Effects of Cepharanthin on the lethality to mice and the cardiovascular disorder in rat induced by Mamushi (Agkistrodon halys blomhoffii) snake venom were studied. The LD 50 of Mamushi snake venom was 1. 22 mg/kg in mice by i.p. administration. Cepharanthin activated slightly the lethal activity when it was administered just after injection of the venom. However, this drug was effective against the venom at 4 to 5 times the lethal dose, if it was administered at the optimal interval. Mamushi snake venom and Cepharanthin showed a lethality and dose relationship that were clearly prolonged by Cepharanthin. In rat, Mamushi snake venom administered intraperitoneally produced an irreversible decrease of blood pressure accompanied by capillary hemorrhage. Moreover, it suppressed the heart rate. On the electrocardiogram, prolongation of ventricular contraction, extension of the relative refractory period and reduction of diastole were induced by the venom. These observations show that the venom suppresses cardiac functions inotropically and chronotropically. Cepharanthin shortened the refractory period and prolonged the diastole, indicating that it activated cardiac function. It was able to produce recovery from several cardiac disorders induced by Mamushi snake venom, for example, increase of blood pressure with inhibition of capillary hemorrage, release of heart rate suppression, partial recovery of the amplitudes of P and R waves, and shortening of extensive relative refractory period. These cardiac recoveries by Cepharanthin will be reflected in the suppression of lethality.

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The anti-platelet activity of KB-2796, 1-Cbis (4-fluorophenyl) methyl)-4-(2, 3, 4-trimethoxybenzyl) piperazine dihydrochloride, was studied in guinea pigs and mice. When guinea pig platelet-rich plasma (PRP) was employed, platelet function was inhibited at high doses of KB-2796. The IC50 value for (³H) 5-HT release was 940 pM, and the IC50 values for collagen and ADP-induced platelet aggregation were 210 and 390 μM, respectively. Oral administration of KB-2796 at 10 ?? 100 mg/kg dose-dependently inhibited the transient thrombocytopenia induced by collagen, but not that caused by ADP. KB-2796 protected mice from death after intravenous injection of collagen plus epinephrine, with an ED50 value of 9.5 mg/kg, p.o. Oral administration of KB-2796 at 10 ?? 100 mg/kg dose-dependently reduced guinea pig platelet retention in glass bead columns and reduced the leakage of ADP and ATP from erythrocytes passing through similar columns. KB-2796, at a concentration of 1 ?? 10 μM, produced a stabilizing effect on guinea pig erythrocytes against hypotonic hemolysis. These results suggest that KB-2796 is an inhibitor of platelet function and that its inhibition is related mainly to the inhibition of leakage of ADP and ATP from erythrocytes.

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The electroencephalographic (EEG) and cardiovascular effects of milnaciplan hydrochloride (TN-912) were compared with those of imipramine (IMP) and maprotiline (MPT) in rats, guinea pigs and dogs. In conscious rats with chronic electrode implants, TN-912 (10 ?? 100 mg/kg, p.o.) had little effect on either the EEG activity or the EEG arousal response to auditory stimulation (2000 Hz). Both IMP (10 ?? 100 mg/kg, p.o.) and MPT (10 ?? 100 mg/kg, p.o.) tended to increase the drowsy EEG pattern period in the cortical and hippocampal EEG and inhibited the EEG arousal response to auditory stimulation. In conscious rats with a chronic arterial catheter, TN-912 (100 mg/kg, p.o.) slightly elevated the mean blood pressure (MBP) and decreased the heart rate (HR), while both IMP (10 ?? 100 mg/kg, p.o.) and MPT (10 ?? 100 mg/kg, p.o.) dose-dependently increased MBP and HR. In anesthetized dogs, i.v. injection of TN-912 (1 ?? 10 mg/kg), IMP (0.3 ?? 10 mg/kg) and MPT (1 ?? 10 mg/kg) produced a dosedependent fall in MBP. IMP and MPT but not TN-912 dose-dependently increased HR. TN-912 did not show typical effects on femoral blood flow. TN-912 (30 mg/kg) had little effect on lead II electrocardiogram (ECG), while IMP and MPT markedly increased height of the T-wave on ECG. In the in vitro study with the isolated guinea pig atrium, TN-912 caused a slight positive inotropic and negative chronotropic effect, while both IMP and MPT showed marked negative inotropic and chronotropic actions. These results suggest that TN-912 has less EEG effect and cardiac toxicity, indicating that TN-912 may be safe in clinical use.

