Since the discovery of rapid eye movement period of sleep (REMP) by Aserinsky and Kleit man, it has been widely accepted that sleep is consisted of two kind of sleep, i.e., REMP and non-REM (NREM) sleep. In this paper, the nature of sleep was at first considered from the evolutional point of view (Kleitman 1939), and the concept of basic rest activity cycle (BRAC) of Kleitman was introduced. Then the outline of the phenomenology of REMP was described. Onto genetic study on REMP and NREM sleep in man and experimental animals revealed that REMP occupies most part of sleep in the fetus and new born, suggesting a role of REMP in the development of the central nervous system, especially the brain. The relationship between the fetal move ments and REMP was suggested. As to the neural mechnism of sleep, so-called amine hypothesis of Jouvet was described.
Among the clinical studies on sleep, the charac teristics of the sleep in Down's syndrome and phenylketonuria were discussed. Recent poly graphic study on the effect of various hypnotic and psychotropic drugs on sleep was reported, with special emphasis on the importance of the change of eye movements themselves (REM density) beside the increase or decrease of the amount of REMP for the analysis of the mode of action of drugs. Lastly the importance of obser vation of sleep for 24 hours including the daytime was stressed and the results of the author's 24 hour polygraphic study on manic-depressive pateints were reported.

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Neuropharmacological studies on the inhibi tory action of anticonvulsants were reviewed from the standpoint of 1) energy metabolism, 2) electolytes metabolism, and 3) neurotransmitter metabolism.
The following evidences could be directly related to the inhibitory mechanism of anticonvul sants:
1) Diphenylhydantoin (DPH) and trimethadione cat to inhibit the increments in oxygen uptake and anaerobic glycolysis of the brain slices by anelectric stimulation, and are not effective in a static condition.
2-A) DPH acts to suppress convulsion by stimulating metabolic processes involved in the active extrusion of Na from cells.
2-B) Acetazolamide causes CO2 accumulation in brain cell by inhibiting carbonic anhydrase activity, and thereby exerts its anticonvulsant action, inhibiting Na inflex across the excitable membrane.
3-A) Phenobarbital and DPH inhibit acetylcho line biosynthesis and otherwise enhance the for mation of bound type of acetylcholine.
3-B) Trimethadione may inhibit the release of acetylcholine from the nerve terminal.
3-C) Anticonvulsants could prerent the deletion of catecholamine or 5-HT level in the brain, and thereby could keep stability to seizure activity.
3-D) DPH acts to decrease glutamic acid, a putative excitatory neurotransmitter level in the brain, and the other hand, to increase γ-amino butyric acid, a putative inhibitory neurotransmitter level.

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Simple determination method of phenobarbital and phenytoin by TLC by Olsen and some additional ideas were introduced.
Comparing the result determined by TLC and GLC at the same time, simple TLC determination technique is evaluated as a clinical search method.

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The determination methods of antiepileptic drugs have markedly progressed for last five years. Thus almost the whole series of the common drugs are now brought within the reach of our work on blood and cerebrospinal fluid.
The various factors in the drug therapy which influence on the blood levels were discussed and the methods available, such as colorimetry, UV spectrophotometry, thin-layer chromatography, gas chromatography, radioimmunoassay and enzyme immunoassay, were reviewed. The blood and cerebrospinal fluid levels obtained by our gaschromatographic method were reported and some points of their values were discussed.
The use of multiple medication in the drugtheraphy of epilepsy can be explored by quanti fying each constituent drug. The estimation may allude to intoxication knowing which drug was overdosed; may bring to an appropriate level under the varied conditions of individuals; may avoid the switch to another drug remaining subdosage; may help the choice of other drugs knowing which drug was uneffective.
It is proposed that the periodical check of the blood levels for epileptic patients and for pregnant epileptics is necessary to control illness and to avoid hazards.

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Measurements of PB and DPH levels in blood and cerebrospinal fluid were done in 115 child cases of epilepsy. Especially, those of intractable epilepsy were further subjected to analyses of excreted DPH levels in stool and urine and HPPH levels in urine by gas chromatography. On the other hand for chronological radioassay in blood, the cerebrum and the liver, 14C-DPH was ip injected to immature rats. The results obtained are as follows:
1) PB and DPH showed insignificant correlation between dosage and blood concentration and marked individual differences.
2) PB presented correlation between blood and cerebrospinal fluid levels, but the DPH level showed individual differences.
3) ¹⁴C-DPH-administered rats proved varia tions between individuals as to levels in blood, the cerebrum and the liver. Inpatients among the whole human subjects were also examined con cerning absorbency and metabolic ability of DPH, and existence of individual differences was confirmed.
4) As to relationship between convulsant-sup pressive effects and blood levels of PB and DPH, minimum PB and concentrations enough to suppress attacks much varied in each subject and no definite correlation existed, though DPH levels below 2 to 3 μ g were generally characterized by nonefficacy against fits.
5) With regard to free type PB and DPH not combined with proteins, blood levels of higher free-PB percentage showed more suppressive effects on epileptic attacks while DPH presented no such a relationship but high individual differences.
6) Concerning drugs concomitantly administered with PB and/or DPH, in some cases elevation of the blood DPH level induced by the drugs made fits suppress, and in others the drugs dirently worked to suppression, not significantly affecting the blood level.

