Direct actions of expectorants and other secretagogues on the airway system in vivo were investigated. Bronchosecretory, bronchomotor and bronchovascular responses were determined in pentobarbital-anesthetized dogs, the bronchial artery of which was perfused with blood in situ. Pilocarpine and histamine had a direct strong stimulating effect on the airway secretory cells, and potassium iodide and ammonium chloride had a mild effect, while bromhexine had almost no stimulant effect on those cells. Potassium iodide and bromhexine produced a slight bronchoconstriction. Contribution of a transvascular transudate to the respiratory tract fluid produced by expectorants or other secretagogues was suggested to be quite small.

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When the mice were treated with acetazolamide (AZA) 30 min before the administration of pentobarbital, the sleeping time was prolonged. At the moment of awakening from sleep, no change in the brain level of pentobarbital was observed by the AZA pretreatment, which suggests the constant brain sensitivity to the barbiturate. At that time, the plasma level was lowered by the AZA pretreatment. Pentobarbital had no effect on a carbonic anhydrase activity in brain inhibited by AZA. The results similar to those were obtained also in thiopental and norhexobarbital. Thus it was inferred that the prolongation of barbiturate sleep in mice pretreated with AZA is due to a decrease in the rate of removal of the barbiturate from the brain, through brain carbonic anhydrase inhibition followed by the lowering of cerebrospinal fluid flow. Hexobarbital sleeping time was shortened by the AZA pretreatment. At awakening, the brain hexobarbital level was somewhat, but not significantly, increased and the plasma level was significantly raised by the AZA pretreatment. Brain carbonic anhydrase inhibited by AZA was restored to control level with hexobarbital dosing. There seemed to be some particular interaction between AZA and hexobarbital in brain, which may be related to difference in barbiturate structures including N-methyl group.

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The effects of cimetidine, a new histamine H₂ receptor antagonist, were studied electrophysiologically and mechanically in the isolated guinea pig myocardium. Cimetidine did not modify the electrical activity of the sinoatrial pacemaker cells at the concentrations up to 10^-4 M, but depressed the pacemaker potential at the higher concentration, 3×10^-4 M. Increase in the slope of the pacemaker potential produced by histamine was completely inhibited by cimetidine, indicating that the histamine receptor for the positive chronotropism is of H₂-type. Cimetidine did not depress the maximum rate of rise of the atrial and ventricular action potentials ; thus, unlike most of the H₁ receptor antagonists, cimetidine does not have quinidine like actions. The shape of the action potential was not modified significantly. Slow electrical and mechanical activities produced by histamine in the right ventricular myocardium whose fast Na⁺ channels were blocked by elevated external potassium were partially blocked by either cimetidine or diphenhydramine, supporting the view that both types of receptors are present in the right ventricle. Histamine-induced mechanical activity in the depolarized right atrium was inhibited by cimetidine, but that in the left atrium was not inhibited ; these results support the view that the histamine receptor in the left atrium is of H₁-type and suggest that the histamine receptor for the positive inotropism in the right atrium is of H₂-type. In addition, some results were shown suggesting the possibility that cimetidine might have some agonist-like action in the myocardium.

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A method for separatory determination of d- and l-pentazocine in blood plasma by radioimmunoassay has been developed. In order to obtain antiserum optically specific to l-pentazocine a hapten-carrier conjugate was prepared from l-pentazocine 2'-carboxymethyl ether by coupling with bovine serum albumin (BSA) using the mixed anhydride method. The antiserum elicited in the rabbit by immunization with this antigen proved to be highly specific to l-pentazocine by cross-reaction studies with the d-form and principal metabolites. The anti-dl-pentazocine antiserum was similarly produced in the rabbit immunized with the dl-pentazocine 2'-caboxymethyl ether-BSA conjugate. The plasma level of d-pentazocine could be estimated indirectly by subtracting the observed value of the l-enantiomer from that of total pentazocine. The plasma concentration of d- and l-pentazocine in man after administration of an officinal dose of the racemate was determined by the established method.

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Effects of immunosuppressive agents on immunochemical properties of antibody populations produced in guinea pigs were studied with Methotrexate, cyclophosphamide, hydrocortisone, Bredinin (4-carbamoyl-1-β-D-ribofuranosyl imidazolium-5-olate), azathioprine and 6-mercaptopurine. Among these agents, Methotrexate and cyclophosphamide alone suppressed strongly the antibody responses, not depending on the degree of the T cell-dependency of antigens used. Hydrocortisone, Bredinin and azathioprine also suppressed the antibody responses slightly, and no effect was observed with 6-mercaptopurine. With cyclophosphamide and hydrocortisone, no substantial difference in the susceptibility was observed between the IgG1 and IgG2 antibody responses. On the other hand, the IgG1 antibody response appeared to be slightly more sensitive to the immunosuppressive activities of Bredinin and azathioprine, compared with the IgG2 antibody response. With Methotrexate, the difference in the susceptibility between these two responses seemed to vary depending on the kind of antigens used. In addition, the antigen-binding abilities of antibodies produced were not influenced by the treatment with Methotrexate and cyclophosphamide.

