Proxazole or 3-α-phenylpropyl-5-β-diethylaminoethyl-1, 2, 4-oxadiazole citrate, is an unusual drug because it possesses both anti-inflammatory and antispasmodic properties (1) and because each of these two properties has some uncommon features. The antiinflammatory action takes place mostly against edematous responses and is devoid of ulcerogenic effects which are instead produced by most anti-inflammatory drugs; moreover proxazole prevents indomethacin-induced ulcers without exerting any anti-secretory effect (2-3). The antispasmodic activity results in a specific inhibition of smooth muscle spasm, both at the vascular and at the intestinal level, without significant interferences with the physiologic activity of that tissue (1-4).
The above data suggested a potential interest in the use of proxazole in pathological situations sustained by ischemic-inflammatory processes. Therefore experiments were undertaken to test proxazole in rats operated according to Grollman (6). In such animals the induced hypertension may be measured and used as an index of renal alterations.

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The Open Field Test situation is reported to produce autonomic nervous system reactivity determined emotional freezing and defecation (1, 2), cortical excitation determined rearing activity (3), and corpus striatum activity determined stereotyped ambulation (4, 5). Thus autonomic depressant drugs reduce emotional freezing (6), cortical excitant drugs augment rearing (7, 8), and hallucinatory drugs facilitate stereotyped ambulation (4).
It has been reported (3) that selective stimulation of stereotyped ambulation with suppression of interrupting responses of rearing or preening is a typical action of increasing doses of LSD or iproniazid. This typical drug effect can be differentiated from that of amphetamine which in increasing doses facilitates rearing and simultaneously blocks preening as well as stereotyped ambulation; a third type of drug effect being that of imipramine which in increasing doses inhibits preening but failing to modify ambulation or rearing in rats. In the present study, attempts have been made to extend this approach to other stimulant drugs, i.e. methyl phenidate, pentylene tetrazol, mescaline, caffeine and pargyline for arriving at some definite conclusions regarding the multidimensional Open Field performance and the pharmacological manipulation there of.

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Panax ginseng C.A. Meyer (Araliacea) has been known for thousands of years in the Far East as a remedy effective against a multitude of ailments. Recently ginseng preparations have been tested for antineoplastic properties by Soviet and American investigators. Lazarev (1) reported that an extract of ginseng roots inhibited the growth of the murine Ehrlich carcinoma by 15 to 48%, while Yaremenko (2) obtained variable results in tests with Ehrlich cells, and no effect against the Walker tumor of rats. Abbott and co-workers (3) tested water and ethanol extracts of Panax quinquefolius L. (American ginseng) against murine tumors sarcoma 180 (S 180), adenocarcinoma 755 (Ca 755), and leukemia 1210 (L 1210) with negative results. A sample of Formosan Panax ginseng was ineffective in various test system (J. Hartwell, personal communication). The source of ginseng roots may be related to their pharmacologic effectiveness, as slight differences have been reported (4) in the composition of ginseng root varieties from different localities.

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In the previous paper, we reported of rats treated chronically with ethanol; that sidechain oxidation of hexobarbital, N-demethylation of aminopyrine and p-hydroxylation of aniline in vitro from 9, 000 g supernatant of liver homogenates were identical with those of control rats when ethanol was withdrawn and substituted for tap water 24 hours prior to sacrifice and that, in contrast, the activity of aniline hydroxylase of the rats which continued to ingest ethanol ad libitum up to the time of sacrifice was about 2-fold increased, compared with that of controls, in spite of no change detected in hexobarbital oxidase and aminopyrine demethylase (1).
We also reported that the addition of ethanol in a concentration of 8.5 mM to the incubation medium caused an inhibition of p-hydroxylation of aniline and that the type of inhibition was, at least superficially, competitive (2).
The present experiments were conducted to examine the kinetic behavior of aniline hydroxylase of rat liver microsomes when rats continued to drink ethanol ad libitum up to the time of sacrifice.

