Benign prostatic hyperplasia (BPH) is an age-related disorder characterized by urinary outlet obstruction. This obstruction is due to both mechanical compression of the urethra by the hypertrophied prostate and to functional contraction of the prostate and urethra by sympathetic stimulation. We invented a novel compound tamsulosin hydrochloride, a sulphamoyl-phenethylamine derivative which possesses potent and selective α1-antagonism, and showed that this compound selectively reduced the intra-urethral pressure in the prostatic segment of the urethra in vivo. We also found that the α1-adrenoceptor plays an important functional role in the prostate and urethra. For clinical use, a control release formulation was developed. This formulation did not induce orthostatic hypotension and could be administered at a fixed dose. A placebo-controlled double-blind dose finding study resulted in 0.2mg/d as the optimal dose. This formulation significantly improved urinary outlet obstruction without affecting blood pressure as compared with placebo in P-III study, and was approved in 1993 for use in the treatment of bladder outlet obstruction associated with BPH. Tamsulosin hydrochloride is the first α1-antagonist which improves bladder outlet obstruction associated with BPH without affecting blood pressure, and the treatment can be initiated and maintained at a fixed dose. Recently, the α1-adrenoceptor subtypes α1A, α1B and α1C were identified. The α1C subtype is predominant and plays an important role in the human prostate. Tamsulosin hydrochloride shows high selectivity for this subtype, further supporting the clinical findings that tamsulosin hydrochloride improves bladder outlet obstruction associated with BPH with no effect on the cardiovascular system.
Pollutants in water environment are briefly reviewed concerning the water quality standard, especially the new items listed in the standard. They are disinfection byproducts, organohalogen compounds, and agrochemicals. Effects of chlorination and ozonation in the water treatment process on these contaminants and the contribution of the free radical to their toxicity are also discussed. Chlorination and ozonation in the water treatment process are believed to produce various active oxygen species, which seem to participate in the reaction with fumic acid, pollutants and bacteria. Main active oxygen species generated during the water treatment was a hydroxy radical, because DMPO-OH adduct was detected by the spin-trapping electron spin resonance (ESR) technique using 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin-trapping reagent. Besides DMPO-OH, several DMPO adducts detected in both treatments were also described.
Fuzzy adaptive least-squares (FALS), a pattern recognition method of the correlating chemical structure with activity rating, has been developed to generate quantitative structure-activity relationship (QSAR) models for the drug design and screening hazardous chemicals. It is a novel feature of FALS that the degree to which each sample belongs to its activity rating is given by a fuzzy membership function. The method and its application contributed by the author and his coworkers were briefly reviewed. Using FALS, congeneric QSAR analyses of 29 allergenic α-methylene-γ-butyrolactones and 31 calmodulin inhibitors, and non-congeneric QSAR analyses of aquatic toxicity of 394 organic chemicals and human acute toxicity of 504 compounds were performed to construct predictive QSAR models. Furthermore, predictive accuracies of rodent carcinogenicity of 25 organic compounds issued from U.S. National Institute of Environmental Health Sciences were compared using several methods including a QSAR model with FALS. Finally a revised method of calculationg log P (partition coefficient in octanol/water) was proposed for the QSAR studies. The revised method is not only simple and convenient but also reliable compared with the Rekker method and the Hansch-Leo method.
The whole blood of human, rabbit and dog spiked with dilazep was fractionated by discontinuous density gradients of Ficoll-Paque, and the species difference of distribution to blood components was elucidated. In order to quantatively evaluate its blood distribution, the binding property of dilazep to the isolated erythrocytes and platelets was also studied. Dilazep undergoes saturable binding to the erythrocytes. Therefore, the fitting of the data sets to binding models was carried out using the nonlinear least-square method, and binding parameters were calculated. This technique could be also applied to analyze directly the binding parameters for several whole blood components. In human and rabbit, dilazep was bound to the erythrocytes with a high affinity (human, KERY=0.466nM ; rabbit, KERY=0.0417nM), however, the affinity to the erythrocytes in dog was very low. On the other hand, the binding affinity to the platelets decreased in the order of rabbit>dog>human.
We studied that the morphological and histological characteristics, and the content (%DW) of saikosaponins on the root of Bupleurum falcatum cultivated in an Ebb & Flood system (E&F), a kind of soilless culture system, by both the direct sowing and the transplanting methods, and that effects of pinching on the root growth and the content (%DW) of saikosaponins in each part of root. Yield of root and content (%DW) of saikosaponins in each part of root, 8-months-old, cultivated in E&F by both methods were at the same level as that cultivated for the same period in soil conditoin by generally standard procedures. Morphological characteristics of the root cultivated by the direct sowing method were the same appearance as that by soil condition, but by the transplanting method main root branched off in all direction and the lateral root were more developed than by the direct sowing method. By pinching lignification in xylem on the main root were inhibited, but the dried weight of total root part and content (%DW) of saikosaponins in each part of the root were not shown to be significantly changed.
The hypolipidemic effects of ethyl all-cis-5, 8, 11, 14, 17-icosapentaenoate (EPA-E) on cholesterol diet-fed rabbits were studied. EPA-E (300mg/kg, p.o.×4 weeks) decreased total cholesterols in the lipoprotein fractions of very lowdensity lipoprotein and intermediate lipoprotein+low-density lipoprotein (LDL), but not in high-density lipoprotein. Furthermore, the properties of LDL were investigated in rabbits given EPA-E (300mg/kg, p.o.×2 weeks). EPA-E had no influence on the lipid composition in LDL, and the cholesterol accumulation into macrophages was not increased by the incubation with EPA-E-treated LDL. However, the ω3 polyunsaturated fatty acids contents of LDL were increased by the administration of EPA-E. EPA-E-treated LDL was also studied on the binding to the hepatic membranes. The binding of EPA-E-treated LDL to the hepatic membranes was higher than that of ordinary LDL. These results suggest that EPA-E causes a modification of LDL, such that EPA-E has an enhancing effect on the hepatic uptake of LDL. These effects may contribute to the hypolipidemic action of EPA-E.
Pharmacological effects on anti-diuresis, anti-ulceration, anti-dementia and learning function of 50% ethanolic extract (AO-ext) from Alpiniae Fructus (fruit of Alpinia oxyphylla) removed seedvessel were investigated in order to prove the evidence of the efficacy of Alpiniae Fructus on the ancient herbal literature. AO-ext showed the effects of anti-diuresis, anti-ulceration, anti-dementia and on increase in the learning function in animals. And also, AO-ext exhibited the increasing effect on the serum 11-hydroxycorticosteroid (11-OHCS) level in the above-described experimental animals and in intact and hypophysectomized rats.
The reaction of gem-dibromocyclopropanes (1) with a higher-order organocuprate prepared from CuCN and commercially available MeLi, followed by the addition of MeI in situ, afforded dimethylcyclopropanes (2) in good yields. The differential substitution reaction of dibromide (1a) in one pot with the higher-order organocuprate and allyl bromide gave a compound (8) in the moderate selectivity as shown in Table 3. Its stereochemistry was deduced by the reaction mechanism.