In a previous study2 a method was

Treatment of epilepsy with diphenylhydantoin (5,5-diphenylhydantoin, phenytoin, Dilantin) or phenobarbital (5-ethyl-5-phenylbarbituric acid) aims at the maintenance of constant and therapeutically effective concentrations of the drugs in the central nervous system. A rational drug regimen requires knowledge as to the serum level requisite for anticonvulsant effect, the relationship between the serum level and the dosage given, and the rate of accumulation. There is evidence that the concentration of both drugs in human serum is equal, or proportional, to that in brain. In rats, rabbits, and dogs diphenylhydantoin and phenobarbital are distributed A preliminary report has been published (reference 1). about equally in serum and brain,2-4 and a few determinations of phenobarbital post mortem indicate that the same is true in man.5Similarly, a single dose of phenobarbital applied intramuscularly to the mother resulted in identical concentrations in fetal serum and cerebral cortex, whereas concentrations more than twice as high occurred in the region of the fourth ventricle.6Adult patients with seizures once a day to once a week before treatment with diphenyl¬ hydantoin were controlled at serum levels 7 of 10^g/ml-20jag/ml. At the same levels the electroencephalogram (EEG) was normalized or the incidence of paroxysmal abnormalities was considerably reduced. Similarly, in 21 of 27 outpatients with mild epilepsy (convul¬ sions once a month or less) the number of seizures was reduced with diphenylhydantoin levels above 10/j.g/ml; in 17 of 24 patients with levels below 10jug/ml there was no clinical improvement.7 With phénobarbital, normalization of the EEG occurred at serum levels 8 of &^g/m\-2lpg/m\. On the average, Downloaded From: http://archpedi.jamanetwork.com/ by a Western University User on 06/09/2015

SUMMARY AND CONCLUSIONS Findings are reviewed concerning the distribution and fate of phenytoin and pheno‐barbital in animals and in man. The serum concentration of these drugs can be considered an adequate expression of their concentration in the brain and hence of their anticonvulsant effect. The serum level increased approximately linearly with increasing dose, 1 mg/kg phenytoin by mouth giving about 3 μg/ml in the serum and 1 mg/kg phenobarbital giving about 10 μg/ml in the serum. The scatter of the ratio of level to dosage was greater for phenytoin than for phenobarbital. In most of the patients who had taken phenytoin for several years the serum level per mg/kg given was above 3 μg/ml per mg/kg. In the individual patient it may therefore be difficult to predict the serum concentration from the amount given and the determination of serum phenytoin has proved of considerable value for the institution and maintenance of therapy. In patients who were given only phenytoin, clinical and electroencephalographic improvement was not observed with serum concentrations below 10 μg/ml. Convulsions in most patients with severe grand mal epilepsy were controlled or significantly reduced in number when the dosage was adjusted so that the serum concentration was about 15 μg/ml (0.3–0.4 g daily to a 70 kg patient). For patients who were on phenobarbital only no information is available as to the correlation between serum level and anticonvulsant effect. In institutionalized patients who had been given combined phenytoin and phenobarbital medication for years serum levels averaged 18 μg/ml of phenytoin and 20 μg/ml of phenobarbital. In patients who had not previously received phenytoin it took about a week to reach a level of 10–15 μg/ml. The time required for the serum concentration to become at equilibrium increased with increasing dosage. With phenobarbital it took still longer, a level of 20 μg/ml being reached after about 1 month. The rate of fall after withdrawal of the drug was about proportional to the serum concentration, the rate of elimination being 35–55 % for phenytoin and 11–25 % for phenobarbital per 24 h. When a serum level had been attained the maximum variation between two daily doses given by mouth at twelve hour intervals did not exceed 10% for phenytoin and was still less for phenobarbital. Thus the administration of phenytoin more often than twice a day and of phenobarbital more often than once a day is unnecessary. Toxic side‐effects (fatigue and signs of incoordination) were not seen with phenytoin serum concentrations below 14 μg/ml. Half of the patients with phenytoin serum levels of 30 μg/ml showed side‐effects. Gum hyperplasia is not included in this compilation. Its occurrence was not correlated to the phenytoin concentration in saliva. The development of an increased tolerance to phenytoin is indicated by the more frequent occurrence of side‐effects in patients who had been given phenytoin treatment for less than six months as compared with those who had been given a longer treatment. With pheno...

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The effect of deuterium oxide on the isometric contraction of frog's muscle was investigated. In 99.8 per cent deuterium oxide the twitch force was reduced to 2–70 per cent of the force in aqueous Ringer, the rate of force development to 12–30 per cent, the tetanic force to 61–96 per cent while the latency of force development was approximately doubled. The total duration of the twitch was unchanged. The duration of the plateau of maximum intensity of active state remained unaltered by deuterium while its decline was enhanced. The conduction time of the action potential was not affected by deuterium but the reduction in frequency at which a complete tetanus could be maintained indicated an effect on the excitatory processes. It remained undecided whether the reduction in force is due to an effect of deuterium on the contractile elements or on the excitation‐contraction coupling.