"Toxicology"includes a broad range of application such as environmental, clinical and forensic toxicology. These several kinds of applied toxicology forms a mutually connected ring. This ring is supported by a column called as deductive and detective analysis by the author."Deductive toxicology"is a way of thinking to solve toxicological problems more multidimensionally. In this paper, an application of this way to the study of bone lesions observed in Itai-itai diseased patients is described. In cultured embryonic chick bone, both cadmium and copper induced an atrophic change of the osseous tissue. However, zinc induced an osteomalacic change as a result of strong inhibition of calcification. These histological changes were supported by investigation using a culture system of osteoblastic MC3T3-E1 cells. Cadmium stimulated bone resorption in a neonatal parietal bone. In addition, cadmium stimulated the formation of osteoclast-like cells in bone marrow cell culture. It is thus suggested that cadmium and copper are factors of osteoporosis whereas zinc is a factor of osteomalacia when they directly act on bone tissues. A simultaneous exposure of cadmium and zinc to cultured bones resulted in an osteomalacic change with or without inhibition of bone matrix formation. Copper caused an atrophic change in the absence or the presence of zinc. A combination of cadmium and copper induced a severe damage of osteoblasts and osteogenic mesenchymal cells. These results suggested that an interactive exhibition of heavy metal toxicity can cause various bone lesions such as osteomalacia, osteoporosis and osteoporomalacia. The idea that heavy metals can directly act on bone tissues and their interaction can induce various histological changes in the tissue will help an understanding of bone lesions in Itai-itai disease.
The development of the tracer methods in the drug evaluation study during the past thirty five years was reviewed. Several examples where stable isotope tracer techniques fully demonstrated their advantages were described. The applicability of 13C-NMR tracer techniques was discussed. The strategy for the metabolism study of peptides, microplate-radioluminography as a substitute for liquid scintillation counting and a quantitative whole body autoradiography were newly proposed.
2, 4-Dihydroxy-7-methoxy-2H-1, 4-benzoxazin-3 (4H)-one and its desmethoxy derivative (DIMBOA and DIBOA) are major phytoalexins produced by rye, wheat, zea maize and related monocotyledoneae plants. These compounds elicit a wide variety of biological activities including antifungal and mutagenic activities. Structure-activity relationships of these compounds and their derivatives (benzoxazinoids), and the reactivity of benzoxazinoids with nucleophiles are discussed in relation to the molecular mechanism of their biological activity. The electrophilic reaction mechanism of benzoxazinoids and substituent effects of namely 7-methoxy and 2-hydroxy groups are also discussed.
Inhibitory activities of FUT-187 on trypsin-like serine proteases were compared using camostat mesilate (camostat), and 4-(4-guanidino benzoyloxy)-phenyl acetic acid methanesulfonate (GBPA) known as an active metabolite of camostat in the blood. Ki values of FUT-187 on the competitive inhibition mechanism were 0.097 μM for trypsin, 0.029 μM for pancreatic kallikrein, 0.61 μM for plasma kallikrein, 0.57 μM for plasmin, 2.5 μM for thrombin, 20.4 μM for factor Xa and 6.4 μM for Clr. However, FUT-187 acted as a noncompetitive inhibitor for factor XIIa and an uncompetitive inhibitor for Cls, and Ki values for these proteases were 0.021 and 0.18 μM, respectively. Ki values of camostat for these proteases were in the range of 0.037 to 96.4 μM, and those of GBPA for the above proteases except trypsin and plasma kallikrein were higher than those of FUT-187. The inhibitory activity of FUT-187 on trypsin was not reduced by the addition of the serum at 10%, whereas, that of GBPA was reduced (4.3 fold) in terms of IC50 values. The concentration of FUT-187 required to double APTT (activated partial thromboplastin time) was 1.09 μM, while GBPA, by concentrations up to 1 mM failed to double APTT. The kinin formation by glandular kallikrein in the rat plasma was inhibited by FUT-187 with IC50 value of 0.024 μM, while camostat revealed no inhibition by concentrations up to 1 μM. The complement-mediated hemolyses in the classical and alternative pathways were also inhibited by FUT-187 with IC50 values of 0.17 and 3.5 μM, respectively, the corresponding values for camostat being 350 and 150 μM, respectively. It is concluded that FUT-187 is a potent and selective inhibitor of trypsin-like serine proteases, and its inhibitory activities are stronger than those of camostat on glandular kallikrein, factor XIIa and Cls in complement pathway.
