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Journal of Neurology, Neurosurgery, and... Jul 1988A prospective, double-blind, placebo-controlled investigation of possible withdrawal symptoms from phenytoin, carbamazepine and sodium valproate is reported in patients... (Clinical Trial)
Clinical Trial
A prospective, double-blind, placebo-controlled investigation of possible withdrawal symptoms from phenytoin, carbamazepine and sodium valproate is reported in patients with active epilepsy, on combination therapy. There was an increase in seizures on reduction and withdrawal of carbamazepine, but there was no convincing evidence of withdrawal symptoms from any of these drugs.
Topics: Adolescent; Adult; Aged; Carbamazepine; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Phenytoin; Prospective Studies; Substance Withdrawal Syndrome; Valproic Acid
PubMed: 3144581
DOI: 10.1136/jnnp.51.7.924 -
British Medical Journal Jun 1960
Topics: Agranulocytosis; Humans; Hydantoins; Phenytoin
PubMed: 13839955
DOI: 10.1136/bmj.1.5188.1790 -
Journal of Pharmacy & Pharmaceutical... 2018The U.S. Pharmacopeia defines excipients as substances other than the active pharmaceutic ingredient (API) that are added in a drug delivery system in order to aid in...
PURPOSE
The U.S. Pharmacopeia defines excipients as substances other than the active pharmaceutic ingredient (API) that are added in a drug delivery system in order to aid in the manufacturing process and enhance stability, bioavailability, safety, effectiveness and delivery of the drug. The 1968 phenytoin intoxication outbreak in Brisbane, Australia, is a classic example of an API-excipient interaction. When administered with CaSO4 the absorption of phenytoin was reduced due to an interaction between the API and the excipient. When CaSO4 was replaced by lactose, the amount of drug absorbed was much higher, resulting in the observed intoxication. It was hypothesized that phenytoin was converted to a calcium salt prior to ingestion. The purpose of this study was to mechanistically investigate the interactions between excipients and phenytoin to confirm the hypothesis of the previous reports.
METHODS
Titration experiments with phenytoin and calcium salt were performed. Isothermal micro calorimetry was used to determine incompatibilities between excipients, phenytoin and milk. NMR was used to characterize the compounds. Dissolution tests containing CaSO4, lactose or sorbitol as excipients were also performed. Both Canadian and United States of America commercially available capsules were tested with milk and water.
RESULTS
The calorimeter results indicate that phenytoin sodium interacts with CaSO4 in aqueous media and the dissolution profile of CaSO4 containing capsules showed a reduced dissolution rate. In addition, phenytoin sodium also interacts with lactose through a Maillard reaction that can occur at body temperature. Likewise, commercial Phenytoin sodium products interacted with milk and the products containing lactose showed browning in water.
CONCLUSION
In Canada and the USA, the reference product contains lactose as an excipient in the formulation, whereas the Canadian generic formulations do not contain lactose. Any clinical relevance of these difference has not been determined. A new incompatibility between phenytoin and lactose has been discovered and an incompatibility with calcium was confirmed, which may have implications in regard to excipients and food effects. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Anticonvulsants; Calcium Sulfate; Calorimetry; Chromatography, High Pressure Liquid; Humans; Lactose; Phenytoin; Solubility
PubMed: 29702046
DOI: 10.18433/jpps29745 -
Expert Review of Neurotherapeutics Jan 2022Status epilepticus (SE) is a neurological emergency that can occur in patients with or without epilepsy. Rapid treatment is paramount to mitigate risks of neuronal... (Review)
Review
INTRODUCTION
Status epilepticus (SE) is a neurological emergency that can occur in patients with or without epilepsy. Rapid treatment is paramount to mitigate risks of neuronal injury, morbidity/mortality, and healthcare-cost burdens associated with SE. Fosphenytoin is the prodrug of phenytoin designed to enable faster administration and improved tolerability as compared to intravenous (IV) phenytoin in the treatment of SE.
AREAS COVERED
This review evaluates the chemistry, pharmacokinetics, pharmacodynamics, safety, and tolerability of fosphenytoin. Efficacy data for fosphenytoin in the treatment of SE in adults and children are analyzed from initial phase I trials in 1988 through current phase III trials, including the Established Status Epilepticus Treatment Trial (ESETT).
EXPERT OPINION
IV phenytoin is an established treatment of SE, but its alkaline aqueous vehicle is associated with dermatologic irritation and systemic complications when rapidly infused. The water-soluble nature of its prodrug, fosphenytoin, allows for rapid infusion, and it is rapidly converted to phenytoin when administered intravenously or intramuscularly. In the ESETT, IV fosphenytoin demonstrated similar efficacy in treatment of established SE when compared to IV levetiracetam and IV valproate in adults and children, making it a reasonable choice in the treatment of SE that is unresponsive to benzodiazepines.
Topics: Adult; Anticonvulsants; Child; Humans; Levetiracetam; Phenytoin; Status Epilepticus
PubMed: 34726961
DOI: 10.1080/14737175.2021.2001328 -
Molecular Pharmacology Oct 1994The anticonvulsant phenytoin inhibited Na+ currents in rat hippocampal neurons with a potency that increased dramatically at depolarized holding potentials, suggesting...