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When rats were fed on folate deficient diet and given diphenylhydantoin (DPH), it was found that the utilization of single carbon from formimino glutamic acid and formate via folate metabolic pathway proceeded in liver more efficiently than that in folate deficient rats without DPH administration.
A suppressive action of exogenous supply with deoxyuridine upon incorporation of ³H-thymidine into DNA in bone marrow cells was examined, and the result revealed that there was no differnce in the 3H-thymidine incorporation into DNA in bone marrow cells of folate deficient rats with or without DPH administration. This finding suggested that there was no possibility that an increased amount of methylene tetrahydrofolate might be available for DNA synthetic pathway in bone marrow cells of folate deficient rats with DPH administration.

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The major factors which control blood concentrations of drugs and affect the intensity of pharmacological effect were described. To obtain these quantitative data, concentration-time relationships of drugs in various body fluids can be predicted by a kinetic approach based on mathe matical calculations. The principle of superposition was used to clarify the extents and rates of conversion of primidone to phenobarbital and phenylethylmalonamide in rats. The extents of conversion of primidone to phenobarbital and phenylethylmalonamide were shown to be 25 and 65%, respectively, and these rate processes were represented as first-order kinetics with a halflife of 60 minutes. The results were verified by comparing the amounts of the metabolites excreted in the urine and the areas under the concent ration-time curves of the metabolites after intravenous administration of primidone with those of the metabolites after intravenous administration of the metabolites, respectively.

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Side effects of antiepileptic drugs were studied and reviewed.
1) Neurological effects are rather main effects than side effects, and are useful when they are used as a indicator of blood drug levels.
2) Hypersensitivity reaction were encountered rarely, 1 per about 50 patients, most of them were drug exanthemata. In early stage of medication, periodical hematological examinations are needed to avoid advanced hematopoietic disorders.
3) Gingival hypertrophy (14.0%), vilirism (6.8%), and constipation (13.3%) were frequently complained by patients. The former two were related to DPH and modified by other drugs. The latter was induced by diazepam.
4) Depletion of blood Ca levels were related to sulthiame, and depletion of blood hemoglobin were related to DPA.
5) Developments of anemia, liver dysfunction and rickets were frequently encountered in patients who were malnourished and have poor environments.
6) Needed examinations to find out drug-indu ced disorders, and the normal ranges were described.
7) Teratogenecity of antiepileptic drugs have to be noticed. It is recommended that in administering to fertile women the most potentteratogenic drugs have to change to less potent drugs like as PB, and folate and vitamin B12 are given simul taneously.
8) There may be many other side effects than ever found, doctors should be alert to find out new side effects.

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The cerebellum was examined electron-microscopically in about 50-day-old rats whose mothers were given a moderate dose (5-7mg/kg/day) or excessive dose (100-150mg/kg/day) of diphenylhydantoin during pregnancy. In Purkinje cells the enhancement of electron density of the cytoplasm accompanied by the increase in free ribosomes, mitochondria and lipofuscin granules was demonstrated. Irregularities in distribution and shape of the mitochondria, and indentation of the nuclear membrane were also found. These ultrastructural observations were more remarka ble in the youngster rats born from the exces sively dosed mothers, than in those from the moderately dosed mothers, and the so-called “honeycomb structure” was observed in the myelinated axons of the granular cell layer. Both the formation of honeycomb structure and the increase in lipofuscin granules may be the result of derangement in lipid metabolism, or of vitamin E deficiency. These ultrastructural observations in animal experiments indicate the possible hazards of diphenylhydantoin therapy during pregnancy

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1) Serum alkaline phosphatase (AL-P) was assayed in the sera of 153 children on antiepileptic drug therapy. Abnormally high enzyme activity was found in 81 patients (52%).
2) The isoenzyme pattern was studied by agargel electrophoresis in 38 of 81 patients. The hepatic pattern was observed in 12 (32%), the osseous pattern in 23 (61%), and the mixed pat tern in 3.
3) The isoenzyme fractionation of serum AL-P is a clinically useful procedure for assessing the calcium and phosphorus metabolism and the effect on the liver function in patients on antiepi leptic drug therapy as the nature of elevated AL-P cannot be evaluated by serum Ca, P, GOT, GPT, or zinc sulfate turbidity test.

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