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Journal of Neurology Aug 2017In 1908 phenytoin (5,5-diphenylhydantoin) was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865-1943) and subsequently... (Review)
Review
In 1908 phenytoin (5,5-diphenylhydantoin) was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865-1943) and subsequently resynthesized by an American chemist of the pharmaceutical company Parke-Davis in 1923 in Detroit. Screening phenytoin did not reveal comparable sedative side effects as barbiturates and, thus, Parke-Davis discarded this compound as a useful drug. In 1936, phenytoin's anticonvulsive properties were identified via a new animal model for convulsive disorders, developed by Putnam and Merritt, who also evaluated its clinical value in a number of patients in the period 1937-1940. For many diseases, mechanism of action of phenytoin remains obscure. The voltage-gated sodium channel was and is generally regarded as the main target to explain phenytoin's activity as an anticonvulsant and an anti-arrhythmic drug. This target, however, does not explain many of the other clinical properties of phenytoin. We will explore a number of original articles on phenytoin published in its 80 years history and give extra attention to the various hypothesis and experiments done to elucidate its mechanisms of action. Phenytoin has been explored in over 100 different disorders; the last two promising indications tested in the clinic are breast cancer and optic neuritis. Most probably, there are multiple targets active for these various disorders, and the insight into which targets are relevant is still very incomplete. It is remarkable that many pharmacological studies tested one dose only, mostly 50 or 100 μM, doses which most probably are higher than the non-plasma bound phenytoin plasma levels obtained during treatment.
Topics: Animals; Anticonvulsants; Antineoplastic Agents; Breast Neoplasms; Drug Discovery; Epilepsy; History, 20th Century; History, 21st Century; Humans; Phenytoin
PubMed: 28083647
DOI: 10.1007/s00415-017-8391-5 -
Clinical Pharmacy 1983The safety of administering phenytoin sodium by intermittent intravenous infusion was evaluated. Twenty-eight adult patients in a neurosurgical intensive-care unit were...
The safety of administering phenytoin sodium by intermittent intravenous infusion was evaluated. Twenty-eight adult patients in a neurosurgical intensive-care unit were studied; most patients had head trauma. Ninety-three doses of phenytoin sodium 300 mg in 0.9% sodium chloride injection 50 ml were administered according to hospital-approved guidelines, which included administration over 30-60 minutes, initiation of infusion within one hour of solution preparation, and use of a 5-microns inline filter. All patients were monitored for adverse reactions and were on continuous ECG monitoring. Analysis of clinical data before and immediately after phenytoin infusions showed no statistically significant change in blood pressure and a small but significant drop in mean heart rate. There were no cases of hypotension, arrhythmias, bradycardia, or phlebitis. Single occurrences of hypertension, nystagmus, and pain at the i.v. site were noted. It is concluded that careful infusion of phenytoin sodium in 0.9% sodium chloride injection is safe. The use of approved written guidelines to govern important factors of preparation and administration are recommended.
Topics: Adult; Age Factors; Aged; Blood Pressure; Craniocerebral Trauma; Female; Humans; Infusions, Parenteral; Male; Middle Aged; Phenytoin; Seizures
PubMed: 6883941
DOI: No ID Found -
Journal of Intellectual Disability... Dec 1998Phenytoin (5,5-diphenylhydantoin), which has been in use for 60 years, is still an important antiepileptic drug. Its primary mechanism of action is modulation of the... (Review)
Review
Phenytoin (5,5-diphenylhydantoin), which has been in use for 60 years, is still an important antiepileptic drug. Its primary mechanism of action is modulation of the sustained repetitive firing of neurones by direct inhibition and blockage of voltage-gated sodium channels in the neuronal cell membrane, and by delay of cellular reactivation. The plasma protein binding of phenytoin is normally between 90% and 95%. The drug is rapidly distributed from the blood to the tissues and is almost completely metabolized in the liver. The plasma phenytoin concentration normally reaches the steady-state level within 1-2 weeks. The half-life of phenytoin is less than 20 h in low doses, but is prolonged in high doses, newborn infants and elderly people. The half-life is shortened when phenytoin is given concomitantly with an enzyme-inducing drug, such as phenobarbital or carbamazepine. Phenytoin is effective for treating generalized tonic-clonic seizures, partial seizures with or without generalization, and convulsive status epilepticus. Over the years, many new, and even serious, adverse effects of phenytoin have been recognized. Phenytoin encephalopathy, manifesting as cognitive impairment and a cerebellar syndrome, is an important adverse neurological effect, the development of which depends on the saturation kinetics of phenytoin, individual differences in phenytoin metabolism, an inhibitory effect of certain drugs on phenytoin metabolism, or the ability of certain drugs to displace phenytoin from plasma proteins, leading to an increase in the plasma level of unbound phenytoin. Because of its potentially adverse effects, phenytoin is not recommended as the first choice for treating epileptic seizures, except as a co-drug for managing convulsive status epilepticus. In patients with epilepsy who also have intellectual disability, and are susceptible to balance disturbances and cognitive dysfunction, it is wise to replace phenytoin with another drug, such as carbamazepine or oxcarbazepine. The long-term use of phenytoin is not recommended for patients with loss of locomotion, marked cognitive impairment, or symptoms and signs of cerebellar disease. The prevention of phenytoin intoxication, with the subsequent development of phenytoin-induced encephalopathy, depends on careful observation of the patients and frequent monitoring of plasma levels of phenytoin and other concomitantly administered antiepileptic drugs.