The anticonvulsant phenytoin inhibited Na+ currents in rat hippocampal neurons with a potency that increased dramatically at depolarized holding potentials, suggesting weak binding to resting Na+ channels but tight binding to open or inactivated channels. Four different experimental measurements, i.e., steady block at different holding potentials, on and off kinetics at depolarized holding potentials, shifts in the inactivation curve, and dose-dependent slowing of recovery from inactivation, yielded an estimated Kd of approximately 7 microM for phenytoin binding to inactivated channels. Prolonged depolarizations of at least several seconds were necessary for significant block by therapeutic concentrations of phenytoin. The slow development of block does not reflect selective binding of phenytoin to slow inactivated states of the channel, because block developed faster and required less depolarized voltages than did slow inactivation. Instead, it appears that phenytoin binds tightly but slowly (approximately 10(4) M-1 sec-1) to fast inactivated states of the Na+ channels. This tight but slow binding may underlie the ability of phenytoin to disrupt epileptic discharges with minimal effects on normal firing patterns.
Topics: Animals; Binding Sites; Hippocampus; In Vitro Techniques; Kinetics; Membrane Potentials; Neurons; Phenytoin; Rats; Sodium Channels
PubMed: 7969051
DOI: No ID Found -
Archives of Internal Medicine Jul 1978Phenytoin sodium intoxication of subacute onset may occur in cases of nonepileptic patients who receive phenytoin for suppression of cardiac arrhythmias. The case...
Phenytoin sodium intoxication of subacute onset may occur in cases of nonepileptic patients who receive phenytoin for suppression of cardiac arrhythmias. The case reported here is of a syndrome that consisted of dementia, cerebellar dysfunction, and peripheral neuropathy. Withdrawal of phenytoin was followed by a slow improvement in the syndrome. Awareness of the features of subacute phenytoin intoxication in cardiac patients is important because this entity may mimic cerebrovascular disease. Periodic monitoring of serum phenytoin concentrations is advisable.
Topics: Arrhythmias, Cardiac; Cerebellar Diseases; Humans; Male; Mental Disorders; Middle Aged; Peripheral Nervous System Diseases; Phenytoin
PubMed: 208480
DOI: No ID Found -
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 -
Clinical Pharmacy 1984The absorption characteristics of three phenytoin sodium products given orally as loading doses in five healthy men were studied. Extended phenytoin sodium capsules,... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The absorption characteristics of three phenytoin sodium products given orally as loading doses in five healthy men were studied. Extended phenytoin sodium capsules, prompt phenytoin sodium capsules, and phenytoin sodium injection were administered in a randomized, crossover trial as single 18-mg/kg doses and as divided doses of 6 mg/kg every three hours for three doses. Each dose was given with 200 ml of water, and a two-week washout period followed each treatment. The maximum plasma concentration (Cmax), time to reach maximum plasma concentration, time to reach the lower end (10 mg/liter) of the therapeutic range, time to reach a plasma concentration greater than 15 mg/liter, and time within the therapeutic range were determined for each loading-dose regimen. Prompt phenytoin sodium capsules (prompt PHT) given in divided doses produced a mean Cmax of 22.0 mg/liter, which was significantly higher than that observed with any of the other loading-dose regimens. In addition, all subjects receiving prompt PHT in divided doses had plasma phenytoin concentrations of 10 mg/liter within six hours; only this treatment produced plasma concentrations greater than 15 mg/liter at nine hours in all subjects. Plasma concentrations remained within the therapeutic range (10-20 mg/liter) for 81 and 78% of the first 24-hour period for prompt PHT in divided and single doses, respectively. Adverse effects were minimal in all regimens. The prompt-release phenytoin sodium capsules used in this study may provide an alternative means for rapidly achieving therapeutic phenytoin concentrations in situations where i.v. administration is not indicated or practical.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Administration, Oral; Adult; Biological Availability; Humans; Intestinal Absorption; Kinetics; Male; Phenytoin
PubMed: 6509876
DOI: No ID Found -
Epilepsia 1989ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is...
ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Anti-Arrhythmia Agents; Blood Pressure; Epilepsy; Heart Rate; Mice; Phenytoin; Prodrugs
PubMed: 2767010
DOI: 10.1111/j.1528-1157.1989.tb05820.x -
Clinical Toxicology (Philadelphia, Pa.) Oct 2010Seizures are a common sequela of self-poisoning. However, their mechanism differs from seizures of other etiologies. Toxicological seizures result from alterations in... (Review)
Review
INTRODUCTION
Seizures are a common sequela of self-poisoning. However, their mechanism differs from seizures of other etiologies. Toxicological seizures result from alterations in the excitatory and inhibitory balance of otherwise normal neurons. In contrast, idiopathic or trauma related seizures usually start with a focus of abnormal neurons. For both forms of seizures, benzodiazepines are recommended as first-line therapy; however, there is debate about the use of phenytoin or barbiturates for second-line therapy.
METHODS AND RESULTS
In this article, we systematically review the evidence for the use of these drugs as second-line therapy for toxicological seizures. Barbiturates complement the anticonvulsant effect of benzodiazepines at the GABAA receptor by increasing the duration of chloride channel opening; phenytoin blocks voltage-dependent sodium channels to inhibit propagation from active electrical foci, an effect more useful for nontoxicological seizures. We found no randomized controlled trial comparing phenytoin and barbiturates in toxicological seizures refractory to benzodiazepines; similarly no trial was found comparing the use of these drugs in nonpoisoned patients. Animal studies indicate that phenobarbital has greater effectiveness than phenytoin for many poisons; a few case reports suggest a better response in patients.
CONCLUSION
Despite the lack of high-quality clinical trial data, pharmacological knowledge and animal studies suggest that phenobarbital or thiopentone should be second-line agents for controlling toxicological seizures. The role of newer agents such as propofol and levetiracetam in toxicological seizures is currently unclear because of a lack of clinical or animal studies.
Topics: Barbiturates; Humans; Phenytoin; Seizures
PubMed: 20923393
DOI: 10.3109/15563650.2010.521506