Six-month evaluation of Carbatrol (extended-release carbamazepine) in complex partial seizures.

We evaluated the use of a new, controlled-release capsule form of carbamazepine, Carbatrol capsules, in an open-label, multicenter study of 124 patients with complex partial seizures. Ninety-one percent of the patients successfully completed the 6-month trial with good seizure control, with a significant improvement in quality of life. We conclude that switching patients with complex partial seizures from multiple daily-dose carbamazepine to twice-daily Carbatrol on a milligram-to-milligram basis is relatively safe.

Pharmacokinetic evaluation of twice-daily extended-release carbamazepine (CBZ) and four-times-daily immediate-release CBZ in patients with epilepsy.

PURPOSE: A new capsule dosage form of carbamazepine (CBZ) has been developed, consisting of three different types of beads (immediate-release, extended-release, and enteric-release) that may be taken sprinkled on food or swallowed for easy administration. We compared the pharmacokinetics of the extended-release dosage form of CBZ (Carbatrol capsules) twice daily with the conventional immediate-release formulation of CBZ four times daily. METHODS: The randomized, double-blind, two-way, cross-over study was conducted at two sites, with a planned sample size of 24 adult patients with epilepsy. Each treatment was administered for 2 weeks. At the end of the 2-week period, blood samples were obtained hourly for a 24-h period. RESULTS: The 90% confidence intervals (CI) of the ratio of the means of the extended-release formulation twice daily to the immediate-release formulation four times daily were within the range of 0.80-1.25 for each of the pharmacokinetic parameters for CBZ and for the summation of CBZ and CBZ-epoxide (CBZ-E). There was no difference in the frequency of seizures between treatment (p = 0.103). CONCLUSIONS: Our results demonstrate that extended-release CBZ twice daily was bioequivalent to immediate-release CBZ four times daily, with regard to CBZ levels and summation of CBZ and CBZ-E levels, based on the pharmacokinetic parameters evaluated. Substituting one formulation for the other did not cause patients to have a significant change in seizure frequency.

Butyrylcholinesterase: an enzyme antidote for cocaine intoxication.

Cocaine-associated toxicity is the result of effects on the cardiovascular and central nervous systems. Since the primary route of cocaine inactivation is enzymatic degradation by butyrylcholinesterase (BChE), we sought to determine if the administration of purified human enzyme would ameliorate the lethal effects of cocaine. While the cardiovascular, autonomic or central nervous systems were unaffected by BChE, the enzyme reduced the adverse effects of cocaine including hypertension, hyperactivity and convulsions. BChE decreased both the brain and blood levels of cocaine and shifted the metabolites towards the production of the inactive product ecgonine methyl ester and away from the physiologically active metabolites, norcocaine and benzoylecgonine. We conclude that BChE would appear to be an ideal antidote in the treatment of cocaine intoxication and has potential therapeutic application.

Plasma butyrylcholinesterase activity and cocaine half-life differ significantly in rhesus and squirrel monkeys.

In vitro studies have implicated butyrylcholinesterase (BChE, E.C.3.1.1.8) as the major enzyme for metabolizing cocaine in humans, but little is known about endogenous BChE activity in monkeys and other animals often used in preclinical studies of cocaine. We compared BChE activity in 18 rhesus and 11 squirrel monkeys, using the colorimetric method of Ellman with butyrylthiocholine as substrate, and in vitro cocaine half-life in pooled plasma samples measuring cocaine concentrations over 60 minutes by GC-MS. Rhesus monkeys had a significantly higher plasma BChE activity than squirrel monkeys (8.2 +/- 0.5 U/L vs. 2.8 +/- 0.5 U/L), and a three-fold shorter in vitro cocaine half-life (20.1 min vs. 60.2 min). BChE activity in rhesus monkeys was comparable to the activity reported in humans. There was no significant influence of age, weight, or prior cocaine exposure. These results indicate that BChE level can vary between species of non-human primates, a factor that should be taken into account when studying drugs such as cocaine which are metabolized by BChE.

A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis.

In a double-blind placebo-controlled trial of cyclosporine in amyotrophic lateral sclerosis, no differences were observed in the monthly rate of progression or the relative risk of progression in comparing 38 patients randomized to the placebo group and 36 patients randomized to the cyclosporine group. In comparing three subgroups of patients, cyclosporine appeared to benefit men who entered the study within 18 months of the onset of first symptoms, whereas it was of no value to women or to men who entered later than 18 months. For the men with recent onset of disease, the relative risk of progression was 0.403; the monthly rate of progression was 5.2 +/- 1.1 points with placebo and 3.5 +/- 0.7 points with cyclosporine. These provocative results support the need for a full study of cyclosporine in men with recent onset of disease.

Neurotransmitter abnormalities in patients with motor neuron disease.

In 22 patients with motor neuron disease (MND), the mean concentration of serotonin (5HT) in platelets was slightly increased, platelet monoamine oxidase (MAO) activity was significantly increased, and plasma concentrations of total and both free and bound tryptophan were significantly decreased. Though platelet MAO activity was positively correlated with concentrations of 5HT, independent causal mechanisms are probable. When patients were rated according to severity, highest values of platelet 5HT and MAO activity were found in the most severely affected group, whereas concentrations of both total and protein-bound tryptophan were most decreased. Changes in concentrations of 5HT and tryptophan may reflect compensatory changes in response to degeneration of motor neurons or to interruption of their monoaminergic innervation.

Blood tryptophan metabolism in chronic schizophrenics.

Concomitant measures of blood indole metabolism were conducted in 33 chronic schizophrenics who showed significantly elevated mean platelet serotonin (5-HT) values and lower platelet monoamine oxidase (MAO) and plasma amine oxidase activities than normals. When subdivided according to Research Diagnostic Criteria diagnosis, the 20 chronic undifferentiated (CU) schizophrenics showed these same deviations from normal; the 13 chronic paranoid (CP) schizophrenics also had significantly higher mean 5-HT values but significantly lower plasma concentrations of total and bound tryptophan. In CP schizophrenics, platelet MAO activity, but not plasma amine oxidase activity, was significantly lower than in CU schizophrenics and controls. Hyperserotonemia occurred in 11 of the chronic patients (33%); nine were CU schizophrenics. In the latter, total tryptophan concentration was significantly lowered. Hyperserotonemia was not associated with reduced liver tryptophan pyrrolase activity or platelet MAO or plasma amine oxidase activities; rather, it may be a consequence of enhanced tissue tryptophan uptake and utilization.

Blood monoamine metabolism in Huntington's disease.

In 25 patients with Huntington's disease (HD), the mean blood concentration of serotonin (5-HT) and percentage of plasma free tryptophan were significantly increased while plasma concentrations of total and protein-bound tryptophan were significantly decreased. The pattern of changes in tryptophan concentrations was related to clinical severity but not to 5-HT levels. Platelet monoamine oxidase (MAO) activity was significantly increased in patients with HD; kinetic and marker enzyme studies suggested an increased enzyme concentration. Offspring at risk for HD also had elevated platelet MAO activity but normal concentrations of blood 5-HT and plasma tryptophan. In ten patients, plasma epinephrine concentrations were significantly increased; plasma dopamine and norepinephrine concentrations were positively related to MAO activity. The finding of peripheral neurotransmitter abnormalities in HD raises the question of an interaction between CNS and peripheral processes or a systemic disorder of neurotransmitter metabolism.