Topics: Anticonvulsants; Brain; Dose-Response Relationship, Drug; Epilepsy; Humans; Intellectual Disability; Phenytoin
PubMed: 10030428
DOI: No ID Found -
International Journal of Pharmaceutics Mar 2018Phenytoin sodium (PS) has a tendency to convert to its base form; phenytoin base (PHT) during manufacturing, packaging, shelf life and in-use conditions that can...
Phenytoin sodium (PS) has a tendency to convert to its base form; phenytoin base (PHT) during manufacturing, packaging, shelf life and in-use conditions that can influence its clinical performance. The objective of the present work was to develop a non-destructive, quick and easy analytical method for quantification of PHT in the drug product. A formulation was prepared to contain the excipients of commercial capsule formulation of PS. The formulation containing either 100% PHT or PS was prepared and these formulations were mixed in different proportion to achieve 0-100% PHT matrices. FTIR, NIR and Raman spectra of samples were collected. Data were truncated and mathematically pretreated before development of partial least squares (PLS) and principal component analysis (PCA) regressions model. The models were assessed by slope, intercept, R, R, root mean square error (RMSE) and standard error (SEP). The models exhibited good linearity over the selected range of PHT in the formulations with low error as indicated by slope that was close to one and small values of intercept, RMSE and SE. The models of NIR based data were more accurate and precise than Raman data based models as indicated by the low values of RMSE and SE. Prediction accuracy of independent samples containing 25% PHT using NIR models were similar to Raman models. On the other hand, the prediction was more precise for the independent sample containing 5% PHT using NIR data based models compared to Raman data based models as indicated by standard deviation. In conclusion, chemometric models based on NIR and Raman spectroscopies provides a fast and easy way to monitor the disproportionation of PS in the drug products.
Topics: Capsules; Drug Compounding; Models, Statistical; Phenytoin; Spectroscopy, Fourier Transform Infrared; Spectroscopy, Near-Infrared; Spectrum Analysis, Raman
PubMed: 29341912
DOI: 10.1016/j.ijpharm.2018.01.005 -
British Journal of Clinical Pharmacology Jun 19891. Phenytoin protein binding in epileptic patients on phenytoin as monotherapy has been compared with protein binding in patients treated with both phenytoin and sodium...
