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Biomedical subjects

A Tobe

Publications and source records attributed to A Tobe.

At least 37 records · Page 2Linked to original sources
PubMed1986

[General pharmacological action of 4-(o-benzylphenoxy)-N-methylamine hydrochloride (bifemelane hydrochloride, MCI-2016)--influence on the central nervous system].

General pharmacological action of 4-(o-Benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane hydrochloride, MCI-2016) was examined with regard to the effects mainly on the central nervous system. MCI-2016, at 30-100 mg/kg, p.o., only showed a weak sleep prolongation effect (mice), anti-convulsant action (mice) and a moderate facilitation of exploratory behavior, but produced no remarkable behavioral changes. Above the doses of 200 to 300 mg/kg, p.o., MCI-2016 produced a decrease in muscle or body tone, mydriasis and a slight decrease of locomotor activity. The drug, however, showed little influence on exploratory behavior, conditioned avoidance response and normal body temperature (rats). Normal body temperature in rabbits was also little affected by MCI-2016. Effects on EEG was characterized by moderate activation of spontaneous EEG and potentiation of arousal response by stimulation of the midbrain reticular formation (1.5-5 mg/kg, i.v.). The drug, however, did not significantly change the sleep-wakefulness cycle and REM-sleep in rats. MCI-2016 also showed little influence on spinal reflex potentials and neuromuscular junction at high doses (10 mg/kg, i.v.). These results may indicate that MCI-2016 has slight influence on overall behavioral and motor changes. Effects of MCI-2016 on acetic acid-induced writhing, carrageenin edema and corneal reflex were also examined. MCI-2016 showed moderate analgesic and anti-inflammatory actions at 50-100 mg/kg, p.o., and also showed local anesthetic action. The duration of local anesthetic action was relatively long but the drug produced no local damage.

Analgesics↗
PubMed1986

[Effects of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (MCI-2016, bifemelane hydrochloride) on coagulation, fibrinolysis, hemolysis, hemorheological properties and platelet aggregation].

MCI-2016 showed little influence on coagulation (APTT) and fibrinolysis (plasma clot lysis activated by urokinase) at doses (concentrations) as high as 300 mg/kg, p.o. or 8.6 X 10(-4) M. Hemolytic action of MCI-2016 was only observed at the concentrations above 2 mM. The drug also showed no influence on blood glucose level (30-300 mg/kg, p.o.). Effects of MCI-2016 on hemorheological properties were studied either in vitro or ex vivo. Above the doses (concentrations) of 100 mg/kg, p.o. and 10 microM, MCI-2016 suppressed the mechanical hemolysis and accelerated the membrane filtration rate. These effects of MCI-2016 were superior to those of cinepazide, Ca-hopantenate, meclofenoxate and pentoxyfylline. MCI-2016 also inhibited platelet aggregation induced by collagen with the IC 50 of 35 to 60 microM (rabbit and human platelets). Secondary aggregations of ADP and epinephrine were also inhibited by MCI-2016. As for reference drugs, bencyclane showed inhibitory patterns similar to MCI-2016. Other drugs examined exhibited little effect. In summary, it may be suggested that MCI-2016 exhibits beneficial influences in the clinical fields of cerebrovascular diseases.

Animals↗
PubMed1985

[Effect of MCI-2016 (bifemelane hydrochloride) on cerebral ischemia following ligation of both common carotid arteries in Mongolian gerbils].

Cerebral protective effect of MCI-2016 and influence of age on survival time in the cerebral ischemic model induced by bilateral-carotid-arterial ligation in male Mongolian gerbils were studied. Of all animals (6 to 40 weeks old), the mean survival time of the immature group (6 to 7 weeks) was long (3.6 hr), but variable, and that of the 10 to 40 weeks group was relatively stable (1.9-2.4 hr), but that of the older group (30-40 weeks) inclined to be reduced. Effects of drugs on this model were studied in 10 to 15 weeks old male Mongolian gerbils. The mean survival time in the control groups was 2.3-2.4 hr. After a single administration of MCI-2016 at doses of 25 mg/kg, i.p., and 100 mg/kg, p.o., the mean survival time were 8.1 and 6.4 hr, respectively. In these cases, some animals survived over 12 hr, while no animals surviving over 12 hr were observed in the control group. In this model, animals showed severe neurological symptoms. This, however, tended to be depressed by the administration of MCI-2016 at a dose of 25 mg/kg, i.p., which was observed early after ligation. A cerebral metabolic activator, Ca-hopantenate, slightly increased the survival time at a dose of 100 mg/kg, i.p., and a cerebral vasodilator, ifenprodil, was not effective. Subsequently, consecutive administration of MCI-2016 at a dose of 25 and 50 mg/kg, p.o., was more effective than a single administration of MCI-2016 at each dose. The mechanism for the cerebral protective effect of MCI-2016 was discussed.

