The effects of various drugs and extrinsic denervation on the non-adrenergic inhibitory nerves in the rat stomach were examined. Stimulation of the intramural nerves supplying the longitudinal smooth muscle strips taken from the rat stomach produced responses consisting initial contractions followed by relaxations in the presence of guanethidine in case of the tone of the preparation maintained with serotonin. After scopolamine treatment, transmural nerve stimulation (TMS) caused a relaxation or a relaxation followed by a transient after-contraction. All of these responses were abolished reversibly with tetrodotoxin. After cold storage of rat stomach strips for 5 d at 4°C, the TMS-induced response was not observed, but noradrenaline still relaxed these strips. The TMS-induced relaxation reached a maximum amplitude at 2-5 Hz, and was entirely independent of α- and β-blockers, or a combination of them. It was not affected by treatment of 6-hydroxydopamine and reserpine. These results strongly suggested that the relaxation was not myogenic, but neurogenic, and was not elicited by stimulation of adrenergic neurons. Strychnine and poly-L-lysine inhibited the relaxation elicited by TMS even in normal and transection-treated rats. Histochemical studies showed degenerative changes due to the dissection at the axons of a ganglion in the Auerbach's plexuses by transection. The effect of various drugs and extrinsic denervation on the response to TMS in relation to non-adrenergic inhibitory nerves in the rat stomach is discussed.

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The antitumor activity of several 13-alkyl-berberrubine and newly synthesized ester derivatives, using experimental tumors (S-180, NF sarcoma, Ehrlich carcinoma and L-1210) in mice was tested. For chemotherapeutic evaluation, the therapeutic indices and ratios were determined. Our present findings confirmed that in berberrubine derivatives, the 9-demethyl structure was essential for the manifestation of antitumor activity and demonstrated that ester derivatives also exhibit a remarkable antitumor activity, and the 13-methyl derivatives of both berberrubine and palmatrubine alkaloids showed high antitumor activity.

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Physico-chemical properties, dissolution profiles, and bioavailability of the molecular compound composed of equimolar amount of 1-benzenesulfony 1-5, 5-diphenyl-hydantoin (BSDH) and antipyrine were studied. The spectral and thermal analyses suggest that the intermolecular force in the molecular compound is attributed to the hydrogen bond between 3-NH of BSDH and 5-C=0 of antipyrine. In the aqueous media, the molecular compound decomposed to the constituents and there was no interaction between them. The dissolution behavior of BSDH from the molecular compound was characteristic, the high supersaturation being present for a long time, while the dissolution of antipyrine from the molecular compound was slow and continued for a long time. The dissolution profile of the molecular compound was truly reflected on the bioavailability in dogs. With respect to BSDH, the rate and the extent of bioavailability of the molecular compound were excellent. On the other hand, the absorption of antipyrine from the molecular compound was sustained for a long time. BSDH and antipyrine had no influence one another on the intrinsic rate constant of transport through the intestinal membrane and on the pharmacokinetic constants such as the volume of distribution and the elimination rate constant.

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Caffeine augmented formation of gastric lesions in rats exposed to restraint plus water-immersion stress for 3 h, together with inhibition of gastric secretion and gastric motility. The etiology of the lesion aggravation by caffeine was studied by measuring several parameters which were relevant to the mucosal defensive factors. Caffeine increased the susceptibility of gastric mucosa to erosive action of acid when simultaneously combined with the stress procedure. Injection of caffeine via an intraperitoneal route, but not via an intraarterial route, caused a decrease in gastric tissue blood flow when no marked fall in body temperature was seen. This indicates that the caffeine-induced decrease in gastric tissue blood flow is not due to its direct action on the gastric mucosal vessels. Hexosamine content of gastric wall tissues, however, was not significantly changed in caffeine-pretreated rats at 3 h after stress. These results suggest that caffeine aggravates stress-induced gastric lesions through some mechanism in reducing mucosal blood flow which is responsible for liability of mucosal autodigestion.

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The effect of taurine on isolated rat gastric mucosa was examined electrophysiologically in order to clarify the mechanism of taurine-induced effect on drug absorption, Although taurine itself had little effect on the electrical parameters, potential difference (PD), short-circuit current (I_sc), and tissue electrical resistance (R), of the gastric mucosa, sodium lauryl sulfate, an anionic surfactant, was shown to reduce these parameters remarkably. On the other hand, when aspirin was present, taurine showed different effects on the gastric mucosa depending on the concentrations of aspirin. Taurine decreased I_sc significantly in the presence of aspirin at low concentration (1 mM), which has in itself no influence on the electric parameters. In contrast, aspirin at higher concentration (10 mM) was shown to act as a barrier breaker of the gastric mucosa resulting in a marked decline of PD and I_sc. When taurine was added, however, these parameters were reasonably recovered. It seems to be likely that taurine acts as a protector against the aspirin-induced damage in the gastric mucosa.

