Attempts were made to investigate the effect of 2'-carboxymethoxy 4, 4'-bis (3-methyl-2-butenyloxy) chalcone (sofalcone) on necrotizing agents-induced gastric lesions and on prostaglandin E₂ (PGE₂)-like activity of the gastric tissue in rats. 1. Sofalcone, 100 mg/kg i.p. and 300 mg/kg p.o., markedly suppressed 0.6 N HCl-or 100% Et0H-induced gastric lesions. Sofalcone, 100 mg/kg i.p., also significantly suppressed 0.2N NaOH-induced gastric lesions. 2. Sofalcone suppressed 0.6 N HCl-induced gastric lesions with both oral and intraperitoneal routes, and the effect was particularly marked at 60 min. A dose of 100 mg/kg i.p. showed suppression lasting for up to 300 min. 3. 0.6N HCl-induced gastric lesions were significantly aggravated by indomechacin treatment (10 mg/kg s.c.). Oral sofalcone (300 mg/kg) significantly suppressed the aggravation of gastric lesions by indomethacin given before and after sofalcone, but the i.p. (100 mg/kg) did not show significant suppression in the case of pretreatment with indomethacin. 4. PGs-like activity in the gastric tissue was increased in both of the fundus and the antrum by the administration of sofalcone without any dose-dependency. The increase was continuous and lasted for 6 h in the fundus of the stomach.

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Interaction between quercetin and superoxide radicals was investigated using xanthine-xanthine oxidase system and potassium superoxide as superoxide radical generators. Superoxide radical scavenging action of quercetin was demonstrated by measurement of the electron spin resonance spectrum of the 5-hydroperoxy-2, 2-dimethyl-1-1pyrrolidinyloxyl adduct. Degradation of quercetin by the radicals was demonstrated spectrophotometrically. Reduction of the quercetin mutagenicity by the radicals was demonstrated in the Salmonella typhimurium strain TA 98 by the Ames test.

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The first-pass metabolism of ethenzamide (ETB), which is considered to be a prodrug of salicylamide (SAM), was studied in rats in order to compare with that of SAM. The extent of first-pass metabolism after oral ETB estimated by oral and intravenous administration was as much as 82% and remaining 18% ETB entered into systemic circulation. Further, it has been confirmed that the first-pass metabolism of ETB is not due to the intestine but entirely due to the liver in which de-ethylation to SAM occurred at first, followed by exclusive conjugation with sulfuric acid and little SAM enters into the systemic circulation. On the other hand, it was previously demonstrated in rats that per se administered SAM is subjected to first-pass metabolism both in the gut and liver as much as about 60% and the remaining 40% entered the systemic circulation. Thus, the behavior of SAM is considerably different depending upon whether it is per se administered or formed from ETB through metabolism. The fact that little SAM appears in the systemic circulation after oral administration of ETB suggests that the pharmacological activity of ETB comes from its own attributes but not from SAM.

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A pharmacokinetic model of the enterohepatic circulation of acetaminophen glucuronide was investigated in rats with particular attention to a lag time between biliary excretion and reabsorption. The plasma drug data obtained after acetaminophen glucuronide injection into the various sites of the gut confirmed that there is a lag time in the enterohepatic circulation and that the lag time is due to the intestinal transit period of the conjugate to the site of the hydrolysis. The value of the lag time was fairly close to that reported previously in the rat. Based on the result, a compartment model with periodic trigonometric function for the enterohepatic circulation was built and the urinary excretion data were fitted to this model. Same parameters which are considered to be common to other glucuronide conjugates were in good agreement with those reported previously, indicating that the model and those values are useful to study the enterohepatic circulation for glucuronides of other compounds in the rat.

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The low molecular weight form of renin (M.W. 40000) in the extract of rat kidneycortex was converted into the high molecular weight form (M.W. 60000) in the presence of Cu²⁺ and this conversion was abolished following pretreatment of the extract with disodium ethylenediaminetetraacetic acid. Fe³⁺, Fe(CN)₆^3-, Cd²⁺ and Zn²⁺ had no effects on the reaction of the molecular weight conversion of this enzyme. The reactivity in the formation of high molecular weight renin catalyzed by Cu²⁺ increased when the extract was previously dialyzed, indicating the presence of substance (s) that interfere with the binding reaction of renin. The high molecular weight renin produced Cu²⁺ was stable against dithiothreitol, suggesting that the formation of disulphide bridge (s) is not involved in the reaction of renin with the renin binding substance. We also confirmed that for formation of the high molecular weight renin, Cu²⁺ must react with both the renin enzyme and the renin binding substance. Our findings provide new evidence related to the mechanism of molecular weight conversion of renin in the rat kidney.

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Previous results (J.Pharm.Dyn., 7, 342, 1984) from this laboratory indicated that papaverine, a classical phosphodiesterase inhibitor, inhibited the transport of organic anions such as p-aminohippurate (PAH) and urate in rat kidney cortical slices. The transport of papaverine itself, an organic cationic drug, in the kidney is not yet understood. The purpose of this study was to examine the interaction of papaverine with incubated slices and basolateral membrane vesicles prepared from rat kidney cortex, in terms of the possibility of the intracellular action of papaverine in kidney cells. Papaverine was taken up against a concentration gradient by kidney cortical slices and by liver slices. The uptake of papaverine by the former slices was depressed by hypothermia and anoxia with metabolic inhibitors, but that of the drug by the latter slices was not affected by hypothermic condition. Tetraethylammonium (TEA) as a prototype for organic cationic drugs did not depress papaverine transport. TEA also had no effect on the inhibitory effect of papaverine on PAH accumulation in kidney cortical slices. Papaverine, however, inhibited TEA accumulation prominently. Kinetic studies using the slices indicated that papaverine increased the K_m for TEA accumulation and decreased V_max. Then, papaverine inhibition was a "mixed type". TEA uptake by basolateral membrane vesicles was markedly inhibited by papaverine, but PAH uptake by the vesicles was not affected by the drug. The present results indicate that papaverine may be at least partly transported by the same system which handles TEA, but some aspect of the transport system for papaverine may be qualitatively different from that for TEA. Additional studies are required, however, to unequivocally establish the relationships between papaverine and TEA renal transport mechanisms.

