-
Research Communications in Chemical... Dec 1983his study was performed to determine the potential utility of the cumulation profile of phenytoin during multiple oral dosing and to examine, under ideal conditions, the... (Comparative Study)
Comparative Study
his study was performed to determine the potential utility of the cumulation profile of phenytoin during multiple oral dosing and to examine, under ideal conditions, the variability in apparent steady state concentrations. Six male subjects were administered oral phenytoin sodium 5-6 mg/kg/d in divided doses every 12h for six days. Predose serum phenytoin concentrations were measured every 12 hours by gas liquid chromatography. The resulting data were analyzed in order to estimate maintenance doses. Subjects were then placed on the estimated daily dose and pre-dose concentrations measured daily for at least two weeks. At the end of the study, all data were fit using non-linear regression analysis to obtain the best estimates of individual kinetic parameters. Parameter values, particularly the Km value, were dependent upon the input function used, either first- or zero-order. In two subjects there was evidence of modest auto-induction. At steady-state the average coefficient of variation of predose concentrations was 10.6% (Range: 5.2-16.2%).
Topics: Administration, Oral; Adult; Chromatography, Gas; Humans; Kinetics; Male; Phenytoin; Time Factors
PubMed: 6665297
DOI: No ID Found -
Archives of Internal MedicineThis document summarizes the proceedings of an expert panel consensus process addressing the nonemergency use of parenteral phenytoin products for management of seizures... (Review)
Review
Guidelines for nonemergency use of parenteral phenytoin products: proceedings of an expert panel consensus process. Panel on Nonemergency Use of Parenteral Phenytoin Products.
This document summarizes the proceedings of an expert panel consensus process addressing the nonemergency use of parenteral phenytoin products for management of seizures in pediatric and adult patients. The algorithm and consensus statements developed by the expert panel emphasize strategies for lowering the probability of adverse events associated with the use of parenteral phenytoin products. Specific patient characteristics are defined to guide administration and monitoring of parenteral phenytoin therapy. The algorithm provides a decision pathway for the selection of the product and the route of administration of phenytoin sodium or fosphenytoin sodium after it has been determined that a parenteral phenytoin product is appropriate. Key factors covered in the algorithm include a list of patient characteristics and considerations necessary to prevent parenteral phenytoin adverse effects during selection of administration route and recommendations for monitoring of parenteral phenytoin therapy once it has been initiated. Situations requiring rapid attainment of high phenytoin concentrations, such as in the management of acute seizures, are not addressed in these guidelines.
Topics: Adolescent; Adult; Algorithms; Anticonvulsants; Child; Costs and Cost Analysis; Humans; Infusions, Intravenous; Injections, Intramuscular; Middle Aged; Phenytoin; Safety; Seizures; Status Epilepticus
PubMed: 10597754
DOI: 10.1001/archinte.159.22.2639 -
Molecular Pharmaceutics Oct 2020Drug repositioning is an important drug development strategy as it saves the time and efforts exerted in drug discovery. Since reepithelization of the cornea is a...
Drug repositioning is an important drug development strategy as it saves the time and efforts exerted in drug discovery. Since reepithelization of the cornea is a critical problem, we envisioned that the anticonvulsant phenytoin sodium can promote reepithelization of corneal ulcers as it was repurposed for skin wound healing. Herein, our aim is to develop novel crown ether-based nanovesicles "Crownsomes" of phenytoin sodium for ocular delivery with minimal drug-induced irritation and enhanced efficacy owing to "host-guest" properties of crown ethers. Crownsomes were successfully fabricated using span-60 and 18-crown-6 and their size, morphology, polydispersity index, ζ potential, drug loading efficiency, conductivity, and drug release were characterized. Crownsomes exhibited favorable properties such as formation of spherical nanovesicles of 280 ± 18 nm and -26.10 ± 1.21 mV surface charges. Crownsomes depicted a high entrapment efficiency (77 ± 5%) with enhanced and controlled-release pattern of phenytoin sodium. The optimum crownsomes formulation ameliorated corneal drug permeability (1.78-fold than drug suspension) through the corneal calcium extraction ability of 18-crown-6. study was conducted utilizing an alkali-induced corneal injury rabbit model. Clinical and histopathological examination confirmed that crownsomes exhibited better biocompatibility and minimal irritation due to complex formation and drug shielding. Further, they enhanced corneal healing, indicating their effectiveness as a novel drug delivery system for ocular diseases.
