Capsaicin, the pungent component of red pepper, was studied to determine its inhibitory effect on fluid and Na⁺ absorption using rat and hamster everted jejunal sacs. At a mucosal concentration of 14.0 mg% incubated for 60 min, capsaicin reduced the fluid transport into the serosal side by 14.8% in rat and 23.9% in hamster. Similarly, Na⁺ transport was also inhibited by 12.5% and 26.2% in rat and hamster, respectively. Such decrease in serosal sodium coincided with the increase in Na⁺ content of the gut wall and the intracellular Na⁺ concentration in the epithelial layer. It is, accordingly, concluded that capsaicin inhibits the Na⁺ exit through the serosal pole of the epithelium. These observations may also provide an explanation for the previously observed inhibition of glucose transport.

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Cimicifugoside, a triterpenoid from Cimicifuga simplex, is a potent inhibitor of thymidine-³H uptake by Raji cells, L-cells cl 1D cells, HeLa S3 cells and L-5178Y cells without affecting the growth rate of any cell type tested. It has also inhibited the uptake of purine and pyrimidine ribosides and deoxyribosides of adenosine, inosine, uridine and nucleoside analogs in L-5178Y cells. It did not inhibit phosphorylation of thymidine or adenosine, or the transport of nucleic acid bases, sugars, amino acids and arabinosyl analogs of nucleosides. The results suggest that cimicifugoside is a potent and selective inhibitor of nucleoside tranport at the plasma membrane site of mammalian cells.

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Pretreatment of mouse splenocytes with Shigella lipopolysaccharide and concanavalin A followed by 50 ng/ml of cimicifugoside resulted in a 69% and 31% inhibition of blastogenesis compared to controls. The plaque forming colony assay using sheep erythrocytes (SRBC) showed a decreased number of plaque forming colonies after exposure of the splenic cells to 1 μg/ml of cimicifugoside. Cimicifugoside, 0.1 mg/mouse i. p. suppressed the anti-SRBC response in the plaque forming assay. The major inhibition of the antibody response occurred when cimicifugoside was administered 1 day before the primary immunization with SRBC. The delayed type hypersensitivity to picryl chloride was suppressed after i. v. administration of cimicifugoside, 1.0-2.0 mg/mouse. The immunosuppressive activity of cimicifugoside is preferentially directed toward B-cell function with larger doses being required for suppression of T-cell function.

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Aminoguanidine sulfate (AGS) produces a peculiar anomaly in the liver of chick embryos. Incorporation of amino acids and bases into the liver and body was investigated to clarify the mechanism of this effect. After chick embryos of White Leghorns were injected with AGS on the 5th day of incubation, ³H-thymidine (³H-T), ³H-uridine (³H-U), ¹⁴C-glycine (¹⁴C-G) and ¹⁴C-leucine (¹⁴C-L) were each injected once into the albumen at a specified time from the 5th day to the 8th day of incubation. Incorporation of ³H-T into the liver was markedly reduced in the nuclear (or DNA) fraction, apparently being inhibited at 3 to 6 hr, while incorporation into the body was only slightly affected. Incorporation of ³H-U into RNA was only slightly affected in the liver 24 hr after injection, while incorporation into the body did not differ from control. Incorporation of ¹⁴C-G was remarkably reduced with AGS both in the liver and body protein, and the degree of inhibition was around 26-52% at 3 or 24 hr. Incorporation of ¹⁴C-L, however, was reduced only in the liver, and became pronounced on the 8th or the 9th day of incubation. The primary action of AGS seems to be on nucleoprotein synthesis ; namely, on inhibition of DNA synthesis. Those findings are discussed, through comparison of histopathological observations.