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During the investigations of the effect of indoline-derivatives on the smooth muscle have been continued, we have discovered that 1-methyl-5-chloroindoline methylbromide (hereafter referred to as S-6) well contracts the isolated ileum of guinea pig. Thus, the mode of action of S-6 on the guinea pig ileum has been investigated under various conditions. The aim of this paper is to show that S-6 contracts the isolated ileum of the guinea pig possibly by acting on acetylcholine receptor directly.

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The usual cause of death in tetanus is thought to be exhaustion following repeated convulsions and paralysis of respiratory centre (1-4). However, cardiac arrest, pulmonary oedema, hypertension or hypotension have also been observed and attributed to central or medullary intoxication (1, 5-7). Histopathological and elect rocardiographic evidences indicate involvement of the myocardium (8-10). Further, fluctuations in blood pressure and tachycardia often complicate the clinical picture.
Previous investigations carried out in our laboratory had revealed that intravenous injection of tetanus toxin in dogs and rats produces a triphasic response on systemic blood pressure. An initial slight pressor effect is followed by a sharp depressor response which is next followed by a sustained pressor phase. The depressor phase was absent in dogs pretreated with the antihistamine drug, mepyramine and in rats pretreated with cyproheptadine which is both antihistamine and antiserotonin. The delayed pressor phase was absent after treatment with phenoxyhenzamine, a drug with α-adrenergic blocking properties. The toxin was also shown to produce a stimulation of the isolated rabbit heart and reduce the coronary flow in the same preparation. It also reduced the flow through isolated perfused rat hind limbs. The toxin mimicked the action of adrenaline on guinea pig vas deferens and this was blocked by phenoxybenzamine. Thus there was a resemblance between the actions of the tetanus toxin and those of adrenaline. Studies were undertaken to assess this relationship further and are now being reported.

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In all methods for the assay of secretin now in use, the hormone is intravenously injection into the experimental animal and the response of the pancreas is recorded. The animals used have been dogs, cats, rabbits and rats (1). The rat method was elaborated in 1957 by Love (2), and Svatos and Jelinek (3). Although this rat method was shown impractical by Lin and Alphin in consequence of their comparative experiments between rats and dogs (4), it has been used by some groups (5-7). The technique of the rat method has been recently reinvestigated by Heatley and he shows that secretin can be assayed in rats (8).
For several years we have worked up the purification and economic production of secretin. In the course of this work the necessity arose for developing a simple method for the assay of secretin content in large numbers of preparations. Mutt and Soderberg found that if certain precautions were taken, anesthetized cats could be used for the assay of secretin for several days, thereby eliminating the necessity of time-consuming daily operations (9). But their valuable method which can be used to follow the activity of secretin in the course of purification is not suitable for determining precisely the quantity of secretin in preparations. Except Dorchester and Haist who used rabbits, none of the experiments have been statistically done for the estimation of secretin potencies (10).
We chose rats for the assay of secretin, because we could easily obtain the rats whose strain, age and body weight were nearly similar. The following facts were confirmed. Secretin could be satisfactorily assayed in anesthetized rats by the measurement of the volume of pancreatic juice secreted. The technique of the rat method was very simple, and if the twin crossover design which was used to determine various hormone potencies was applied, the expected standard error of the estimate was 10 to 15 percent. Furthermore secretin could be also assayed if the bicarbonate output in the pancreatic juice was determined, which changed linearly with the log doses of secretin.
Because of the lack of the international unit and a stable standard of secretin, there is no precise comparison between the potencies of the various units reported such as rat, dog, cat and Clinical unit yet (1, 5). The variation in the secretin potency between two brands of commercial secretins has been recently found to differ significantly (11). The relative potency between Crick, Harper and Raper unit (12) and Swedish Clinical unit (13), both of which were used in the clinical diagnosis for the pancreatic disorders, was determined by this rat method. The potency of 1 Clinical unit was 2 to 4 times as strong as that of the former.

