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YAKUGAKU ZASSHI, 125(11),833-852, 2005
The cholesterol hypothesis implies that reducing the intake of saturated fatty acids and cholesterol and increasing that of polyunsaturated fatty acid are effective in lowering serum total cholesterol (TC), and thereby reducing the incidence of coronary heart disease (CHD). However, these dietary recommendations are essentially ineffective in reducing TC in the long run, but rather increase mortalitiy rates from CHD and all causes. The reported “apparent relative risk of high TC in CHD mortality” (the ratio of mortality at the highest/lowest TC levels) varied several-fold among populations studied. The incidence of familial hypercholesterolemia (FH) in a population was proposed to be a critical factor in the observed variability, which could be accounted for by assuming that 1) the high CHD mortality rate in high-TC groups is mainly a reflection of the incidence and severity of FH, and 2) high TC is not a causative factor of CHD in non-FH cases. This interpretation is supported by recent observations that high TC is not positively associated with high CHD mortality rates among general populations more than 40-50 years of age. More importantly, higher TC values are associated with lower cancer and all-cause mortality rates among these populations, in which relative proportions of FH are likely to be low (circa 0.2%). Although the effectiveness of statins in preventing CHD has been accepted in Western countries, little benefit seems to resulf from efforts to limit dietary cholesterol intake or to TC values to less than approximately 260 mg/dl among the general population and the elderly. Instead, an unbalanced intake of ω6 over ω3 polyunsaturated fats favors the production of eicosanoids, the actions of which lead to the production of inflammatory and thrombotic lipid mediators and altered cellular signaling and gene expression, which are major risk factors for CHD, cancers, and shorter longevity. Based on the data reviewed here, it is urgent to change the direction of current cholesterol-related medication for the prevention of CHD, cancer, and all-cause mortality.
Key words--cholesterol; atherosclerosis; hypothesis; statin; omega-6/omega-3 fatty acid
YAKUGAKU ZASSHI, 125(11),853-861, 2005
In silico methods for predicting pharmacokinetic properties range from data-based approaches such as quantitative structure-activity relationships (QSARs), similarity searches, and 3-dimensional QSAR, to structure-based methods such as ligand-protein docking and pharmacophore modelling. Data-based modelling approaches are effective for many drug absorption, distribution, metabolism, and excretion (ADME) processes such as passive membrane permeation, where their molecular mechanism is barely delineated. Therefore QSAR approaches have been applied to simulate the relationships between ADME parameters and molecular structure and properties. In the present investigation, we describe the application of the genetic algorithm-combined partial least-squares (GA-PLS) method to QSAR modelling of various ADME properties. By selecting an appropriate set of molecular descriptors automatically using the genetic algorithm, many ADME properties could be well explained by simple molecular descriptors derived from the 2-dimensional chemical structure.
Key words--in silico; ADME; QSAR; genetic algorithm; partial least squares; multivariate analysis
YAKUGAKU ZASSHI, 125(11),863-874, 2005
Variable 7-carboxylpropoxy or (1-phenyl)ethoxybenzo[b]furan derivatives with (E)- and (Z)-2-alkylcarbamoyl-1-methylvinyl groups at the 2-, 4-, and 5-positions were prepared to find novel and selective leukotriene B4 (LTB4) receptor antagonists. (E)-2-(2-Diethylcarbamoyl-1-methylvinyl)-7-(1-phenylethoxy)benzo[b]furan (4v) showed selective inhibition of the human BLT2 receptor (hBLT2). On the other hand, (E)-2-acetyl-4-(2-diethylcarbamoyl-1-methylvinyl)-7-(1-phenylethoxy)benzo[b]furan (7c) inhibited both human BLT1 receptor (hBLT1) and hBLT2. The (E)-2-(2-diethylcarbamoyl-1-methylvinyl) group lay on approximately the same plane as the benzo[b]furan ring, whereas the (E)-4-(2-diethylcarbamoyl-1-methylvinyl) group had a torsion angle (45.7°) from the benzo[b]furan ring plane. However, the (Z)-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans were inactive. The inhibitory activity depended on the conformation of the 2-alkylcarbamoyl-1-methylvinyl groups.
