Hidebumi Hazama

Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan.

Summary: A multi‐institutional collaborative study was conducted concerning the course of pregnancy and delivery and the incidence of abnormal infants delivered of epileptic women. Of 657 women receiving antiepileptic drugs, 73% delivered live infants, 14% had miscarriage or stillbirth, and 13% underwent induced abortion. In contrast to the above findings, 80% of 162 patients not receiving antiepileptic drugs delivered live infants and 4% had miscarriage or stillbirth. The latter outcome was significantly increased in the medicated patients. In this series, 63 (9.9%) of 638 live births were malformed, 55 (11.5%) being from medicated mothers and 3 (2.3%) from nonmedicated mothers. The incidence of fetal malformation in medicated mothers was thus five times as high as that in nonmedicated mothers. Cleft lip and/or palate and malformations involving the cardiovascular system were found frequently in the infants from medicated mothers. General background factors that might exert teratogenic effects on pregnant patients with epilepsy were studied, and the potential toxicity of antiepileptic drugs to the fetus was also analyzed. In this regard, consideration should be given to whether the patient has partial epileptic seizures, whether the patient herself exhibits any malformation, or whether her previous pregnancy resulted in an abnormal outcome. The incidence of fetal malformation was the highest (12.7%) in the medicated patients who had epileptic seizures during the pregnancy. It is presumed on the basis of the results of analysis of the data that a combination of more than three drugs and a daily dose greater than a certain minimal level is likely to produce malformed infants.

Computerized tomography of the brain in schizophrenic patients. A controlled study.

Computer tomography (CT) of the brain was carried out in 49 schizophrenic patients and 38 controls in order to study the organic characteristics of the brain in schizophrenia.

Treatment of depression with clonazepam

ABSTRACT— The antidepressive effect of an anticonvulsant clonazepam was studied with maximum daily dose of 1.5 to 6.0 mg (mean 3.4 mg) in 27 patients with major depression (n= 18) or bipolar disorder (n= 9). Two of them dropped out at an early stage of the treatment, and the antidepressive effect of clonazepam was evaluated for the remaining 25 patients. A marked to moderate improvement was obtained for 21 patients (84%), and the onset of the antidepressive effect of clonzepam appeared within 1 week in most of the cases who responded to the therapy. The total scores on the Hamilton Depression Rating Scale and the Beck Self‐Rating Scale were significantly reduced after the clonazepam treatment. Side effects occurred in 14 patients, but most of them were not severe. From these results, it is thought that clonazepam might be useful as an antidepressant for patients in whom conventional antidepressant treatment are contraindicated.

Age differences in effects on blood pressure, flicker fusion frequency, salivation and pharmacokinetics of single oral doses of dothiepin and amitriptyline

SummaryBlood pressure, critical flicker fusion frequency (CFF), salivary flow rate and pharmacokinetics were compared in 7 young healthy volunteers (average age: 22.7 years) and in 7 elderly healthy volunteers (average age: 70.6 years) after single oral doses of the antidepressants dothiepin (DP) 25 mg and amitriptyline (AMP) 25 mg. Systolic blood pressure fell further and the reduction lasted longer in the elderly than in the young after both drugs. The decrease in CFF after AMP 25 mg, and the reduction in salivary flow rate after either DP 25 mg or AMP 25 mg were larger in the elderly than in the young. Plasma levels, T1/2 and Cl of both drugs in the elderly were also higher, longer and smaller, respectively, in the elderly. Clearance was found to be reduced in the elderly. More cautions dosage regimens of these drug should be considered for elderly patients.

Night‐time hypnopompic visual hallucinations related to REM sleep disorder

Abstract We encountered three patients who had experienced hypnopompic visual night‐time hallucinations. Their clinical manifestations resembled Charles Bonnets syndrome and the content of their experiences were understood as attempts at wish fulfillment. However, abnormal REM findings were recognized on polysomnogram at the occurrence of visual hallucination in two cases. We speculated that dysfunction of REM sleep mechanism might contribute to the night‐time occurrence of such kind of visual hallucination and that their visual experiences might be reflected by dream content.

Clinical efficacy and indication of acetazolamide treatment on sleep apnea syndrome.

The efficacy and indication of acetazolamide treatment on patients with sleep apnea syndrome (SAS) were discussed from assessing the changes of polysomnographic findings with the treatment in 75 SAS patients. For the patients as a whole, respiratory disorder variables improved significantly during the treatment. However, the number of acetazolamide treatment responders who showed a decrease of apnea hypopnea index (AHI) to 50% or less of the pretreatment value numbered only 34 (45.3%). The lower values of body mass index and AHI in the responder group indicated that monotherapy with acetazolamide is the treatment choice only for mild SAS cases without obesity. However, combined treatment with acetazolamide and uvulopalatopharyngoplasty was thought to be beneficial for severe cases.

Computerized tomography of the brain in manic-depressive patients--a controlled study.