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In 1969, the Servier Laboratoires introduced trimetazidine, 1-(2, 3, 4-trimethoxybenzyl)piperazine dihydrochloride (Vastarel®) as a medicament for angina pectoris (1). This drug is assumed to reveal its remarkable action through decreasing cardiac work and lowering the oxygen consumption of the heart (2), but other mechanisms of its action yet awaited clarification.
Since trimetazidine exerts no appreciable effect on normal atria, the present experiments on the actions of this drug had to be carried out in atria under the influence of nicotine, potassium free medium, or electrical stimulation. The isolated guinea-pig atria were chosen as an experimental material, because of its high sensitivity to various drugs. The decreasing effect of trimetazidine on the toxicity of strophanthin-G in guinea-pig atria has already been reported in our previous paper (3), in which it was suggested that trimetazidine might exhibit its action through lessening the out-flow of the intracellular potassium in atria. The anti-nicotinic action of this drug has also been reported in one of our previous papers (4).
Our previous experimental results led us to the present consideration of the relation between the chemical structure of the drug and its pharmacological actions. As the trimetazidine molecule possesses trimethoxybenzene and piperazine in its own chemical structure (Fig. 1), these two substances also were individually tested in reference to atrial actions of trimetazidine.

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So far there seems to have been no practical method for the assay of cardiotonic steroids which measures their positive inotropic activity per se directly on the cardiac muscle preparation. A series of studies on the structure-activity relationship of cardenolides conducted in this laboratory have brought about much newer knowledge on this problem, including dispensability of 3β-hydroxy group or 14β-hydroxy group for cardiotonic action and inactiveness of 15α-hydroxydigitoxigenin (1-4). In the course of the study, it was felt necessary to describe the potencies of important compounds in terms of numerical values. This led us to develop a new assay method which is based on the potentiation of K-contracture of frog ventricular muscle by these compounds, and it has been applied successfully at least to the aglycones. The present paper will report on the new method and the results of the assay of seven aglycones. In addition, the relative potencies of the compounds were compared with those obtained by another method with Straub's isolated frog heart preparation.

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The authors have shown that inosine is the main component responsible for the antagonizing effect of the whale heart extract on vasopressin-induced ST depression in the anesthetized rats (1). Huckabee introduced the concept of “excess lactate” in order to distinguish between pyruvate induced changes in lactate and those related solely to a shift in NAD: NADH redox potential (2, 3). So that, the increase of “excess lactate” in heart, with the measurement of lactate and pyruvate concentrations in the coronary vein and artery, has been considered to represent anaerobic metabolism due to cellular hypoxia.
The present paper reports the effect of inosine on the ischemic changes in myocardial lactate and pyruvate metabolism (increases in “excess lactate”) induced with vasopressin and adrenaline, and the effect of inosine on the ischemic elect rocardiographie change induced with adrenaline in rats.

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Studies have been so far made on the benzodioxane derivatives as a cardiovascular drug which were reported as a peripheral vasodilator, or as a hypotensive agent by Schaper et al. (1) and Green et al. (2). 8-[(1, 4-benzodioxan-2-yl) methyl]-3-oxo-l-thia-4, 8-diazaspiro-[4, 5]-decane maleate (Y-3506) was found desirable as a peripheral vasodilator with low toxicity among the new derivatives synthesized by this laboratory. This report deals with the effects of Y-3506 on the cardiovascular system of the experimental animals in comparison with those of several known vasodilators as reference compounds.

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Active principles of varied chemical structure isolated from plants possess potent anti-inflammatory activity. The anti-inflammatory activity of triterpenoids, saponins and other natural products has been reported from this laboratory (1-3). The flavonoids viz hesperidin, neohesperidin and naringin have been shown to reduce formalin-induced oedema in the mouse foot (4). The present investigation deals with the study of the antiinflammatory activity of taxifolin, a flavonoid obtained from Madhuca Butyracea, and the effect of taxifolin on the serum aminotransferase and tissue adenosine triphosphate (ATP) phosphohydrolase activity to elucidate the possible mechanism of its anti-inflammatory activity. The structure of the compound elucidated by Giessmann and Lichner (5) is shown in Fig. 1.