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The interaction of indomethacin and aspirin or mepirizole was studied in rats. Concomitant oral administration of aspirin and indomethacin had no significant influence on the gastro-ulcerogenicity of indomethacin alone, but caused significantly less intestinal damage than an identical dose of indomethacin alone. In proportion to the inhibitory activity of intestinal lesions, aspirin also showed the activity that antagonized significantly the shortening of small intestinal length, loss of body weight and delay of charcoal transport in the intestine induced by indomethacin alone. Aspirin tended to reduce also the anti-inflammatory and analgesic effects of indomethacin in combined administration. On the other hand, mepirizole significantly reduced both gastric and intestinal ulcerogenicities by indomethacin alone in concomitant oral administration and inhibited dose-dependently the incidence and severity of those lesions. The inhibitory activity of gastrointestinal lesions by mepirizole was in proportion to the activities that antagonized the shortening of the small intestine, loss of body weight and delay of charcoal transport by indomethacin. Moreover, in contrast to aspirin, mepirizole exerted more potent anti-inflammatory and analgesic effects in combined administration than in the single administration of indomethacin. Therefore, aspirin reduced both the intestinal side effect and the anti-inflammatory effect induced by indomethacin in combination, while the combination of mepirizole reduced the gastrointestinal side effects by indomethacin alone, but seemed to be additive in the anti-inflammatory effect.

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The binding of the new diuretic piretanide and two other diuretics (furosemide and bumetanide) to serum proteins (especially albumin) was studied using the in vitro equilibrium dialysis method. Piretanide and bumetanide, similar to each other in chemical structure, were almost equal in the binding constant to purified albumin, while the binding constant of furosemide was greater than that of the other two diuretics. The binding of these loop diuretics in the dilutions of the sera from healthy adults and patients with renal failure or liver disease was also studied by the same method. Protein binding of the drugs was markedly reduced in patients with renal failure. The cause could only partly be explained by some structural changes in the serum albumin molecule of these patients and influences of endogeneous substances present in serum.

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Electrophysiological effects of a new antiarrhythmic agent, lorcainide, were studied in the isolated guinea pig ventricular myocardium and were compared with those of disopyramide ; some of the experiments were also made by using the canine ventricular myocardium. Both lorcainide and disopyramide selectively depressed the maximum rate of rise of the action potential with little effect on the resting and overshooting potential. The action potential duration tended to be shortened slightly, and the prolongation of the refractory period produced by these agents was only slight. Both agents did not produce the substantial modification of the slow response produced by isoproterenol in the depolarized muscle at the concentrations enough to depress the maximum rate of rise of the action potential. Both agents also produced the marked depression of the rate of rise of the action potential of the canine ventricular muscle, and the conduction velocity measured in the canine false tendon was markedly decreased by both agents. It was concluded that both lorcainide and disopyramide are typical Class I agents according to the classification proposed by Vaughan-Williams and that lorcainide is about 10 times (at least 3 times) more potent than disopyramide in this respect.

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11-Oxo-Δ⁸-tetrahydrocannabinol (11-oxo-Δ⁸-THC) was found in the mouse brain and liver extracts as a new in vivo metabolite of Δ⁸-THC. The metabolite was detected by thin-layer chromatography using two aldehyde reagents together with a phenol reagent and identified as a heptafluorobutyrate by ECD-gas chromatography. This identification was further supported by gas chromatography-mass spectrometry. Content of the metabolite in the mouse liver was 0.09 or 0.19 μg/g at 15 min after the i. v. injection of Δ⁸-THC or 11-hydroxy-Δ⁸-THC (11-OH-Δ⁸-THC) at a dose of 10 mg/kg. On the contrary, 11-oxo-Δ⁸-THC was not precisely quantified (<0.01 μg/g) in the brain after the injection of Δ⁸-THC, although its content after the injection of 11-OH-Δ⁸-THC was 0.03 μg/g.