Administration, Oral↗
PubMed1985

[Effect of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane hydrochloride, MCI-2016) on cerebral glucose metabolism].

To predict the influence of MCI-2016 on cerebral energy metabolism, the activity of MCI-2016 on uptake of 2-deoxy-D-[14C]glucose ([14C]-DG) into the brain under normal or hypoxic conditions, formation of 14CO2 from 14C-glucose in the brain, and local cerebral glucose utilization (LCGU) were examined. Cerebral uptake of [14C]-DG in mice were significantly enhanced by 6 day repeated administration of MCI-2016 (25 mg/kg, i.p.) and Ca-hopantenate (100 mg/kg, i.p.). The two drugs showed a slight enhancing effect on [14C]-DG uptake after single administration. As an index of cerebral glucose metabolism, 14CO2 formation from 14C-glucose was also stimulated by 6 day repeated administration of MCI-2016 (100 mg/kg, p.o., mice and rats) and Ca-hopantenate (250 mg/kg, i.p., rats). MCI-2016 moderately attenuated the decreased [14C]-DG uptake under the hypoxic condition in rats after 6 day repeated administration (100 mg/kg, p.o.). In addition, local cerebral glucose utilization (LCGU) in rats was also significantly potentiated by MCI-2016 (100 mg/kg, p.o., 6 days) in the areas of the visual cortex, thalamus ventral nucleus and uvula. From these results, MCI-2016 may be suggested to have a moderate activating effect on cerebral energy metabolism.

Administration, Oral↗
PubMed1985

[Effects of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (MCI-2016, bifemelane hydrochloride) on spontaneous motor activity under different experimental conditions].

Effects of MCI-2016 on SMA changes were examined under several experimental conditions (normal conditions, hypoxia and head injury). Under normal conditions, MCI-2016 showed a significant increase of SMA after single administration of 12 mg/kg, i.p. Other doses (12.5-50 mg/kg, p.o. and 3-6 mg/kg, i.p.) of MCI-2016 were without significant effect. Under the same condition, MCI-2016 produced a dose-dependent increase of SMA after repeated doses of 12.5 to 50 mg/kg, p.o. (9-10 days administrations). After 5 days repeated administration, MCI-2016 significantly improved the decreased SMA due to hypoxia (rats) at 50 to 100 mg/kg, p.o. Furthermore, the drug also improved the decreased spontaneity due to head injury (mice) at 50 to 400 mg/kg, p.o. These improving effects of MCI-2016 were superior to those of Ca-hopantenate. The SMA increasing effect of MCI-2016 (12 mg/kg, i.p.) was antagonized more strongly by phenoxybenzamine than by haloperidol. In addition, the drug was shown to be rather antagonistic to the effects of anticholinergic agents. These effects may indicate the existence of qualitative differences between MCI-2016 and methamphetamine in the SMA increasing actions. It is also suggested that MCI-2016 may exhibit the above pharmacological effects through possible activation of noradrenergic and/or cholinergic mechanisms.

Animals↗
PubMed1985

Effects of bifemelane hydrochloride (MCI-2016) on acetylcholine level reduced by scopolamine, hypoxia and ischemia in the rats and mongolian gerbils.

Effects of bifemelane hydrochloride (MCI-2016) on acetylcholine (ACh) level in the cerebral cortex and hippocampus of rats and Mongolian gerbils were examined. In normal rats, MCI-2016 (30 mg/kg, i.p.) slightly increased ACh content in the cerebral cortex. Scopolamine (1 mg/kg, i.p.) or hypoxia (95% N2 +5% O2, 9 min) decreased ACh level and pretreatment of MCI-2016 attenuated the decrement of ACh level in the rats. ACh level in the brain of Mongolian gerbils was significantly decreased following ligation of bilateral carotid arteries. In this case, MCI-2016 also attenuated the decrement of ACh level. These results suggest that improvement by MCI-2016 of behavioral impairment observed in the animals treated with scopolamine, hypoxia or ischemia may be, at least partly, attributed to the amelioration of decreased ACh level in the brain.

Acetylcholine↗
PubMed1985

Effects of bifemelane hydrochloride (MCI-2016) on experimental amnesia (passive avoidance failure) in rodents.

