Intoxication effect on mouse thyroid by prolonged administration of either CH₃HgCl or HgCl₂ was studied. It was found by giving CH₃²⁰³HgCl and ²⁰³HgCl₂ through stomach intubation at either a single or a 30 d treatment that thyroid is a moderately susceptible organ to both mercurials. Animals were given 50, 100 and 150μg/d of either mercurial in drinking water for a month. At the lowest amount of HgCl₂, body weight was increased, whereas at the highest dose, there was a transient delay in growth. With lower amounts of CH₃HgCl, no change in growth was observed. However, at the highest amount, a severe growth inhibition occurred. The thyroid weight was unaffected by lower amounts, but was significantly reduced by 150μg/d of either mercurial. The 24 h radioiodide uptake in the thyroid, expressed by cpm/mg organ weight, was reduced by lower levels of mercurials. CH₂HgCl and HgCl₂ suppressed tha rate of radioiodide incorporation into the iodothyronine fraction, but not into the iodotyrosine fractions, indicating that mercurials do not interfere with organification of iodide but do inhibit the coupling process. Serum thyroxine (T₄) level was affected by mercurials, but serum triiodothyronine (T₃) was not. This result suggested that even thyroidal secretion of T₄ was inhibited by mercurials, but the peripheral conversion of T₄ to T₃ may not be affected in the maintenance of an active hormone level.

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Anti-complementary active arabinogalactan IIb-1 (AGIIb-1) and inactive arabinogalactan IIb-2 (AGIIb-2) were isolated from an extract of the root of Angelica acutiloba KITAGAWA. AGIIb-1 mainly consisted of arabinose, galactose, rhamnose and galacturonic acid in a molar ratio of 2.2 : 1.0 : 0.3 : 0.4, and AGIIb-2 mainly consisted of arabinose, galactose, galacturonic acid, and glucuronic acid in a ratio of 1.0 : 1.0 : 0.08 : 0.1. AGIIb-1 was found to form molecular aggregates as the result of self-aggregation in water. The aggregated form was found in the void volume by gel filtration using Sepharose CL-2B in water. However, AGIIb-2 did not show this behavior. When the AGIIb-1 aggregate was applied to a gel filtration column in 8 M urea or NaCl solution, the position of the peak fraction shifted to a lower molecular weight region, and the molecular weight of AGIIb-1 decreased with the increase of NaCl concentration in the gel filtration. These results suggested that the molecular aggregation of AGIIb-1 was caused by hydrogen bonding and ionic interaction and was Ca²⁺ ion independent. The anti-complementary activity of AGIIb-1 was seen to be dependent upon the degree of molecular aggregation, and the AGIIb-1 aggregate in water showed the highest activity. The results of methylation analysis indicated that AGIIb-1 contained a large amount of 3, 5- or 3, 4-di-O-substituted arabinosyl residues whereas AGIIb-2 contained a large amount of 6-O-substituted galactopyranosyl residues. These results suggested that the self-aggregation of AGIIb-1 was concerned in the expression of anti-complementary activity and that the higher branching structure of arabinogalactan may be involved in the formation of the molecular aggregate.

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In order to elucidate the mechanism of ajmaline-quinidine interaction previously observed in humans, the effects of quinidine on pharmacokinetics of ajmaline were investigated in rats. Concurrent oral administration of 10 mg/kg of quinidine markedly increased the plasma concentration of ajmaline at a dose of 2 mg/kg. On the other hand, it did not affect the pharmacokinetics of ajmaline after intravenous dose. The availability of ajmaline after oral dose showed an increase from 13% to nearly 100% by the presence of quinidine, which suggests a change in the presystemic clearance of ajmaline. In fact, when ajmaline was administered into the intestinal loop, its concentration in mesenteric venous plasma increased approximately 5-fold by the combination with quinidine. Furthermore, quinidine delayed the elimination rate of ajmaline from the perfused rat liver. These results indicate that quinidine prevents presystemic elimination of ajmaline in the intestine and liver, and increases the systemic availability of ajmaline.

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A sustained-release property of gelatin microcapsules of piretanide was evaluated by pharmacodynamic parameters. The gelatin microcapsules of piretanide showed longlasting, slow-release properties, when compared with its ordinary tablet form in the plasma piretanide level, piretanide excretion rate, urine excretion rate and urinary electrolyte (Na⁺, K⁺, Cl^-) excretion rate without any loss in diuretic and saluretic activities, which fully satisfied the criteria for a sustained-release preparation.

