Folic acid improves phenytoin pharmacokinetics.

Phenytoin (PHT) therapy to control seizures decreases serum folate levels in half of epileptic patients, thus increasing the risk of folate depletion. Supplementation with folic acid prevents deficiency but also changes PHT pharmacokinetics. Kinetic monitoring of PHT when folic acid is provided as a supplement has not been reported in women of child-bearing age. This study of six fertile women examined the interdependence of PHT and folic acid in a randomized crossover study of two treatments: treatment 1 consisted of 300 mg sodium PHT per day and treatment 2 consisted of 300 mg sodium PHT plus 1 mg folic acid per day. Dietary folic acid intake was calculated daily. During treatment 1, serum folate level decreased 38.0 +/- 18.6% (mean +/- standard deviation) and serum PHT concentration was in the low therapeutic range (43.92 +/- 14.52 mumol/L). During treatment 2, serum folate level increased 26.0 +/- 33.4%, and serum PHT level (39.04 +/- 14.16 mumol/L) was similar to that in treatment 1. Only one subject attained PHT steady state during treatment 1, but four subjects achieved steady state during treatment 2. Dietary folate intakes during treatments 1 and 2 were not significantly different. This study suggests an interdependence between PHT and folic acid and supports the observation that fertile women treated with PHT require folic acid supplementation to maintain a normal serum folate level.

Phenytoin pharmacokinetics: before and after folic acid administration.

Phenytoin (PHT) exhibits linear and Michaelis-Menten pharmacokinetics. PHT decreases serum folate; the vitamin folic acid (FA) is hypothesized to be a cofactor in the metabolism of PHT. The depletion of serum folate may explain the unpredictability of measured total serum PHT concentrations and time to steady state as compared with the Michaelis-Menten predictive calculations. We examined PHT pharmacokinetics before and after FA supplementation in 13 healthy male volunteers. The study was divided into two phases. Phase I determined V(max) (mg/day) and Km (micrograms/ml) of PHT to calculate PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km - 1 and Km + 5, respectively. Predicted versus measured total serum PHT concentrations, t90% (days to steady state), and the effect of FA were calculated for Km - 1 and Km + 5 before and after 1 or 5 mg FA. The measured total serum PHT concentration was always greater than the calculated concentration (p less than 0.05), and t90% was always longer than the calculated t90% (p less than 0.05) for Km - 1 before FA (all subjects decreased serum FA); the same was observed for Km + 5. If folate is assumed to be a cofactor in PHT metabolism, these results are expected, because depletion of the vitamin would indicate less folate to drive the metabolism of PHT, resulting in higher total serum PHT concentrations and longer time to reach steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

Parkinsonism treatment: Part III--Update.

OBJECTIVE: The purpose of this review is to update clinicians with recent advances in the management of parkinsonism, including drug therapy, transplantation, and diet. DATA SOURCES: Pertinent articles were obtained from an English-language literature search using MEDLINE (1970-1991), Index Medicus (1987-1991), Current Contents (1990), and bibliographic reviews of review articles. Index terms included parkinsonism, selegiline, pergolide, vitamin E, and transplantation. Fifty-five articles (representing 85 percent of the complete literature search) were selected by multiple reviewers for their contribution to the stated purpose. Emphasis was placed on double-blind, placebo-controlled, and randomized studies. Data from cited articles were examined by multiple reviewers for support of their stated hypothesis and were included as background for justification of major points in this article; critical studies were abstracted in more detail. RESULTS: New therapeutic measures have been added to the treatment of parkinsonism. Selegiline, a monoamine oxidase inhibitor type B, has shown beneficial results, especially in early stages. Pergolide, a dopamine agonist, may be an efficacious alternative to bromocriptine resistance or intolerable adverse effects. Vitamin E may have protective antioxidant properties, but very few clinical data are available. Fetal tissue transplantation needs continued research and remains very controversial. Diet modification may maximize the results of therapy with exogenous dopamine therapy. CONCLUSIONS: Clinicians should familiarize themselves with new alternatives for the management of parkinsonism in order to be reliable consultants for both professional and lay persons.

Bradycardia and syncope as manifestations of partial epilepsy.

Although transient increases in heart rate typically occur, bradycardia has infrequently been noted in association with partial seizures. Five patients with temporal lobe epilepsy are described in whom sinus bradyarrhythmias and syncope were prominent manifestations of seizure activity. Partial improvement occurred in one of two patients in whom a permanent pacemaker was implanted before a diagnosis of epilepsy was established. Treatment with phenytoin or carbamazepine resulted in nearly complete resolution of symptoms in all five patients. Because pacemaker implantation does not prevent recurrent symptoms, but anticonvulsant therapy does, this experience underscores the importance of considering the diagnosis of partial epilepsy in selected patients with sinus bradyarrhythmias and syncope.

Decrease of serum folates in healthy male volunteers taking phenytoin.

The effect of phenytoin (PHT) on serum folate and the effect of additional oral folic acid (FA) on serum folate during continued treatment with PHT were studied in 13 healthy male subjects 20-35 years of age. The study was divided into two phases: Phase I determined Vmax (mg/kg/day) and Km (microgram/ml) of PHT in order to calculate the PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km-1 and Km+5, respectively. Both phases examined the effect of PHT on serum folate. In Phase I, serum folate decreased by a mean and standard deviation of 42.15 +/- 21.44% after an average of 24.15 +/- 5.63 days of PHT administration, with a mean steady-state total serum PHT concentration of 8.45 +/- 2.70 micrograms/ml. Mean percentage decreases in serum folate before the addition of 1 and 5 mg FA in Phase II were 12.80 +/- 31.45% and 23.24 +/- 21.24% for Km-1 and Km+5, respectively. The average numbers of days of PHT administration and total serum PHT concentrations before FA administration were 9.52 +/- 3.34 and 15.84 +/- 7.02 days, and 2.60 +/- 2.18 and 8.64 +/- 3.44 micrograms/ml, for Km-1 and Km+5, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventriculomegaly in neurofibromatosis-1. Association with Chiari type I malformation.

