The relationship between the structures and the choleretic actions of iridoid compounds was examined. Only patrinoside and villoside accelerated bile secretion among the iridoid glucosides but all of the iridoid aglycones increased it after intravenous administration in rats. The choleretic effects of villoside, patrinoside aglycone, and 11-deoxy patrinoside aglycone were far weaker in comparison with those of other active iridoid compounds. When an equimolar amount of patrinoside, its aglycone, or 11-deoxy patrinoside aglycone was administered intravenously, their periodical patterns of choleretic activities nearly paralleled with those of isovaleric acid excreted in the bile. Patrinoside was partly hydrolyzed into its aglycone by the artificial gastric juice or the intestinal content. After intraduodenal administration of patrinoside (1 g/kg), the amount of patrinoside enough to exert a choleretic action was detected in the portal blood. These findings indicate that the hemiacetal moiety of iridoid compounds plays an important role in exerting a strong choleretic action and that patrinoside shows the same action following the saponification of isovalerate at C-1 position in the liver.

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The effect of a single or repeated intraperitoneal injection (s) of various therapeutic agents on peripheral leukocyte count in mice was studied. The result revealed a great deal of initial variation of leukocyte number in the animals and also variations in the capability of the animals to restore the decreased leukocyte level. On the other hand, a simple reproducible and highly sensitive method for the evalution of the toxic effect of the chemicals on leukopoiesis has been provided by culturing mouse bone marrow cells in a semi-solid agar medium in the presence of purified colony stimulating factor (CSF). There were three groups of chemicals in regard to the effect on the proliferation of the myeloid stem cells (CFU-C) in culture : (1) Anticancer drugs such as mitomycin C and 5-fluorouracil were inhibitory to CFU-C at 10^-8-10^-7 M. (2) Many drugs such as erythromycin, cephalosporin etc. showed apparent toxicity in 10^-5-10^-4 M. (3) Drugs like penicillin, streptomycin, cysteine etc. showed no significant toxicity at concentrations higher than 10^-4 M. It was noted that the inhibition of CFU-C proliferation either by mitomycin C (an inhibitor of DNA synthesis) or by erythromycin (an inhibitor of protein synthesis) occurred in a manner competitive to the added CSF activity. The results suggest that CSF is capable of specifically protecting the myeloid stem cells from the toxic action of the chemicals.

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The blood level and brain distribution of immunoreactive TRH after intravenous administration of TRH tartrate monohydrate (TRH-T) were investigated by radioimmunoassay in rats. Optimal condition for complete inactivation of TRH-degradative enzymes in brain by a microwave irradiation was found to be a 5kW power for 1.5 seconds. The endogenous TRH was present at the highest concentration in the hypothalamus, followed by the brain stem and thalamus, and was the lowest in the cerebral cortex including hippocampus and cerebellum. The time-course of TRH blood levels following administration of TRH-T at 0.5, 5 and 25 mg/kg fitted to a two compartment open model, and the half-lives in β-phase increased dose-dependently. The administered TRH was incorporated rapidly from blood into whole brain, and the peak brain level corresponding to 0.108-0.166% of the total dose administered was attained 1 min after the administration. The brain TRH was eliminated with a half-life of about 3 min. The administered TRH was distributed throughout the brain, at the highest concentration in the hypothalamus, followed by the brain stem, cerebellum, thalamus and cerebral cortex. TRH tended to be eliminated most rapidly from the cerebellum.

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Following previous demonstration that isoproterenol stimulated and norepinephrine inhibited gastric acid secretion induced by secretagogues, role of adrenergic agonists was studied by measuring acidity and peptic activity of the effluent of the perfused rat stomach. Response of gastric secretion to isoproterenol was increased by theophylline treatment but was not affected by metiamide treatment. N⁶, O^2'-Dibutyryladenosine 3', 5'-cyclic monophosphoric acid sodium salt monohydride (dibutyryl-c-AMP) stimulated gastric secretion in a dose-dependent manner. These results suggest the possibility that the action of isoproterenol in gastric acid secretion is mediated by c-AMP. However, gastric secretion induced by pentagastrin, histamine, or carbamylcholine was not affected by theophylline treatment. N², O^2'-Dibutyrylguanosine 3', 5'-cyclic monophosphoric acid sodium salt (dibutyryl-c-GMP) did not exert any effect on gastric secretion. Depression of pentagastrin-induced gastric secretion by norepinephrine was reversed by EGTA infusion. Moreover, Ca²⁺ depressed pentagastrininduced gastric secretion. These results suggest that the action of norepinephrine is closely related to the concentration of Ca²⁺.

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The methanol extracts of Aconitum roots have shown inhibition of increased vascular permeability induced by acetic acid and of hind paw edema produced by carrageenin in mice. The extract of A. carmichaeli has been fractionated, monitored by the capillary permeability test, to yield the aconitines as active principles. The aconitines have inhibited the increased vascular permeability induced by acetic acid in mouse peritoneal cavity and that induced by histamine in rat intradermal sites, and the hind paw edema formation induced by carrageenin in rats and mice at low doses. The benzoylaconines have exhibited inhibitory effects on the aforementioned acute inflammations but at the higher doses. The aconitines have reduced the granulation tissue formation of the chorio-allantoic membrane of the chick embryo. On the other hand, the Aconitum alkaloids have elicited no effects on the ultraviolet erythema formation in guinea pigs at lower doses than the lethal ones and failed to show positive responses on the vascular permeability in the granuloma pouch and on adjuvant arthritis in rats at the doses employed.

