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RYUICHI KATO
1967 Volume 17 Issue 4 Pages
499-508
Published: December 01, 1967
Released on J-STAGE: February 02, 2007
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Repeated administration of many drugs, especially central acting drugs, cause a development of tolerance to same or related drugs. The development of drug tolerance is an important problem for the evalution of drug actions and for the determination of a schedule of drug administration. However, the mechanism of development of drug tolerance is still in obscure. On the other hand, it is recently well demonstrated by several investigators that single or repeated administration of various drugs induces an increase in the activities of drug-metabolizing enzymes of liver microsomes (1-4). Thus, the actions of the same drugs or other drugs given successively are markedly decreased through the increased rates of drug metabolisms (2, 4, 5). It has been well known that most of the central acting drugs are the inducers of drug-metabolizing enzymes of liver microsomes (2, 4, 5). The purpose of present communication, therefore, is to analyse and differentiate the mechanism of the development of drug tolerance. The results of the present investigation showed that there are two kind of drug tolerances and the first one would be called as
apparent tolerance and the second one would be called as
real tolerance. The development of the first one is mainely due to the induction of drug-metabolizing enzymes of liver microsomes and the second one is mainely due to the decreased tissue sensitivity to the drug. A simple and effective method to differentiate the two kinds of drug tolerance is the joint injection of inhibitors of enzyme protein synthesis, such as ethionine, with the designed drugs.
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RYUICHI KATO, AKIRA TAKANAKA, YOSHITO OMORI
1967 Volume 17 Issue 4 Pages
509-518
Published: December 01, 1967
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Octamethylpyrophosphoramide (OMPA) is a potent inhibitor of cholinesterase
in vivo. However, OMPA itself is a very weak inhibitor, but it is converted to a potent inhibitor following oxidation by liver microsomes (1-4). In a pervious paper it is reported that the administration of thiopental or phenaglycodol markedly increased the toxicity of OMPA in female rats (5). Since the joint administration of ethionine with thiopental or phenaglycodol completely blocked the effect of thiopental or phenaglycodol, it was postulated that the induction of microsomal enzyme which activates the metabolism of OMPA was involved in the increased toxicity after thiopental or phenaglycodol treatment. In the present investigation, the effect of phenobarbital and methylcholanthrene on the toxicity and metabolism of OMPA in female and male rats were studied to confirm this postulation. Phenobarbital and methylcholanthrene are well known inducers of drug-metabolizing enzymes of liver microsomes (6-8). However, the administration of both drugs likely give different effects on the microsomal enzymes (9-11). The typical difference were also evidenced in the present works. In addition the marked sex difference was observed on the metabolism of many drugs by liver microsomes, and the metabolism of OMPA in male rats was much faster than that in female rats (2, 12-16). In the present studies the marked sex difference was also observed in the effect of phenobarbital and methylcholanthrene on the metabolism and toxictity of OMPA. These results may offer a typical example for the role of the metabolism of drugs by liver microsomes for the determination of drug toxicity.
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TATSUO FURUKAWA, SIGERU ISOBE, ICHIRO YANO
1967 Volume 17 Issue 4 Pages
519-524
Published: December 01, 1967
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It has been noted that administration of adrenocortical hormones as well as synthetic adrenal steroids give rise to a marked inhibition of adrenal function. However a few reports referring to a counteraction against this depressive effect of adrenal steroid have been presented. Onuki
et al. (1) have reported that, although xylitol seems to slightly protect a depression of corticoid biosynthesis in the adrenals resulting from prednisolone administration, the effect is not statistically significant. Recently, it has been reported that reserpine obviously counteracts a inhibitory effect of dexamethasone on the adrenals, and this effect is presumably not due to a depression of corticotrophin secretion by reserpine but due to its stimulative effect on the hypophysial-adrenal axis (2). These results are elicited of some interest in view of counteraction between the corticoid-induced adrenal inhibition and the stress which is proposed to stimulate the hypophysial-adrenal system.