To further predict the possible activity on memory disorders, the effect of MCI-2016 (bifemelane hydrochloride) was examined using the passive avoidance (PAR) failure technique as an experimental model of amnesia. The amnesia was produced either by post training treatments of electroconvulsive shock (ECS), scopolamine (mice) and cycloheximide or by pre-test injection of scopolamine (rats). In ECS-PAR failure model, the retention test was carried out 3 hr (3 hr experiment) or 24 hr (24 hr experiment) after ECS. MCI-2016 showed a significant improvement when administered just after ECS (3 hr experiment, 30 mg/kg, i.p.) or 0.5 hr before the retention test (24 hr experiment, 10-30 mg/kg, i.p.). Cahopantenate was only active in the 3 hr experiment (500 mg/kg, i.p.), and piracetam was rather active in the 24 hr experiment (60 mg/kg, i.p.). MCI-2016 (30 mg/kg, i.p.) prevented the scopolamine-induced PAR-failure. In this model, physostigmine (0.3 mg/kg, i.p.) exhibited a tendency to improve the failure. In another scopolamine-induced PAR failure model in mice, all of the test drugs showed a significant improvement at different dose levels. The effect of MCI-2016 (25-100 mg/kg, p.o.) was superior to those of piracetam, aniracetam and choline chloride. Higher doses of MCI-2016 were required to improve the cycloheximide-induced PAR failure. Considering the experimental conditions and results, it may be suggested that MCI-2016 ameliorates the amnesia possibly through its influence on memory consolidation and retrieval processes.

Animals↗
PubMed1985

Effects of bifemelane hydrochloride (MCI-2016) on acetylcholine and norepinephrine release from cortical slices of bilaterally carotid-artery-ligated Mongolian gerbils.

Effects of bifemelane hydrochloride (MCI-2016) on acetylcholine (ACh) and norepinephrine (NE) release from cortical slices of bilaterally carotid-artery-ligated Mongolian gerbils were examined. ACh and NE release from cortical slices of Mongolian gerbils were increased 1 hr after the ligation of bilateral carotid arteries. Pretreatment of MCI-2016 (25 mg/kg, i.p.) attenuated the increase in the release of both neurotransmitters. These effects may participate in the protective effect of MCI-2016 on cerebral ischemia in Mongolian gerbils.

Acetylcholine↗
PubMed1985

Effects of bifemelane hydrochloride (MCI-2016) on acetylcholine release from cortical and hippocampal slices of rats.

Bifemelane hydrochloride (MCI-2016) increased high K+-evoked acetylcholine (ACh) release from cortical and hippocampal slices of rats. The increasing effect of MCI-2016 was abolished in the absence of Ca ion and by pretreatment of reserpine (2.5 mg/kg, i.p.). These results suggest that monoaminergic neurons may be related to the enhancement of ACh release by MCI-2016. High K+-evoked ACh release from cortical slices was significantly decreased during aging. The decrease in ACh release was ameliorated by pretreatment of MCI-2016 (30 mg/kg, i.p.).

Acetylcholine↗
PubMed1985

[The activating effect of MCI-2016 (bifemelane hydrochloride) on EEG in cats].

In order to make clear the activating effect of MCI-2016 on EEG, power spectrum analysis was performed and the interaction in EEG between MCI-2016 and some drugs were studied in succinylcholine-immobilized cats. MCI-2016 at doses of 5 and 10 mg/kg iv produced apparent arousal pattern in cortical EEG characterized by low amplitude fast wave, and evoked the right-shift in power spectrum. In the case of meclofenoxate at doses of 20 and 40 mg/kg iv, the shifts in power spectra were similar to that of MCI-2016, very slight changes were observed by Ca-hopantenate at a dose of 200 mg/kg iv and typical left-shift was introduced by imipramine at a dose of 2 mg/kg iv. MCI-2016 tended to suppress the SWS state induced by alpha-methyl-p-tyrosine and scopolamine at a dose of 350 mg/kg ip and 0.015 mg/kg iv, respectively. Subsequently, the duration of arousal state in EEG induced by physostigmine at a dose of 0.01 mg/kg iv was enhanced by MCI-2016 at a dose of 1.5 mg/kg iv whose injection does not produce any arousal pattern in EEG. The activating effect of MIC-2016 on EEG was indicated quantitatively and it is suggested that the cholinergic mechanism and the catecholaminergic mechanism would be involved in the EEG activating effect of MCI-2016.

