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.

A three-dimensional pharmacophore model of mesangial cell (MC) proliferation inhibitors was generated from a training set of 4-(diethoxyphosphoryl)methyl-N-(3-phenyl-[1,2,4]thiadiazol-5-yl)benzamide, 2, and its derivatives using the Catalyst/HIPHOP software program. On the basis of the in vitro MC proliferation inhibitory activity, a pharmacophore model was generated as seven features consisting of two hydrophobic regions, two hydrophobic aromatic regions, and three hydrogen bond acceptors. Using this model as a three-dimensional query to search the Maybridge database, structurally novel 41 compounds were identified. The evaluation of MC proliferation inhibitory activity using available samples from the 41 identified compounds exhibited over 50% inhibitory activity at the 100 nM range. Interestingly, the newly identified compounds by the 3D database searching method exhibited the reduced inhibition of normal proximal tubular epithelial cell proliferation compared to a training set of compounds.

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.

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Seventeen murine monoclonal antibodies (mAbs) against horseshoe crab clotting factor, factor C, were prepared and characterized. When the binding sites of these mAbs were analyzed by immunoblotting, ten mAbs recognized nonreduced factor C, five mAbs were directed against the heavy chain, and two mAbs were directed against the B chain. Three mAbs, 1H4, 2C12, and 2A7, one selected from each group, were used for further study. The mAb 1H4, which recognized only nonreduced factor C molecule, inhibited the factor C activity in a dose-dependent manner. It also inhibited lipopolysaccharide (LPS)- and alpha-chymotrypsin-mediated activations of the zymogen factor C, suggesting that 1H4 binds close to the active site and/or the substrate-binding site located in the serine protease domain (B chain) of factor C. On the other hand, 2C12 and 2A7 recognized, respectively, an epitope located in the heavy and the B chains, and inhibited LPS-mediated activation of factor C, but not alpha-chymotrypsin-mediated activation of factor C or factor C activity. Both F(ab')2 and Fab' fragments derived from 2C12 inhibited LPS-mediated activation in the same manner. These three mAbs did not bind with LPS, although a factor C-mAb complex was able to bind LPS, suggesting that the LPS-mediated activation of the zymogen factor C was induced through intermolecular interaction between the LPS-bound factor C molecules. The dissociation constants (Kd) for 1H4, 2C12, and 2A7 binding to factor C were determined as 1.9 x 10(-9), 0.6 x 10(-10), and 1.8 x 10(-10) M, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)