Imino acid and related alicyclic amine concentrations in blood and urine of mammals including humans were concurrently determined by a selected ion monitoring technique. Nanomole levels of proline and pipecolic acid, and pyrrolidine and piperidine as well, were found in human urine. Proline levels but not pipecolic acid levels were higher in blood of humans than in urine. Pyrrolidine and piperidine levels in blood of humans were picomole levels and much lower than those in urine. Similar tendencies were also recognized when these 4 compounds were analyzed using animal blood and urine, although the levels were generally higher in animals than in humans. Significantly high concentrations of the imino acids and the amines were found also in animal semen.

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The effect of Vesiculogen (a hot-water extracted B cell mitogen from Peziza vesiculosa) on antibody production in mouse spleens was studied. The number of plaqueforming cells (PFC) elicited by injection with Vesiculogen and/or 2, 4, 6-trinitrophenyl substituted sheep red blood cells (TNP-SRBC) were comparatively assayed. In the mice injected with 100 μg of Vesiculogen (i. p.), an obvious increase in the numbers of anti-SRBC and anti-TNP SRBC PEC in spleens was observed after 2 d of injection, and the numbers of PFC reached a maximum on day 3. Injections to 1-1000 μg of Vesiculogen were effective. This effect was shown when Vesiculogen was administered by i. p. or i. v. injections. In some cases, the numbers of PFC in mice injected with Vesiculogen and antigen exceeded the sum of each number of PFC elicited by polycolonal B cell activation activity of Vesiculogen and by antigenic stimulation of TNP-SRBC. Pretreatment with Vesiculogen within 4 d before immunization markedly reduced the PFC response. These results suggest that the effect of Vesiculogen on antibody response in mice attributes to its activities as a polyclonal B cell activator and adjuvant.

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The pharmacokinetic parameters of nipradilol (NIP), a new potent antihypertensive and antianginal agent, and propranolol were determined after oral, intravenous and intraportal administration to the beagle dog implanted with cannula in portal vein at a dose of 1 mg/kg. Orally administered NIP underwent extensive first-pass metabolism leading to low bioavailability (11%), despite of complete gastrointestinal absorption. On the constant infusion for 30 min into the portal vein, hepatic extraction ratio was 0.71. The reduction in the systemic availability of orally administered NIP could partly be attributed to the fact that denitration and glucuronidation of NIP occur primarily in the intestinal tract and liver, respectively. Following oral administration of NIP, smaller amount of unchanged drug (1.9%) was excreted into the urine than that of intravenous administration (5.8%). However, in the qualitative and the quantitative aspects on urinary metabolic patterns, there was no appreciable influence of the route of administration. On the other hand, the systemic availability and the hepatic extraction ratio of propranolol were 11% and 0.86, respectively, suggesting that the first-pass metabolism through the liver actually contributes to the reduced availability.

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The administration of matrine, which has antiulcerogenic activity against stress ulcer, exhibited clear contraction on the preparation of the fundus strip of rats at high concentration (from 2×10^-4 g/ml). The contractile response of the fundus strip to matrine was not inhibited by treatment with tetrodotoxin, and was not modified with atropine at 10^-4 g/ml, while pretreatment of the fundus strip with antihistamines abolished or reduced the contractile response. The maximum contractile response of the fundus strip was not altered significantly by pretreatment of the rat with indomethacin.

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7-Oxo-24, 25-dihydrolanosterol (7-oxo-DHL), an ihibitor of cholesterol biosynthesis from lanosterol in vitro, lowered the serum total-cholesterol and triglyceride at a level of 0.1% in a diet on male Wistar rats. This effect was slightly lower than that of clofi-brate (CF) which was examined as a reference. Further, the reduction in serum totalcholesterol levels were associated with a slight reduction in the levels of high density lipoprotein (HDL) cholesterol, resulting in a decrease in the atherogenic index. The rate of decrease of liver total-cholesterol by 7-oxo-DHL was higher than that of CF soon after taking off the diet. Although CF produced a marked increase of liver size, no significant increase was observed in the rats fed with 7-oxo-DHL. The effects of 7-oxo-DHL in the rats fed with 3% cholesterol in a diet were examined and compared with that of control. These results strongly suggest that 7-oxo-DHL is considerably hypolipidemic in rats.