A new 1, 4-dihydropyridine derivative, CS-905, currently under development as a Ca antagonist, showed a gradual onset and long duration in its antihypertensive effect upon single oral administration. The partition coefficient for CS-905 was measured along with 11 known dihydropyridine Ca antagonists by the HPLC method to clarify its mode of action. The log PHPLC for CS-905 was, 5.18, almost the same as that of manidipine and this value is the highest among the measured drugs. Its pharmacokinetic profile in SHR was also discussed.
The discoloration of shikonin (1) and β-carotene (2), occurring during storage of their ethanol solutions in the presence of oxygen in an illuminated room, was remarkably suppressed by hydrolyzable tannins, such as geraniin (4) and tannic acid JP (3) in the solution. The inhibitory effect of tannins was enhanced by the coexistance of metalic ion. The irradiation with ultraviolet lamp (254 and 365 nm) gave, at the first stage of the discoloration, two products, one of which was found to be 5, 8-dihydroxy-2-(1-hydroxy-3-oxo-4-methyl-4-pentenyl)-1, 4-naphthoquinone (7). The presence of hydrolyzable tannins induced higher accumulation of these two products in the solution, showing that the secondary structural transformations of these two products were strongly inhibited by these coexisting tannins. These results suggest that tannins could be efficient inhibitors of discoloration of natural pigments.
Partial solubility parameters of lactose packed into a glass column were calculated from adsorption energies of n-decane, acetonitrile and ethyl alcohol determined by gas-solid chromatography. Three kinds of crystalline lactoses, α-lactose monohydrate, anhydrous α-lactose (desiccated) prepared by desiccation with methyl alcohol, and anhydrous α-lactose (heated) prepared by heating, were used. It was characterized from the results that the partial solubility parameter, δp, due to dipole interaction, of anhydrous forms had two-fold value than that of the hydrous form. In addition, it was suggested that the affinity of lactose for water vapor and the solubility of lactose for water were able to be evaluated using the three dimensional plot of partial solubility parameters and the interaction radius calculated from partial solubility parameters. It was shown that the appropriate information for the evaluation of physicochemical properties of active ingredients and excipients in the formulation study could be obtained from the data determined using partial solubility parameters.
A simultaneous analysis of ginsenosides in Panax ginseng by high performance liquid chromatography recently established by us was applied to the analysis of various Ginseng Radix. The contents of ginsenosides in P. ginseng were examined according to the differences of the growth year, the used part of the plant, the method of processing and the cultivated location. In the case of P. ginseng cultivated in Nagano, Japan, the ratio (total ginsenosides content/total dry root weight) increases annually for three years. And it decreased at the fourth year and increases again at the fifth and the sixth years. Concerning the distribution of ginsenosides in the parts of the plant, they were contained at the highest level in a lateral root and in succession, in a rhizome>in a root hair>in a main root. They were also distributed much richer at periderm than at phloem or at xylem of a main root. The contents of panaxadiol-and panaxatriolsaponins gradually increase with the growth year, whereas an oleananesaponin, ginsenoside-Ro, drastically increases at the sixth year and goes to 15-fold, which suggests that the content of ginsenoside-Ro needs to be estimated much more when Ginseng Radix is evaluated. The fact that the processing for preparation of Red Ginseng increases the total content of saponins was clearly revealed by the present study. The highest contents of saponins among Red Ginsengs (all 6-year-old) were observed in ones prepared in Korea, and in Japan>in China, successively.
Suppressive effects of several iodinated contrast media on stimulus-induced aggregation of human platelets were demonstrated. All contrast media, including ionic (iothalamate and ioxaglate) and non-ionic ones (iohexol, ioversol and iopamidol), suppressed the collagen-and thrombin-induced aggregation in a concentration-dependent manner. The effects of the former were much stronger than those of the latter. With ioxaglate, a similar inhibitory effect was also observed on PAF-and U46619-stimulated aggregation. The suppressive effect of ioxaglate on collagen-stimulated aggregation almost disappeared upon dilution of the medium with the platelet-poor plasma, suggesting that the effect is reversible.
2, 6-Disubstituted 5-acetylpyrimidin-4-one oximes were heated in formic acid under reflux to undergo Beckmann rearrangement, giving 2, 6-disubstituted 5-acetylaminopyrimidin-4-ones (5a-d) in good yields.