Influence of anticholinergic activity in serum on clinical symptoms of Alzheimer's disease.

Alzheimer's disease (AD) is well known as a disease characterized by degeneration of cholinergic neuronal activity in the brain. It follows that patients with AD would be sensitive to an 'anticholinergic burden', and also that medicine with anticholinergic properties would promote various clinical symptoms of AD. Despite the relevance of this important phenomenon to the clinical therapeutics of AD patients, few reports have been seen concerning the relationship between anticholinergic burden and clinical AD symptoms. Therefore, we wished to investigate the relationship between serum anticholinergic activity (SAA) and the severity of clinical symptoms of AD patients. Twenty-six out of 76 AD patients referred by practitioners to our hospital were positive for anticholinergic activity in their serum, and the remaining 50 patients were negative. Cognitive and psychiatric symptoms in AD patients were compared between the positive SAA (SAA+) group and the negative SAA (SAA-) group. The SAA+ group showed a significantly (p < 0.05) lower total score on the Mini-Mental State Examination, and significantly (p < 0.05) higher scores on the Functional Assessment Staging and the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). In particular, certain subscales of the BEHAVE-AD, i.e. the items of paranoid and delusional ideation, hallucinations and diurnal rhythm disturbances, had higher scores in the SAA+ group. Moreover, it was shown that many more psychotropic medicines were prescribed to the SAA+ group. By means of logistic regression analysis, the items of paranoid and delusional ideation and diurnal rhythm disturbances in the BEHAVE-AD were positively correlated with SAA in patients. We hypothesized that SAA in AD patients would be associated with clinical symptoms, especially delusion and diurnal rhythm disturbances.

Mechanism of clobazam-induced thyroidal oncogenesis in male rats.

In order to elucidate the mechanisms by which long-term treatment with clobazam (CLB), 1,5-benzodiazepine, induces thyroid follicular cell tumors in male rats, male Sprague-Dawley (SD) rats were treated orally with 400 mg/kg of CLB for up to 4 weeks, and the contribution of feedback through elevated thyroid stimulating hormone (TSH) was investigated. Measurements taken after 1, 2, and 4 weeks of treatment revealed that thyroxine (T4)-UDP-glucuronosyltransferase (T4-UDPGT) activity was higher than that of untreated animals. This change was accompanied by increase in liver weights and centrilobular hepatocyte hypertrophy. In addition, plasma total triiodothyronine (T3) and T4 levels were lower than in the untreated rats when measured after 1 week of treatment. However, a high plasma TSH level was sustained throughout the 4-week treatment. Thyroid follicular cell hypertrophy began after 1 week of treatment, followed by increased thyroid weight after 2 weeks. Clearance of exogenous [125I] T4 from the blood of treated rats, determined after 4 weeks of treatment, was significantly faster than that in untreated rats, whereas iodine uptake and organification in the thyroid glands were not affected. These results suggest that CLB increases hepatic T4-UDPGT activity leading to acceleration of T4-clearance, which results in decreased plasma thyroidal hormones followed by compensatory increase of TSH biosynthesis and secretion. Chronic high levels of TSH would exert a continuous growth pressure on the thyroid, under which hypertrophic follicular cells can ultimately progress to frank neoplasms.

Uptake mechanism of pitavastatin, a new inhibitor of HMG-CoA reductase, in rat hepatocytes.

To understand the mechanism underlying the highly liver-selective distribution of pitavastatin, uptake experiments were performed using rat hepatocytes. The uptake of pitavastatin into rat hepatocytes is carrier-mediated and involved nonspecific diffusion in the presence of Na(+). The michaelis constant (K(m)) was 26.0 micromol/L, maximal uptake velocity (V(max)) was 3124 pmol/min/mg protein, and non-specific uptake (P(dif)) was 1.16 microL/min/mg protein. There were no remarkable differences in these kinetic parameters between the presence and absence of Na(+). Experiments using metabolic inhibitors revealed that energy-dependent systems contribute to the uptake of pitavastatin in the liver. Some organic anions reduced the uptake into rat hepatocytes in a concentration-dependent manner. The observed rates of inhibition of pitavastatin uptake by BSP, TCA and pravastatin were compared with the predicted rates. The predicted values were calculated, assuming that BSP, TCA and pravastatin inhibit the uptake of pitavastatin in a competitive manner. The observed inhibition by BSP and TCA was similar to that predicted, but the observed inhibition by pravastatin was considerably less than that predicted. In conclusion, most of the pitavastatin taken up into the liver is transported by multiple carrier-mediated transporters such as Na(+)-independent multispecific anion transporters and energy-dependent transporters. In addition, these systems for pitavastatin may have features in common with the BSP and TCA transport system, and may partially involve the pravastatin transport system.