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The role of gastric mucous glycoprotein (GP) in cytoprotection by prostaglandin E₂ (PGE₂) and an anti-ulcer drug, sofalcone, which increases the endogenous prostaglandins (PGs), was investigated in rats with ethanol-induced gastric lesions. Oral administration of absolute ethanol in rats caused a marked increase in low-molecular weight luminal GP and a marked decrease in macromolecular weight GP in the gastric tissue. These changes were significantly prevented by pretreatment with PGE₂ or sofalcone. The adhesive intensity of mucous GP to the surface epithelium was estimated by comparing the amount of GP relased into the medium in an in vitro incubation system. Our observations indicate that the adhesion of mucous GP is markedly decreased by oral administration of absolute ethanol, and this decrease is prevented by pretreatment with PGE₂ or sofalcone. The adhesion of the secreted mucous GP to the gastric epithelium is probably one of important factors in prostaglandin cytoprotection.

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The transport characteristics of β-lactam antibiotics was investigated in rat jejunum using the Ussing-type chambers in vitro. Not only the transmural flux rate, but also the influx rate and accumulation into the mucosal epithelium were measured to clarify the sequential processes of drug transport. β-Lactam antibiotics examined were cephalexin (CEX), cephradine (CED), ampicillin (AB-PC) and cefazolin (CEZ). The transport characteristics of these drugs were compared with that of L-phenylalanine (L-Phe). The results suggested that specialized transport systems are involved in all processes of mucosal-to-serosal transport for CEX and CED. From the kinetical analysis, it was demonstrated that these two drugs have similar capacity and affinity to carriers in the influx process or components which contribute to the cellular accumulation, while their transmural flux rates were different from each other. L-Phe was shown to have a much greater activity, affinity and capacity in the intestinal transport process than those of CEX, CED, AB-PC and CEZ.

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The effects of 8 imidazoline derivatives on pre- and postsynaptic α-adrenoceptors and [³H] norepinephrine release were investigated in the rat vas deferens and were compared with those of reference drugs, yohimbine, phentolamine, tolazoline, and prazosin. K-6341 and K-6343 activated postsynaptic α₁-adrenoceptor and were antagonized by prazosin. The order of potency series as α₁-antagonist, prazosin > phentolamine > yohimbine > K-4011 > K-3827 > K-4300, tolazoline was found in antagonism against phenylephrine. Many derivatives exhibited an antagonistic action against clonidine, and the potency series as α₂-antagonist was revealed as follows : phentolamine > yohimbine > K-3827 > K-4011 > K-6341 > K-6343 > K-4300, tolazoline > prazosin > K-4299. The antagonistic effect was more selective on presynaptic (α₂) than postsynaptic (α₁) adrenoceptor and the rank order of selectivity (K_B-post/K_B-pre) was K-3827 > yohimbine > K-4011 > tolazoline, K-4300 > phentolamine > prazosin. Imidazoline derivative increased [³H]norepinephrine release, the actions of K-3827, K-6341 and K-4300 being particularly potent. From these results, the structure-activity relationship was summarized. First, when 2', 3'-methylenedioxyphenyl group is connected with the imidazoline ring via an amino or methylene residue, these compounds become α₁-agonist. Secondly, when the methylenedioxyphenyl group and the imidazoline ring are connected via an amino residue, these compounds show a weak agonistic and potent antagonistic characteristics at the presynaptic α₂-adrenoceptor. Thirdly, an addition of a methylenedioxy radical to the phenyl ring increased the affinity of the compounds to presynaptic α₂-receptor.

