We examined the effects of certain gastrointestinal hormones on gastric motility using rat stomach preparatios in vivo. Changes of water level caused by the movement of the stomach which was filled with saline were recorded. Single injections of cholecystokinin (1, 2 and 4 μg/kg) induced relaxation of the stomach. Single injections of bombesin in low doses (below 0.2 μg/kg) induced relaxation and in high doses (over 0.2 μg/kg) contraction after brief relaxation. Single injections of neurotensin (1, 2, 4 and 8 μg/kg), somatostatin (5, 10 and 20μg/kg) and substance P (1, 2, 4 and 8 μg/kg) induced relaxation followed by contraction, but their dose-response relations were obscure. Infusions of neurotensin (1, 5 and 25 μg/kg/h) and somatostatin (2.5 and 5 μg/kg/h) enhanced the stomach tension, whereas substance P (1, 5 and 25 μg/kg/h) reduced it. Single injections and infusions of neurotensin, somatostatin or substance P showed different effects on gastric motility. On the other hand, Met-enkephalin (1, 10 and 100 μg/kg) and porcine motilin (1, 10 and 100 μg/kg) did not affect gastric motility in our rat stomach preparations. These results suggest that some gastrointestinal hormones take part in stomach movements.

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Peptostreptococcus intermedius, one of the dominant bacteria of human intestine, reduced sennidin and sennoside to rheinanthrone and 8-glucosyl-rheinanthrone, respectively, and these reduction rates were stimulated by the addition of nicotinamide adenine dinucleotide (reduced form) (NADH), flavin adenine dinucleotide (FAD) and glucose. The reduction was accelerated by removing oxygen from the incubation tubes, which indicates the inhibition of the reduction by O₂. Thus, for the maximal activity, the reaction system required an anaerobic condition and cofactors, NADH and FAD. This bacterium also reduced methyl orange, whose mode of reduction resembled that of sennidin reduction. More than 80% of these activities were recovered in the supernatant fraction after sonication of the bacterial suspension, and these activities were purified together by means of Sephadex G-200 gel-filtration and diethylaminoethyl-cellulose column chromatography. The purified enzyme reduced FAD and benzyl viologen in the presence of NADH under an anaerobic condition.

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In an attempt to develop an appropriate infusion program in a continuous subcutaneous insulin infusion system, a conventional pharmacodynamic model (the Bolie model) for describing the relationship between blood glucose and serum insulin levels was evaluated, using a depancreatized dog preparation. The Bolie model was found useful in estimating the basal insulin infusion rate. However, the model could not predict the serum insulin concentration-time profile required to maintain the postprandial blood glucose levels within a physiological range. It will be necessary to develop a more appropriate model for determining the prandial subcutaneous insulin infusion rates in the continuous subcutaneous insulin infusion system.

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We studied the relationship between the rate of intravenous glucose infusion and the blood glucose concentration at two different physiological levels of hyperinsulinemia in a depancreatized dog. The same degree of changes in the glucose infusion rate generated progressively larger increments in the blood glucose concentration. We then developed a Michaelis-Menten type kinetic model which could appropriately describe this nonlinear relationship of blood glucose response under the condition of hyperinsulinemia. In oder to determine the prandial insulin infusion program, we used more simplified equations based on a nonlinear model. The simplified equations were demonstrated to be applicable for estimating the prandial subcutaneous insulin infusion program in the continuous subcutaneous insulin infusion system.

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Intestinal absorption of various drugs was examined by means of in situ recirculation technique during local anaphylaxis. The antibody was determined by passive cutaneous anaphylaxis technique in rats immunized once or three times. The optimal condition of local anaphylaxis was determined by the leakage of Evans Blue. The most significant increase in leaks of the dye was observed by the intraluminal challenge with 400 mg of ovalbumin for 10 min in ovalbumin-immunized rats, and this condition was chosen as the optimal condition of local anaphylaxis. Under this condition, intestinal absorption of caffeine, phenylbutazone, and bromthymol blue (BTB) significantly decreased in ovalbumin-immunized rats compared with the control, whereas no significant effect was noted in the intestinal absorption of salicylic acid, quinine, pralidoxime iodide (2-PAM), tetracycline, and phenol red. In normal rats, no significant decrease was obtained in the intestinal absorption of caffeine, phenylbutazone, and BTB. On the other hand, the decreased absorption of BTB was not found in ovalbuminimmunized rats by the intraluminal challenge with bovine γ-globulin. Furthermore, there was no significant change in the decreased absorption of BTB between rats immunized once and three times. The most effective condition for decreased BTB absorption was observed by the intraluminal challenge with 200 mg of ovalbumin for 10 min in ovalbuminimmnized rats, which almost correlated with the data of Evans Blue leakage. From these observations, it appears that the mucosal immune responses affect the intestinal absorption of low molecular weight drugs.