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The effects of NC-1100 on the central nervous system were analyzed behaviorally and electroencephalographically in mice, rabbbits and mongolian gerbils, using ifenprodil as a control material. NC-1100 showed potentiating effects on spontaneous locomotor activities and excitatory motor activities induced by methamphetamine, but did not affect the rotarod test, traction test, sleeping time induced by pentobarbital, analgesic test, anticonvulsant test (MES and pentetrazol test), body temperature and group toxicity induced by methamphetamine. Following i.v. injection of NC-1100 to rabbits with chronically implanted electrodes, electroencephalographic properties in spontaneous EEGs such as fast waves with low voltages in the neocortex became distinguished slightly. Seizure dischages produced by stimulation of the dorsal hippocampus were slightly inhibited, but arousal responses produced by stimulation of the midbrain reticular formation or the posterior hypothalamic area were not inhibited. Furthermore, the effects of NC-1100 on functional recovery after transient cerebral ischemia in gerbils were not distinct. Based on these results, NC-1100 was considered to be an agent that improves cerebral metabolism and selectively increases cerebrovascular blood flow with few central nervous actions.

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This study was performed to establish a circular excisional wound model treated with hydrocortisone (HC-P) and to estimate the following parameters in this model: wound area, hydroxyproline (Hyp) content, histological characteristics and microscopical measurements of histological sections. HC-P inhibited the reduction of wound area, the increase in Hyp content and proliferation of granulation tissue in a dose-dependent manner. The application of ZnO ointment significantly accelerated the reduction of wound area and the increased Hyp content in rats treated with HC-P. From these results, we concluded that this experimental model is useful for the objective evaluation of the efficacy of drugs that promote wound healing.

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Changes in the electrocardiogram following bilateral common carotid arteries ligation was observed during the awake state and pentobarbital anesthesia; and the influences of cerebral ischemia, pentobarbital or halothane anesthesia on the cardiotoxicity induced by continuous infusion of ouabain were also studied in Mongolian gerbils. Following ligation, all awake-animals died in about 60 min of ligation, all exhibiting severe neurological symptoms and ventricular arrhythmias. These changes did not appear in the animals under pentobarbital anesthesia. With regards to the amount of ouabain infusion needed to cause cardiotoxicity in pentobarbital-anesthetized animals, there were no significant differences between the vagus-intact group and the vagotomized group. However, the cardiotoxic dose of ouabain in the ligation group during pentobarbital anesthesia was larger than the cardiotoxic dose in the non-ligation group. In halothane anesthesia, the cardiotoxic dose of ouabain decreased more prominently than in pentobarbital anesthesia. The arrhythmias observed with isoproterenol were not enhanced by the halothane anesthesia and vagotomy. Therefore, these findings may indicate that during the cerebral ischemia, there is a heterotopic stimulus formation in the impulse conducting system of the heart; ouabain-induced cardiotoxicity appears to be enhancement via ouabain distribution into the cerebrum; and ventricular fibrillation had no definite effect for lowering sensitization of the myocardium to catecholamine by halothane in Mongolian gerbils.

