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Therapeutic Drug Monitoring 1986Numerous letters and reports located in the Parke, Davis and Smithsonian files add to the story of Merritt's and Putnam's discovery of the anticonvulsant (AC) properties...
Numerous letters and reports located in the Parke, Davis and Smithsonian files add to the story of Merritt's and Putnam's discovery of the anticonvulsant (AC) properties of phenytoin. The major events preceding this work were the fortuitous discovery of phenobarbital as an AC agent, structure/hypnotic activity studies with barbiturates and hydantoins in the early 1920s by A. W. Dox in the Parke, Davis laboratories, and the development of AC assay techniques in animals, by a number of laboratories. Phenytoin was the first item on the list of compounds sent to Putnam by Dox and W. G. Bywater in April 1936. It was found to have AC properties in animals late in 1936, but no public reports were issued until the following year. Clinical efficacy was established in 1937, but no public reports were issued until 1938. Dilantin sodium capsules were prepared by Parke, Davis & Co. and were ready for marketing the same year.
Topics: Animals; Anticonvulsants; Drug Evaluation, Preclinical; History, 20th Century; Humans; Phenytoin
PubMed: 3547783
DOI: 10.1097/00007691-198612000-00021 -
Drug Intelligence & Clinical Pharmacy Sep 1984Interaction between a vaccine and a drug has been reported only with influenza vaccine and four drugs (aminopyrine, phenytoin sodium, theophylline, and warfarin sodium),... (Review)
Review
Interaction between a vaccine and a drug has been reported only with influenza vaccine and four drugs (aminopyrine, phenytoin sodium, theophylline, and warfarin sodium), and with BCG vaccine and theophylline. Some of these interactions still are unconfirmed. The underlying mechanism of the interaction is thought to be due to the vaccine (as an interferon-inducer) inactivating the hepatic cytochrome P-450 system; this results in depressed drug metabolism and reduced clearance. Because this is a nonspecific mechanism it could occur with other vaccines and it is possible that other vaccine-drug interactions are unrecognized. The clinical significance of vaccine-drug interactions is not fully determined; available evidence suggests that adverse reactions to warfarin or theophylline are rare after influenza vaccination and their possibility should not deter physicians from vaccinating those elderly patients at risk from influenza. Physicians should, however, monitor the response of these patients to medication in the immediate period following vaccination in case an adverse reaction occurs.
Topics: Aminopyrine; BCG Vaccine; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Influenza Vaccines; Pertussis Vaccine; Phenytoin; Risk; Theophylline; Vaccination; Vaccines
PubMed: 6383754
DOI: 10.1177/106002808401800904 -
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 monotherapy in newly diagnosed generalised epilepsy (tonic clonic type)? What are the effects of additional treatments in people with drug-resistant generalised epilepsy? What are the effects of surgery in people with drug-resistant generalised 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 eight 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: monotherapy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second-line drugs (lamotrigine or levetiracetam) for drug-resistant epilepsy; and hemispherectomy for drug-resistant epilepsy.
Topics: Anticonvulsants; Carbamazepine; Epilepsy; Epilepsy, Generalized; Humans; Incidence; Phenytoin; Remission Induction; Valproic Acid
PubMed: 21418687
DOI: No ID Found -
Epilepsia Feb 1981Thirty-three epileptic patients were randomly divided into two treatment groups. One group of 18 patients was given sodium valproate; the other 15 patients were given... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Thirty-three epileptic patients were randomly divided into two treatment groups. One group of 18 patients was given sodium valproate; the other 15 patients were given phenytoin. Periods of treatment ranged from 9 t0 48 months (mean, 30 months). Any patient who developed a seizure while on the first drug was changed to the other drug, provided the serum level of the first drug was in the accepted therapeutic range. Six required the change from phenytoin to sodium valproate, and three from sodium valproate to phenytoin. Side effects were not a major problem with either drug during the trial period. Phenytoin has been widely prescribed alone; our results indicate that sodium valproate may also be used as a single drug in the treatment of several types of epilepsy.
