Masaya Hasegawa

Dissociation of impairment between spatial memory, and motor function and emotional behavior in aged rats

We investigated changes in learning and memory in aged rats, in relation to motor function and emotional behavior. Male Kbl Wistar aged rats (108-weeks-old) were divided into two groups, memory impaired and non-impaired, based on performance during six training trials in the Morris water maze task. Aged rats with a goal latency longer than the mean plus the 99% confidence limit of young rats, were regarded as memory impaired, whereas those with a goal latency within the range of the 99% confidence limit of the mean of young rats, were considered as memory non-impaired. Although the performance of the memory impaired aged rats in the standard test of the Morris water maze improved after six re-training trials to the level of the non-impaired aged rats and young rats, working memory impairment was evident. There were no differences in motor function and emotional behavior between the impaired and non-impaired aged rats. These results suggest that deficits of learning and memory in memory impaired aged rats can be dissociated from changes in motor function and emotional behavior.

Pharmacokinetic Characteristics of 5‐Fluorouracil and Mitomycin C in Intraperitoneal Chemotherapy

Abstract— Eight patients with malignancies confined to the peritoneal space participated in this study. Five hundred milligrams 5‐fluorouracil or 10 mg mitomycin C was diluted in 1 L saline. The mixed solution was injected intraperitoneally through the semi‐permanent peritoneal catheter. Blood and peritoneal fluid were collected after injection. 5‐Fluorouracil concentrations in the peritoneal fluid were 1000 times those in serum, while mitomycin C concentrations were 100 times those in serum. Areas under the concentration vs time curve (AUC) were calculated by the trapezoidal method with extrapolation to infinity. The ratio of peritoneal fluid AUC to serum AUC was about 1400 for 5‐fluorouracil and 80 for mitomycin C. Patterns for the absorption and elimination from systemic circulation were similar for both compounds. Drug concentrations in the peritoneal fluid and serum were analysed according to the compartment model. The half‐life in the peritoneal fluid (t½p) and the rate constant from the peritoneal fluid to the systemic circulation (ka) were nearly equal for both 5‐fluorouracil and mitomycin C (t½p, 1·0 h for 5‐fluorouracil and 1·3 h for mitomycin C; ka 0·71 h−1 for 5‐fluorouracil and 0·68 h−1 for mitomycin C), although the apparent volume of distribution (Vds/F) and clearance in the peritoneal cavity (CLp) for mitomycin C (78 Lm−2 and 1.8 L h−1 m−2) were about twice the values for 5‐fluorouracil (149 L m−2 and 0·8 L h−1 m−2).

MK-801 increases endogenous acetylcholine release in the rat parietal cortex: a study using brain microdialysis

Glutaminergic and cholinergic neuronal interactions were investigated by using the brain microdialysis method in freely-moving rats. Acute administration of (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (MK-801) increased dose-dependently the extracellular acetylcholine (ACh) level in the rat parietal cortex. Significant increases in the extracellular ACh level were observed at doses of 0.4 and 0.5 mg/kg of MK-801, compared with the saline-treated group. The increase of extracellular ACh level was eliminated by infusion of 10(-2) M N-methyl-D-aspartate (NMDA). These results suggest that the glutaminergic neuronal system regulates functions of the cholinergic neuronal system.

Effects of the subacute administration of nefiracetam on abnormal behavior in aged rats

We investigated the effects of nefiracetam on learning and memory by the Morris water maze task and water-finding test, and on emotional behavior by forced swimming, hole-board and open-field tests in old male Kbl Wistar rats aged 90 and 108 weeks. In the water maze task, the acquisition of the task in aged rats was slower than that in young rats. Subacute administration of nefiracetam (1 and 3 mg/kg daily) for 24 days tended to shorten the goal latency to escape onto the platform in a dose-dependent manner in the retention test, conducted 24 days after acquisition training. Nefiracetam (1 mg/kg) administration for 49 days decreased the duration of immobility in aged rats in the forced swimming test. Locomotor activity in young rats during the dark period was significantly higher than that during the light period, while there was no difference in locomotor activity between the light and dark periods in aged rats, suggesting that locomotor activity during the dark period and nocturnal habits may be impaired in aged rats. Subacute administration of nefiracetam for 14 days significantly increased the locomotor activity during the dark, but not light, period in a dose-dependent manner. In addition, nefiracetam given for 38 days, significantly shortened the increased time elapsed before animals started exploring the environment in aged rats compared with young rats in the water-finding tests. These findings suggest that nefiracetam may improve the impaired nocturnal habits and some of emotional behavior in aged rats.