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Chymotryptic activation of adenylate cyclase from rat heart was examined with respect to guanosine triphosphate (GTP), adenosine triphosphate (ATP) and Mg²⁺ concentrations. The activation was inhibited by aprotinin. In the absence or presence of GTP, chymotrypsin stimulated the cyclase at the same ratio. GTP exerted stimulatory (up to 0.1 mM) and inhibitory (at 1 mM) effects on the cyclase. Both effects were not affected by chymotrypsin. ATP at low concentrations increased the cyclase activity dose dependently and at high concentrations decreased the cyclase activity. Chymotrypsin retarded the appearance of the decreasing phase. This effect of chymotrypsin was similar to that of increasing the concentration of Mg²⁺ in the reaction mixture. According to double-reciprocal plots of Mg²⁺ concentrations and the cyclase activity, chymotrypsin diminished K_m for Mg²⁺ with little effect on the V_max. Hill plots of the same data showed that the Hill coefficient was about 1 and was not altered by chymotrypsin. These results suggest that chymotryptic activation of adenylate cyclase is mainly due to increasing the affinity for Mg²⁺ of the system.

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The effects of diethyldithiocarbamate (DDC), a metabolite of disulfiram which is known as Antabuse, on the blood concentrations of alcohol and acetaldehyde were determined simultaneously by head space gas chromatography in rats. After an intravenous injection of alcohol, the blood concentration of acetaldehyde was much lower than that of the alcohol. A pharmacokinetic model featuring the liver compartment for acetaldehyde was used to estimate pharmacokinetic parameters on the assumption that the distribution volumes of the central compartments were same for alcohol and acetaldehyde, and that the elimination rate of acetaldehyde from liver was large enough to isolate the liver compartment from the central compartment. The results showed that the clearance of alcohol was 0.0226 l/min/kg and the elimination rate constant of acetaldehyde from the liver compartment was very large and 35 min^-1. The administration of DDC decreased the above significantly to 0.0132 l/min/kg and 20 min^-1, respectively. After intravenous infusion of acetaldehyde, the time course of the blood concentration of acetaldehyde was analyzed by the one compartment model. The estimated elimination rate constants from blood and the distribution volume were in good agreement with those calculated from blood and the distribution volume were in good agreement with those calculated from alcohol injection, indicating the appropriateness of the method used in this study. DDC had no effect on the elimination of infused acetaldehyde from blood indicating that the elimination may be due to the loss from lungs into breath, from skin surfaces and/or from the kidney but not by metabolism in the liver.

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Changes of alkaline phosphatase in small intestine, liver, kidney, bone and serum of rats administered 100 ppm (890 nM) of Cd²⁺ in the drinking water were observed during a 12 months period. After 2 weeks of cadmium administration, decreases in bone and small intestine alkaline phosphatases in serum of Cd-exposed rats were observed by a polyacrylamide gradient gel electrophoresis and the alterations continued through the 9th month of administration. At one month, the activities of the alkaline phosphatase fractions, p-1 and p-2, obtained from Sephadex G-200 column gel filtration of bone extracts from Cd-exposed rats were 32% and 43% of those in the controls, respectively, whereas Cd accumulation in the bone was very low (9 nmol/g wet weight). After 3 months, osteoporotic changes of bone and erosion of submucosa layer of the small intestine were observed by light microscopy. Alkaline phosphatase in small intestine of the Cd-exposed rats was 60% of that in the controls after 3 months. At 12 months, the decreased activity of bone alkaline phosphatase in Cd-exposed rats recovered to the same level as activity in the non-exposed rats. Moreover, the activity in kidney of the Cd-exposed rats was 80% of that in the controls. However, histological conversion from osteoporotic to osteomalacic changes in bone and kidney lesions by Cd administration were not oberved by light microscopy. Liver alkaline phosphatase activity of the Cd-exposed rats did not oberved by light microscopy. Liver alkaline phosphatase activity of the Cd-exposed rats did not change even at 12 months, whereas 1.2 μmol of Cd per g wet weight accumulated in this organ.