1. Phenytoin protein binding in epileptic patients on phenytoin as monotherapy has been compared with protein binding in patients treated with both phenytoin and sodium valproate. In addition the relative value of assayed total phenytoin plasma concentrations and assayed unbound phenytoin plasma concentrations and the value of predicted unbound phenytoin plasma concentrations in predicting phenytoin toxicity has been assessed. 2. The mean phenytoin unbound fraction for patients taking sodium valproate (0.122) was significantly greater than for those on monotherapy (0.082). 3. There were six episodes of clinical toxicity. In five toxic episodes the assayed unbound phenytoin plasma concentration was a better reflection of toxicity than the assayed total phenytoin plasma concentration, and four of these occurred in patients on sodium valproate. 4. Unbound phenytoin plasma concentrations were predicted from a single regression equation correlating all assayed total phenytoin plasma concentrations with assayed unbound phenytoin plasma concentrations, from two separate regression equations for each group of patients, and from the correlation between phenytoin protein binding and plasma albumin concentration. 5. The unbound phenytoin plasma concentrations predicted from the two regression equations were statistically no less effective than the assayed unbound phenytoin plasma concentrations in assessing toxicity. 6. Despite a correlation between plasma albumin concentrations and phenytoin protein binding, the use of albumin concentrations in predicting unbound phenytoin plasma concentrations appeared to be of little additional benefit.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Phenytoin; Predictive Value of Tests; Protein Binding; Serum Albumin; Valproic Acid
PubMed: 2503019
DOI: 10.1111/j.1365-2125.1989.tb03448.x -
Neurotoxicology and Teratology 1995Gravid Sprague-Dawley CD (VAF) rats were administered sodium phenytoin suspended in corn oil by gavage once per day on embryonic days 7-18 at a dose of 100 mg/kg.... (Comparative Study)
Comparative Study
Gravid Sprague-Dawley CD (VAF) rats were administered sodium phenytoin suspended in corn oil by gavage once per day on embryonic days 7-18 at a dose of 100 mg/kg. Controls were administered corn oil alone by gavage on E7-18. Litters were randomly culled to 10. Offspring were regularly weighted, mortality noted, and males checked for preputial separation. At approximately 50 days of age offspring were evaluated in a straight water-filled channel for swimming proficiency and motivation to escape. Following this, rats were tested in the Cincinnati multiple T-water maze and scored for errors, latency to find the goal, and presence of phenytoin-induced abnormal circling behavior while swimming. Sodium phenytoin-exposed dams gained weight normally and delivered normally. Offspring mortality in the sodium phenytoin group was not increased above controls. No treatment effects on preputial separation or offspring growth were observed. No differences between groups in swimming proficiency in straight channel performance were obtained. In the Cincinnati maze, phenytoin offspring committed significantly more errors and had longer latencies to find the goal than controls. Among the phenytoin offspring, those exhibiting abnormal circling committed more errors than noncircling animals. When compared to previous data using the same maze and test protocol, it was found that 100 mg/kg of sodium phenytoin induced performance deficits similar to those induced by a dose of 200 mg/kg of phenytoin acid. Accordingly, the present data help explain why other investigators have reported sodium phenytoin to be more developmentally neurotoxic than phenytoin acid. Because the prenatal neurotoxic effects seen with the salt of phenytoin occur at lower doses, it suggests that phenytoin is more developmentally neurotoxic than previously believed.
Topics: Animals; Dose-Response Relationship, Drug; Female; Male; Maze Learning; Phenytoin; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley
PubMed: 8747744
DOI: 10.1016/0892-0362(95)02005-5 -
Clinical Pharmacokinetics 1979Phenytoin (diphenylhydantoin) is still the most commonly used anticonvulsant drug. It has certain physicochemical characteristics which make it liable to bioavailability... (Review)
Review
Phenytoin (diphenylhydantoin) is still the most commonly used anticonvulsant drug. It has certain physicochemical characteristics which make it liable to bioavailability problems. Due to the dose dependent metabolism of phenytoin and to its narrow therapeutic range even small changes in the bioavailability can cause major changes in serum phenytoin concentration and have serious clinical consequences. Numerous studies have demonstrated that there are products in general use with considerable differences in their bioavailiability. If the epilepsy is well controlled, a change from one phenytoin product to another should be avoided. Such a change might lead to phenytoin intoxication or to poor control of epilepsy, if the products do not have the same bioavailability. There seems to be no systematic difference in the bioavailability of phenytoin sodium and phenytoin acid, if products of high quality are used. On the other hand, various biopharmaceutical factors, e.g. particle size of phenytoin and the nature of excipients in the product, can have a marked effect on the oral absorption of phenytoin. Gastrointestinal diseases, the concomitant use of other drugs and dietary factors might also modify the bioavailability of phenytoin. The absorption of intramuscularly given phenytoin is rather slow and erratic. The existence of phenytoin products with different bioavailability is a serious practical problem which should be corrected as soon as possible.
