Yoichi Nakazawa

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.

Effects of acute and repeated alcohol ingestion on hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal functioning in normal males

We investigated the effects of acute and repeated alcohol ingestion on plasma levels of hormones associated with the functioning of the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) systems in normal males. In the first experiment, 7 normal male subjects were given ethanol (1.3 g/kg) in the form of a 43% alcohol solution of whiskey and water over a 30-min period (from 19:00 h to 19:30 h); blood samples were collected 30 min and immediately before the beginning of alcohol ingestion and then at intervals of 30 min for 180 min. Blood ethanol levels rose sharply and reached their maximum at 60 min, remaining above 1.0 mg/ml until 180 min. Prolactin levels increased, reaching a peak at 60 min, gradually returning to the initial value at 180 min. Decreased testosterone levels were observed only at 30 min. Luteinizing hormone (LH), adrenocorticotrophic hormone (ACTH) and cortisol levels did not show any increases. In the second experiment, 9 normal males were given the same dose of alcohol, but this was given on 7 consecutive evenings and the hormonal changes were examined on the 1st and 7th days, only at 30 and 60 min after alcohol ingestion began (during the period that blood ethanol levels were ascending to their peak). The results on the 1st day reconfirmed the findings in the first experiment and on the 7th day, the last alcohol ingestion produced increases in prolactin levels and decreases in testosterone levels at 30 and 60 min, but did not change other hormone levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian rhythm of REM sleep of chronic alcoholics during alcohol withdrawal

Sleep structures were polygraphically investigated during the alcohol withdrawal periods of six male alcoholics. Polygraphic recordings were taken 10 days, 1 month and 3 months after hospitalization. Total sleep time was almost equal among the three recording nights for each patient. Stages 3 and 4 sleep were remarkably reduced on all the recording nights. REM sleep time was normal throughout the study. REM latency decreased in many patients on the 10th day, and gradually increased on the following nights. A very important change was observed in the distribution of REM sleep. Maximal duration was noted in the first REM episode on the 10th day in four of the six. On the second recording night the second REM episode was the longest in five of the six subjects. On the last recording night many patients exhibited a normal distribution of REM sleep. These findings which suggest that the acrophase of REM sleep is advanced by several hours for a few months after alcohol withdrawal have also been observed in patients with endogenous depression. Although our patients did not show any depressive symptoms during the study, one of them developed a severely depressive state after he began to drink alcohol thereafter.

Serum folic acid levels and antipyrine clearance rates in smokers and non-smokers

Serum folic acid (FA) levels and antipyrine clearance rates were determined in 15 healthy male subjects who had not been administered any drug and alcohol for a month preceding the study. Eight of the 15 subjects smoked cigarettes daily while the remaining seven did not. The serum FA levels were measured by Lactobacillus casei bioassay. The antipyrine clearance rates were estimated in plasma or saliva obtained after oral administration of antipyrine for evaluating the activity of hepatic microsomal oxidase. The serum FA levels in the smokers were significantly lower than those in the non-smokers and the antipyrine clearance rates were significantly higher in the smokers compared with the non-smokers. The increase of the antipyrine clearance rates in the smokers was supposed to be caused by an increase in the activity of hepatic microsomal oxidase since it has been established that polycyclic aromatic hydrocarbons contained in cigarette smoke induce these enzymes. The association of the decrease in the serum FA levels and the increase of the antipyrine clearance rates was investigated.

Cerebral atrophy and slow wave sleep of abstinent chronic alcoholics

Although a considerable decrease of slow wave sleep (SWS) has been observed in abstinent chronic alcoholics, the under-lying mechanism is still obscure. In the present study CT scans and polysomnographic recording were repeatedly conducted in nine chronic alcoholics. SWS was remarkably reduced in all the patients, but it was slightly restored in six patients on the 6th month after abstinence. On the other hand, enlargement was observed in the cortical sulci, cerebral fissures and ventricles in these patients. The enlargement of the cortical sulci was improved in five patients, and four of the patients showed increase of SWS. Although enlargement of the cerebral fissures and ventricles was improved in a few patients, in most of the patients who showed improvement in the cortical sulci SWS was increased. The results indicate that the decrease in SWS in abstinent alcoholics may have resulted from the atrophy of the cerebral cortex.