Role of dopaminergic neuronal system in dizocilpine-induced acetylcholine release in the rat brain.

SummaryThe effects of dopaminergic receptor antagonists on dizocilpineinduced increase in extracellular acetylcholine (ACh) levels in the rat parietal cortex were examined in freely-moving rats, using an in vivo brain microdialysis method.Dizocilpine (0.5 mg/kg) significantly increased extracellular ACh levels in the rat parietal cortex and hippocampus, but not in the striatum. Pretreatment with α-methyl-p-tyrosine methyl ester (αMpT) delayed the onset but prolonged the duration of the dizocilpine-induced increases in extracellular ACh levels. The dopamine D2 receptor antagonist, haloperidol, showed dual effects similarly to αMpT, while the dopamine D1 receptor antagonist, SCH23390, prolonged, but did not delay, the onset of the dizocilpine-induced increases in ACh levels.These results suggest that the dopaminergic system is involved in the dizocilpine-induced increase in the extracellular ACh level in the parietal cortex in two ways, through both dopamine D1 and D2 receptors.

Is free fraction measurement of phenytoin always necessary in pediatric epileptic patients

Sixty-two serum samples from 28 pediatric epileptic patients under treatment with phenytoin [diphenylhydantoin (DPH)] were obtained to study the correlation between total and free serum DPH concentrations. The effect of coadministered antiepileptic drugs on DPH protein binding was also studied. Binding of DPH to serum protein was assessed by ultrafiltration, and total and free DPH concentrations were determined by fluorescence polarization immunoassay. A strong correlation existed between the total and free concentrations [r = 0.958, p < 0.001, standard error of estimate (± 1Sγ) = 0.214]. The mean value for the DPH free fraction was 8.9% (range 5.7–16.3%). The samples obtained from patients on combination therapy with valproic acid (VPA) showed a larger DPH free fraction and greater variation. Exclusion of the 16 samples from patients concomitantly taking DPH and VPA yielded a better correlation (n = 46, r = 0.983, p < 0.001, ± 1Sγ = 0.145). The mean free fraction in the patients not taking VPA was 7.7% (range 5.7–9.0%). The effect of VPA on the protein binding of DPH was also studied by addition of the same antiepileptic drugs to normal human plasma; the results were similar to those obtained for epileptic patients. These findings suggest that the free DPH fraction can be predicted from the total concentration, even when the drug is coadministered with other antiepileptic drugs, the sole exception being VPA

Clinical evaluation of theophylline binding to plasma protein in bronchial asthmatic patients.

Theophylline binding to plasma protein was studied with seven bronchial asthmatic inpatients. The extent of protein binding was monitored using an ultrafiltration device, EMIT® FreeLevelTM System 1, whose performance is pH independent between 7·5 and 8·5 and concentration independent between 2 and 10 mcg/ml. When protein‐free theophylline solutions are used a linear pH dependency was observed between 7·0 and 8.3. With theophylline‐spiked human plasma using the same samples, the binding was found to be concentration‐independent in the range 5 to 40 mcg/ml. The intra‐ and inter‐individual variations in theophylline binding to plasma proteins were relatively large. A calculation procedure for predicting free fractions at normal physiological plasma pH, 7.4, using the observed free fraction at a given plasma pH is proposed. A good correlation was obtained between plasma and salivary theophylline concentrations. Salivary levels alone, however, are unreliable for monitoring theophylline therapy.