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MAMORU SUZUKI, KATSUHIRO MOTOYOSHI, HIROSUKE ARAI, HISAO HORIKAWA
1967 Volume 17 Issue 4 Pages
525-537
Published: December 01, 1967
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It has been reported that Tween 20, one of the nonionic surfactants, liberates tissue histamine (1-3), and that various surfactants are locally irritating at the conjunctival (4), intramuscular (5), percutaneous (6) and intracutaneous (7) sites of application. Therefore, the irritating effect is possible due partially to the histamine liberation. However, the increased capillary permeability by the intracutaneous injection of nonionic surfactants differed somewhat in mode of action from that caused by the same procedure of histamine (7-9). Especially, the increased capillary permeability by the procedure of polyoxyethylene monolauryl ether (a nonionic surfactant) is scarcely influenced by the repeated pretreatment of the animal with Tween 20 or by the previous administration of the antihistamine (10). These evidences led the present authors to conclude that the increased capillary permeability induced by the nonionic surfactants did not derive from the histamine liberation alone. The present study deals with the effects of the antihistamine, inorganic salts, a fatty solvent and cholesterol feeding on the increased capillary permeability induced by the intracutaneous injection of the nonionic surfactants in the rabbits.
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KIYOMI YAMATSU, KIICHI OHTSU, YOSHITOSHI KASE, TAKESHI MIYATA, TOMOKAZ ...
1967 Volume 17 Issue 4 Pages
538-549
Published: December 01, 1967
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1-(2-Benzylphenoxy)-2-piperidinopropane phosphate (abbreviated as ASA 158/5) which was introduced by the Pharmacia Research Laboratory (Sweden) is a compound with the following chemical structure (1). According to an unofficial and unpublished report from the Laboratory (2), it has the antitussive potency 2 to 4 times as potent as that of codeine phosphate and its antitussive action may be mainly due to the prevention of impulses from the pulmonary stretch receptors. The present purpose of this study is to confirm the site of antitussive action of the drug.
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FUMIO ITO
1967 Volume 17 Issue 4 Pages
550-556
Published: December 01, 1967
Released on J-STAGE: February 02, 2007
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Succinylcholine is a non-competitive blocking agent with both depolarizing and desensitizing actions. The drug produces a contracture in avian (1) and mammalian (2) muscles containing slow fibres. Katz and Eakins (2) have suggested that succinylcholine produces excitation of the slow fibres and depression of the fast fibres. The present study was undertaken to clarify the mechanism of the succinylcholine contracture of frog slow muscle fibres.
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NORIMITSU L. SATO, IKUZO HIMURO, AKITOSHI SHIOYA
1967 Volume 17 Issue 4 Pages
557-571
Published: December 01, 1967
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As is well known, intravenously administered dye extravasates at the site of inflammation (1-4). This phenomenon has been used as one of the bases for the bioassay of experimentally induced inflammation (5-10). However, estimation of the extravasated dye either directly or by comparison to standard color chart, was not always satisfactory because of being influenced by subjective bias. Subsequently, Sachs and Lummis (11) recommended the spectrophotemetric measurement of the dye extracted from the inflammed tissue. In this paper, the authors propose a convenient method for the quantitative estimation of extravasated dye at the site of inflammation in mice using a photoelectric technique. The technique was utilized to demonstrate the anti-inflammatory activity of cortisone, salicylates, aminopyrine, tripelennamine, and glucuronic acid derivatives.