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Effects of antiepileptic drugs on various components (TF : tonic extension of forelimb, TH : tonic extension of hindlimb and CL : clonic convulsion or MCL : myoclonus) of maximal seizures induced by electroshock or pentylenetetrazol in mice were examined in order to classify these drugs. In addition, experiment was conducted similarly on the new anticonvulsant agent, 3-sulfamoylmethyl-1, 2-benzisoxazole (AD-810), in order to assess this compound on the basis of the results with clinically useful antiepileptic drugs. From the results obtained in the present study, irrespective of the method, i.e. chemically or electrically induced seizures, anticonvulsant drugs tested can be classified into four main groups ; 1) drugs (trimethadione, ethosuximide, nitrazepam, diazepam, ethotoin and metharbital) with an effect to antagonize all the whole seizure components (TF, TH and CL or MCL) in an almost same antagonism, 2) drugs (phenacemide, dipropylacetate, pheneturide, acetylpheneturide and phenobarbital) which inhibit all forms of seizures at relatively dissociated doses for the prevention of each component of seizures, 3) drugs (diphenylhydantoin and carbamazepine) which selectively abolish both components (TF and TH) of tonic seizures, and 4) drugs (acetazolamide, sulthiame and primidone) exclusively blocking TH of tonic seizures. AD-810 demonstrated an antagonistic effect on tonic seizures but not on clonic ones with the same manner as seen with diphenylhydantoin and carbamazepine.

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For the purpose of seeking a possible base for the oral clinical application of an anthracycline antibiotic, aclacinomycin A (ACM), ACM was given orally to the mice bearing Lewis lung carcinoma, colon adenocarcinomas 26 and 38, and compared with the effect of adriamycin (ADM). Oral administration of ACM at 5 or 10 mg/kg for 10 times suppressed the growth of Lewis lung carcinoma. There was no significant difference in survival times of the tumor-bearing mice given ACM orally at various dosages tested. ADM was not effective orally as long as the antitumor effect was examined at the dose levels tested. However, significant increase in the survival time of the mice implanted s.c. with colon adenocarcinoma 26 or 38 was noted by oral administration of ACM at 5-10 mg/kg for 10 times. That is, at 10 mg/kg of ACM, T/C% was 187% against colon 26 and 141% against colon 38, respectively. ADM was not effective against these mouse tumors when given orally. Clinical application of ACM by oral administration, however, will need further studies including preclinical pharmacology, drug formulation and others.

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It was shown that there were clear differences between the effects of norepinephrine and dibutyryl cyclic AMP on the cultured chick embryonic heart cells. Norepinephrine and dibutyryl cyclic AMP were applied to the cultured chick embryonic heart cells, and the changes in the beating rate and the action potential configuration were examined. Norepinephrine increased the beating rate, but dibutyryl cyclic AMP produced the significant negative chronotropic effect. Norepinephrine increased the slope of the diastolic depolarization with little affecting the duration of the action potential. In contrast, dibutyryl cyclic AMP significantly prolonged the action potential duration without changing the slope of the diastolic depolarization. Thus, it was shown that dibutyryl cyclic AMP did not always produce the positive chronotropism, and it was suggested that the negative chronotropism on the cultured chick embryonic heart cells was related to the prolongation of the action potential duration.

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EG-626, 7-ethoxycarbonyl-6, 8-dimethyl-4-hydroxymethyl-1 (2H)-phthalazinone, was found to be a considerably potent cardiotonic agent. It produced both the positive chronotropic and inotropic actions in the guinea pig heart muscle. Positive inotropic action of isoproterenol was potentiated by EG-626 at the concentration which did not produce a substantial positive inotropic action by itself. Cardiac action potential was not modified by EG-626 at concentrations sufficient to produce positive inotropic actions. EG-626 has a strong activity to produce slow responses in the depolarized myocardium, indicating that it can increase the density of the slow channels. The possibility was shown that the increase in the density of the slow channel may play an important role in the positive inotropic action of EG-626. The increase in the intracellular cyclic AMP due to the phosphodiesterase inhibition is tentatively most likely to be the cause of the EG-626 induced increase in the density of the slow channels.

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Cholesterol α-epoxide (5, 6α-epoxy-5α-cholestan-3β-ol), cholesterol β-epoxide (5, 6β-epoxy-5β-cholestan-3β-ol), and cholestanetriol (5α-cholestane-3β, 5, 6β-triol) were isolated from plasma and liver of rabbits by high performance liquid chromatography and identified by gas-chromatography-mass spectrometry. The 5, 6-oxygenated cholestanols in the plasma and liver of rabbits fed for two months on a diet supplimented with cholesterol were elevated to 2-5 times and 5-8 times the normal level, respectively. Among the 5, 6-oxygenated steroids, the β-epoxide existed at the highest level in tissues of both control and cholesterol-fed rabbits. The ratios of the β-epoxide to the α-epoxide were 2-3 in all the examined biological specimens just as the previously demontsrated ones in the in vitro lipid peroxidation-mediated reaction of cholesterol. These results strongly suggest that the epoxidation of the cholesterol double bond in the animal may be mediated by lipid peroxidation. The elevated 5, 6-oxygenated cholestanol levels on long term cholesterol feeding will be discussed in relation to a possible physio ogical role of cholestanetriol in regulation of tissue cholesterol levels.

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