Effects of estradiol and progesterone on seizure sensitivity in oophorectomized DBA/2J mice and C57/EL hybrid mice.

We investigated the effects of 17 beta-estradiol (E2) and progesterone (PG) on seizure sensitivity in two genetically epilepsy-prone strains, the DBA/2J and the C57/EL hybrid. In the DBA/2J, subject to audiogenic seizures when juvenile, oophorectomy produced a marked decrease in seizure sensitivity, both with and without E2 or PG replacement. In the C57/EL, subject to vestibular seizures, E2 significantly reduced seizure frequency and increased lag time to seizure onset. PG did not affect these variables. Both E2 and PG significantly prolonged seizure duration. These results support a role of ovarian hormones in regulating paroxysmal activity in collicular and tegmental regions associated with audiogenic seizures in the DBA/2J and in temporal structures associated with vestibular seizures in the C57/EL.

Pharmacokinetics and safety of a phenytoin prodrug given i.v. or i.m. in patients.

ACC-9653, a prodrug of phenytoin synthesized to be water soluble, is converted to phenytoin by phosphatases. In this study, 43 patients received ACC-9653 IV or IM. Side effects were transient and minor. The conversion half-lives of ACC-9653 after intravenous and intramuscular administration averaged 8.4 and 32.7 minutes, respectively. Peak phenytoin concentrations occurred 42 minutes after IV and 151 minutes after IM administration.

Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group.

BACKGROUND: Preclinical studies have demonstrated that nerve growth factor may prevent or reverse peripheral neuropathy. We have therefore tested the effects of recombinant human nerve growth factor in patients with diabetic polyneuropathy. METHODS: A total of 250 patients with symptomatic diabetic polyneuropathy randomly received either placebo or one of two doses of recombinant human nerve growth factor for 6 months. Patients were assessed for symptoms and signs of polyneuropathy before and after treatment. RESULTS: Compared with placebo, recombinant human nerve growth factor led to significant improvement after 6 months of treatment, as measured by the sensory component of the neurologic examination, two quantitative sensory tests, and the impression of most subjects that their neuropathy had improved. Three prospectively identified multiple endpoint analyses indicated improvements in the nerve growth factor treatment groups over the placebo group in all three analyses (p = 0.032; p = 0.008; p = 0.005). Recombinant human nerve growth factor was well tolerated, with injection site discomfort reported as the most frequent adverse event. CONCLUSIONS: Recombinant human nerve growth factor appears to be safe and shows preliminary evidence of efficacy in patients with symptomatic diabetic polyneuropathy.

Biological actions of nerve growth factor in the peripheral nervous system.

Since the discovery of nerve growth factor (NGF), its role in the physiology/pathophysiology of nerve function has been under intense investigation. More recently, the potential of recombinant human NGF (rhNGF) as a putative treatment for peripheral neuropathies, in particular diabetic polyneuropathy and HIV-associated sensory neuropathy, is being explored. In animal models of diabetes, depletion of endogenous NGF levels has been demonstrated in foot skin and skeletal muscle; these levels reduce further with increasing disease duration. Preclinical studies in animal models of diabetes have shown that administration of NGF can reverse or alleviate impairment in nerve function.

Pharmacokinetics of antiepileptic drugs during pregnancy.

During pregnancy, a number of physiologic changes occur that can affect the pharmacokinetics of antiepileptic drugs. Because of its nonlinear kinetics, phenytoin is most affected, with concentrations decreasing to half of prepregnancy values. Carbamazepine and valproate levels also decrease but to a lesser degree. Phenobarbital and primidone levels decrease as well. Some of the changes may be more apparent than real, however, because of changes in antiepileptic drug binding to plasma proteins. It is recommended that concentrations be measured frequently during pregnancy and dose adjustments made as needed. Unbound (free) levels should be measured when drugs known to alter binding are also being taken.

Clinical manifestations in children with occipital spike-wave paroxysms.

The pattern of occipital-posterotemporal spike-wave paroxysms (O-PT SWPs), is a distinctive EEG abnormality observed primarily with occipital epilepsy of childhood and basilar artery migraine. We studied EEG and clinical features in 30 children and young adults with this EEG pattern. Prolonged and brief O-PT SWPs were observed. Prolonged discharges (greater than 6 s) were observed only in children with seizures (p less than 0.001), and brief discharges (1-6 s) were observed immediately after eye closure. Generalized SWPs (11 patients, 37%) and background abnormalities (17 patients, 57%) were common. Photic activation of O-PT SWPs was not observed. Twenty-four patients (80%) manifested paroxysmal phenomena-seizures (20 patients, 67%) and migraine (12 patients, 40%, 4 alone and 8 with seizures). Fifteen patients (75%) had partial seizures, and 5 (25%) had absence seizures. In 7 patients with partial seizures, an etiology was evident. Neurologic examination was more often abnormal in patients with secondary partial seizures than in those with idiopathic partial seizures (p less than 0.05) and absence seizures. Conversely, migraine was more often associated with idiopathic partial seizures than with secondary partial seizures (p less than 0.05) and absence seizures. Six children (20%) had no paroxysmal events. Generalized SWPs were uncommon in patients with idiopathic partial seizures. We conclude that O-PT SWPs is a nonspecific epileptiform abnormality that may occur in children with (a) idiopathic partial, (b) symptomatic partial, and (c) absence epilepsies, but it may also occur in patients with no evidence of seizures.

Phenytoin prodrug: preclinical and clinical studies.

The currently available phenytoin (PHT) solution has many disadvantages stemming from poor aqueous solubility of PHT. A novel approach to solve the problem has been the synthesis of a phosphate ester of PHT (PHT prodrug ACC-9653). This water-soluble compound is metabolized rapidly into PO4 and PHT. A four center open-label, baseline-controlled study of 43 patients with epilepsy maintained on oral twice-daily PHT monotherapy was performed to evaluate the safety and pharmacokinetic profile of the prodrug. Patients received an i.v. or i.m. dose of ACC-9653 at a dose equivalent to the patients' morning dose of PHT. Intravenous dosages were infused at a rate of 75 mg/min, and i.m. dosages were given as one or two injections. After a period of 6 days, during which patients were again maintained with oral PHT, they were given a dose of ACC-9653 via whichever route they had not yet received. The Tmax of the prodrug averaged 5.7 and 36 min (0.095 and 0.606 h) after i.v. and i.m. administrations, respectively. The elimination half-life of ACC-9653 (conversion from prodrug to PHT) after i.v. and i.m. administration was 8.4 and 32.7 min (0.140 and 0.545 h), respectively, and both were independent of the dose. The plasma clearance of ACC-9653 was not dependent on dose or route of administration and averaged 19.8 +/- 1.16 and 17.8 +/- 0.83 L/h after i.v. and i.m. administrations, respectively. The area under curve ratio of PHT after i.m. and i.v. ACC-9653 was 1.17 +/- 0.13 which was not significantly different from 1.(ABSTRACT TRUNCATED AT 250 WORDS)