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R.K. SRIVASTAVA, A.K. GHOSH, O.P. SRIVASTAVA, P.R. PABRAI
1967 Volume 17 Issue 4 Pages
572-576
Published: December 01, 1967
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The selection of a potent anaesthetic agent is mainly guided by its margin of safety. “Safety index” or therapeutic coefficient of intravenously administered barbiturates has been determined in the past by employing various methods in different laboratory animals. Consequently results obtained are neither uniform nor comparable. The ratio of minimal lethal dose/minimal head drop dose in 50% of rabbits has been considered as the therapeutic coefficient by Werner, Pratt and Tatum (1). Swanson and Chen (2) determined the median anaesthetic dose (AD
50) and median lethal dose (LD
50) in rabbits, rats, cats and dogs for predicting safety of intravenous barbiturates. While some believe that toxicity of these agents runs parallel to their hypnotic potency others feel that doses of the various barbiturates required to produce sedative, hypnotic and anaesthetic grades of depression bear a rather fixed relationship to the median fatal dose. This is believed to be because of lack of a suitable method for accurate measurement of various grades of central depression in laboratory animals [Goodman and Gilman (3)]. Recently Ghosh, Srivastava and Ghosh (4, 5) and Srivastava and Ghosh (6) described a method for determining the margin of safety of volatile anaesthetics. Herein individual anaesthetic and fatal doses have been measured accurately in mice, rats and guinea-pigs. In the present study margin of safety of seven ultra-short acting intravenous barbiturates has been determined in rabbits by a method which permits accurate measurement of different stages of central depression in individual animals.
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IZURU MATSUOKA
1967 Volume 17 Issue 4 Pages
577-590
Published: December 01, 1967
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Numerous studies on electrophysiological aspects of the single neuron in the vestibular nuclei have been presented since the investigation by Adrian (1). The vestibular nuclei consist of four groups: Schwalbe's, Bechterew's, Deiters' and Roller's nuclei. Among them the Deiters' nucleus is located in the most lateral region and its nerve cells are the largest in size. The pattern of the afferent and efferent fiber connections of the central vestibular system is extremely complex. The vestibular nuclei project the ascending fibers to the flocculonodular lobe and fastigial nucleus of cerebellum and to the reticular formation and motor nuclei in the brain stem. The descending fibers terminate near the spinal motor cells passing through the lateral vestibulo-spinal tract (2-7). There are several technical difficulties for recording the unitary discharges from the vestibular nuclei. Orientation of the structure is somewhat uncertain due to covering by the cerebellum. Vertical insertion of the microelectrode is obstructed by the tentorium cerebelli, and respiratory movement evokes the fluctuation of the recording areas. Many efforts to eliminate the difficulties, such as deep anesthesia, application of muscle relaxants and resection of the cerebellum have hitherto been devised. However, these procedures may affect the vestibular activity. Relative long-term recordings of the unitary discharges from the same single neuron in the vestibular nuclei have been developed by improvement of the microelectrode technique and the stable immobilization technique of the recording sites (8-11), but most of these experiments have been carried out in the anesthetized animals. In order to investigate the function of the vestibular nuclei in the experimental animals, following stimuli have been employed: afferent electrical stimulation of the vestibular nerve (12-20), postural rotation (14, 15, 21-24), tilting (21, 25-27), acoustic stimuli (28, 29), proprioceptive stimulation of the extremities (2, 30) and caloric stimulation (24, 31-34). Recently, direct and nongravidity stimulation in space attitude is also introduced (35). It is well-known that caloric stimulation is originally a clinical test of the vestibular function as the reliable diagnosis method for lesions of the vestibular system, but the responses of the vestibular nuclei to caloric stimulation in the unanesthetized animals still remain to be settled. In the present experiments, an attempt has been made to know the responses of the unitary discharges in the vestibular nuclei, mainly in the Deiters' nucleus, to caloric stimulation of the middle ear cavity in the pentobarbital-anesthetized cats and in the
encéphale isolé preparations of unanesthetized cats.
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TATSURO SHIGEI, AKIRA SAKUMA, TSUNE ENOMOTO, SACHIKO OH-ISHI, RYOJI HA ...
1967 Volume 17 Issue 4 Pages
591-602
Published: December 01, 1967
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In spite of the vast accumulation of informations over many years, the key mechanism of the adrenaline induced pulmonary edema still remains to be elucidated. We have carried out a series of experiments attempting to obtain further clues for solving the problem. The present paper is concerned with the following subjects:
1) Setting up of a procedure for producing pulmonary edema by continuous infusion of adrenaline solution. This procedure seems to be more appropriate than a single injection for analysis of the sequence of events in the cardiovascular and respiratory systems.