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To clarify the mechanism of aspirin analgesia, the relationship among analgesic and hypocalcemic effects and pharmacokinetics of aspirin was investigated in 20 healthy subjects at 20-23 years old. Four experimental groups were made, that is, (1) aspirin 1.0 g, (2) aspirin 1.0 g+calcium gluconate 1.5 g×2, (3) calcium gluconate 1.5 g×2, (4) control (placebo). Calcium gluconate was administered orally twice, that is, 30 and 90 min after oral administration of aspirin. The experiments were carried out under a double blind method. As an analgesic test, the ultrasonic method was used. Aspirin (1.0 g) caused a significant analgesia, the effect reaching the maximum at 90 min and prolonging for about 3 h. Simultaneously, plasma calcium level significantly decreased and kept going down, at least, until 180 min after administration of aspirin. However, when calcium gluconate was loaded at 30 and 90 min after administration of aspirin, both the analgesic and hypocalcemic effects of aspirin were significantly inhibited. The plasma aspirin concentration reached a maximum 30-60 min after administration of aspirin in both groups : aspirin alone and aspirin with calcium gluconate. On the other hand, plasma salicylic acid concentration kept increasing up to 180 min after administration of aspirin in either group. The plasma aspirin and salicylic acid levels in both groups were similar. The above results indicate that the calcium-lowering effect of aspirin is significantly involved in the aspirin analgesia, and that the analgesic effect of aspirin depends on plasma aspirin by itself in terms of inhibition of prostaglandin biosynthesis, but at least in a part, depends on plasma salicylate which may cause the hypocalcemic effect and thus lead to desensitization of a calcium-dependent pain-enhancing mechanism.

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This study was carried out to investigate the effect of tinoridine (2-amino-3-ethoxycarbonyl-6-benzyl-4, 5, 6, 7-tetrahydrothieno [2, 3-c] pyridine), a non-steroidal antiinflammatory drug, on the lipid peroxidation and renin release in the renin granule fraction. The renin granule fraction was prepared from the kidney cortex homogenate by a discontinuous sucrose density gradient centrifugation. Incubation of this fraction at 37°C resulted in an increase in lipid peroxide formation, accompanied by increased release of renin from the granules. When the renin granule fraction was incubated with 50 μM tinoridine at 37°C, lipid peroxide formation in this fraction was completely inhibited. Simultaneously, the rate of renin release from the granules was significantly suppressed. Tinoridine, at concentrations from 5 μM up to 100 μM, produced a concentration-dependent inhibition on the simultaneous increases in lipid peroxide formation and renin release induced by 50 μM ascorbic acid in the renin granule fraction. On the other hand, indomethacin, hydrocortisone and prednisolone, which had no ability to inhibit the lipid peroxidation in the renin granule fraction, did not influence the release of renin from the granules. The results suggest that tinoridine suppresses renin release by inhibiting the oxidative disintegration of membranes of renin granules.

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The effect of gonadectomy on the antihypertensive action of pindolol in male spontaneously hypertensive rats (SHR) was investigated. And we also examined the relationship between the antihypertensive effect of this drug and the renal prostaglandin E₂ (PGE₂) level. In gonadectomized SHR, the reduction of blood pressure was not observed by the oral administration of pindolol, although the drug exhibited a marked antihypertensive activity in sham operated SHR. Urinary PGE₂ in sham operated SHR was increased following the administration of pindolol, but not in gonadectomized SHR. Similar results were obtained in the experiments using Wistar rats. The PG synthesis inhibition induced by indomethacin suppressed the antihypertensive action of pindolol. Results in the present study suggest that renal PGs, particularly PGE₂, are involved in the antihypertensive mechanism of pindolol, and that male gonad takes part in the regulation of the stimulation of the renal PGE₂ producing system induced by pindolol.

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The characteristic of the antinociceptive effect of a tetrapeptide, Asn-Ala-Gly-Ala (NAGA), was examined. Intracisternal (i. cist.) administration of NAGA to mice produced does-dependent and long-lasting antinociceptive effect as evaluated by the hot plate and tail flick methods. NAGA-induced antinociception was reversed by naloxone (2 mg/kg), reserpine (2 mg/kg×2 d) and α-methyl-p-tyrosine (100 mg/kg). NAGA (10 μM) did not significantly affect the actions of opioid peptides on the electrically evoked twitches of the myenteric plexus-longitudinal muscle strips from the guinea-pig esophagus and strips of the mouse vas deferens. NAGA-induced antinociception was scarcely affected by p-chloro-phenylalanine (PCPA, 300 mg/kg×2 d) and methysergide (2 mg/kg). From the above results, it was suggested that the antinociceptive effect of NAGA may involve the participation of endogenous opioid peptides and endogenous catecholamines.

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Intestinal absorption and hepatic and intestinal bacterial biotransformations of norcholic acid, the C₂₃ homologue of cholic acid, were studied in the rats. Norcholic acid, like cholic acid, was effeciently absorbed from the intestine and quickly secreted into the bile. Unlike the C₂₄ bile acid, however, which is secreted by rat liver as its taurine conjugate, the C₂₃ bile acid appeared in the bile predominantly as the unconjugated form. conjugated form. Bacterial modification of norcholic acid was similar to but less extensive than that of cholic acid. A considerable part of norcholic acid was left unchanged during its passage through the intestinal tract. A major bacterial metabolite of norcholic acid was the 7-dehydrogenation product, 7-detonordeoxycholic acid, rather than the 7-dehydroxylation product, nordeoxycholic acid, though the reverse is true for cholic acid.