Animals↗
PubMed1984

Substituted (omega-aminoalkoxy) stilbene derivatives as a new class of anticonvulsants.

A series of substituted (omega- aminoalkoxy )stilbene derivatives has been synthesized and screened for anticonvulsant activity. The effect of structural modification of these molecules on the activities has been systematically examined. Potent anticonvulsant activity was displayed by 2-[4-(4-methyl-1 piperazinyl)butoxy]stilbene (20) and some 2-[4-(3-alkoxy-1-piperidino)butoxy]stilbene derivatives (21, 37, 38, and 40), as determined by maximal electroshock seizure (MES) and pentylenetetrazol-induced convulsion tests in mice. Compound 21 exhibited more potent anti-MES activity than diphenylhydantoin and carbamazepine in further pharmacological tests in rats, and its therapeutic index was superior to those of two antiepileptic drugs.

Animals↗
PubMed1983

Synthesis of porcine leumorphin and some of its biological activities.

The carboxy-terminal nonacosapeptide sequence of porcine preproenkephalin B contains the sequence of Leu-enkephalin at its amino terminus. The endogenous existence of this peptide, leumorphin, has not yet been proved. Synthesis of leumorphin was carried out by a solid-phase technique and the purity and structure of the synthetic peptide were confirmed. Synthetic porcine leumorphin exhibited a dose-dependent opiate effect (ED50 4.70 X 10(-9) M) on electrically stimulated contraction of the guinea pig ileum preparation. The potency was about 100 times as high as that of Leu-enkephalin. Leumorphin was less potent than dynorphin(1-13) (ED50 0.38 X 10(-9) M) but it was more active than beta h-endorphin (ED50 18 X 10(-9) M). The opiate activity was only partially reversed by naloxone. Intracisternal injection of synthetic leumorphin caused significant analgesia in mice (ED50 7.31 nmol/mouse). The potency was lower than that of beta h-endorphin (ED50 0.60 nmol/mouse) but higher than that of dynorphin(1-13) (ED50 16.10 nmol/mouse). Intracisternally injected leumorphin did not produce such a violent behavioral effect as did dynorphin(1-13), and it exhibited a mild sedative effect. The data supports the concept that leumorphin is a new type of opioid peptide and that the synthetic preparation will be useful for further biological and immunological studies on this peptide.

Analgesia↗
PubMed1983

Synthesis and antianxiety activity of (omega-piperazinylalkoxy)indan derivatives.

A series of (omega-piperazinylalkoxy)indan derivatives has been synthesized and screened for potential antianxiety activities. The effect of structural modification of these molecules on activities has been systemically examined. Antianxiety activity was displayed by 5-[3-(4-phenyl-1-piperazinyl)propoxy]indan (2), 5-[3-[4-(4-fluorophenyl)-1-piperazinyl]-propoxy]indan (8), 6-fluoro-5-[3-(4-phenyl-1-piperazinyl)propoxy]indan (33), and 6-methyl-5-[3-(4-phenyl-1-piperazinyl)propoxy]indan (42), as determined in antifighting and anti-morphine tests. These derivatives in antianxiety tests were equipotent or more potent than chlordiazepoxide with less muscle-relaxant effect. They also showed weak neuroleptic-like action.

Animals↗
PubMed1983

Effect of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (MCI-2016) on the scopolamine-induced deficit of spontaneous alternation behavior in rats.

To predict the possible activity on memory disorders, the effect of MCI-2016 was compared with those of physostigmine, choline chloride, methamphetamine, apomorphine, imipramine and calcium hopantenate by applying scopolamine-induced deficit of spontaneous alternation behavior (scopolamine-SA) as a proposed animal model for senile dementia. MCI-2016 was shown to improve the scopolamine-SA at doses of 25 to 100 mg/kg p.o. without producing any remarkable behavioral abnormalities. As for the effect of reference drugs, two types of cholinomimetic drugs (physostigmine and choline chloride) and methamphetamine were shown to be active. In the cases of physostigmine and methamphetamine, however, behavioral abnormalities were observed at those dose levels effective on scopolamine-SA. MIC-2016 potentiated the effect of physostigmine on scopolamine SA at non active doses of 10 to 20 mg/kg p.o. In comparison with the deleterious effect of scopolamine on spontaneous alternation (SA) behavior itself, none of the test drugs except for imipramine were shown to disrupt the SA. Considering the disruptive or improving actions of various agents on SA or scopolamine-SA, it may be suggested that the present model is relatively sensitive to those drugs which affect the cholinergic mechanism either directly or indirectly. Mechanisms of the actions of MCI-2016 and methamphetamine were also discussed with reference to possible involvement of cholinergic mechanisms.

