A Study on Time- and Radiation-dependent Changes in the Frequency of Lymphocytes with Chromosome Aberrations in the Circulation, Following Multiple Exposures of the Pelvis to ggr-Irradiation

Unstable chromosome aberrations ofperipheral lymphocytes were observedduring the course of radiotherapy in patients with cervical cancer. They did notincrease monotonously with repeated exposures, but a plateau was observedaround the second week of treatment.Similar tendencies were observed in both72-hour and 50-hour culture experiments, although the number of abberrations was lower in the former. Thedistribution of numbers of dicentrics percell fitted well the Poisson patternthroughout the period of observation.Peripheral lymphocyte counts reached alow plateau before the fifth exposure,and dropped again in the third week.It was speculated that the "member exchange" and/or mobilization of lymphocytes caused the nonlinear increase inchromosome aberrations.

Submitted on December 7, 1969 Accepted on January 22, 1970     

Daytime sleepiness and automobile accidents in patients with obstructive sleep apnea syndrome

Abstract We evaluated the rate of automobile accidents and daytime sleepiness using the Epworth sleepiness scale (ESS) in 44 patients with obstructive sleep apnea syndrome (OSAS). We defined the automobile accident score as a sum of two points for every one automobile accident and one point for every near-miss accident. Automobile accidents and near-misses were found in 54.5% and 50.0% in patients with OSAS. Automobile accident score was significantly correlated with the ESS score ( r = 0.56, P < 0.01). Our findings suggest that ESS score may be useful in detecting patients with the potential risk of automobile accidents associated with daytime sleepiness.     

PREDICTION OF THE THERAPEUTIC DOSE FOR BENZODIAZEPINE ANXIOLYTICS BASED ON RECEPTOR OCCUPANCY THEORY

Many benzodiazepines (BZPs) are now used as anxiolytics with nearly 200-fold variety of therapeutic doses. The variation of the doses of BZPs is due to differences both in their pharmacokinetics and in their receptor binding characteristics. The purpose of this study is to clarify the mechanism of the differences in therapeutic dose by retrospective analyses and to develop a system for the quantitative estimation of optimal doses of BZPs. The values of receptor dissociation constant (K_d), which indicates the binding affinity of each BZP at the receptor site, were obtained from a number of works based on in vitro binding experiments. The plasma unbound concentrations of the BZPs and their active metabolites were calculated using the reported values of their total plasma concentrations after average oral doses of the BZPs and the values of their plasma unbound fractions, which were also taken from the literature. There were log-linear relationships between the K_d values of BZPs and their average therapeutic doses or maximum plasma concentrations, but the correlation coefficients were relatively small (r >0·77). In contrast, a good log-linearity (r =0·96) was observed in the correlation between their K_d values and the effective plasma unbound concentrations considering the active metabolites. This finding indicates that the receptor occupancy after administration of therapeutic dose of BZPs is consistent (52·3±3·2%) among the BZPs. In this study, we also develop a possible system for estimating the appropriate doses of BZPs based on receptor occupancy theory. ©1997 by John Wiley & Sons, Ltd.