Topics: Adolescent; Adult; Aged; Child; Epilepsy; Female; Humans; Male; Middle Aged; Phenytoin; Pregnancy; Time Factors; Valproic Acid
PubMed: 6781888
DOI: 10.1111/j.1528-1157.1981.tb04330.x -
Pharmaceutical Development and... Jul 1996The objective of this investigation was to formulate and prepare sustained-action microcapsules of phenytoin sodium (diphenyl hydantoin sodium salt). Using...
The objective of this investigation was to formulate and prepare sustained-action microcapsules of phenytoin sodium (diphenyl hydantoin sodium salt). Using ethylcellulose and methyl acrylic acid copolymers (Eudragit S-100 and L-100) as coating materials, microcapsules of phenytoin sodium were formulated by an organic phase separation and a granule coating method. The phase diagrams were used to study the phase separation in an ethylcellulose-petroleum ether-toluene system, and the effect of temperature and amount of petroleum ether on the ethylcellulose left in the organic solvent mixture was investigated. The phase diagrams showed that increase in temperature did not significantly affect the ethylcellulose residue, and 60 ml of nonsolvent was found adequate for microencapsulation. In vitro release of the formulated microcapsules and the commercially available preparations was performed in CO2-free distilled water using the USP XXIII rotating basket method, and the profiles were evaluated by Higuchi kinetics. Geometric mean diameters of the microparticles prepared by two different methods showed differences due to different core:wall ratios. A 4 x 5 factorial design was utilized and multiple regression was applied to the dependent variables (ethylcellulose content, percent dissolved) against the independent variables (amount of nonsolvent, temperature, core:wall ratio); the optimum phenytoin sodium-to-ethylcellulose ratio was 1:2.3. Utilizing second-order polynomial equations, response-surface graphs and contour plots pointed out the time necessary for 40%, 55%, and 70% release of phenytoin sodium. The desired release profiles were obtained with formulations E-5, ES-2 and ESL-2.
Topics: Anticonvulsants; Capsules; Cellulose; Delayed-Action Preparations; Drug Compounding; Excipients; Kinetics; Particle Size; Phenytoin; Solubility
PubMed: 9552344
DOI: 10.3109/10837459609029892 -
Small (Weinheim An Der Bergstrasse,... Jul 2023Phenytoin (PHT) is a first-line antiepileptic drug in clinics, which could decrease neuronal bioelectric activity by blocking the voltage-operated sodium channels....
Phenytoin (PHT) is a first-line antiepileptic drug in clinics, which could decrease neuronal bioelectric activity by blocking the voltage-operated sodium channels. However, the intrinsically low blood-brain-barrier (BBB)-crossing capability of PHT and upregulated expression level of the efflux transporter p-glycoprotein (P-gp) coded by the gene Abcb1 in epileptic neurons limit its efficacy in vivo. Herein, a nanointegrated strategy to overcome PHT resistance mechanisms for enhanced antiepileptic efficacy is reported. Specifically, PHT is first incorporated into calcium phosphate (CaP) nanoparticles through biomineralization, followed by the surface modification of the PEGylated BBB-penetrating TAT peptide. The CaP@PHT-PEG-TAT nanoformulation could effectively cross the BBB to be taken in by epileptic neurons. Afterward, the acidic lysosomal environment would trigger their complete degradation to release Ca and PHT into the cytosol. Ca ions would inhibit mitochondrial oxidative phosphorylation to reverse cellular hypoxia to block hypoxia-inducible factor-1α (Hif1α)-Abcb1-axis, as well as disrupt adenosine triphosphate generation, leading to simultaneous suppression of the expression and drug efflux capacity of P-gp to enhance PHT retention. This study offers an approach for effective therapeutic intervention against drug-resistant epilepsy.
Topics: Humans; Phenytoin; ATP Binding Cassette Transporter, Subfamily B, Member 1; Epilepsy; Seizures; Anticonvulsants; Neurons; Calcium Phosphates
PubMed: 37029709
DOI: 10.1002/smll.202300395 -
Pharmacotherapy 1998To compare the absolute bioavailability of phenytoin (PHT) sodium solution and PHT acid suspension in healthy volunteers receiving continuously infused enteral feedings. (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
STUDY OBJECTIVE
To compare the absolute bioavailability of phenytoin (PHT) sodium solution and PHT acid suspension in healthy volunteers receiving continuously infused enteral feedings.