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General pharmacological studies were performed on (6)-gingerol and (6)-shogaol whhich are the pungent constituents of ginger (Zingiber officinale ROSCOE). Intravenous (i.v.) administration of (6)-gingerol (at 1.75-3.5 mg/kg) or (6)-shogaol (at 1.75-3.5 mg/kg) and oral administration of them (at 70-140 mg/kg) produced an inhibition of spontaneous motor activity, an antipyretic and analgesic effects, prolonged hexobarbital-induced sleeping time, and these effects of (6)-shogaol were mostly more intensive than that of (6)-gingerol. (6)-Shogaol showed an intense antitussive effect in comparison with dihydrocodeine phosphate. In the electro-encepharogram of cortex, the low amplitude fast wave pattern was observed for 5 min after i.v. administration of (6)-shogaol, and then changed to the drowsy pattern, which was restored after 60 min. In the gastro-intestinal system, (6)- shogaol intensively inhibited the traverse of charcoal meal through the intestine in contrast with (6)-gingerol after i.v. administration of 3.5 mg/kg, but (6)-shogaol facilitated such an intestinal function after oral administration of 35 mg/kg. Both (6)-shogaol and (6)-gingerol suppressed gastric contraction in situ, and the suppression by the former was more intensive than that by the latter. In the cardiovascular system, both (6)-shogaol and (6)-gingerol produced depressor response at lower doses on the blood pressure. At high doses, both drugs produced three phase pattern.

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A lectin which we purified from the mucous of Ophidiidae Genypterus blacodes showed a potent mitogenic activity which was comparable to that of concanavalin A (con A). On the other hand, the lectin treated with 2-mercaptoethanol showed an anti-mitogenic activity against con A and lipopolysaccharide (LPS). Lymphocytes were separated into a T cell rich fraction and B cell rich fraction by soybean agglutinin. The mitogenic activity of G. blacodes lectin was examined using these cells. It was suggested that the mitogenic activity of G. blacodes lectin was based on the stimulation of T cells. The lectin was also subjected to both the sperm agglutination and the in vitro fertilization tests in mouse. It was demonstrated that : a) the lectin receptors were ubiquitous on sperm ; b) in vitro fertilization of mouse ova was completely blocked by the binding of the lectin to the zona pellucida of the ova.

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The effect of medium chain glyceride on the rectal absorption of cefmetazole sodium is investigated using an in situ experiment in rats. Each glyceride component of medium chain glyceride was separated using a high-performance liquid chromatographic method. The promoting effect of medium chain glyce-ride was found to be mainly due to glycerylmonocaprylate and dependent on the concentration of glycerylmonocaprylate. When cefmetazole sodium in medium chain glyceride solution was administered into the rectal lumen of rats, rapid absorption of the drug was observed leading to a residual amount of about 45% at 15 min after administration. The promoting effect of medium chain glyceride was found to be more effective in the rectum than in the small intestine.

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The gastric cytoprotective action of prostaglandin E₂ (PGE₂) and sofalcone was studied in rats. The in vitro incorporating activity of ³H-glucosamine into the gastric macromolecular glycoproteins was examined when PGE₂ (0.1 mg/kg, p.o.) or sofalcone (100 mg/kg, i.p.) was administered 5, 15 or 30 min before the oral administration of absolute ethanol. The cytoprotective effect of PGE₂ against gastric mucosal damage was demonstrated 5 min after PGE₂ was given orally. The cytoprotective effect by sofalcone was seen after 15 min. However, during this period, the decrease in gastric macromolecular glycoprotein synthesis induced by the ethanol damage could not be restored by pretreatment with PGE₂ or sofalcone. On the other hand, the reduction in the content of the gastric macromolecular glycoproteins by the ethanol damage was found to be prevented to a significant extent by pretreatment with PGE₂. The same phenomenon was also observed in the administration of sofalcone. Accordingly, PGE₂ has stimulating effect on the gastric glycoproteins biosynthesis, but this effect can not be considered as the mechanism responsible for cytoprotection, if indeed a single mechanism exists. Thus, it is suggested that the adhesion or maintenance of secreted macromolecular glycoproteins to the gastric tissue is closely related to cytoprotection.

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Renal Microsomal N-nitrosodimethylamine (NDMA) N-demethylation was measured in several species by a sensitive radiometric method using [¹⁴C] NDMA as a substrate and 2, 4-dinitrophenylhydrazine (DNPH) as a trapping agent of the [¹⁴C] formaldehyde formed. The activities were the highest in mice and lowest in hamsters. The activities in rats could not be detected. Among several strains of mice studied the DDY strain was the highest in its activities. Although nicotinamide adenine dinucleotide supported NDMA demethylation by about 32% of nicotinamide adenine dinucleotide phosphate in kidney and only 16% in liver, other properties (pH profiles, k_m values, and effects of inhibitors) exhibited almost similar results in liver as compared to kidney.

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