Topics: Administration, Oral; Biological Availability; Chemical Phenomena; Chemistry; Drug Interactions; Gastrointestinal Diseases; Humans; Injections, Intramuscular; Intestinal Absorption; Kinetics; Particle Size; Phenytoin; Solubility; Time Factors
PubMed: 378503
DOI: 10.2165/00003088-197904020-00002 -
Neurology Jun 1996Fosphenytoin sodium, a phosphate ester prodrug of phenytoin, was developed as a replacement for parenteral phenytoin sodium. Unlike phenytoin, fosphenytoin is freely... (Review)
Review
Fosphenytoin sodium, a phosphate ester prodrug of phenytoin, was developed as a replacement for parenteral phenytoin sodium. Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions, including standard i.v. solutions, and is rapidly absorbed by the i.m. route. Fosphenytoin is metabolized (conversion half-life of 8 to 15 min) to phenytoin by endogenous phosphatases. Therapeutic free (unbound) and total plasma phenytoin concentrations are consistently attained after i.m. or i.v. administration of fosphenytoin loading doses. Fosphenytoin has fewer local adverse effects (e.g., pain, burning, and itching at the injection site) after i.m. or i.v. administration than parenteral phenytoin. Systemic effects related to the CNS are similar for both preparations, but transient paresthesias are more common with fosphenytoin.
Topics: Animals; Anticonvulsants; Epilepsy; Humans; Phenytoin
PubMed: 8649612
DOI: 10.1212/wnl.46.6_suppl_1.3s -
Clinical Neuropharmacology Feb 1997Fosphenytoin is a phosphate ester prodrug of phenytoin developed as a replacement for standard injectable sodium phenytoin. After absorption, phenytoin is cleaved... (Review)
Review
Fosphenytoin is a phosphate ester prodrug of phenytoin developed as a replacement for standard injectable sodium phenytoin. After absorption, phenytoin is cleaved (conversion half-life 8-15 min) from fosphenytoin. Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions (including standard intravenous solutions) and rapidly absorbed by the intramuscular route. Fosphenytoin has been tested successfully for three indications in humans: intramuscular maintenance dosing, intramuscular loading dose administration, and intravenous treatment of status epilepticus. Local toxicity (pain, burning, itching) is less by the intramuscular or intravenous route for fosphenytoin than for standard injectable sodium phenytoin. Systemic toxicity is similar with both preparations except that hypotension is less common and paresthesias are more common with fosphenytoin.
Topics: Animals; Anticonvulsants; Chemistry, Pharmaceutical; Humans; Phenytoin; Prodrugs
PubMed: 9037568
DOI: 10.1097/00002826-199702000-00001 -
Medicine Dec 2018In this study, we aimed to review the literature on phenytoin intoxication induced by compound phenytoin sodium, ephedrine hydrochloride and theophylline tablets...
OBJECTIVE
In this study, we aimed to review the literature on phenytoin intoxication induced by compound phenytoin sodium, ephedrine hydrochloride and theophylline tablets (CPEHTT).
METHOD
A literature search was performed in the following databases: WANFANG DATA, HowNet, National Library Reference and Consultation Alliance, Full-text Database of Foreign Medical Journals, PubMed and Ovid. The search terms were "Compound Phenytoin Sodium, ephedrine Hydrochloride and Theophylline Tablets," and "poisoning," or "toxicity," in Chinese and in English.
RESULT
Ten articles including 104 patients with CPEHTT intoxication were identified. The ages of the patients ranged from 52 to 82 years. Sixty-seven patients were male and thirty-seven patients were female (the male/female ratio, approximately 2:1). The most common clinical manifestations were dizziness (85%) and ataxia (85%), followed by limb weakness (65%), diplopia (25%), binocular horizontal nystagmus (24%), limb numbness (13%), nausea and vomiting (12%), somnolence (10%), tremor and high muscle tension (7%), lag in response (5%), dysarthria (6%), choking cough (2%), auditory hallucination and visual fantasy (1%), and involuntary movement (1%). All patients had chronic lung disease, and the most common disease was chronic bronchitis. The dosage ranged 4 to 15 tablets per day with medication duration of more than 1 year for most patients.
CONCLUSION
The CPEHTT intoxication caused by phenytoin toxicity represents a drug safety problem in China. The common clinical manifestations, serum phenytoin concentrations, and associated factors of CPEHTT intoxication are important for diagnosis and prevention. These findings may help guide clinicians to correctly attend to the use of CPEHTT and avoid its toxicity.
Topics: Bronchodilator Agents; China; Drug Combinations; Ephedrine; Humans; Phenytoin; Tablets; Theophylline
PubMed: 30572493
DOI: 10.1097/MD.0000000000013689