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Volume 84, Issue 1
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Akira SHIMADA, Hiromi IIZUKA, Takeshi KAWAGUCHI, Tomoji YANAGITA1984 Volume 84 Issue 1 Pages 1-10
Published: 1984
Released on J-STAGE: March 07, 2007
JOURNAL FREE ACCESSThe acute toxicity and pharmacological effects of d-nicotine were examined in several species of animals and compared with those of l-nicotine. The LD50s for intravenous administration of d and l-nicotine were 6.15 and 0.33 mg/kg, respectively. In unanesthetized rhesus monkeys, EEG activity was not influenced by d-nicotine, 64 μg/kg, i.v., while the same dose of l-nicotine produced seizure-like waves with some spindles. In rats, d-nicotine increased spontaneous motor activity, and in the experiment under a DRL 20-sec schedule, it increased lever press responding, decreased the number of reinforcements and shortened interresponse time. Similar effects were also observed by administration of l-nicotine at lower doses than for the d-isomer. In anesthetized rats, d-nicotine elevated the blood pressure and increased the heart rate with a potency of about one-eighth that of the l-isomer. Further, tachyphylaxis and cross tachyphylaxis were developed to the blood pressure-raising effect in rats after repeated administration of both isomers. d-Nicotine elicited contraction of isolated rat ileum preparations, but with a potency of about one-tenth that of the l-isomer. Both isomers at the same concentration blocked transmission at the neuromuscular junction in isolated rat phrenic nerve-diaphragm muscle preparations. These results indicate that the pharmacological effects of d-nicotine are qualitatively similar to but quantitatively less potent than those of l-nicotine.View full abstractDownload PDF (4631K) -
Yasuo ABE, Haruo SEKIGUCHI, Kiyoyuki TSURU, Tsutomu IRIKURA1984 Volume 84 Issue 1 Pages 11-18
Published: 1984
Released on J-STAGE: March 07, 2007
JOURNAL FREE ACCESSEffects of KU-54 on the biosynthesis of glycoprotein in the gastric mucosa and the liver, as measured by the rate of incorporation of 14C-glucosamine, were investigated in rats under various conditions after a single administration of 14C-glucosamine (9.88 μCi/animal, ip). 14C-glucosamine was incorporated with relative ease in the acid-insoluble fraction of the gastric mucosa. KU-54 at 100 mg/kg was orally administered twice daily for 5 days in rats (though it was given once on the 5 th day) before injection of 14C-glucosamine. The rate of 14C-glucosamine incorporation into the acid-insoluble fraction of the gastric mucosa was significantly increased by KU-54, but that of the hepatic tissue was not increased. In addition, hydrocortisone (20 mg/kg) also produced a drop of incorporation of 14C-glucosamine in the gastric mucosa, but oral KU-54 at 100 mg/kg twice daily for 5 days (though it was given once on the 5 th day) significantly inhibited the drop of incorporation of 14C-glucosamine in the gastric mucosa, but that in the hepatic tissue was not inhibited. Therefore, the effects of KU-54 were greater in the gastric mucosa than in the hepatic tissue. On the 5 th day of the ulcer produced by acetic acid in rats, the specific radioactivity in the mucosa of the margin of the ulcer increased significantly compared with that in the normal (non-ulcerative) mucosa, but this phenomenon was not affected by KU-54. On the 10 th day of the ulcer produced by acetic acid, the increase of specific radioactivity in the marginal mucosa disappeared in the control group; but in the KU-54 (100 mg/kg, p.o.)-dosing group, the specific radioactivity in the marginal mucosa increased successively and significantly compared with the non-ulcerative mucosa. On the other hand, the incorporated radioactivity in the gastric mucosa reduced gradually at 24 or 48 hr after 14C-glucosamine dosing and oral KU-54 at 100 mg/kg did not affect the rate of reduction of radioactivity in both the acid-soluble and the acid-insoluble fraction of the gastric mucosa.View full abstractDownload PDF (3722K) -
Assessment of morphine-type physical dependence liability in mice using the drug-admixed food methodTsutomu SUZUKI, Toshio YOSHII, Saizo YANAURA1984 Volume 84 Issue 1 Pages 19-24
Published: 1984
Released on J-STAGE: March 07, 2007