Two cases of von Recklinghausen neurofibromatosis with a hitherto unreported association of ventriculomegaly and a Chiari type I malformation are described. Both cases had skeletal abnormalities at the cervicomedullary junction, contributing to neurological symptoms in 1. The literature on nontumor-related ventriculomegaly in neurofibromatosis is reviewed. The Chiari type I malformation should be considered as a cause of nontumoral ventricular enlargement in patients with von Recklinghausen neurofibromatosis.

Phenytoin binding in healthy volunteers.

The pharmacologic effect of phenytoin is directly related to the unbound concentration in the serum, which previously has been reported in the literature to be approximately 10%. The results of 13 out of 14 20-35 year-old healthy male volunteers studied indicate that less than 10% unbound phenytoin is present in the majority of subjects taking two different doses of phenytoin.

Parkinsonism--drug treatment: Part II.

This article, second in a two-part review, discusses investigational drug therapy and miscellaneous drug management of parkinsonism. Drug therapy should be individualized according to signs and changed as the disease progresses or if the patient develops intolerable side effects. Investigational drugs being examined include sustained-release and injectable dopaminergic formulations. Drug-induced parkinsonism is also examined.

Parkinsonism--drug treatment: Part I.

The purpose of this two-part review is to explain current drug treatment in part I and discuss investigational drug therapy and miscellaneous drugs in the management of parkinsonism in part II. The medical approach to this disease is still based on the imbalance between a deficiency of dopamine and a functional increase in acetylcholine. Anticholinergic agents are used to treat the tremors in the early stages of the disease.

Effect of charcoal and sorbitol-charcoal suspension on the elimination of intravenous phenobarbital.

The effects of two different oral charcoal suspensions on the elimination of a 200 mg/70 kg, 1 h intravenous (i.v.) infusion of phenobarbital and the tolerances of the two regimens were determined in a randomized crossover study in six healthy male volunteers. Phenobarbital was given i.v. alone or together with 105 g of oral activated charcoal suspension or with 105 g of a commercially available sorbitol-charcoal suspension over a 36-h period. A 13-34% decrease in the area under the serum concentration time curve (AUC) for 0-60 h occurred with the administration of the activated charcoal, and a 19-52% decrease occurred with the commercial sorbitol-charcoal regimen. The mean apparent systemic clearance of total phenobarbital increased from 0.089 +/- 0.019 ml/min/kg to 0.141 +/- 0.029 and 0.146 +/- 0.036 ml/min/kg with the charcoal and sorbitol-charcoal treatments, respectively. No significant change in the fraction of phenobarbital bound to protein was detected. The charcoal regimen caused constipation in one subject. All subjects taking the sorbitol-charcoal preparation experienced diarrhea; there were no changes in electrolytes with either charcoal suspension. All subjects preferred the sorbitol-charcoal preparation.

Bilateral focal cortical atrophy and chronic ergotamine abuse.

A 67-year-old patient took 5 mg of ergotamine daily for 18 months. His headaches and dysphoria were greatly improved by stopping this drug. Brain imaging by CT and magnetic resonance techniques showed numerous atrophic lesions that may represent infarcts due to occlusion of superficial cortical vessels.

Electroencephalographic absence status with minimal behavior change.

Difficulty in correlating EEG abnormalities with clinical seizures is emphasized in this case report of an epileptic patient with electrical status epilepticus and normal behavior. In addition, the usefulness of dichotic listening tests in the identification of subtle perceptive and expressive impairments is illustrated in this same patient at a time of noncompliance with anticonvulsant therapy.

Decreased phenytoin levels in antineoplastic therapy.

A case history is reported illustrating the difficulties which may be encountered in maintaining seizure control in patients being treated with antineoplastic therapy. The maintenance of therapeutic serum levels of phenytoin during combined cis-platinum and bleomycin sulfate therapy suggests an absorptive defect, possibly related to damage of the intestinal mucosa. This defect did not appear to alter the absorption of primidone or phenobarbital, since increased dosages were not necessary to maintain these drugs within therapeutic ranges.

Use of phenytoin serum levels in a case of status epilepticus.

Serum anticonvulsant determinations made possible the identification of an unusual cause of status epilepticus and assisted with appropriate therapy in an epileptic patient with second-degree burns. The seizures were associated with a serum phenytoin concentration of 3.5 mug per milliliter. This suboptimal concentration of drug developed despite continuation of the patient's customary oral dose of phenytoin led to the conclusion that the unexpected decrement in serum anticonvulsant concentration was related to an experiment in absorption of that drug, possibly caused by the concurrent administration of oral oxacillin.

Alexia with left homonymous hemianopia without agraphia. A case report with autopsy findings.

Unusual findings at autopsy prompted this case report of a patient with the syndrome of alexia without agraphia. The expected disconnection of the left angular gyrus from both visual cortices was not found at postmortem examination. Multiple cerebral metastases were identified, but none were present in the presumed pathways connecting the left occipital lobe and the left angular gyrus.