The present study was carried out to elucidate the effect of clove and its active principles in view of cholagogue. The cholagogue effect was observed in acetone extract of clove and eugenol. Acetyl-eugenol also possessed cholagogue property.

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The mechanism of anti-inflammatory action of papyriogenin A and C, obtained from Tetrapanax papyriferum, were investigated by the following methods; the cotton pellet granuloma test in normal and adrenalectomized rats, the blockade by anti-glucocortucoids of vascular permeability caused by serotonin in mice and the competition on 5β-reduction of steroidal compounds. The anti-inflammatory activity was observed in the decreasing order; papyriogenin C>papyriogenin A on the carrageenin-induced paw edema in mice, as reported in our previous paper.¹⁾ In a serotonin-induced paw edema, pretreatment with progesterone (50, 100 and 200 mg/kg) blocked completely the anti-inflammatory effects of papyriogenin A or C at 10 and 50 mg/kg. When actinomycin D (l and 2 mg/kg) or cycloheximide (6 mg/kg) was given twice, simultaneously with papyriogenin A or C, during the latent period for the manifestation of the anti-inflammatory effect, the anti-inflammatory effects of papyriogenin A and C were blocked completely by s.c. administration. The effects of papyriogenin A or C, 30 mg/kg p.o., on the cotton pellet granuloma test in adrenalectomized rats were similar to those of normal rats. On the other hand, the competitive effects of papyriogenin A and C on 5β-reduction of testosterone and cortisol were recognized to be significant. These activities of papyriogenin A and C are explained by their steroidal actions in the target cell and their competitive effects in endogenous corticoid metabolism in liver.

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Effect of acetazolamide (AZA) on the anticonvulsant potency of several antiepileptics was investigated in mice by maximal electroshock seizure test. By the coadiministration of AZA, a remarkable increase in the anticonvulsant activity was brought about not only for the barbiturates including barbital (BA), mephobarbital (MB) and metharbital (MET), but also for the other antiepileptics such as phenytoin (PHT), valproic acid (VPA) and trimethadione (TMO). This potentiating effect of AZA, however, was relatively weak for PHT, MET and TMO (about 2.5 fold) in contrast to those for phenobarbital (PHB), BA, MB and VPA (4-5 fold). The brain-serum concentration ratio (B/S) of PHB was elevated by the coadiministration of AZA, while the B/S of PHT was not changed. Thus it was inferred that the difference in the potentiating effect of AZA on the activity of the antiepileptics was due to the difference in its effect on the brain levels of the antiepileptic drugs. However, the potentiating effect of AZA was still observed for PHT, VPA and MET, as well as PHB, in reserpinized mice. Therefore, some pharmacodynamic effect of AZA other than its increasing effect on the brain levels of the antiepileptic drugs may partly contribute to the potentiation of the activity of the antiepileptic drugs.

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Effects of smooth muscle relaxants on histamine-, Ba²⁺-and Ca²⁺-induced contractions, or on electrical activities were examined in the longitudinal smooth muscle of guineapig ileum or taenia coli, respectively. Papaverine, D-600 and diltiazem effectively inhibited the Ca²⁺ responses and the tonic components of the histamine and Ba²⁺ responses. Especially, D-600 and diltiazem depressed the Ca²⁺ responses in much lower concentrations than papaverine and theophylline. In contrast, benactyzine and etomidoline were not specific antagonists against the Ca²⁺ responses, and they were effective inhibitory agents on the phasic responses to histamine and Ba²⁺. Nitroprusside failed to reduce the three types of contractions effectively. These results suggest that these seven relaxants can be divided into four types. Influence of those relaxants on spontaneously-and Ba²⁺-evoked electrical activities are compatible with the above differentiation. The four types of relaxants used in this study seem to exert their actions on smooth muscle in different way. Nitroprusside, however, is not a potent relaxant against contractions of the intestinal smooth muscles.

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The effects of BR-227 on secretory activities of canine tracheal secretory cells including behavior of mucus glycoproteins were investigated histologically and histochemically. Following BR-227 treatment at a concentration range of 10^-6 to 10^-4 M, the total number of goblet cell stained positively with a combination of alcian blue at pH 2.5 and periodic acid-Schiff (AB (pH 2.5)/PAS) decreased in a concentration-dependent manner. Furthermore, a decrease in the thickness of the acini of submucosal glands and an marked increase in the ratio of acinar inner diameter of the gland to tracheal wall were induced after application of BR-227 at a concentration range of 10^-7 to 10^-4 M. The numbers of goblet and submucosal glandular cells which stained blue and purple with AB (pH 2.5)/PAS were decreased by BR-227 treatment in a concentrations-dependent way, whereas the cells which stained red were markedly increased. In the experiment using a combination of AB at PH 1.0 and PAS, a decrease in sulfated glycoproteins in those secretory cells was observed. Total saccharide and protein concentrations in the incubation fluid increased with BR-227 treatment, while N-acetylhexomsamine concentration tended to decrease. These findings suggest that BR-227 stimulates secretory activities of both goblet cells and submucosal glands, and lowers mucus viscosity in the secretory cells

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In order to clarify the change of disposition kinetics accompanied by growth, the whole-blood levels and whole-body autoradiography following intravenous administration of creatinine and urea, which are considered to pass through the water-filled pores of biological membranes easily, were investigated in 1-day-old, 1-week-old, 3-week-old and 8-week-old mice. For both creatinine and urea, the total body clearance was considerably lower in 1-day-old and 1-week-old mice than in more aged mice. Relatively lower renal clearance (i. e. rather incomplete renal function) in 1-day-old and 1-week-old mice was considered to be the major reason for this observation. Moreover, the lower metabolic clearance also seemed to be the cause in the case of urea, because te expiratory excretion of ¹⁴CO₂ following intravenous administration of ¹⁴C-urea was almost negligible in 1-day-old and 1-week-old mice in contrast to more aged mice (16 -21%). The whole-body autoradiograms obtained following intravenous administration of ¹⁴C-creatinine indicated that creatinine was more rapidly transferred from blood to muscle in 1-day-old and 1-week-old mice, especially in 1-day-old mice, than in more aged mice. This might be caused by the difference in muscular blood flow rate or muscular cell membrane permeability to creatinine.