JOURNAL FREE ACCESSPhysical dependence on morphine-type drugs (morphine, codeine and pethidine) in mice were examined by the drug-admixed food method. Mice were treated with drug-admixed food of increasing concentration (1, 2 and 3 mg/g food) every third day for 9 days. Morphine and codeine-treated mice showed withdrawal signs when they were given naloxone (5 mg/kg, s.c.), while pethidine-treated mice did not show the withdrawal signs. However, mice treated with pethidine-admixed food (1 ?? 6 mg/g food) for 28 days showed naloxone precipitated withdrawal signs. Thus, the data obtained with mice indicate that pethidine produces a weak physical dependence. On the other hand, codeine (40 mg/kg, s.c.) and pethidine (100 mg/kg, s.c.) administration suppressed the abrupt withdrawal signs of morphine-dependent mice that were treated with morphine-admixed food, while the withdrawal signs were completely suppressed in mice administered only 5 mg/kg morphine. These results suggest that the physical dependence liability of morphine type drugs can be predicted by the drug-admixed food method.View full abstractDownload PDF (3071K) -
Sleep-inducing activity and effect on the motor systemKen-ichi YAMAMOTO, Akira MATSUSHITA, Tohru SAWADA, Yukio NAITO, Kohji ...1984 Volume 84 Issue 1 Pages 25-89
Published: 1984
Released on J-STAGE: March 07, 2007
JOURNAL FREE ACCESSThe sleep-inducing activity and effect on the motor system of the 1H-1, 2, 4-triazolyl benzophenone derivative 450191-S were examined behaviorally, electroencephalographically and electro-physiologically with various species of animals and were compared with those of diazepam, nitrazepam, estazolam and triazolam. In the rhesus monkey, rabbit and rat with chronically indwelling brain electrodes, 0.6 to 3 mg/kg, p.o. of 450191-S caused a shorter latency of sleep onset, an increase of and a stable continuity of slow wave deep sleep (SWDS) with higher amplitude, and the appearance of clear spindle bursts in the slow wave light sleeping (SWLS) state with little muscle relaxation. Animals treated with nitrazepam and/or estazolam showed a smaller increase in SWDS and its unstable continuity with remarkable disturbance of gait. The doses needed to induce sleep in the rhesus monkey were 0.6 to 1 mg/kg p.o. for 450191-S, 3 mg/kg for nitrazepam, 1 mg/kg for estazolam and 0.3 mg/kg for triazolam. The cat treated with 450191-S showed the phenomena caused by benzodiazepines (BDZ), i.e., behavioral excitation and decrease of frequencies in the hippocampal theta waves. The suppressive effects of 450191-S on the EEG arousal reaction and/or blood pressure elevation induced by hypothalamic stimulation in the rabbit suggested that the inhibitory effects acted on the posterior hypothalamus to the limbic system. The inhibitory effect of 450191-S on the amygdaloid kindling in the rat was as potent as those of diazepam and nitrazepam. Successive daily oral administration of both 3 mg/kg of 450191-S and/or 3 to 6 mg/kg of nitrazepam for 15 days in the rabbit caused slight decrease of SWDS and increase of fast wave (REM) sleep (FWS). During the withdrawal period of both compounds, a slight but insignificant increase in the waking state was noticed for I to 2 days, but not a rebound increase of FWS. Intravenously administered 450191-S showed the same action as BDZ on the spinal reflex and the dorsal root potential of the rat; it particularly acted on the crossed extensor reflex in the same manner as the commercial BDZ sleep inducers. Various examinations showed that the muscle relaxation effect of 450191-S was the weakest among the control sleep inducers, and the ratio between the increase in SWDS and the disturbance of gait in the rhesus monkey and/or the ratio between the suppressive effect on the hypothalamically induced blood pressure elevation and the inhibition of respiratory movement in the cat indicated that the compound might be a safe sleep inducer characterized by a wide dissociation between its major effect of sleep induction and its side effect of muscle relaxation. The pharmacological effects of active metabolites of 450191-S in blood such as M-1, M-2, M-A, M-3 and M-4 were compared with those of 450191-S, and the superiority of the mother compound was clarified.View full abstractDownload PDF (32871K) -
Masayuki HORI, Hideaki TAKAHASHI, Toshiyuki KONNO, Junji INOUE, Teruo ...1984 Volume 84 Issue 1 Pages 91-98
Published: 1984
Released on J-STAGE: March 07, 2007
JOURNAL FREE ACCESSEffect of elcatonin, a synthesized analogue of eel calcitonin, on experimental osteoporosis in beagles induced by ovariectomy and a low calcium diet was studied. Twelve female beagles, 15-18 months old, were divided equally into 3 groups. The first group of beagles were ovariectomized and then fed a low calcium diet, Ca: 0.08%, (ovariectomy plus low Ca diet group) ; the second group was subjected to the same procedure and diet plus daily injection of elcatonin, 1.0 u/kg, i.m., (elcatonin group); and the third group was fed a standard diet, Ca: 1.36%, (control group) for 6 months. The undecalcified bone sections from the iliac crest were analyzed using histomorphometric methods following in vivo double labeling with Calcein®. In the ovariectomy plus low Ca diet group, there were a decrease in trabecular bone volume and an increase in both resorption and formation surface of the trabeculae compared with the control group. These changes of trabecular bone volume and resorption surface were significantly prevented by daily injection of elcatonin. The increase of formation surface of trabeculae and mineral appositional rate was noted in the elcatonin group in comparison with the ovariectomy plus low Ca diet group. These results suggested that elcatonin could prevent bone loss caused by deficiency of sex hormone and dietary calcium.View full abstractDownload PDF (4037K) -