2) Comparison of edema-producing activity of some sympathomimetic amines. This trial may suggest whether the edema production is related to the
alpha or
beta adrenergic action, or else.
3) Designing of a screening scheme to single out such a pretreatment as would effectively prevent the adrenaline induced pulmonary edema. The effects of some operative procedures, autonomic blocking agents, proteolytic enzymes as well as their inhibitors were examined, and some of them proved to be effective. Parts of the present study were reported previously (1-4).
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HIDEAKI KARAKI, MIYOSHI IKEDA, NORIMOTO URAKAWA
1967 Volume 17 Issue 4 Pages
603-612
Published: December 01, 1967
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It was reported that the contractions in taenia coli induced by carbachol (1), ACh (2), phosphatidic acid (3) and high-potassium (K) (1, 4, 5) are all dependent on external calcium. On the other hand, Yukisada and Ebashi (6) have reported that rat, guinea pig, and rabbit ileum and rat uterus respond to barium (Ba) in the absence of external calcium. These results have been supported by experiments with rat uterus (7). In the first series of experiments in this paper, the relationship between Ba-induced tension development and external calcium was re-examined using isolated taenia coli preparations. K-induced contracture in taenia coli was reported to be composed of two phases, namely, phasic and tonic responses (5, 8). Furthermore, the tonic response was abolished in the presence of various inhibitors of metabolism and active transport (8). The second series of experiments were designed to examine the effect of the above mentioned inhibitors on Ba-induced tension development. Some of the results have already been reported (9).
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JIRO SUGIMOTO, TOSHIKO ITO, ETSUKO NAKAMURA, MASAO MORITA
1967 Volume 17 Issue 4 Pages
613-621
Published: December 01, 1967
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Bertler, Carlsson and Rosengren (1) found that the pressor effect of tyramine is decreased in animals that have previously been reserpinized, and Burn and Rand (2) have reported that in such animals the change in blood pressure, response of vessel wall, or nictitating membrane to tyramine recovers after the treatment of noradrenaline. It has also been reported that the catecholamine content of various organs decreases after the administration of reserpine (3-5). The generally accepted explanation of these findings has been that the decreased response to tyranime in reserpinized animals may be due to the decrease in endogenous catecholamine available to tyramine after reserpine administration. On the other hand, tyramine and ephedrine show similar pharmacological effects both
in vivo and
in vitro. The action mechanism of ephedrine also remains to be clarified, despite the many investigations that have been carried out since Chen and Schmidt (6) reported on the pharmacological effects of this drug. Ephedrine is also effective as a bronchodilator and, in some cases, as a pressor drug. Clinically, however, a decrease in response to ephedrine after repeated administration has often been encountered, especially in blood pressure response, but tyramine yields to tachyphylaxis scarcely. It is generally held that mechanism of this so-called “tachyphylaxis” phenomenon is due to receptor occupation by ephedrine (7). We have previously carried out a series of experiments on rabbit and guinea-pig atria with a number of drugs assumed to have the ability to mobilize and activate endogenous catecholamine (8, 9). We have used the similar experimental procedure in our attempt to clarify the action mechanisms of tyramine and ephedrine, and to explain the mechanism of tachyphylaxis phenomenon that displays following repeated administration of ephedrine. In the present experiments also, reserpine and nicotine were used as experimental means, reserpine for its reduction of endogenous catecholamine, and nicotine for its indirect activation.
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A. AHMAD, M.M. VOHRA, G. ACHARI
1967 Volume 17 Issue 4 Pages
622-630
Published: December 01, 1967
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In an investigation of the pharmacological activities of a large number of substituted diaminopyridine and the corresponding imidazo- and triazolo pyridines it was found that imidazo- and triazolo (c) pyridines, in general, produced central depressant action and amongst these 1-(β-phenylethyl) triazolo (4, 5-c) pyridine hydrochloride (PCA9) showed relatively better sedative and tranquillizing effects in mice (1, 2). In view of the tranquillizing activity of PCA9 a study on some neuro-psychopharmacological and other pharmacodynamic effects of this compound was carried out to elucidate the pattern of activity and the results of which are embodied in the present communication.