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The effects of 8 imidazoline derivatives on α-adrenoceptor-mediated contraction or relaxation of various kinds of smooth muscle preparations were investigated. In rabbit aortic strips, K-6341, K-6343 and K-4011 produced α-agonistic action which was antagonized by prazosin. In the study of α-antagonistic action of imidazoline derivatives, i.e. antagonism against norepinephrine- or phenylephyrine-induced contraction of the rabbit aortic strip, the order of potency series, prazosin > phentolamine > yohimbine > K-4011, K-3827, K-4300 > tolazoline was found. Reserpine pretreatment did not affect the results. In the study of α-antagonistic effect on the relaxing response to norepinephrine of methacholine-contracted rat ileum, the potency series was revealed as follows : prazosin > phentolamine > yohimbine > K-4011, K-3827, K-4300, tolazoline. A similar experiment was performed on histamine-contracted guinea-pig taenia coli, and the results were nearly identical to the case of the rat ileum, except that K-6341 and K-6343 also exhibited α-antagonistic action which was not detected in the rat ileum. This suggests that α₂-receptor may exist in the postsynaptic α-adrenoceptor in the guinea-pig taenia coli. The results of the present study indicate that the potency of imidazoline derivatives to inhibit norepinephrineinduced contraction of some smooth muscle is almost identical to that which inhibited norepinephrine-induced relaxation of other smooth muscles. Furthermore, K-4300 was found to possess anti-acetylcholine and anti-histamine actions in the guinea-pig taenia coli and anti-serotonin action in the rat fundus strips.

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The effects of 8 imidazoline derivatives on the cardiovascular system and their acute toxicity were investigated. In anesthetized rats, K-6341 and K-6343 produced relatively long-lasting elevation of blood pressure. This hypertensive response was prevented by prazosin. In contrast, K-4011, K-3827 and K-4300 exerted long-lasting hypotensive actions. Norepinephrine-induced increase in blood pressure was competitively antagonized by these three derivatives. Therefore, the hypertensive and hypotensive actions of imidazoline derivatives are conceivably exerted by activating and blocking α₁-adrenoceptors. In the isolated guinea-pig atrial preparations, K-4011, K-3827, K-6341 and K-6343 produced positive inotropic responses which were independent of β-adrenoceptor activation. The positive inotropic effect of K-6341, which was the most potent, was specifically attenuated or abolished by diltiazem, suggesting that a change in Ca²⁺ movement across the cell membrane is contributing to K-6341-induced increase in atrial contractions. The main symptoms of mice manifested when injected with imidazoline derivatives were a decrease in spontaneous movement, exophthalmos, an increase in palpebral opening, paralysis of four limbs and respiratory depression. Acute LD₅₀ values of imidazoline derivatives in mice (i.v., i.p.) were between these of tolazoline and naphazoline.

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The neuromuscular junctions of genetically diabetic KK-CA^y mice are reported to be hypersensitive to succinylcholine (SuCh) but not to d-tubocurarine (d-TC). Spinal cord-muscle cocultures from normal ddY and diabetic KK-CA^y mouse embryos were studied to examine the involvement of genetic factors in this hypersensitivity to SuCh. KK-CA^y myotubes were morphologically normal, as determined by light microscopy. KK-CA^y myotubes showed a progressive increase in the resting membrane potentials and acetylcholine (ACh) sensitivity with development, but this development was delayed when compared with ddY myotubes. The ACh receptor clusters, fluorescently labeled by fluorescein isothiocyanate conjugated α-bungarotoxin (FITC-αBuTX), were formed on the surface membrane of KK-CA^y myotubes. The developmental increase of the total amount of fluorescence within ACh receptor clusters on KK-CA^y myotubes was also slower than that of ddY myotubes. Depolarization by SuCh was sustained at a higher level in KK-CA^y myotubes. In regards to the inhibition of ACh potentials, KK-CA^y myotubes were not hypersensitive to both SuCh and d-TC when compared with ddY myotubes. These results suggest that the hypersensitivity to SuCh is not dependent on the genetic difference between ddY and KK-CA^y mice, and is probably due to the developmentally diabetic state of the neuromuscular junction.

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The pharmacokinetics of biperiden in rabbits were examined at three doses (0.2, 0.8, and 3.2 mg/kg i.v.). The data were interpreted in terms of a three-compartment open model with a linear excretion rate. The serum unbound fraction and the blood-to-plasma concentration ratio were determined as 0.39 and 1.2, respectively, over a wide concentration range (25-10000 mg/ml). Rapid and complete absorption from the injection site in muscle to the systemic circulation was observed. The bioavailability of muscular injection was unity. The hepatic extraction ratio was 0.94, and the high plasma clearance could be explained in terms of hepatic blood flow rate-limited elimination. The major tissues in which biperiden was distributed were fat and muscle. The highest tissue-to-plasma partition coefficient in the steady-state was obtained for the lung. These three tissues comprised 56% of the total distribution volume.