Key words--leukotriene B4 antagonist; BLT; 2-alkylcarbamoyl-1-methylvinyl groups; conformation; benzo[b]furan
YAKUGAKU ZASSHI, 125(11),875-879, 2005
We studied a reverse phase HPLC method employing a simple acetonitrile: 0.1% phosphoric acid aqueous solution gradient as the mobile phase for the determination of furanocoumarin (FC) derivatives, such as bergamottin (BG) and 6',7'-dihydroxybergamottin (DHB), using UV detection. Anthracene was added to samples as an internal standard. A Capcell Pak SG-Phenyl column (4.6 mm [inner diameter]×25 cm; particle size 5 mm; Shiseido) was used, and the flow rate was set at a constant 1 ml/min. A photodiode array detector was used because it reveals the characteristic UV-absorption spectrum of FCs, commonly with 311 nm as the maximum wavelength. Furanocoumarin derivatives in pomelo juice (PJ) were detected by the method and compared with those in grapefruit juice (GJ) and orange juice (OJ). GJ contained 3 kinds of FCs, BG, DHB and bergaptol (BT). OJ had no FCs. On the other hand, PJ contained 8 kinds of FCs including BT, BG and DHB. This FC detection system may be effective for identifying foods and beverages that interact adversely with drugs.
Key words--HPLC; furanocoumarin; grapefruit juice; drug interaction; pomelo juice
YAKUGAKU ZASSHI, 125(11),881-887, 2005
Rheumatoid factor (IgM-RF) has been widely used to diagnose rheumatoid arthritis (RA) in clinical practice. We investigated the RA diagnostic performances of anti-cyclic citrullinated peptide antibody (anti-CCP), matrix metalloproteinase-3 (MMP-3), anti-agalactosyl IgG antibody (CA·RF), and anti-calpastatin antibody (ACA) in comparison with IgM-RF. Among 68 RA patients, IgM-RF was positive in 31 (45.6%) and negative in 37 (54.4%). In the IgM-RF-positive group, positivity in anti-CCP, CA·RF, and ACA was 97%, 100%, and 97%, respectively, although that in MMP-3 (74%) was inferior to the others. On the other hand, in the IgM-RF-negative group, positivity in anti-CCP, MMP-3, and ACA was 73%, 81%, and 86%, respectively, although that in CA·RF was only 59%. We conclude that the combination of IgM-RF and anti-CCP/ACA will provide an accurate diagnosis of RA in clinical practice.
Key words--rheumatoid arthritis; rheumatoid factor; cyclic citrullinated peptide; anti-calpastatin antibody
YAKUGAKU ZASSHI, 125(11),889-893, 2005
It has been reported that grapefruit juice (GJ) causes pharmacokinetic interactions with many drugs after co-ingestion, but the effects of the juice of sweetie fruit, a cross between a pomelo and a grapefruit, on the pharmacokinetics of medicines have not been clear. The present study investigated the drug interaction capability of sweetie juice (SJ). The effect of SJ on nifedipine (NFP) pharmacokinetics in rats was studied. Two milliliters of SJ, GJ, or saline was administered to the rat duodenum. After 30 min, NFP was administered intraduodenally at a dose of 3 mg/kg body weight. The NFP concentrations in the plasma samples were determined by high performance liquid chromatography (HPLC). Although GJ increased the area under the plasma concentration-time curve (AUC) of NFP (1.6-fold), SJ had no significant effect on the NFP pharmacokinetics in rats. Furthermore, concentrations of furanocoumarin derivatives in SJ were measured by HPLC equipped with a photodiode array detector, and compared with those in GJ. SJ contained lower concentrations of bergamottin (0.53 μg/ml), 6', 7'-dihydroxybergamottin (0.19 μg/ml), and bergaptol (0.2 μg/ml) than the GJ used in this study (6.3 μg/ml, 3.6 μg/ml, and 9.4 μg/ml, respectively). In conclusion, the results suggest that SJ had no effect on the NFP pharmacokinetics in rats due to low furanocoumarin concentrations in SJ.
Key words--sweetie juice; pharmacokinetics; grapefruit juice; furanocoumarin; nifedipine; drug interaction
YAKUGAKU ZASSHI, 125(11),895-898, 2005
There is a prevailing legend that grapes and alfalfa were introduced to China from West Asia by Zhang Qian in 126 BC. This paper intends to show the legend to be a misconception. The three crucial documents were thoroughly examined, and the author believes he can demonstrate that it was a later traveler who actually brought these two plants to China following the trade route pioneered by Zhang Qian.
Key words--grapes; alfalfa; Zhang Qian; China