Animals↗
PubMed1983

[Anti-anoxic effect of 4-(o-benzlphenoxy)-N-methylbutylamine hydrochloride (MCI-2016)].

Anti-anoxic effects of MCI-2016 were compared with those of drugs for cerebrovascular diseases, tricyclic antidepressants and physostigmine in mice. Minimal effective doses of MCI-2016 which significantly increased the survival time or gasping duration were 12.5 mg/kg, p.o. for hypoxia, 50 mg/kg, p.o. for KCN-induced anoxia, and 100 mg/kg, p.o. for decapitation-induced gasping. As a whole, these effects of MCI-2016 were superior to those of reference drugs for cerebrovascular diseases. MCI-2016 was also shown to be effective under a consecutive administration schedule. In marked contrast to the effect of MCI-2016, tricyclic antidepressants significantly shortened the survival time under hypoxia. Considering that atropine shortened and physostigmine markedly increased the survival time under hypoxia, involvement of anti-cholinergic action may be postulated for the shortening effect of tricyclic antidepressants. The anti-hypoxic effect of MCI-2016 as well as physostigmine was diminished by atropine treatment. Furthermore, MCI-2016 exhibited a combination effect with physostigmine at optimal doses. Although the influence of norepinephrine uptake inhibitory action on the hypoxic condition are not clear in the present study, these results may suggest that activation of CNS cholinergic system is involved as one of the causative mechanisms for anti-anoxic effect of MCI-2016.

Animals↗
PubMed1983

[Effects of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (MCI-2016) on monamine metabolism in the brain].

Effects of MCI-2016 on the uptake, contents and turnover rate of monoamines were studied in the rat brain. MCI-2016 exhibited more potent inhibitory effect on the noradrenaline (NA) uptake than on dopamine (DA) and serotonin (5-HT) uptake. Especially, the inhibitory effect of MCI-2016 on the NA uptake in the hypothalamus was comparable to that of imipramine with the IC50 value of 4 X 10(-8) M. The levels of NA and its metabolite, MHPG-SO4, in the whole brain were significantly increased by 30 mg/kg, i.p. of MCI-2016. The peak effects were reached between two to 4 hrs after administration. The increase in 5-HT contents at the cortex were also observed by MCI-2016 (30 mg/kg, i.p.), with little changes in 5-HIAA contents. The levels of DA, HVA and DOPAC in the whole brain were not significantly influenced by MCI-2016. The turnover rate of NA was facilitated by 61.1% by 15 mg/kg, i.p. of MCI-2016. DA and 5-HT turnover rates were little affected by the same dosage of MCI-2016. In the case of imipramine (15 mg/kg, i.p.), however, it didn't increase the NA turnover, and in addition, it inhibited the 5-HT turnover. The increase in NA turnover rate induced by MCI-2016 was antagonized by 54.5% by 30 mg/kg, i.p. of atropine. Physostigmine (1 mg/kg, i.p.) also increased NA turnover rate which was also partially (62.6%) inhibited by atropine. These results may suggest that the effects of MCI-2016 on noradrenergic mechanisms were qualitatively different from those of tricyclic antidepressants. In addition, the results with atropine on the turnover rate may in part suggest a possible participation of the cholinergic mechanism on the turnover increasing effect of MCI-2016.

Animals↗
PubMed1983

The influence of 2-(4-methylaminobutoxy)diphenylmethane hydrochloride (MCI-2016) on gastric ulcer and gastric acid secretion.

The effect of 2-(4-methylaminobtoxy)diphenylmethane hydrochloride (MCI-2016) on the development of ulcers and on gastric secretion were examined in comparison with imipramine and amitriptyline. In various experimental ulcer models (Shay, water-immersion restraint, cold stress, swimming stress and reserpine ulcers), MCI-2016, at the doses ranging from 6.25 to 100 mg/kg p.o., exhibited a dose-dependent inhibition of ulceration with high therapeutic index. MCI-2016 showed little influence on the spontaneous and stimulated gastric secretion at the doses effectively suppressing the ulcer formation. In contrast, both imipramine and amitriptyline caused a significant inhibition of spontaneous and carbachol-stimulated gastric secretion. These results suggest that anti-cholinergic action is not involved in the anti-ulcer effect of MCI-2016. It may be further postulated that central norepinephrine (noradrenaline) uptake inhibition is related with the anti-ulcer action of MCI-2016.

Animals↗