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TAKASHI HONJO, MOTOHATSU FUJIWARA, KIRO SHIMAMOTO
1967 Volume 17 Issue 4 Pages
631-637
Published: December 01, 1967
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The scheme of biosynthesis of noradrenaline from dopa in the mammalian tissues was presented by Blaschko (1). The conversion of dopamine to noradrenaline, mediated by dopamine-β-hydroxylase (2), was shown to occur in the intracellular granules of the adrenal medulla (3) and heart (4, 5). The administration of tyrosine-
14C (6) or dopa-
14C (7, 8) to rats results in formation of noradrenaline-
14C in sympathetically innervated tissues. Though the biosynthesis of noradrenaline from the exogenously administered dopamine is established, little information is available regarding the amount of dopamine-
14C remaining in tissues and its conversion to noradrenaline-
14C against time after the injection of labelled dopamine. The increased formation of noradrenaline following stimulation of the sympathetic nerve has been demonstrated in the submaxillary gland (9) and vas deferens (10). The facts suggest a possible regulation of catecholamine synthesis by sympathetic nerve activity. The present experiments were undertaken to examine further the role of sympathetic nerve activity in the turnover rate of dopamine. The rate of disappearance of dopamine-
14C in salivary glands after the injection, and the formation of noradrenaline-
14C were measured on the decetralized rat submaxillary gland. Additional studies were made on other sympathetically innervated tissues.
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I. RELATIONSHIP BETWEEN PRODUCTION OF ULCERS AND CHANGES IN TISSUE MONOAMINES
MASAMI DOTEUCHI
1967 Volume 17 Issue 4 Pages
638-647
Published: December 01, 1967
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In recent years a number of methods for producing psychogenic ulceration have been reported. Ulcers could be formed by treatment with reserpine combined with stress such as restraint(l), conflict (2), electrical stimulation of the hypothalamus (3), and electrical shock through a grid in the floor (4). Kido (4) has described production of ulcers in cats by exposure to stress such as electrical or mechanical shock after the tissue monoamines had been exhausted by reserpine treatment. When the stress was given during the release of monoamines by reserpine no ulcer could be formed. This shows that monoamines such as serotonin and norepinephrine are involved in the formation of ulcers. The present paper describes
1) the cellular localization of serotonin and norepinephrine in the gastrointestinal tract of cats by the method developed by Carlsson
et al. (5, 6),
2) correlation between manoamine contents and ulcer and
3) the role of stress in the formation of ulcers.
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K.N. DHAWAN, J.N. SINHA, G.P. GUPTA
1967 Volume 17 Issue 4 Pages
648-651
Published: December 01, 1967
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There are a number of observations which suggest that acetylcholine exerts an excitatory influence over the medullary vasomotor center. Dhawan
et al. (1) reported that both acetylcholine and carbachol produce a pressor response on intracerebroventricular (i.c.v.) administration in dogs and this pressor response is blocked by atropine. Sinha
et al. (2) observed that hemicholinium, which blocks the synthesis of acetylcholine depresses the responsiveness of vasomotor center on i.c.v. administration as well as after topical application to the floor of the fourth ventricle. Release of acetylcholine by tyramine has been suggested to be involved in the pressor response produced by i.c.v. administration of tyramine (1). Pfeiffer
et al. (3) studied several compounds to find out longer acting parasympathomimetic agents or precursors of acetylcholine which might affect the central nervous system. They reported parasympathomimetic and central effects of 2-dimethyl aminoethanol (deanol) and suggested that it owes the actions to its conversion to acetylcholine. We, therefore, thought it worthwhile to study the central vasomotor effects of deanol and to investigate if these effects are due to its conversion into acetylcholine.