Topics: Administration, Ophthalmic; Animals; Cornea; Corneal Ulcer; Crown Ethers; Disease Models, Animal; Drug Carriers; Drug Liberation; Drug Repositioning; Humans; Nanoparticles; Ophthalmic Solutions; Particle Size; Permeability; Phenytoin; Procaine; Rabbits; Wound Healing
PubMed: 32845650
DOI: 10.1021/acs.molpharmaceut.0c00742 -
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 -
Clinical Pharmacy 1983The relationships between phenytoin dose, pharmacokinetic variables, patient data, and serum phenytoin concentrations were studied. One hundred sixty-eight adult...
The relationships between phenytoin dose, pharmacokinetic variables, patient data, and serum phenytoin concentrations were studied. One hundred sixty-eight adult epileptic patients who were receiving phenytoin were randomly selected and studied retrospectively. The method of Ludden et al. or a Bayesian forecasting technique was employed to estimate the patients' pharmacokinetic values for maximum rate of drug metabolism (Vmax) and the Michaelis-Menten constant (Km). Resulting steady-state serum concentrations were estimated. The daily doses of phenytoin necessary to produce steady-state serum phenytoin concentrations of 10 and 20 micrograms/ml were also determined in patients whose values were definable. Analysis of variance was used to test possible correlations between patient demographic data, pharmacokinetic values, and doses. The majority of patients (85.6%) failed to achieve concentrations between 10 and 20 micrograms/ml when receiving phenytoin sodium 300 mg daily. Patients receiving more than one phenytoin dosage regimen had significant but weak correlations between Vmax and Km. The data suggest that low Km and Vmax values occur concurrently. Initial phenytoin dose based on patients' weights or body surface areas may be useful in determining initial dosage requirements, but estimated pharmacokinetic values for Vmax and Km provide the best guide for dosage adjustment.
Topics: Adult; Age Factors; Body Weight; Female; Humans; Kinetics; Male; Middle Aged; Phenytoin; Seizures; Sex Factors
PubMed: 6883953
DOI: No ID Found -
Epilepsia 1992Chronic phenytoin (PHT) treatment has long been associated with folate deficiency. It has been suggested that pH changes in the gut associated with PHT ingestion may be...
Chronic phenytoin (PHT) treatment has long been associated with folate deficiency. It has been suggested that pH changes in the gut associated with PHT ingestion may be responsible for decreased folate uptake either by direct inhibition of folate transport into the intestinal mucosa or by inhibition of folate conjugase activity. To examine these possibilities, rats were gavaged chronically with PHT using either the sodium salt (NaPHT) or the free acid (HPHT) in the presence of folic acid as the dietary source of folate. The NaPHT caused a greater depletion of folate in the liver and brain and a significant increase in methylenetetrahydrofolate reductase activity in the liver. The HPHT caused a significantly decreased weight gain over the 8 weeks of treatment and resulted in a much higher liver PHT concentration and a slightly lower plasma PHT concentration. These data support the hypothesis that PHT-induced changes in pH in the gut affect the enterohepatic circulation of folate.
Topics: Animals; Brain Chemistry; Disease Models, Animal; Enterohepatic Circulation; Folic Acid; Folic Acid Deficiency; Gastric Acid; Humans; Hydrogen-Ion Concentration; Liver; Phenytoin; Rats; Rats, Inbred Strains; Weight Gain
PubMed: 1547769
DOI: 10.1111/j.1528-1157.1992.tb02330.x -
American Journal of Hospital Pharmacy Aug 1978Drug treatment of status epilepticus is reviewed. Tonic-clonic, focal motor, complex partial and absence status epilepticus are discussed. In managing tonic-clonic... (Review)
Review
Drug treatment of status epilepticus is reviewed. Tonic-clonic, focal motor, complex partial and absence status epilepticus are discussed. In managing tonic-clonic status epilepticus one should: (1) maintain vital functions at all times, (2) identify and treat precipitating factors and (3) administer an intravenous loading dose of phenytoin sodium or phenobarbital sodium. Careful use of i.v. diazepam sometimes helps to achieve these objectives. Intravenous phenytoin sodium and phenobarbital sodium provide definitive, long-term control of tonic-clonic seizures but must be administered slowly and require time to reach peak brain concentrations. Intravenous diazepam appears to enter and exit from the brain rapidly and may control seizures while therapeutic brain concentrations of long-acting drugs are being achieved. Phenytoin, phenobarbital and diazepam should not be administered intramuscularly in treating status epilepticus. Treatment of focal motor and complex partial status epilepticus is similar to that of tonic-clonic status epilepticus, but i.v. diazepam is required less frequently and loading doses of phenytoin and phenobarbital sometimes can be given more slowly. Status epilepticus of the absence type is managed with i.v. acetazolamide sodium or diazepam. Paraldehyde, muscle relaxants, general anesthesia and lidocaine may be tried when conventional therapies fail.