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The inhibitory activity of 2-(8-methyl-10, 11-dihydro-11-oxodibenz [b, f] oxepin-2-yl) propionic acid (AD-1590) against prostaglandin (PG) generation in the rabbit brain was compared with that of indomethacin in vitro. AD-1590 inhibited PGE₂ generation by hypothalamus microsomes at concentrations of 0.1μg/ml or more, its IC₅₀ value being 0.258μg/ml. On the other hand, PGE₂ generation by cerebral cortex slices was suppressed by about 10 times lower concentrations of AD-1590 in comparison with that by hypothalamus microsomes ; its IC₅₀ value was 0.0292 μg/ml. The potency of AD-1590 was 3.4 and 2.6 times that of indomethacin in the hypothalamus microsomes and cerebral cortex slices, respectively. The inhibitory activity of AD-1590 against PGE₂ generation by hypothalamus microsomes was similar to the result with renal medulla microsomes ; the ratio of renal medulla to hypothalamus IC₅₀ values of AD-1590 (0.496) was nearly equal to that of indomethacin (0.384) and aspirin (0.452). The present studies confirmed that AD-1590 inhibited PGE₂ generation within the hypothalamic region. However, these results suggest that the inhibitory potency of AD-1590 against brain PG synthetase cannot explain the 20-50 times more potent antipyretic activity than that of indomethacin, previously reported. The mode of potent antipyretic action of AD-1590 is discussed.

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The effect of polyriboinosinic acid-polyribocytidylic acid [poly (I)·poly (C)] on glucuronyltransferase activities toward 4-nitrophenol and 4-hydroxybiphenyl in liver microsomes of Wistar rats was examined by its single or co-administration with 3-methylcholanthrene and phenobarbital. The increased 4-nitrophenol glucuronyltransferase activity by treatment with 3-methylcholanthrene was significantly suppressed following the coadministration with poly (I)·poly (C), although the activity was not affected by the treatment with poly (I)·poly (C) alone. In addition, 4-hydroxybiphenyl glucuronyltransferase activity decreased or tended to decrease by the treatment with poly (I)·poly (C) alone, and the activity induced by phenobarbital was strikingly decreased following the co-administration with poly (I)·poly (C). This result suggested that poly (I)·poly (C) comprehensively decrease the induction of glucuronyltransferases regardless of their multiple forms. Furthermore, contents of cyto chromes P-450 and b₅ were also decreased by the treatment with poly (I)·poly (C) alone or the co-administration with the inducers. Concomitantly, arylhydrocarbon hydroxylase and benzphetamine N-demethylase activities were significantly decreased by the treatment alone or the co-administration with the inducers. These findings supported a view that the suppressive effect of poly (I)·poly (C) may be derived from the prevention of de novo synthesis of the apoprotein of the enzymes and/or the increased degradation.

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Benzodiazepines, chlordiazepoxide and diazepam reversed the antinociceptive action of caerulein in mice. Benzodiazepines (1-5 mg/kg) were administrated intraperitoneally and 100 ng of caerulein was injected intracisternally to mice. Benzodiazepines did not change the basal pain threshold of mice but significantly antagonized the antinociceptive effect of caerulein. Proglumide (200 mg/kg, i.p.), which has been claimed to be a specific cholecystokinin receptor antagonist, could also antagonize the antinociceptive effects of caerulein. Naloxone (5 mg/kg) partially but significantly antagonized the antinociceptive effect of caerulein, suggesting that one of the mechanisms of antinociceptive action of caerulein is related to endogeous opioid peptides since benzodiazepines do not act on opioid receptors. Benzodiazepines may decrease the antinociceptive effect of caerulein through acting on cholecystokinin receptors in the central nervous system.

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The anti-inflammatory activity of a proteinase inhibitor on carrageenin-induced inflammation was studied by using N-(2, 4-dinitrophenyl)-benzisothiazolinone-1, 1-dioxide, a selective inhibitor of elastase, cathepsin G and chymotrypsin. The selective inhibitor suppressed leukocyte chemotaxis in vivo and in vitro, vascular permeability and development of granulation tissue. These results suggest that a selective inhibitor of elastase, cathepsin G and chymotrypsin is an effective agent for suppression of induction and development of carrageenin-induced inflammation in rats.

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