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The central mechanism mediating the discriminative effects of nicotine was studied using rats. Rats were trained to discriminate subcutaneously administered nicotine at 0.5 mg/kg from saline in a 2-lever operant chamber situation for food reinforcement. 1) Nicotine administered into the lateral ventricle at both 100 pg and 120 μg substituted for subcutaneously administered nicotine at 0.5 mg/kg. This result indicates that the discriminative effects of nicotine are mediated centrally. 2) Among the drugs, acetylcholine at 0.5 ?? 10 μg administered into the lateral ventricle and methamphetamine at 5 ?? 40 μg and dopamine at 1 ??10 μg administered into the nucleus accumbens, none substituted for subcutaneously administered nicotine. These results indicate that the discriminative effects of nicotine differ from those of the above drugs. 3) Nicotine at 100 μg administered into the nucleus accumbens almost completely substituted for subcutaneously administered nicotine. In addition, mecamylamine at 180 μg administered into the nucleus accumbens attenuated the discriminative effects of subcutaneously administered nicotine. These results suggest that nicotinic receptors in the nucleus accumbens may be involved in the discriminative effects of nicotine. However, further studies are needed, since the nucleus accumbens is regarded not to be a major site of action of nicotine for these effects because of its low susceptibility to nicotine and mecamylamine.

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To clarify the action of lormetazepam, 3-hydroxybenzodiazepine, on the benzodiazepine (BZ) receptor subtypes, effects of lormetazepam on motor performance in the traction test and hexobarbital-induced loss of righting reflex in mice and the binding to BZ receptor subtypes were investigated in comparison with those of other BZ hypnotics. Lormetazepam prolonged the duration of hexobarbital-induced loss of righting reflex. The minimal effective dose (1 mg/kg, p.o.) was higher than that of flunitrazepam, lower than those of diazepam and zopiclone, and the same as those of triazolam and brotizolam. Lormetazepam showed the ataxic effect at 10 mg/kg, p.o., but the separation between its effective doses for the hypnotic and ataxic effects was the largest among the hypnotics tested. In the displacement study on (³H)flumazenil binding to cerebellar and spinal cord membranes, lormetazepam bound with a higher affinity to ω₁ receptor (Ki = 10 nM) than to ω₂ receptor (Ki = 29 nM). The GABA-ratios of lormetazepam to ω₁ and ω₂ receptors were 3.9 and 4.0, respectively; and they were higher and lower than those of flunitrazepam to ω₁ and ω₂ receptors, respectively. In the displacement study on (³H) Ro5-4864 binding to kidney membranes, lormetazepam bound with a lower affinity to the ω₃ receptor (Ki = 213 nM) than flunitrazepam. Thus, lormetazepam was suggested to be a potent hypnotic with weaker ataxic effects than other BZ hypnotics, which may be due to its selective and potent agonistic action on central ω₁ receptors.

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In the case of dermal application of the drugs to croton oil-induced ear edema in rats and picryl chlorideinduced delayed type hypersensitivity in mice, the anti-inflammatory effect of methylprednisolone aceponate (MPA) was slightly weaker than those of clobetasol 17-propionate and diflucortolone 21-valerate, but stronger than those of hydrocortisone 17-butyrate and hydrocortisone 17-butyrate 21propionate. Betamethasone 17-valerate applied dermally was less and more effective than MPA to ear edema in rats and delayed type hypersensitivity in mice, respectively. The anti-inflammatory effect of MPA was weaker in subcutaneous administration than in topical application to the two inflammatory models. It was suggested that MPA has strong anti-inflammatory effects and weak systemic effects by topical application. Methylprednisolone 17-propionate (MP-17P) and methylprednisolone (MP), unesterified in only the C-21 position and in both the C-17 and 21 positions of MPA, respectively, showed weaker anti-inflammatory activities than MPA by topical application to croton oil-induced ear edema. The ratio of the anti-inflammatory effects by topical application to subcutaneous administration of MPA was higher than those of MP-17P and MP. The excellent characteristics of MPA as a dermal anti-inflammatory drug are suggested to be derived from di-esterification of MP, which has a weak activity intrinsically.

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