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The mechanism of the development of tolerance to and of physical dependence on morphine has been examined from a wide range of aspects. One of the approaches is to investigate the participation of brain biogenic amines in the actions of morphine. In 1954 Vogt (1) found a reduction of the content of hypothalamic norepinephrine after a subcutaneous morphine in the cat. Following her studies, some investigations were made on the change of the level of brain norepinephrine, dopamine and 5-hyroxytryptamine (5-HT) after either single or repeated administration of morphine.
Recently it was found that the analgesic action of morphine was abolished when either catecholamine releasers such as reserpine and tetrabenazine (2), or a potent inhibitor of tyrosine hydroxylase, α-methyltyrosine (3), was given several hours before morphine in mice. This fact has suggested an important role played by catecholamines in the analgesic action of morphine. This suggestion has been further supported by the observation that the abstinence symptoms manifested by nalorphine in morphinized rats is deteriorated by a pretreatment with α-methyltyrosine or disulfiram (4).
The present study deals with the development of tolerance to analgesic action of morphine and the change of brain norepinephrine content after intraventricular injection of morphine into the rat. The abstinence symptoms induced by levallorphan in the rat that received repeated intraventricular injections of morphine are also reported.

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It has been generally accepted that adenine nucleotides exhibit a smooth muscle relaxing action and this is caused by adenosine moiety of their molecules (1-4). However, as shown by Stafford (1), Bennet (5) and Deuticke (6), guinea-pig uterus contracts in response to adenine nucleotides as well as to adenosine. Furthermore, several workers (7-11) observed on rat uterus or goldfish intestine that ADP and ATP exhibited a contraction but 5'-AMP or adenosine did not.
On the other hand, it has been reported that the pretreatment of ATP or cyclic 3', 5'-AMP modified the contractile responses of adenine or uridine nucleotides, though the influences varied in each cases (3, 10, 11). Although these sensitization mechanisms are not still clarified, these studies will give a clue to the elucidation of the contractile mechanism of ATP.
In order to know the mechanism of smooth muscle contraction induced by adenine nucleotides or adenosine, present study was performed on the effects of 5'-AMP and its related compounds on the ATP-induced contraction of isolated guinea-pig ileum.

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A new adrenergic β-stimulant, l-1-(3, 4, 5-trimethoxybenzyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline HCI (trimetoquinol), exhibits strong bronchodilator effect as well as hypotensive, positive inotropic and chronotropic actions (1-7). Recently, the metabolic fate of this compound was studied in detail and it was found that part of trimetoquinol (TMQ) was O-methylated to form both 6 and 7-methoxytrimetoquinol (6 and 7-MeTMQ). Conjugated TMQ and conjugated MeTMQ with glucuronic acid were also found in the urine (8, 9).
It has been reported that 3-methoxyisoproterenol, a metabolite of isoproterenol (Iso), acts like an adrenergic β-receptor blocker. Thus it inhibits the positive chronotropic and vasodepressor responses to Iso in the dog and cat (10, 11). The antagonistic relationship between epinephrine or norepinephrine and the corresponding methoxymetabolites (metanephrine or normetanephrine) was also observed on the isolated guinea-pig tracheal muscle (12), on the isolated perfused rat heart (13), or on the non-pregnant uterus of the cat (14). On the other hand, the nictitating membrane of the cat, the seminal vesicle of the guinea-pig and the heart rate of the dog in situ were sensitized to epinephrine by metanephrine (14).
The present experiments were performed to investigate the possible adrenergic β-stimulating and β-blocking properties of the methoxymetabolites (6- and 7-MeTMQ) of TMQ, and the effects on the heart rate, blood pressure and histamine-induced bronchoconstriction were examined in the anesthetized cat. As to the conjugated metabolites with glucuronic acid, the experiments were not carried out in the present study, since their pharmacological activities were very weak, as examined on the isolated tracheal muscle of the guinea-pig, and also the acute toxicities of these metabolites were very low.

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