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The contractile response to acetylcholine (ACh) of the isolated duodenum from the restraint and water immersion stressed (RWIS) mouse was found to be enhanced by the stress for 1 hr and reach a maximum in 3 hr stress followed by a decrease. It was clarified that this rise in the response is not due to the change in the affinity to ACh but due to the increase of the intrinsic activity. The contractile response to KCl was augmented only when concentration of KCl was high, while the response to BaCl₂ was little enhanced in the stressed animal. The relaxing response to noradrenaline (NA) of the isolated duodenum from rat, on the other hand, was reduced by the stress. Such reduced response to NA was observed to be more marked than the enhanced response to ACh in the vas deferens isolated from the stressed animal. The pretreatment to the RWIS mouse with either antiadrenergic or cholinergic drugs resulted in the clear-cut blockade of the enhancement of response to ACh of the isolated duodenum from this animal. These results contrasted to the effects on the reduced response to ACh of the isolated duodenum from the SART stressed (repeated cold stressed) mouse. The pre-administration of psychotropic drugs showed marked suppression on the enhancement of response of the duodenum of the RWIS animal, though there was a quantitative difference between the RWIS and SART animals. The pretreatment with a neurosedative, Neurotropin^[○!R](NSP) was also found to show similarly marked suppressive action. From these results, it was considered that the duodenum and the vas deferens of the RWIS animal are in the state of the sympathicotonia, namely partial sympathicotonia.

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Dry agar beads containing theophylline were prepared. The release rate of theophylline from the agar beads in vitro was smaller than the dissolution rate of the drug from pure drug powders. The salivary levels of the drug following oral administration of the agar beads to three healthy volunteers were determined by reversed-phase high pressure liquid chromatography. Results of pharmacokinetic analyses indicated sustained absorption of the drug following the administration of the agar beads.

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KW-5338 (domperidone), a new dopamine antagonist, is considered to be an agent to cross the blood-brain barrier with difficulty. The antagonistic activities of KW-5338 against L-DOPA were investigated. KW-5338 showed a strong anti-emetic action against L-DOPA induced emesis in beagle dogs (ED₅₀=0.056 mg/kg (p. o.)) and restored the L-DOPA induced depression of intestinal motility to some extent, while it did not antagonize anti-tremorine activities of L-DOPA and trihexyphenidyl in mice. These results suggest that KW-5338 prevents side effects of L-DOPA such as nausea, vomiting and constipation, without reduction in therapeutic effects of L-DOPA in Parkinson's disease.

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The effects of KW-5338 (domperidone) on gastric motility were studied by the balloon method in pentobarbital anesthetized mongrel dogs. KW-5338 was found to enhance the antrum motility. Its enhancement pattern showed the following characteristics : (1) The tonus was not affected, (2) the contraction pressure increased, (3) the frequency of contraction decreased slightly, and (4) the enhancement was long lasting. Metoclopramide showed strong but short enhancement of antrum motility. KW-5338 augmented also the gastric body motility, although the enhancement pattern was different from that in the antrum : (1) The action did not last so long, and (2) an increase in tonus was observed. The augmentation of the gastric motility by KW-5338 was observed even after vagotomy and splanchnicotomy, but it was weaker and shorter than in the intact state. The KW-5338 induced augmentation was diminished by tetrodotoxin treatment. The gastric relaxation response to dopamine was blocked by KW-5338. These results show that KW-5338 activates the gastric motility not noly by central mechanism but also by stimulation to intramural neurons. The dopamine blocking activity of KW-5338 might play some role in the enhancement of gastric motility.

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After intravenous injection of heparin, the plasma protein binding of 1-anilino-8-naphthalenesulfonate (ANS) was remarkably decreased in rats. This effect ocurred within one min after the injection of 1000 units/kg of heparin and lasted for about 30 min. The change in the binding of ANS was closely related to the plasma concentration of free acids (FFA), which was suggested as one of the heparin-induced inhibitors. The free fatty fraction of salicylate in plasma after the intravenous injection of heparin, had a pronounced variation, and also had a statistically significant correlation with the plasma free fraction of ANS. It was suggested that ANS might be useful for the prediction of the heparin-induced changes in the plasma protein binding of acidic drugs.

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