DESIGN
Randomized, open-label, single-dose, three-period crossover study.
SETTING
University clinical research center.
SUBJECTS
Ten healthy volunteers age 23-43 years.
INTERVENTIONS
The three phases of the study were separated by at least 7 days. During phase A, subjects received PHT sodium 435 mg intravenously over 30 minutes. During phases B and C, subjects had a nasogastric feeding tube placed through which PHT acid suspension 400 mg and PHT sodium solution 435 mg were administered, respectively. For phases B and C, continuous enteral feedings were given by feeding tube for 14 hours before and after the PHT dose. Blood samples were collected over 72 hours after each PHT dose, and the serum was analyzed for PHT.
MEASUREMENTS AND MAIN RESULTS
The rate and extent of PHT absorption and PHT pharmacokinetics were determined using an empirical quadratic function of time method. Bioavailability, rate of absorption, maximum concentration (Cmax), and time to maximum concentration (Tmax) were compared for the two enteral doses by paired Student's t test. There were no significant differences in bioavailability for PHT acid suspension and PHT sodium solution (0.88 +/- 0.15 vs 0.91 +/- 0.7, p=0.57, 90% CI -0.14-0.071). The Cmax was greater (7.4 +/- 0.9 mg/L vs 5.5 +/- 1.7 mg/L, p=0.019) and Tmax was less (2.5 +/- 3.8 vs.14.8 +/- 11.2 hrs, p=0.004) for the sodium solution. The time to 50% fractional absorption (0.33 +/- 0.08 vs 3.2 +/- 2.4 hrs, p=0.004) and 90% fractional absorption (7.9 +/- 6.2 vs 22.3 +/- 17.2 hrs, p=0.021) was also significantly shorter for the sodium solution.
CONCLUSION
The absolute bioavailability of the two dosage forms of PHT administered with concomitant enteral feedings were not significantly different, however, the absorption patterns were significantly different, with the sodium solution being more rapidly absorbed.
Topics: Adult; Anticonvulsants; Biological Availability; Enteral Nutrition; Female; Food-Drug Interactions; Humans; Injections, Intravenous; Male; Phenytoin
PubMed: 9620116
DOI: No ID Found -
European Journal of Drug Metabolism and... 2002The purpose of this study was to evaluate and compare plasma phenytoin concentration versus time profiles following intravenous (i.v.) and intramuscular (i.m.)...
The purpose of this study was to evaluate and compare plasma phenytoin concentration versus time profiles following intravenous (i.v.) and intramuscular (i.m.) administration of fosphenytoin sodium with those obtained following administration of standard phenytoin sodium injection in the rabbit. Twenty-four adult New Zealand White rabbits (2.1 +/- 0.4 kg) were anaesthetized with sodium pentobarbitone (30 mg/kg) followed by i.v. or i.m. administration of a single 10 mg/kg phenytoin sodium or fosphenytoin sodium equivalents. Blood samples (1.5 ml) were obtained from a femoral artery cannula predose and at 1, 3, 5, 7, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240 and 300 min after drug administration. Plasma was separated by centrifugation (1000 g; 5 min) and fosphenytoin, total and free plasma phenytoin concentrations were measured using high performance liquid chromatography (HPLC). Following i.v. administration of fosphenytoin sodium plasma phenytoin concentrations were similar to those obtained following i.v. administration of an equivalent dose of phenytoin sodium. Mean peak plasma phenytoin concentrations (Cmax) was 158% higher (P = 0.0277) following i.m. administration of fosphenytoin sodium compared to i.m. administration of phenytoin sodium. The mean area under the plasma total and free phenytoin concentration-time curve from time zero to 120 min (AUC(0-120)) following i.m. administration was also significantly higher (P = 0.0277) in fosphenytoin treated rabbits compared to the phenytoin group. However, there was no significant difference in AUC(0-180) between fosphenytoin and phenytoin-treated rabbits following i.v. administration. There was also no significant difference in the mean times to achieve peak plasma phenytoin concentrations (Tmax) between fosphenytoin and phenytoin-treated rabbits following i.m. administration. Mean plasma albumin concentrations were comparable in both groups of animals. Fosphenytoin was rapidly converted to phenytoin both after i.v. and i.m. administration, with plasma fosphenytoin concentrations declining rapidly to undetectable levels within 10 min following administration via either route. These results confirm the rapid and complete hydrolysis of fosphenytoin to phenytoin in vivo, and the potential of the i.m. route for administration of fosphenytoin delivering phenytoin in clinical settings where i.v. administration may not be feasible.