Toshio SUZUKI1984 Volume 84 Issue 1 Pages 99-108
Published: 1984
Released on J-STAGE: March 07, 2007
JOURNAL FREE ACCESSEffects of benzodiazepines on spinal reflex potentials, especially on the dorsal root reflex potentials (DRR), were studied in the spinal preparation of cats. All benzodiazepines used in this study (diazepam, chlordiazepoxide, bromazepam, flurazepam, medazepam, nitrazepam, oxazepam, oxazolazepam, lorazepam, estazolam and triazolam) were administered into the duodenum via a rubber tube implanted previously. These drugs consistently increased the amplitude of DRR. Presynaptic inhibition was increased, but postsynaptic inhinition was not affected by the drugs. DRR was decreased gradually by intravenous administration of semicarbazide, and pretreatment with semicarbazide completely blocked the spinal effect of diazepam. Pyridoxine given intravenously recovered the amplitude of DRR and restored the effect of diazepam on the spinal cord. Pretreatment of AOAA potentiated the increasing effect of diazepam on DRR. Occlusion of the thoracic aorta for 47 min with simultaneous clamping of the mammary arteries produced permanent hind-limb rigidity in cats (Murayama-type rigid cats). The ischemic spinal rigidity is characterized by an enhanced monosynaptic reflex and markedly reduced polysynaptic reflex potentials. Furthermore, DRR was not grossly detectable in the preparation. In these ischemic spinal rigid cats, diazepam administered intravenously or intraduodenally did not enhance DRR at all. These results suggest that the effect of diazepam is closely related with GABA content. Normal levels of GABA in the spinal cord are required for the increasing effect of diazepam on DRR and presynaptic inhibition. These benzodiazepines may act on the releasing mechanism of GABA from the spinal interneuron, or they presumably enhance the sensitivity of the GABA receptor in the spinal cord.View full abstractDownload PDF (5829K) -
Ken-ichi YAMAMOTO, Katsumi HIROSE, Akira MATSUSHITA, Kohji YOSHIMURA, ...1984 Volume 84 Issue 1 Pages 109-154
Published: 1984
Released on J-STAGE: March 07, 2007
JOURNAL FREE ACCESSThe behavioral effects of 450191-S and its metabolites were investigated in mice, rats, cats and rhesus monkeys, and they were compared with those of related benzodiazepines (BDZ) such as diazepam and nitrazepam. Oral administration of 450191-S consistently caused sedation without excitability in mice and rats, and it was only 1/2 to 1/266 as potent as the BDZ in producing motor incoordination as assessed by traction, rotarod performance and inclined screen tests in mice, induced much less ataxia in cats and monkeys, and inhibited respiration in anesthetized cats. The locomotor activities of mice and rats measured by Animex and the open field test were not affected by 450191-S, but rearing and preening decreased with 450191-S as with the BDZ. 450191-S was equipotent with nitrazepam and 2 to 6 times more potent than diazepam and estazolam in potentiating chlorprothixene-induced hypnosis and thiopental-Na-induced anesthesia. These effects were not different with successive 14-day administration of 450191-S. Anti-pentylenetetrazol, picrotoxin and bicuculline convulsions of 450191-S had the same potency as nitrazepam, but caused much less anti-electroshock convulsion than the BDZ. 450191-S had potent antianxiety activity as observed by anti-aggressive and anti-conflict activities and had almost the same effect as diazepam on operant behavior. The metabolites M-1, M-2, M-A and M-3 showed approximately the same potency as 450191-S in inducing anesthetic potentiation and antianxiety activity, but they were much more potent in causing disturbance of the somatic functions. These results indicate that 450191-S possesses inhibitory effects on the central nervous system, including a potent sleep-inducing effect, and is characterized by markedly weak muscle relaxant activity and motor incoordination.View full abstractDownload PDF (23970K)
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