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TETSUO SATOH
1967 Volume 17 Issue 4 Pages
652-658
Published: December 01, 1967
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It has been widely recognized that solanine (Fig. 1) is contained in Solarium species, especially in fresh potato sprouts as a toxic alkaloid. There have been reports concerning sola n i ne, namely, Kline
et al. (1) reported that potato sprouts were shown to be toxic to pregnant rats when fed at a level of 10% of the diet. Solanine and solanidine, aglycon of solanine, inhibit human plasma cholinesterase
in vitro (2, 3). No other pharmacological and biochemical studies on toxicities of solanine have been published. The present investigation was undertaken to determine the alteration of blood sugar level of rat treated with solanine. Hyperglycemia has been reported as one feature of poisoning by some toxic substances, i.e., guthion (4), paracetamol (5), parathion (6) and amphetamine (7). It seemed possible, therefore, that changes of disturbance of carbohydrate metabolism.
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NORIYUKI KUMADAKI, MASAHIRO HITOMI, SIGENOBU KUMADA
1967 Volume 17 Issue 4 Pages
659-667
Published: December 01, 1967
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Hyperemotionality manifested by violent attack or flight reactions in response to previous neutral or innocuous stimuli, has been observed in rats with lesions of the septal area of the brain (hereinafter referred to as “septal rats”) (1-4). The hyperemotionality of septal rats was restored to normal by making other lesions in the amygdaloid or administering certain tranquilizing drugs (2, 4-7). From these observations, it was possible to assume that the limbic system exerted an important function in the “physiological tranquilization” of rats and that tranquilizing drugs might have an effect on this part of the brain. It has recently been reported that rats in which the olfactory bulb had been removed (hereinafter referred to as “O.B.-rats”) exerted hyperemotionality similar to that of the septal rats (14, 18), and this hyperemotionality of O.B.-rats was also corrected by making other lesions in the amygdaloid (8). In this report, change in emotional behavior of O.B.-rats was analyzed using the scoring method and the effect of various psychotherapeutic drugs on the hyperemotionality of these animals was observed. The effects of these drugs are compared with the general activity of normal rats and the taming effect of these drugs is also discussed herein.
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KOTOBUKI HANO, AKIRA AKASHI, YUKIKO SUZUKI, ITARU YAMAMOTO, SHIGEHIKO ...
1967 Volume 17 Issue 4 Pages
668-677
Published: December 01, 1967
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In previous works from our laboratory (1-3) we reported that 4-diazoimidazole-5-carboxamide (diazo-ICA) and 4-(mono- or di-substituted) triazenoimidazole-5-carboxamide (mono- or dialkyl-TICA) showed marked inhibitory effects on the growth of tumors and bacterial cells. During examination of their toxicity in mice, behavioral sedation caused by these compounds was also observed (2). These observations led us to investigate the pharmacological properties of these compounds. The present report is on the effects of these compounds on the respiration, blood pressure, peripheral blood vessel and isolated intestine of the rabbit and the electroencephalogram (EEG) and electrocardiogram (EEG) of cats.
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B.P. JAJU, R.C. SRIMAL, K.N. DHAWAN, G.P. GUPTA
1967 Volume 17 Issue 4 Pages
678-679
Published: December 01, 1967
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G. ACHARI, S.P. SINHA
1967 Volume 17 Issue 4 Pages
679-680
Published: December 01, 1967
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TAKAO KUBO, HIROSHI TAKAGI
1967 Volume 17 Issue 4 Pages
681-682
Published: December 01, 1967
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B.R. MADAN, R.S. GUPTA
1967 Volume 17 Issue 4 Pages
683-684
Published: December 01, 1967
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KENJIRO YAMAMOTO, HIROSHI TANAKA, KUNISUKE HORIUCHI, JURO UEDA
1967 Volume 17 Issue 4 Pages
685-686
Published: December 01, 1967
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YOSHIO AIZAWA, HIDEO NISHIGORI
1967 Volume 17 Issue 4 Pages
686-687
Published: December 01, 1967
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