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Effects of intracerebroventricular injection of bombesin on gastric mucosal glycoproteins and acid secretion were studied to clarify its action mechanism for experimental ulcers in rats. Bombesin (10 μg) prevented stress ulcers and indomethacin ulcers. Aspirin (300 mg/kg p.o.) reduced the high molecular weight glycoproteins extracted from the gastric mucosa, and increased the degraded glycoproteins extracted from gastric juice in pylorus-ligated rats. Bombesin inhibited the aspirin-induced changes of the glycoproteins. Bombesin also inhibited basal gastric acid secretion. These results support the hypothesis that bombesin may affect the central nervous system's control of both gastric defensive and aggressive factors, which contributes to its antiulcerogenic action.

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Oral pretreatment with diethyldithiocarbamate (DTC) and carbon disulfide (CS₂) prevented mice from methemoglobinemia induced by phenacetin. This treatment resulted in marked elevation of plasma p-phenetidine concentrations, prolongation of phenacetin levels, and lowering of N-acetyl-p-aminophenol and p-aminophenol levels. Both DTC and CS₂ also suppressed p-phenetidine-induced methemoglobinemia with a delay in plasma p-phenetidine disappearance. In vitro, methemoglobin formation by p-phenetidine was decreased in liver microsomes isolated from DTC- or CS₂-treated mice. The liver microsomal phenacetin and p-phenetidine O-deethylation activities and p-phenetidine N-hydroxylation activity decreased 1 h after administration of DTC or CS₂, whereas deacetylation of phenacetin and N-acetyl-p-aminophenol by microsomes and acetylation of p-phenetidine by a soluble fraction from a liver homogenate were scarcely affected. The suppression of methemoglobinemia by DTC and CS₂ may result from an inhibition of metabolic conversion of p-phenetidine to methemoglobin-forming substances such as N-hydroxy-p-phenetidine which is of most importance, p-aminophenol and 2-hydroxy-p-phenetidine by the microsomal cytochrome P-450-containing monooxygenase system in the liver.

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The possibilities of participation of adenosine in the peristaltic reflex of guinea pig ileum was studied pharmacologically and histologically. Adenosine apparently depressed the peristaltic activity induced by elevation of intraluminal pressure from zero to 1-8 cm H₂O, and the extent of the depression somewhat decreased in proportion to the elevation in intraluminal pressure. Also, dipyridamole depressed the peristaltic activity by itself ; however, the extent of the depression significantly increased in proportion to the elevation in intraluminal pressure. On the other hand, in the presence of dipyridamole, the elevation of the intraluminal pressure from zero to 1-8 cm H₂O elicited an ³H-output increase from ³H-adenosine preloaded guinea pig isolated ileum, with the effect being more pronounced as the pressure was increased. In contrast, the peristaltic activity was more pronounced at lower pressurization. Atropine greatly depressed the peristaltic response but did not affect ³H-output induced by 4 cm H₂O pressurization. Tetrodotoxin depressed both markedly. Fluorescence histochemical localization of quinacrine, which binds to adenosin triphosphate (ATP), revealed dense nerve cell bodies and fine interconnecting strands in the ileal myenteric plexus of Auerbach. Also, in microradioautographs of ileal longitudinal muscle incubated with ³H-adenosine, the concentration of developed silver grains was localized in the ganglion cells and in the musculature as varicose fibre. From these results, evidence is provided that the peristalsis of guinea pig ileum may be physiologically modulated by endogenous adenosine, which may be released from neuronal elements of the myenteric plexus in response to the applied intraluminal pressure.

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By using a human tumor clonogenic assay, cisplatin plus vindesine regimen was evaluated in 17 carcinoma of the lung. The cisplatin (0.2 μg/ml) plus vindesine (0.005 μg/ml) combination was synergistic and additive cell killing in 10 and 4, respectively, of 17 specimens. On the other hand, only three specimens showed antagonistic cell killing from this drug combinatin. Our results indicated that this in vitro assay provides a new method which can predict the effects of the combination of drugs on individual patients.

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