This article is a summary of the molecular patho-pharmacological studies continuously investigated for more than 30 years in Toyama Medical & Pharmaceutical University. The aim of this study was to develop the motivation and the strategy for the original drug-design by targeting the pharmacological mechanism of receptor modified by the pathological state in the animal models for the diseases, followed by searching the pathoreceptor-sensitive drugs as a probe of new medicines. The drug activity consists of two factors, affinity and intrinsic activity to the receptor, depend on their chemical structures of supporting moiety and radical moiety, respectively. The former can be discovered from the natural products, composing Japanese traditional Sino-medicines, and the latter can be modified by chemical synthesis. By using this strategy, several new findings, a large number of new compounds and/or new pharmacological activity, were obtained as follows. I. On the molecular pharmacology of nicotinic ACh receptor. II. On the development of new drugs affecting on smooth muscle. III. On the pathopharmacological investigation with a model of diabetic mice. IV. On the applied pharmacology of Japanese traditional Sino-medicines.
Cimicifugae Rhizoma have been used as an anti-inflammatory, analgesic and antipyretic remedy in the traditional Chinese medicines. Many 9, 19-cyclolanostane glycosides have been isolated from Cimicifuga and related genera. Two biogenetically key compounds, acetylshengmanol xyloside and cimicifugoside H-1, were isolated and their chemical structures were elucidated by our group. The former compound seems to be the parent component of the other glycosides such as cimigenol xyloside, 25-O-acetylcimigenol xyloside, 25-O-methylcimigenol xyloside and cimigol xyloside from C. dahurica, C. iaponica and C. acerina. The latter glycoside, cimicifugoside H-1 was isolated together with cimicifugosides H-2-H-6 from commercial Cimicifugae Rhizoma. They are novel glycosides having a hydroxyl group at C-11, and cimicifugosides H-3, H-4 and H-6 were trinor-triterpenol glycosides. Cimicifugoside H-1 changed into H-2, H-3 and H-4 under acidic or alkaline conditions. In this review, the structure elucidation of the above glycosides and their chemical transformation into the other Cimicifuga glycosides are described.
The physicochemical properties of the enantiomer and racemates of suplatast tosilate (ST) were investigated by means of infrared spectroscopy, solid-state 13C CP/MAS NMR spectroscopy, thermal analysis, and X-ray diffraction analysis, and by measuring the solubility and hygroscopy. The infrared and NMR spectra and X-ray diffraction pattern of the enantiomer were distinctly different from those of the racemate. The melting point of the enantiomer was lower than that of the racemate by 5°C, while the solubility of the enantiomer was 1.3 times higher than that of the racemate. The hygroscopic rate of the enantiomer was greater than that of the racemate. These results suggested that ST was classified into a racemic compound crystal. Furthermore, by comparing the relative peak intensity ratios on X-ray diffraction patterns of crystals with various optical purities prepared by recrystallization, it was found that a mixture of racemic compound crystals and either of racemic mixture crystals or racemic solid solutions was obtained by recrystallization of ST in the content of 0 to 64%ee, while the recrystallization of ST in the content of more than 64%ee led to the formation of racemic mixture crystals or racemic solid solutions.
A new prediction method of vancomycin (VCM) pharmacokinetics has been developed using the modified Bayesian forecasting method involved in time-dependent pharmacokinetics in clearance. We investigated to evaluate the usefulness of this new prediction method compared with that of the ordinary Bayesian forecasting method. Serum samples, obtained from 4 patients at least 3 different days during the period for the VCM treatment were assayed by fluorescence polarization immunoassay. VCM pharmacokinetic parameters and predicted serum VCM concentrations were calculated using this new method and the ordinary one according to the one-compartment model. The precision of the predicted serum VCM concentrations by these two methods at the third experimental day were evaluated with the mean prediction error (ME), mean absolute prediction error (MAE) and root mean squared error (RMSE). The most precise and least-bias prediction of serum VCM concentrations were observed using this new prediction method (ME : -0.36±1.40, MAE : 1.13±0.82 and RMSE : 1.37). The time-dependent decrease of VCM clearance was observed in all patients. Therefore, the fitting of the actual serum VCM concentrations obtained using the ordinary method produced less precise results than that using this new method. These results suggest the usefulness of this new prediction method considering time-dependent changes in VCM clearance.
We examined the pharmacological profiles of a novel tachykinin NK-2 receptor antagonist, Nα-(tert-butylcarbamoyl)-L-glutaminyl-L-tryptophyl-α-azaphenylalanine 2-benzyloxyethylamide (TAC-363). In vitro studies showed that TAC-363 caused a rightward shift of the contraction response curve with a slight inhibition of maximal response for the neurokin A (NKA)-induced contraction of the hamster trachea and parallel rightward shift of the curve for the substance P (SP)-induced contraction of the guinea-pig ileum. The pA2 values were 9.82 and 8.42 on the contraction by NKA and SP, respectively. The selectivity of TAC-363 to NK-2 receptor was 25 times higher than that to NK-1 receptor. The compound did not affect the histamine and acetylcholine-induced contraction of the guinea-pig ileum. Intravenous administration (0.1-1 mg/kg) of the compound inhibited dose-dependently both NKA-and capsaicin-induced bronchoconstriction in guinea-pigs. The inhibitory effect of the compound lasted up to 60 min on NKA-induced bronchoconstriction in guinea-pigs. These results suggest that TAC-363 is a potent and selective NK-2 receptor antagonist, which is effective in vitro and in vivo. It may be useful in the treatment of NKA-dependent pathology, especially bronchial asthma.
An O/W-type emulsion of soybean oil (φv=0.05) was prepared in the presence of various concentrations of hydroxypropylcellulose (HPC) and sodium dodecylsulfate (SDS). The mean diameter (d) of secondary particles of the oil droplets decreased with concentrations of SDS and HPC after attaining a maximum at [SDS]=5 mmol/dm3 and [HPC]=10-3g/dl, while the relative viscosity (ηrel) of the emulsion increased with an SDS concentration after attaining a minimum around 5 mmol/dm3 when the HPC concentration was kept constant. These facts were explained in terms of the formation of a surface complex by hydrophobic interaction between SDS and HPC adsorbed on the surface of the droplets. When the concentration of SDS is low, it bridges between the HPC segments intra-and intermolecularly on and between the particles, resulting in shrinking of the HPC surface layers as well as in bridging among the particles. Therefore, the total volume of the secondary particles effective on ηrel decreases while the d-value increases with the SDS concentration. When the concentration becomes high, the binding ratio of SDS to HPC also increases and the segments are repulsive each other owing to the negative charges given by the bound SDS. As a result, the adsorption layer swells and the secondary particles are redispersed. This fact causes an increase in ηrel and a decrease in the d-value with a concentration of added SDS.