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The urinary and fecal excretion of three new metabolites of butylated hydroxytoluene (BHT) were revealed by gas chromatography after intraperitoneal administration of this compound to male Wistar rats. The structures of these metabolites, 2, 6-di-tert-butyl-p-benzoquinone (M-I), 2, 6-di-tert-butylhydroquinone (M-II), and 2, 6-di-tert-butyl-4-[(methylthio) methyl] phenol (M-III), were identified by comparison of gas chromatographic and mass spectral data with those of authentic samples. The possible formation of 2, 6-di-tert-butyl-4-hydroperoxy-4-methyl-2, 5-cyclohexadien-1-one (1) as an intermediary metabolite to account for the occurrence of M-I was also discussed.

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In mice with unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesions, morphine produced marked ipsilateral and slight contralateral rotations. Apomorphine and methamphetamine induced contralateral and ipsilateral rotations, respectively. Ipsilateral rotation produced by morphine increased in a dose-dependent manner. Pretreatment with α-methyl-p-tyrosine suppressed ipsilateral rotations induced by morphine or methamphetamine, but not contralateral rotation by apomorphine. Spiroperidol inhibited rotations induced by morphine, methamphetamine or apomorphine. Repeated administrations of morphine caused a development of tolerance to ipsilateral rotation. Contralateral rotation induced by morphine did not increase dose-dependently. Pretreatment with α-methyl-p-tyrosine or spiroperiodol did not suppress significantly morphine-induced contralateral rotation. Development of tolerance to contralateral rotation was not observed after repeated administrations. It is concluded that morphine induces ipsilateral rotation by mechanisms similar to those of methamphetamine, while mechanisms of contralateral rotation induced by morphine appears to be different from those of ipsilateral rotation. In rats with unilateral intranigral 6-OHDA lesions, morphine produced ipsilateral rotation in parallel with a decrease of catalepsy and an increase of behavioural excitation. Tolerance to ipsilateral rotation developed following repeated administrations of morphine. Contralateral rotation produced by levallorphan in tolerant rats was suggested to be an abstinence sign.

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The absorption characteristics of p-aminobenzoic acid (PABA) from the rat intestine was investigated comparing with that of p-acetamidobenzoic acid (Ac-PABA). The ionized form of PABA was well absorbed from the small intestine and the pH-profile of the absorption rate of PABA was inconsistent with the pH-partition theory. This phenomenon was not observed in the large intestine. In contrast, the absorption of Ac-PABA was consistent with the pH-partition theory in both small and large intestine. The transfer rate of PABA from mucosal side to serosal side was markedly faster than that in the opposite direction. This directional difference in the transfer rate was not observed with Ac-PABA. The uptake against a concentration gradient was found during the absorption process of PABA. This phenomenon disappeared in the presence of 2, 4-dinitrophenol, p-chloromercuribenzene sulfonate or by the pretreatment of the intestine with HgCl₂. These findings indicate the anomalous aspects of the absorption of PABA from the rat small intestine at pH 6.5. Furthermore, the absorption of PABA was inhibited by the mercurial modification of the brush border membrane. This suggests that protein and sulfhydryl groups within the brush border membrane are involved in the absorption process of PABA.

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An allergic footpad inflammation of mice was induced by using azobenzenearsonateacetyl bovine serum albumin conjugate as an antigen. Sensitization was made with the aid of Freund's complete adjuvant and the allergic reaction was elicited by using an emulsion consisting of Freund's incomplete adjuvant and 0.9% NaCl solution as a carrier of the challenging antigen. Allergic footpad swelling reached a maximum 24 hr after the challenge dose. D-Penicillamine, an anti-rheumatic drug, exerted a strong inhibitory effect on the allergic process, if animals were treated with this drug for 21 days at a dose of 600 mg/kg/day.

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Acetylcholine contents of the rat vasa deferentia were measured after surgical denervation, daily reserpine treatment or 6-hydroxydopamine pretreatment, all of which are known to cause a decrease in norepinephrine contents. Denervation and reserpine treatment are known to cause nonspecific supersensitivity to agonists. Denervation caused a decrease in acetylcholine content but reserpine and 6-hydroxydopamine failed. It is suggested that surgical denervation causes adrenergic and cholinergic denervation and that acetylcholine content per se is not causally related to the appearance of nonspecific supersensitivity.

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