Phenytoin Therapy Research Articles

Toxic Reaction to Improperly Administered Phenytoin Suspension

To the Editor. —A 73-year-old man was brought to the emergency room from his nursing home to be evaluated for a three-day history of increasing confusion, worsening ataxia, and several falling episodes without associated loss of consciousness or seizure activity. The patient had been receiving phenytoin therapy for a seizure disorder secondary to a prior cerebro vascular accident. He had been receiving a daily dose of 300 mg in the form of 4 mL of suspension (125 mg/5 mL), three times per day. Prior serum phenytoin levels obtained at the nursing home had all been therapeutic (10 to 20 mg/dL). On physical examination, the patient was confused, oriented to person only, and demonstrated bilateral horizontal nystagmus along with marked ataxia. His phenytoin level on arrival at the emergency room was 35 mg/dL. There had not been any recent change in his dosage of phenytoin, nor a change in any of

Serum phenobarbital concentration predictions by a personal computer software system.

The ability of a personal computer software system to predict actual serum phenobarbital concentrations (SPC) in outpatients taking phenobarbital chronically was assessed by comparing actual with predicted SPC for accuracy, bias, and precision. Data for a four-year period were collected on patients at an outpatient clinic's pharmacokinetic consultation service. The study group included 50 adults and children with at least one SPC taken at a known time after dose administration. Input variables were weight, sex, height, age, concomitant drugs and diseases, phenobarbital dosage regimen, and the time and reported value of all SPC. Initially, SIMKIN (SIMulated KINetics) simulated dosing regimens on the basis of literature estimates of pharmacokinetic parameters; SPC were then estimated for these regimens and compared with actual values. One or two additional SPC were added to the input data and analyzed, and the predicted SPC compared with actual values. Although SIMKIN's accuracy and bias as measured by regression analysis and mean prediction error, respectively, were within clinically acceptable limits, the precision was not. However, these results are limited by the population studied. Patient compliance, concomitant phenytoin therapy, changes in phenobarbital pharmacokinetic parameters with chronic dosing, and disease interactions may significantly affect predictive ability. The clinical effects of these factors need to be evaluated to further improve predictions.

Nonconvulsive Status Epilepticus in a Patient With Leptomeningeal Cancer

A 56-year-old man sought medical assistance because of recurrent nonconvulsive status epilepticus without a history of prior seizure activity. Examination of the cerebrospinal fluid disclosed leptomeningeal cancer. To our knowledge, the association of partial complex status epilepticus and leptomeningeal cancer has not been reported previously. If the results of computed tomographic and magnetic resonance imaging studies are normal, examination of cerebrospinal fluid should be considered in patients with nonconvulsive status epilepticus.

The effect of phenytoin on the magnitude and duration of neuromuscular block following atracurium or vecuronium.

Patients chronically receiving anticonvulsants have been reported to be resistant to the long-acting competitive neuromuscular blockers. This study examines the effects of atracurium and vecuronium on 100 neurosurgical patients; 50 receiving chronic phenytoin therapy (group I) and 50 controls (group II). During O2/N2O/halothane anesthesia, five patients in each group were given a bolus of vecuronium 0.1 mg/kg, and a different five patients in each group were given atracurium 0.5 mg/kg, to produce neuromuscular blockade in excess of 95%. The time to maximum blockade and the recovery from atracurium was unaffected by phenytoin therapy. Recovery from vecuronium was enhanced in the phenytoin group, as demonstrated by the recovery index, defined as the time required for recovery from 25-75% of the control neuromuscular response (7.9 +/- 2.2 min compared with 17.8 +/- 5.1 min in controls, P less than 0.005). Similarly, the total duration of neuromuscular blockade, defined as recovery to 90% of control response, was significantly shorter in the phenytoin group (31.9 +/- 6.0 min compared with 69.7 +/- 12.9 min in controls, P less than 0.001). The remaining 40 patients from each group were given a preselected dose of either vecuronium (0.02-0.06 mg/kg) or atracurium (0.10-0.25 mg/kg) during anesthesia with O2/N2O/fentanyl, to generate dose-response curves for the relaxants. Using analysis of covariance, the slopes and elevations for atracurium were found to be essentially identical in the two groups; as were the calculated ED50 and ED95. Patients receiving chronic phenytoin therapy were resistant to vecuronium-induced neuromuscular blockade. With vecuronium, the dose-response curves for the two groups were parallel; the curve for phenytoin patients was shifted to the right.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenytoin and 5-(p-hydroxyphenyl)-5-phenylhydantoin do not alter the effects of bacterial and amplified plaque extracts on cultures of fibroblasts from normal and overgrown gingivae.