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The effects of the tryptamine metabolite, indoleacetic acid (IAA) on body temperature and serotonin (5-HT) metabolism in mice were investigated. IAA at 300 mg/kg i. p. induced significant hypothermia in mice. It caused a remarkable decrease in concentration of total tryptophan (TRP) and a considerable increase in free TRP in serum. IAA increased 5-HT, 5-hydroxyindoleacetic acid and TRP in the brain, but decreased 5-HT synthesis in the brain. The 5-HT antagonist, methysergide and the 5-HT depleter, p-chlorophenylalanine did not affect IAA-induced hypothermia.

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Six skeletal congeners of polychlorinated quaterphenyls (PCQs), namely polychlorinated o-quaterphenyl (2, 2'-PCQ), 2, 3'-diphenylbiphenyl (2, 3'-PCQ), 2, 4'-diphenylbiphenyl (2, 4'-PCQ), m-quaterphenyl (3, 3'-PCQ), 3, 4'-diphenylbiphenyl (3, 4'-PCQ) and p-quaterphenyl (4, 4'-PCQ), were orally administered to Wistar rats at a dose of 10 mg/rat. On the 5th day after administration of PCQs, the rats were examined for accumulation of PCQ congeners, hepatic enzyme activities and organ weight changes. Accumulation of 3, 3'-PCQ, 3, 4'-PCQ and 4, 4'-PCQ were 1.5-3.2% of dose in the liver, while those of 2, 2'-PCQ, 2, 3'-PCQ and 2, 4'-PCQ were only 0.1 to 0.2%. The amount of 4, 4'-PCQ accumulated in the mesenteric adipose tissue, 20 μg/rat, was much higher than those of other PCQ congeners. Large amounts of the PCQ congeners administered were excreted in the feces on the first day, accounting for 96 to 98% of dose for 2, 2'-PCQ and 4, 4'-PCQ, and 55 to 75% for the other PCQ congeners, and the daily excretions of PCQs after the second day were very small, less than 10% of the dose. Benzo [α] pyrene 3-hydroxylase activity was significantly depressed by the treatment with 3, 3'-PCQ, 3, 4'-PCQ and 4, 4'-PCQ, contrasting to the toxic congeners of polychlorinated biphenyls and dibenzofurans which enhanced markedly this enzyme activity. DT-Diaphorase activity was also depressed by the treatment with 2, 3'-PCQ, 2, 4'-PCQ and 3, 4'-PCQ. Significant atrophy of the thymus was observed by the treatment with 4, 4'-PCQ.

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The effect of a dihydroxy bile salt, sodium taurodeoxycholate (STDC), on drug absorption from rat small intestine was investigated in comparison with that of trihydroxy one, sodium cholate (STC). The enhancement or inhibitory effects on the absorption of various model drugs by STDC bore similar tendency to those by STC, and the magnitude was greater than the latter. The absorption of sulfaguanidine was enhanced by STDC, which solubilized the phospholipids from the mucosal barrier membrane in addition to the STC-like, or ethylenediaminetetraacetate-like action. STDC inhibited the absorption of sulfadimethoxine contrary to the insignificant effect by STC. The direct action of STDC on the mucosal membrane reduced the absorption in addition to the physicochemical action, such as micellar complex formation. Quinine absorption was inhibited in the presence of STDC, which can be explained by the micellar complex formation. Possible mechanisms of the differences in the effect of STDC and STC were discussed in relation to their micellar properties.

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An experimental glomerulonephritis was produced in mice by an injection with a sub-nephrotoxic dose of nephrotoxic serum after immunization with rabbit IgG. In oder to examine the susceptibility of disease, we tested the onset of nephritis in 6 different strains (ICR, C57BL/6, C3H, DBA/2, nu/nu and DDY) of mice. Strain C57BL/6 mice indicated the highest susceptibility to the disease with a high degree of reproducibility. The excretion of protein in urine, the elevation of serum cholesterol and blood urea nitrogen level and the decrease of serum albumin were observed in nephritic mice. Typical histopathological changes in the kidney were crescent formation in glomeruli, thicknening of glomerular basement membrane and cast of urinary tubuli. Cyclophosphamide, at doses of 5 and 10 mg/kg, inhibited the development of nephritis in C57BL/6 mice. These results suggest that the experimental glomerulonephritis model in C57BL/6 mice is useful for immunopharmacological studies of nephritis.

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