Abstract: A computerized tomography (CT) of the brain was carried out on 40 manic‐depressive patients and 40 controls in order to study the organic characteristics of the brain in manic‐depressive psychosis. In the age group of 49 years and below, the left septum‐caudate distance (LSC) showed a lower value in the manic‐depressive group, but the other measurements for the ventricular system did not differ between both groups. The age group of 50 and over revealed a significant enlargement of maximum width of the inter‐hemispheric fissure (IF) and maximum width between the sylvian fissure and inner skull (SFIS) in the manic‐depressive group compared with the controls. The tendency to an enlargement of the third ventricle (IIIV) and maximum width of the right anterior horn (RAH) was also seen in the manic‐depressive patients. Cortical atrophy tended to appear in the temporal and occipital lobes earlier in the manic‐depressive group than in the controls. The patients showing a cerebral asymmetry of the hemisphere in the manic‐depressive group tended to show a reversed cerebral asymmetry.

Long-term observation of a manic-depressive patient with rapid cycles

For the past 35 years we have been treating a patient with regularly recurring MD episodes. Through longitudinal observations of this patient, we presented some characteristic findings in her biological rhythms, and the observed biological rhythm disturbances were speculated on

Regional distribution of type B monoamine oxidase activity towards β-phenylethylamine in the individual rat hypothalamic nuclei

Two types of monoamine oxidase (MAO) [EC 1.4.3.4.] have been classified by their specificity for substrates and their sensitivity to inhibitor drugs in homogenates of the rat brain 8. 5-Hydroxytryptamine (5-HT) 8 and norepinephrine (NE) 4 are specific substrates for type A MAO, and fl-phenylethylamine (fl-PEA) 13 and benzylamine (BA) 5 are for type B MAO. Dopamine (DA), tyramine and tryptamine are metabolized by both types of the enzyme 5,14. The regional distributions of MAO activity towards 5-HT 6,7,9, tyramine 7 and DA 6 have been measured in the individual rat brain nuclei. Concerning the regional distribution of type B MAO activity, it has been presumably suggested from either the relative ratios of 5-HT MAO to tyramine MAO 7 or the activity (DA MAO-type B) obtained with DA as a substrate and clorgyline as an inhibitor of type A MAO 6. However, the detailed distribution of type B MAO towards the typical substrate for the type such as fl-PEA has never been reported. In this paper, the methods of the micromeasurement of the activity of fl-PEA MAO were newly devised and thereby the regional distribution of type B MAO activity in the rat brain was studied in connection with that of type A MAO and DA MAO-type B. Male, 12-week-old Wistar rats kept in a group, were killed by decapitation at 09.00 h. Frontal serial sections of 60/~m thickness out of the blocks including the hypothalamus were made in a cryostat (--15 °C) and the freeze-dried samples were made 6. MAO activities were not reduced during these procedures. The individual nuclei or other regions were dissected from the freeze-dried sections and weighed as described in previous reports6, 7. The weight of each sample was 1.0-7.0/zg. To measure 5-HT MAO activity6: two/~1 of 0.1 M phosphate buffer, pH 7.2 and 2 #1 of ice-cold 5-HT buffer solution were added to the weighed sample in a microtube (the final concentration of the substrate: 1.1 mM [2-14C]5-hydroxytryptamine binoxalate, 45 mCi/mM, New England Nuclear). After an incubation at 38 °C for 45 min, the reaction was stopped with 1/zl of 3 N HCI. The reaction products were extracted in ethyl acetate and the radioactivity was measured by a liquid scintillation spectrometer.

Chemical kindling with Met-enkephalin and transfer between chemical and electrical kindling

The role played by Met-enkephalin (ME) in epileptic seizures was investigated, using 57 ME kindled rats and 10 saline injected control rats. Repeated microinjection of 10 micrograms ME into the right amygdala (AM) of male Wistar rats led to development of generalized convulsions. One week after the completion of ME kindling, 1 or 2 electrical stimulations (200-400 microA, 60 Hz, 1 sec) of the right AM of ME kindled rats resulted in generalized convulsions in 5 rats. The duration of after-discharge (AD) in the first generalized convulsion induced by electrical AM stimulation in the ME kindled rats was significantly longer than that in the first generalized convulsion induced by electrical stimulation in the saline treated control rats (P less than 0.05). One week after the completion of ME kindling, naloxone (10 or 20 mg/kg, i.p.) given 10 min before the infusion of ME into the other 3 ME kindled rats attenuated both convulsive behavior and electrographical seizures. With the progress of convulsive behavior, the frequency of wet-dog shakes (WDS) tended to decrease and was significantly lower after ME injection in the first stage 5 seizures than after the first ME injection (P less than 0.01). These results strongly suggest that ME has a potent epileptogenic effect on the rat brain which is caused by the opioid receptors. There are some differences between chemical kindling with ME and electrical kindling as indicated by the development of the AD duration and the WDS frequency.