Primary and secondary depression in alcoholism — clinical features and family history

One hundred thirty-six alcoholic inpatients were studied with regard to the association between alcoholism and depression. They fell into three groups: primary depression, secondary depression and non-depressive alcoholism. The main results obtained are as follows: (1) Depression was found in 46 patients (33.8%) in the present or past history; 13 were regarded as primary depression and 33 as secondary depression. (2) The clinical symptoms and the background of the primary group resembled those of endogenous depression. (3) The clinical features, including the duration of depressive episodes in the secondary depression group differed from those in the primary group. (4) No statistically significant differences were noted as to the rates of family-history of alcoholism and depression among the three groups. Clinical and biological differences between the primary and secondary groups were discussed on the basis of these results.

Effects of caffeine on event-related potentials: Comparison of oddball with single-tone paradigms

We investigated the acute effects of caffeine (500 mg) on event‐related potentials (ERP) in 10 healthy subjects using standard oddball and single‐tone paradigms. Event‐related potentials were recorded before oral ingestion of caffeine or placebo and 30 min and 210 min after. The oddball paradigm, but not the single‐tone paradigm, showed that the P300 amplitude and the area were significantly increased 30 min after ingestion of caffeine and significantly decreased 30 min after ingestion of placebo. The effects of caffeine disappeared at 210 min. Neither the P300 latency nor the reaction time changed significantly with the oddball paradigm. However, the reaction time was shortened 30 min after ingestion of caffeine with the single‐tone paradigm. These findings suggest that the caffeine‐induced increase in the P300 amplitude may have resulted from the increased allocation of attentional resources to the discriminating process which was not, however, accompanied by facilitation of the process and that caffeine may specifically stimulate the discriminating process involved in the oddball paradigm. In addition, the simple psychomotor performance of button‐pressing in response to a tone signal was accelerated by caffeine.

Amplitude and area of the auditory P300 recorded with eyes open reflect remission of schizophrenia

Schizophrenic patients reportedly demonstrate smaller P300 amplitudes, which have been related to cognitive deficits, as well as structural and chemical abnormalities (Ford et al 1994a; Pritchard 1986). Auditory P300 amplitude is known to be resistant to changes in neuroleptic medication or clinical state, so it has been deemed a candidate for a trait marker for vulnerability to schizophrenia (Blackwood et al 1987; Eikmeir et al 1992; Ford et al 1994a, 1994b; Pritchard 1986). Duncan et al (1987), however, have shown that the visual P300 ampiitude is negatively correlated with clinical improvement as measured by brief psychiatric rating scale (BPRS) scores. Thus they suggested that visual P300 amplitude may serve as a state marker in schizophrenia (Duncan et al 1987). We recorded serial sessions of auditory event-related potentials (ERPs) in schizophrenic patients during the course of their treatment for up to 6 months following admission. Since withinsession and between-session reliabilities of P300 measures recorded with eyes open are usually higher than those recorded with eyes closed (Maeda et al 1995), eyes-open and eyes-closed recordings were both made to provide further data regarding the long-term reliability of P300 recorded under these two sets of conditions. In addition, P300 area seems to be more reliable than P300 amplitude (Maeda et al 1995), so P300 area was measured as well.

Effects of acetazolamide on the sleep apnea syndrome and its therapeutic mechanism

Abstract Twenty male patients with sleep apnea syndrome were treated with acetazolamide (AZM), a carbonic anhydrase inhibitor. In 14 of the patient a significant decrease was found in the number of apnea, apnea index and % apnea time (percentage of time spent with apnea to the total sleep time) with improvement in sleep structure, clinical symptoms, such as insomnia, daytime excessive sleepiness and snoring. A significant decrease was also observed in arterial blood pH and HCO−3 in the 14 improved patients. On the other hand, no improvement occurred in the parameters of sleep apnea and sleep with AZM in the remaining six patients. Moreover, metabolic acidosis and an improvement in arterial blood gases did not occur with AZM in the six patients.

Changes in sleep pattern after sleep deprivation.

Total sleep deprivation (TSD) was performed for one night with 11 healthy male students and three‐consecutiverevery night‐sleep was recorded. Special attention was paid to the analysis of the individual difference in SWS(min, %) on the baseline and recovery nights. The total sleep time increased on the first recovery night compared to the baseline, but it decreased significantly on the second and third recovery nights.