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The whole blood levels and whole-body autoradiography following intravenous administration of thiourea, which is considered to covalently bind to the macromolecules in the body, were investigated in 1-day-old, 1-week-old, 3-week-old and 8-week-old mice in order to clarify the change of disposition kinetics accompanied by growth. The total body clearance for thiourea was remarkably lower in 1-day-old and 1-week-old mice than in more aged mice. The lower metabolic clearance as well as renal clearance in 1-day-old and 1-week-old mice seemed to be responsible for this observation. The whole-body autoradiograms obtained at 60 min following intravenous administration of ¹⁴C-thiourea showed the homogeneous distribution of radioactivity throughout the body in 1-day-old and 1-week-old mice and the high radioactivity localized in the liver and lung in more aged mice. This remarkable difference was assumed to be brought about by the difference in quantity of the macromolecules in the liver and lung which can covalently bind with thiourea This assumption was supported by the result of gel filtration on Sephadex G-10 of the liver and lung homogenates.

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In vitro interaction profiles of mercuric mercury and selenice in rabbit blood under various reaction conditions were investigated. The most remarkable changes in the incorporations into the erythrocytes and gel filtration profi1es of mercury and selenium in blood were observed when 10^-5M mercuric chloride and 10^-5M selenite were added to rabbit blood. Under this condition, the mercury and selenium added always behaved with each other on gel filtration suggesting that most of mercury and selenium existed in a complex at a molar ratio of 1. When the concentration of mercuric chloride was 10^-7M in blood, however, the incorporation of mercury into erythrocytes was also increased by the simultaneous addition of selenite, but 10^-7M mercury did not stimulate the selenium incorporation. The behaviors of mercury and selenium in blood were altered by the order of addition of mercuric chloride and selenite to the blood. Compared to the simultaneous addition of both compounds, the final amount of mercury and selenium incorporated into erythrocytes were reduced by the addition of mercuric chloride prior to selenite, whereas the rates of incorporation of mercury and selenium were lowered by the addition of selenite prior to mercury. The gel filtration patterns of mercury and selenium in the plasma and stroma-free hemolysate of the blood preincubated with selenite before the addition of mercury were dfferent from the case of simultaneous addition of both compounds or addition of mercury prior to selenite. The variety of interaction profiles of mercuric mercury and selenium in blood under different reaction conditions as observed in the present in vitro study may reflect the complex modes of interaction actually occurs in vivo.

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Thioacetamide and one of its metabolite, thioacetamide-S-oxide, were shown to increase heme oxygenase and to inhibit δ-aminolevulinic acid (ALA) synthetase when administered in vivo to male rats. Concomitant with the increase of heme oxygenase and the decrease of ALA synthetase, concentration of cytochrome P-450 and drug metabolizing enzyme activities were decreased by in vivo administration of thioacetamide and thioacetamide-S-oxide to rats. The results of these studies indicate that thioacetamide and thioacetamide-S-oxide are not only inhibitor of ALA synthetase, but also inducer of heme oxygenase in rats. Further, thioacetamide-S-oxide is generally more effective than thioacetamide with respect to the effects on cytochrome P-450, ALA synthetase and heme oxygenase

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Effects of sodium ursodeoxycholate, hyodeoxycholate and dehydrocholate on serum and liver cholesterol levels, bile flow, biliary cholesterol, phospholipid and bile acid secretions, and fecal sterol and bile acid excretions were examined with Wistar strain male rats fed ordinary and 2% cholesterol supplemented diets. Dehydrocholate increased the liver cholesterol level, bile flow and biliary lipid secretion, but ursodeoxycholate and hyodeoxycholate did not. The serum cholesterol level was not changed by the treatments. Ursodeoxycholate and hyodeoxycholate increased their own secretion into the bile and decreased cholic acid secretion, while dehydrocholate increased deoxycholic acid and oxo bile acid secretion. Ursodeoxycholate increased but dehydrocholate decreased the fecal sterol excretion, and hyodeoxycholate caused no change. Dehydrocholate decreased the fecal coprostanol level. The total amounts of the fecal bile acids were similar in all the treated groups, but ursodeoxycholate increased lithocholic acid, α-, β- and ω-muricholic acids and ursodeoxycholic acid; hyodeoxycholate increased hyodeoxycholic acid, 3α, 7β, 12α-trihydroxy-5β-cholanoic acid and oxo bile acids; and dehydrocholate increased deoxycholic acid, cholic acid, ω-muricholic acid and oxo bile acids and decreased hyodeoxycholic acid. These data suggested that ursodeoxycholate was transformed into lithocholic and muricholic acids, and dehydrocholate into cholic and deoxycholic acids during the enterohepatic circulation, but hyodeoxycholate showed almost no change. Ursodeoxycholate and hyodeoxycholate caused neither accumulation of cholesterol in tissues nor increase in bile flow and biliary lipid secretion as well as chenodeoxycholate did. The biological effect of dehydrocholate was similar to that of cholate, and this was partially due to its conversion into cholic acid and deoxycholic acid.

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