Topics: Animals; Drug Evaluation, Preclinical; Female; Infusions, Intravenous; Injections, Intramuscular; Male; Phenytoin; Rabbits
PubMed: 12064376
DOI: 10.1007/BF03190421 -
American Journal of Health-system... Nov 1996Fosphenytoin sodium is reviewed, and its safety is compared with that of phenytoin. After i.v. or i.m. injection, fosphenytoin, a phenytoin prodrug, is rapidly... (Comparative Study)
Comparative Study Review
Fosphenytoin sodium is reviewed, and its safety is compared with that of phenytoin. After i.v. or i.m. injection, fosphenytoin, a phenytoin prodrug, is rapidly hydrolyzed to phenytoin. Free-phenytoin concentrations equivalent to those obtained with i.v. phenytoin can be achieved with fosphenytoin given at equimolar loading doses by selecting the appropriate rate of fosphenytoin administration. Fosphenytoin can be expected to interact with the same drugs that interact with phenytoin. The dosage is expressed as phenytoin sodium equivalents (PE). The standard loading dose for adults with status epilepticus is 15-20 mg PE/kg i.v. infused at 100-150 mg/min; i.m. administration is not recommended for this condition. For nonemergency situations, a 10- to 20-mg PE/kg loading dose can be given i.v. or i.m. Fosphenytoin has advantages over phenytoin injection that are related to its greater aqueous solubility, which obviates the extreme alkalinity, propylene glycol, and ethanol needed in the injectable phenytoin formulation. Intravenous fosphenytoin has been associated with less soft-tissue injury and fewer adverse effects in general than phenytoin. Fosphenytoin, when administered i.m., is completely absorbed, is relatively well tolerated, and provides more predictable serum drug concentrations than i.m. phenytoin. Fosphenytoin offers practical and clinical advantages over i.v. phenytoin.
Topics: Adult; Anticonvulsants; Biological Availability; Chemistry, Pharmaceutical; Drug Interactions; Epilepsy; Humans; Injections, Intravenous; Phenytoin; Prodrugs
PubMed: 8931812
DOI: 10.1093/ajhp/53.22.2707 -
Journal of Pharmaceutical Sciences Mar 1993Physicochemical factors influencing the release of phenytoin sodium from slow-release dosage forms were studied. Some of these factors were solubility and intrinsic... (Comparative Study)
Comparative Study
Physicochemical factors influencing the release of phenytoin sodium from slow-release dosage forms were studied. Some of these factors were solubility and intrinsic dissolution rate as functions of pH, type of dosage form, pH of dissolution medium used, and conversion of the sodium salt to free acid (phenytoin). The innovator's product, Extended Phenytoin Sodium Capsule (Dilantin Kapseal, 100 mg, Parke-Davis), and two experimental formulations (one nondisintegrating tablet containing polymeric materials and the other a solid dispersion in an erodible matrix) served as the slow-release dosage forms. The sodium salt converts to practically insoluble phenytoin in the gastrointestinal pH range of 1 to 8. Due to such a conversion inside or at the surface of slow-release dosage forms, the release of drug in this pH range was incomplete. The extent of drug release also varied with the type of formulation used. In contrast, complete dissolution could be obtained in water because the pH of the medium gradually rose from approximately 6 to approximately 9.2 where the drug solubility was higher. Although several phenytoin sodium products might have similar dissolution rates in water, the extents of drug release under gastrointestinal pH conditions (pH 1-8) could differ greatly, thus supporting the Food and Drug Administration recognition that the similarity in dissolution profiles in water does not assure that the products are bioequivalent. The reported lower steady-state level of phenytoin in human plasma following oral administration of a slow-release dosage form may be related to incomplete drug release.
Topics: Chemistry, Pharmaceutical; Delayed-Action Preparations; Hydrogen-Ion Concentration; Kinetics; Phenytoin; Solubility; Water
PubMed: 8450427
DOI: 10.1002/jps.2600820318