Local irritation of gingival tissue by plaque is among the factors which affect development of gingival overgrowth in patients undergoing chronic phenytoin (PHT) therapy. Variability in the cytotoxicity of plaque components or of plaque substances plus PHT and/or its metabolites toward gingival fibroblasts may relate to whether gingival overgrowth forms in a particular patient. Fibroblasts from healthy and overgrown gingivae were incubated with (a) PHT and its major human metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), (b) microbial and "amplified" plaque extracts, and (c) microbial and "amplified" plaque extracts plus PHT and HPPH. Cell numbers and cell-associated protein were determined for each incubation preparation. A wide range in cytotoxic response to a particular microbial or plaque extract occurred among cell strains. Plaque extracts from different subjects had variable cytotoxicity toward a cell strain. The differences among fibroblast strains in response to an extract and the variability in cytotoxicity of different plaque extracts toward a cell strain were not related to their source from normal or overgrown gingivae. Cell numbers and cell-associated protein were similar for incubation mixtures containing extracts with and without PHT and HPPH. These data do not show differences among cytotoxicity levels of plaque extracts, the response of particular gingival fibroblast strains to plaque components, or interaction between drugs and certain plaque samples which explain development of gingival overgrowth in some subjects receiving chronic PHT therapy.

Serum phenytoin during pregnancy, labor and puerperium

111 pregnancies of epileptic women on phenytoin therapy were observed in a prospective study. Maternal serum phenytoin concentrations were measured monthly or bi-weekly during pregnancy, labor and puerperium. The concentration decreased towards the end of pregnancy and was lowest at delivery. In 48% of the patients the drug dosage had to be increased to combat the increased seizure frequency.

Severe thrombocytopenia due to combined cimetidine and phenytoin therapy

Severe thrombocytopenia due to combined cimetidine and phenytoin therapy

New developments in understanding phenytoin-induced gingival hyperplasia

In approximately half of the patients taking phenytoin, gingival fibroblasts proliferate, causing tissue overgrowth and gingival hyperplasia. Recent clinical and basic research is reviewed, describing the conditions associated with phenytoin therapy and gingival hyperplasia.

血清中抗てんかん薬濃度測定へのセラライザーシステムの適用 フェニトイン，フェノバルビタール

Apoenzyme reactivation immunoassay system with Seralyzer reflectance photometer for the determination of serum phenytoin (PHT) and phenobarbital (PB) concentration (Seralyzer method) was evaluated. Each coefficient of variation of within-run and between-run precision for 3 concentrations of PHT or PB in serum was less than 4.0%. The serum PHT (33 samples) or PB (31 samples) concentrations were determined by Seralyzer method and compared with those determined by high-performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA method). There were good agreements between HPLC and Seralyzer method results and FPIA method and Seralyzer method results, where all correlation coefficients were more than 0.992. The cross-reactivities of p-hydroxyphenylphenylhydantoin in PHT reagent strips, and p-hydroxyphenobarbital and several barbiturates in PB reagent strips were found. However, these cross-reactivities are not serious problems in clinical condition. Therefore, the Seralyzer method may be useful for serum drug-level monitoring of patients under PHT or PB therapy.

Congenital defects among the offspring of epileptic fathers: role of the genotype and phenytoin therapy in a mouse model.

The progeny of coisogenic C57BL/6J mice homozygous for either the tottering (tg/tg) or wildtype (+/+) allele were examined to determine the role of parental seizure disorders and paternal anticonvulsant drug therapy on the incidence of congenital malformations. Pregnancy outcomes in which one, both, or neither of the parents had an epileptic genotype were compared for various maternal and fetal reproductive parameters. In addition, the progeny from phenytoin-treated male tottering (tg/tg) mice with a spontaneous seizure disorder and from control untreated (+/+) male mice were similarly examined for evidence of congenital defects. The results of these experiments suggest that neither the parental genotype with respect to seizure disorders nor paternal anticonvulsant treatment with phenytoin is responsible for an increased incidence of congenital malformations.

