feedings, and (2) concomitant enteral feedings before phenytoin and continued at 100 ml/h for ten hours. The areas under the concentration versus time curves from 0-48 hours (AUC0-48) were not significantly different between the two phases (p greater than 0.5). The percent relative bioavailability of phenytoin with enteral feedings was 101.7 percent. This study suggests that enteral feedings do not affect the serum concentrations of phenytoin after a single dose given in capsule form.
Topics: Adult; Capsules; Enteral Nutrition; Female; Humans; Intestinal Absorption; Phenytoin
PubMed: 3127188
DOI: 10.1177/106002808802200205 -
Journal of Pharmaceutical Sciences May 2019The objective of the present study was to understand quality of brand and generic products of phenytoin sodium by in vitro methods. Three commercial products were...
The objective of the present study was to understand quality of brand and generic products of phenytoin sodium by in vitro methods. Three commercial products were selected for the study, 1 brand and 2 generics (product-A, product-B, and product-C). Products were repacked in pharmacy vials and stored for 12 weeks at 30°C/75% RH to simulate in-use conditions. The products were examined visually and microscopically for morphologic changes, spectroscopic and diffractometric methods for chemical changes, and dissolution, assay, and impurities for performance evaluation. Capsules content of the product-A turned yellowish to dark orange color from initial white powder, which indicated a possible chemical interaction between lactose and the drug in addition to disproportionation. This was supported by pH, microscopic, spectroscopic, and X-ray diffraction data. Product-A failed to meet United States Pharmacopoeia dissolution specification of 75% in 120 min after 2-weeks whereas product-B and product-C failed at 6-weeks of in-use stability conditions exposure. Furthermore, product-A also failed to meet United States pharmacopoeia assay and impurities specifications in 12 weeks in-use period. In summary, this study indicated salt disproportionation, chemical interactions, and phase transformations of drug and excipients in the commercial products of phenytoin sodium, which may affect the clinical performance of the product.
Topics: Capsules; Drugs, Generic; Excipients; Hydrogen-Ion Concentration; Lactose; Phenytoin; Solubility
PubMed: 30611751
DOI: 10.1016/j.xphs.2018.12.022 -
Bioorganic & Medicinal Chemistry Oct 2009The voltage-gated sodium channel remains a rich area for the development of novel blockers. In this study we used comparative molecular field analysis (CoMFA), a...
The voltage-gated sodium channel remains a rich area for the development of novel blockers. In this study we used comparative molecular field analysis (CoMFA), a ligand-based design strategy, to generate a 3D model based upon local anesthetics, hydantoins, and alpha-hydroxyphenylamides to elucidate a SAR for their binding site in the neuronal sodium channel. Correlation by partial least squares (PLS) analysis of in vitro sodium channel binding activity (expressed as pIC(50)) and the CoMFA descriptor column generated a final non-cross-validated model with q(2)=0.926 for the training set. The CoMFA steric and electrostatic maps described a binding site predominately hydrophobic in nature. This model was then used to design and predict a series of novel sodium channel blockers that utilized overlapping structural features of phenytoin, hydroxy amides, and the local anesthetic lidocaine. Synthesis and evaluation of these compounds for their ability to inhibit [(3)H]-batrachotoxin revealed that these compounds have potent sodium channel blockade. Furthermore, the CoMFA model was able to accurately predict the binding of these compounds to the neuronal sodium channel. Synthesis and subsequent sodium channel evaluation of compound 37 (predicted IC(50)=7 microM, actual IC(50)=6 microM), established that novel compounds based on overlapping regions of phenytoin and lidocaine are better binders to the sodium channel than phenytoin itself (IC(50)=40 microM).
Topics: Drug Design; Expert Systems; Inhibitory Concentration 50; Lidocaine; Ligands; Models, Molecular; Phenytoin; Sodium Channel Blockers; Structure-Activity Relationship
PubMed: 19346132
DOI: 10.1016/j.bmc.2008.10.031 -
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 -
The Journal of the Association of... Aug 1991Ninety four patients of generalised and partial epilepsy were randomly assigned to treatment with sodium valproate (49 cases) or phenytoin (45 cases). Serum levels were... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Ninety four patients of generalised and partial epilepsy were randomly assigned to treatment with sodium valproate (49 cases) or phenytoin (45 cases). Serum levels were monitored. Cases were evaluated after 4, 12, 24 weeks of treatment. Both drugs were found to be equally effective in controlling generalised seizures. However, valproate is better in partial seizures. No correlation could be established. Side effects were minor with both the drugs.
Topics: Adolescent; Adult; Child; Epilepsies, Partial; Epilepsy, Generalized; Female; Humans; Male; Middle Aged; Phenytoin; Valproic Acid
PubMed: 1814875
DOI: No ID Found -
Pacing and Clinical Electrophysiology :... Dec 2022Phenytoin is a versatile drug with utility in neurological, dermatological, and even cardiac disease processes. Though phenytoin is widely available due to its excellent... (Review)
Review
Phenytoin is a versatile drug with utility in neurological, dermatological, and even cardiac disease processes. Though phenytoin is widely available due to its excellent anti-epileptic properties, it is now rarely used as an antiarrhythmic. Phenytoin has well-studied sodium-channel blocking abilities which can be taken advantage of to treat ventricular arrhythmias. Thus, it should remain in the arsenal of antiarrhythmics for any electrophysiologist. We present two cases of intractable ventricular arrhythmia in children that were controlled with phenytoin at supra-therapeutic serum levels, preventing the need for heart transplantation.
Topics: Child; Humans; Phenytoin
PubMed: 35903996
DOI: 10.1111/pace.14565