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The changes of femoral calcium and acid phosphatase activity were examined in rats orally administered zinc sulfate (10 mg Zn/100 g body weight) for 3 d. Zinc administration to intact rats produced significant decreases of calcium levels in the serum, and femoral diaphysis and epiphysis, while it caused remarkable elevation of acid phosphatase activity in the femoral diaphysis and epiphysis. Thyroparathyroidectomy significantly prevented the alterations of the calcium content and the enzyme activity in the femoral diaphysis and epiphysis caused by zinc administration to intact rats. The present results suggest that comparatively high dose of zinc may stimulate bone resorption mainly mediated through the actions of parathyroid hormone, due to maintain calcium homeostasis.

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Morphine-7, 8-oxide (morphine epoxide) is assumed to be a metabolite of morphine. Morphine epoxide in antinociceptive action was practically as potent as morphine. The development of tolerance in antinociceptive action was slower in the rats treated with morphine epoxide than in the rats with morphine. Furthermore, morphine epoxide was less potent than morphine in the inhibition of abstinence syndrome.

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In order to clarify the mechanism taurine-induced enhancement of drug absorption, some comparison was made between the actions of taurine and sodium lauryl sulfate (SLS), an anionic surfactant, by using the loop of rat stomach in situ. SLS enhanced the gastric absorption of aspirin and salicylamide, and the SLS-induced enhancement seems to be Na⁺-dependent. SLS failed to enhance the absorption of both drugs when NaCl was completely replaced by mannitol or in the presence of ouabain even in the NaCl medium. In addition, even at the lower concentration of 0.05 mM, SLS enhanced the absorption of the two drugs, the extent of which is nearly corresponding to those of taurine. The actions of SLS and taurine on drug absorption are considered to have some similar points. The mechanism of the action was discussed in relation to the cyclic AMP system.

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The chemotherapeutic action of 5-fluorouracil (5-FU) monotherapy on L-1210 leukemia in mice was compared with combinations of pyrimidines (uracil, uridine, deoxyuridine, cytosine, cytidine, deoxycytidine, thymine and thymidine) or purines (adenine, adenosine, deoxyadenosine, guanine, guanosine, deoxyguanosine and inosine) with 5-FU. The antitumor activity of 5-FU was enhanced by coadministration of uracil, thymine or guanosine, but the toxicity of the first two compounds was also enhanced. Only when 5-FU was administered with guanosine, was not only the antitumor activity but also the therapeutic ratio potentiated without increasing its toxicity. A time interval between the administration of 5-FU and guanosine diminished the survival effect. Therefore, the 5-FU-guanosine combination produced its optimal chemotherapeutic effect by simultaneous injection. The potentiation of antitumor effect of 5-FU by guanosine was prevented completely by cytidine or uridine. and partially by deoxyuridine, adenosine or deoxyadenosine.

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Determination of oxycodone metabolites excreted in urines and feces of several mammalian species was studied by use of the tritium labeled compound. It was found that the radioactivity was excreted more in the urines than in the feces in rabbits, guinea pigs and mice, but not in rats, who eliminated it equally into the urines and feces. Most of the radioactivity was excreted in 48 h after the administration. Seven metabolites, oxymorphone, 6α-oxycodol, 6/β-oxycodol, 7/β-hydroxy-6/β-oxycodol, noroxycodone, oxycodone N-oxide, and 6α-oxycodol, N-oxide, as well as unchanged oxycodone, were found to be excreted into urines of rabbits in both free and conjugated forms except two N-oxides, which were found only in the free form. It was discussed that analgesic effect of oxycodone would mainly be attributable to the oxycodone itself, but not to the metabolites.

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The distribution and metabolism of secretin and aprotinin were studied in isolated perfused rat pancreas, which were kept under physiological conditions. At ¹²⁵I- [Tyr¹]secretin perfusion study the radioactivity appeared in the effluent, rapidly attaining an equilibrium with the perfusate. While the intact secretin concentration decreased to 55% of the perfusate ; the distibution space of secretin was estimated to be about 0.11 ml/g pancreas. The ratio of intact secretin to degradated products in the pancreas increased concomitantly with the perfusion of 82 nM secretin. When unlabeled secretin was perfused, immunoreactive secretin concentration in the portal effluent reached also a rapid equilibrium to about 60% of the perfusate. These results suggested that pancreas might clear about 40% of the entering secretin. In the case of ¹²⁵I-aprotinin perfusion, intact aprotinin fraction was predominant both in the effluent and in the pancreas. The apparent distribution space was about 40% of the volume of pancreas.Meanwhile, when ¹²⁵I-reduced aprotinin or ¹²⁵I-[S-carboxamidomethyl]aprotinin was perfused, the decomposed products were significantly increased. These findings indicate that the disulfide bonds in aprotinin molecule play an important role for its stability as well as its antiproteolytic activity.

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The renal secretion of an endogenous N¹-methylnicotinamide (NMN) and its usefulness as an index of the renal secretion clearance of tetraethylammonium bromide (TEA), a representative organic cationic drug, was examined in the rats treated with folic acid, glycerol and uranyl nitrate, respectively. There was a statistically significant correlation between the renal secretion clearance of TEA and that of NMN in the intact and acute renal failure rats (r=0.969, p<0.001). It was suggested that the renal secretion clearance of the endogenous NMN could be used as an index to assess the renal tubular function for the secretion of organic cationic drugs like TEA.

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