Topics: Anesthesia, General; Diazepam; Epilepsies, Partial; Epilepsy, Absence; Epilepsy, Temporal Lobe; Epilepsy, Tonic-Clonic; Humans; Kinetics; Lidocaine; Neuromuscular Nondepolarizing Agents; Paraldehyde; Phenobarbital; Phenytoin; Status Epilepticus
PubMed: 150228
DOI: No ID Found -
American Journal of Hospital Pharmacy Feb 1980The pharmacokinetics and side effects of a single oral 900-mg dose of phenytoin sodium were studied in six healthy men. Nine 100-mg phenytoin sodium capsules were...
The pharmacokinetics and side effects of a single oral 900-mg dose of phenytoin sodium were studied in six healthy men. Nine 100-mg phenytoin sodium capsules were administered with water to six fasting healthy men. Phenytoin plasma levels were measured by gas chromatography for up to 48 hours after dosing. Patients were observed and tested for gastrointestinal, cardiovascular, and neurologic side effects. Peak total (bound and free) plasma phenytoin levels were within the therapeutic range (10--20 microgram/ml) for two subjects and close (not less than 8.39 microgram/ml) for the remaining four. Peak free drug levels were 1.01--1.60 microgram/ml. Time to reach total and free peak plasma levels was long and variable (6--14 hours and 2--10 hours, respectively). Phenytoin protein binding (11.9--13.6%) was relatively stable among patients and at various plasma levels. A few mild transient side effects were noted; most occurred within two to four hours after dosing. Sinus bradycardia and a shortened PR interval were noted in two patients but did not correlate with peak plasma phenytoin levels. It appears that an oral loading dose of phenytoin sodium may be useful in ambulatory patients but further study of its side effects is recommended.
Topics: Adult; Blood Proteins; Cardiovascular Diseases; Gastrointestinal Diseases; Humans; Kinetics; Male; Nervous System Diseases; Phenytoin; Protein Binding
PubMed: 7361796
DOI: No ID Found -
Journal of Neurology, Neurosurgery, and... Oct 1999To determine the efficacy, tolerability, and impact on quality of life and cognitive functioning of anticonvulsant prophylaxis with phenytoin or sodium valproate in... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVE
To determine the efficacy, tolerability, and impact on quality of life and cognitive functioning of anticonvulsant prophylaxis with phenytoin or sodium valproate in patients after craniotomy.
METHODS
A prospective, stratified, randomised, double blind single centre clinical trial was performed, comparing two groups of 50 patients each, who underwent craniotomy for different pathological conditions and who were treated for 1 year after surgery with either 300 mg phenytoin/day or 1500 mg sodium valproate/day. During the study period patients were seen in the outpatient clinic at 1.5, 3, 6, and 12 months, when medical history, adverse events, and drug plasma concentrations were evaluated. Neuropsychological functioning and quality of life were assessed on the last three visits. In cases of a seizure an EEG was performed, drug plasma concentration assessed, and medication subsequently increased.
RESULTS
Of the 100 included patients 14 (seven in each group) experienced one or more postoperative seizures. Severity of the seizures was comparable in the two groups. In all patients, drug plasma concentrations were in the low or subtherapeutic ranges at the time of the first postoperative seizure. Five patients in the phenytoin group and two in the valproate group had to stop their treatment due to drug related adverse events. Sixty patients completed the 12 month period. Analysis of neuropsychological and quality of life data showed no significant differences.
CONCLUSION
For efficacy, tolerability, impact on cognitive functioning, and quality of life, no major differences were found between phenytoin and valproate prophylaxis. Valproate is an alternative for anticonvulsant prophylaxis in patients after craniotomy.
Topics: Adult; Aged; Brain Diseases; Cognition; Craniotomy; Double-Blind Method; Epilepsy; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Phenytoin; Quality of Life; Time Factors; Valproic Acid
PubMed: 10486394
DOI: 10.1136/jnnp.67.4.474 -
Journal of Pharmaceutical Sciences Mar 1983Dissolution profiles for 11 brands of phenytoin sodium capsules were carried out by the basket and paddle methods (USP) and the spin-filter method. The results from the...
Dissolution profiles for 11 brands of phenytoin sodium capsules were carried out by the basket and paddle methods (USP) and the spin-filter method. The results from the dissolution studies have been correlated with observed differences in in vivo parameters (Cmax and tmax). The dissolution by the basket method at 50 rpm in water gave a correlation greater than 0.9. The results suggest the existence of two types of phenytoin sodium products on the market.
Topics: Biological Availability; Capsules; Humans; Phenytoin; Solubility
PubMed: 6687736
DOI: 10.1002/jps.2600720325