Phenytoin hypersensitivity: A case of severe acute rhabdomyolysis

A 22-year-old black man was hospitalized with fever, rash, myalgias, and marked periorbital and facial edema three months after beginning phenytoin therapy. His hospital course was marked by an initial serum creatine phosphokinase level of 85,000 IU/liter, which rose to a peak value of 242,000 IU/liter on the third hospital day and a striking eosinophilia (8,400/μl). Muscle biopsy revealed only early fiber necrosis with partial dissolution of the sarcoplasm without evidence of inflammation, vasculitis, regeneration, or parasitic infection. When therapy with phenobarbital, a structural congener of phenytoin, was begun, the patient had an exacerbation of his rash and became febrile again.

Serum gamma-glutamyl transpeptidase activity in patients receiving chronic phenytoin therapy.

To better define the incidence and range of elevated gamma-glutamyl transpeptidase (GGT) activity in patients taking a drug known to induce hepatic microsomal enzymes, GGT was measured in the sera of 58 patients before and after six months of phenytoin therapy. Enzyme activity at six months was greater than baseline in 52 of 58 patients (90%). GGT activity (normal, 0-50 units/liter) was 45.2 +/- 9.9 (mean +/- SEM) at baseline and 135.8 +/- 18.1 after six months of therapy, a mean threefold increase (P less than 0.001). Of the 45 patients with normal baseline GGT activity, some had marked elevation of serum GGT activity with values rising over 200 units/liter in eight patients and over 300 units/liter in four patients. Mean serum GGT activity remained significantly elevated at 12 and 24 months. This elevation in GGT activity was not influenced by age, sex, or additional anticonvulsant drug therapy. Both baseline and six-month GGT activity was lowest in patients who drank no alcohol, higher in patients who drank 0-1 pint/week, and greatest in patients who drank greater than 1 pint/week. All 13 patients with elevated baseline GGT activity were regular users of alcohol and/or taking other enzyme-inducing drugs. In conclusion, increase in serum GGT activity occurs in 90% of patients on long-term phenytoin therapy, most often to moderate but occasionally to high levels, and this rise in GGT activity is accentuated by regular consumption of alcohol.

The effect of a plaque control program on the development of phenytoin-induced gingival overgrowth. A 2-year longitudinal study.

The effect of a plaque control program on the development of phenytoin(PHT)-induced gingival overgrowth was studied in 16 epileptic children, 8-16 years of age during a 2-year longitudinal study. The parameters studied were: visible plaque index (VPI), gingival bleeding index (GBI), probing depth and gingival overgrowth. A preventive program was instituted before the start of the PHT-medication and included oral hygiene instruction and frequent professional tooth cleaning during the observation period. When gingival overgrowth was evaluated on the basis of probing depth, no patients on PHT therapy for 2 years developed pseudopockets (greater than or equal to 4 mm). During the 2-year observation period, there was a statistically significant increase (p less than 0.01) in the thickness of the marginal gingiva bucco-lingually in all patients. This gingival enlargement was already evident (p less than 0.01) after 1 month. The degree of gingival enlargement in this patient group did not increase significantly after the 1st year of PHT-medication and was not significantly correlated to the plasma concentration of PHT. The results of this study show that the development of PHT-induced gingival overgrowth could not be prevented by this specific plaque control program.

Diphenylhydantoin-induced Lymphocytic Interstitial Pneumonia

A patient developed diffuse lymphocytic interstitial pneumonia after receiving diphenylhydantoin therapy for 14 months. Withdrawal of medication resulted in reversal of the disease process. This case illustrates the value of combined transbronchial biopsy and bronchoalveolar lavage sampling in establishing a diagnosis, and the utility of serial bronchoalveolar lavage in monitoring disease evolution.

Some ultrastructural alterations in brain of a patient with both down'S syndrome and Alzheimer's disease

OG, a 40 year old white male was admitted to the hospital with a diagnosis of Non-psychotic Organic Brain Syndrome with Mogolism. On admission he walked with a shuffling gait and had hypoactive deep tendon reflexes. He had an IQ of 17 on the Stanford Binet scale. The patient was on Dilantin therapy for seizures. Shortly after the third seizure, he suffered from hemorrhagic pneumonia and expired, ending his nearly sixteen years of hospitalization at Saint Elizabeths.

Oral health in non-institutionalized epileptic children with special reference to phenytoin medication.

The periodontal condition and caries experience was studied in non-institutionalized epileptic children (n = 55) who had not been subjected to any additional preventive measures. The children were distributed in a phenytoin (PHT) group with a mean age of 13.2 yr and a control group (mean age 11.8 yr) consisting of children treated with other anticonvulsants. The PHT group had a DF-s mean value of 5.4 in comparison to 7.2 in the control group. Determinations of gingival overgrowth based on the presence of gingival units with increased probing depth (greater than 4 mm) as well as the thickness of the marginal gingiva in buccolingual dimension measured on stone casts were performed. Although the plaque level and degree of gingival inflammation were similar in the two groups, 43% of the children in the PHT group showed one or more gingival units with increased probing depth (greater than 4 mm), but none in the control group. The thickness of the marginal gingiva was significantly (P less than 0.001) higher in the phenytoin-treated children compared to children who had never had phenytoin medication. In the PHT-group gingival overgrowth based on gingival units with increased probing depth was statistically significantly and positively associated with the variables gingivitis (P less than 0.05), visible plaque index (P less than 0.01), age (P less than 0.01) and years on PHT therapy (P less than 0.05).

Phenytoin-induced thrombocytopenia

A 15-year-old boy developed thrombocytopenia and purpura two weeks after starting phenytoin therapy. The blood phenytoin level was in the toxic range. There was an increase in immature neutrophils but no abnormalities were present in other cell lines. Recovery was complete after drug therapy was discontinued. Thrombocytopenia is a rare isolated complication of phenytoin therapy. The probable autoimmune etiology distinguishes this syndrome from other phenytoin-induced blood dyscrasias.

Effects of anti-convulsants on fatty acid metabolism in human serum.

The effects of diphenylhydantoin and phenobarbital on lipids metabolism were studied by quantification of lipids in human serum with GC-MS. The ratios of palmitic acid to stearic, oleic and linoleic acids decreased in patients on diphenylhydantoin therapy. Increases of free palmitic, stearic and oleic acids concentrations as well as higher cholesterol ester levels were observed in patients receiving either diphenylhydantoin or phenobarbital. With respect to fatty acids composition of cholesterol esters and phosphatidyl-choline, higher concentrations of palmitic, oleic and linoleic acids were observed in patients on diphenylhydantoin and phenobarbital therapy. Although the concentration of palmitic acid in serum phosphatidylcholine remained the same for all groups, a marked decrease in stearic, oleic and linoleic acids concentrations in serum phosphatidylcholine was observed in diphenylhydantoin treated group, and oleic acid in phenobarbital treated group. These results suggested the relationship to lecithin-cholesterol acyltransferase activity by these drugs.

Prevalence of hepatitis B markers in patients and staff in a hospital for the mentally handicapped

Patients and staff at a hospital for the mentally handicapped were screened for markers of infection with hepatitis B virus. Of 436 patients, 14 (3·2%) were carriers of hepatitis B surface antigen (HBsAg), of whom four were carriers of hepatitis B e antigen (HBeAg) and were considered to be ‘infectious’. One-quarter of the patients had markers of hepatitis B infection. Males were four times more likely to have markers than females; and 13 of the 14 carriers of HBsAg were male. Patients with Down's Syndrome (DS) were six times more likely to be HBsAg positive, but were not more likely to have markers of infection than other patients. Phenytoin therapy did not predispose to carriage of HBsAg. Of 439 staff members, 26 (5·9%) had markers of hepatitis B infection. It was not considered that staff were at increased risk of infection with hepatits B virus at the hospital, and that post-exposure prophylaxis for hepatitis B should continue. It is suggested that patients with DS who are not immune to hepatitis B should be offered immunization.

Interaction between 8-methoxypsoralen and phenytoin. Consequence for PUVA therapy

A patient with epilepsy and psoriasis in phenytoin therapy was treated with PUVA with no effect at all. The PUVA treatment failure was demonstrated as being due to abnormally low serum levels of 8-methoxypsoralen (8-MOP) during phenytoin therapy, while normal serum levels of 8-MOP were observed after phenytoin was discontinued. The effect is probably due to an induction of the hepatic enzyme system by phenytoin, leading to an increased metabolism of 8-MOP. Other drugs with hepatic enzyme inducing properties might possibly also interfere with psoralen metabolism with further consequences for PUVA therapy.