Adult cats were administered oral threshold doses of copper sulfate every week. As the cats vomited in 70 out of 80 cases, the reproducibility was 88%. Peripheral vomiting threshold dose was 40 mg/head or less, while the threshold dose for oral copper sulfate emesis after T4 transection and vagotomy was more than 160mg/ head. The following method is thus proposed for application in evaluating an antiemetic for oral copper sulfate. Adult cats are to be given the emetic once a week. The threshold dose should be determined in three dose levels; 10, 20, 40 mg/head. The cats with a threshold of more than 40 mg or latency of less than 5 min or of more than 45 min are to be excluded. Inhibition of emesis or a considerable prolongation of latency is the sign of an antiemetic action. A positive action of an antiemetic must be followed by another test with the threshold dose of copper sulfate alone. If the cat does not respond to the threshold dose after 2 administrations, the case must be excluded. It is considered positive when 3 cases are inhibited among 4 or more than 50% among more than 5.

View full abstract

Long marketed antiemetics, which are still used in medicine or veterinary medicine and whose sites of actions were either assumed to be peripheral or unknown, were subjected to evaluation as antiemetics, against oral copper sulfate emesis. In cats, ethyl aminobenzoate 0.5 g/head, cerium oxalate 0.1 g/head, pinelliae tuber 0.5 g/head and gelatin 2.0 g/head were not effective. In dogs, ethyl aminobenzoate 0.5 g/head, pinelliae tuber 2.0 g/head and hange-syasintoo 2.0 g/head were not effective. Cerium oxalate 0.1 g/head was found to have a slight antiemetic action.

View full abstract

The effects of oral administration of clonazepam, a new benzodiazepine derivative (F. Hoffmann-La Roche), on the central nervous system were compared with those of diazepam and several anticonvulsants in mice and rats. 1) Clonazepam exhibited a moderate inhibitory effect on the locomotor activity observed with openfield situation in mice and no effect in rats, while it inhibited markedly the rearing behavior in both animals, the duration of action being approximately six hours. 2) Clonazepam potentiated the methamphetamineinduced hyper-locomotor activity in mice whereas trimethadione had no effect. 3) Clonazepam inhibited with a moderate potency the conditioned avoidance response and response to a fixed-ratio (FR 20) schedule of food reinforcement in rats, the potency being a little weaker than that of diazepam. 4) The muscle relaxant effect of clonazepam determined by the traction test was slightly more potent as compared with that of diazepam. Thiopental hypnosis was markedly potentiated after clonazepam. 5) The clonic (CL), tonic-flexor (TF) and extensor convulsions (TE) induced by pentetrazol were strongly inhibited after clonazepam in mice, anticonvulsant potency against CL and TE of clonazepam being approximately 23 and 21 times stronger than that of diazepam, 3333 and 3846 times that of trimethadione, and over 3047 and 178 times that of phenytoin, respectively. Clonazepam reduced markedly CL and TE elicited by bemegride with about 12 to 14 times stronger potency than diazepam. On the contrary, the anticonvulsant effect of clonazepam against TE of maximal electroshock seizure evoked by supramaximal current was weak, the potency being 0.71 times weaker than that of phenacemide, 0.14 times than phenytoin and 0.24 times than Phenobarbital. By the combined administration of clonazepam with other anticonvulsants such as trimethadione and phenytoin against pentetrazol convulsion, and phenacemide, phenytoin and phenobarbital against maximal electroshock seizure, the antagonistic effect of these anticonvulsants was potentiated by 4 to 5 times. 6) The acute toxicity (LD50) of clonazepam was weak but that of phenacemide or phenytoin was potentiated to a certain degree by combined administration with clonazepam. The results suggest that clonazepam has a psychopharmacological profile similar to that of benzodiazepines with a particularly potent anticonvulsant effect on pentetrazol and bemegride convulsions, and the anticonvulsant effect is synergistic with that of other anticonvulsants.

View full abstract

A study was carried out to investigate the effect of ursodesoxycholic acid and cholic acid on intestinal absorption of cholesterol-4-¹⁴C administered p.o. to lymph-fistula rats. The results indicated that within 24 hours, the labeled cholesterol detected in thoracic duct lymph of the control group was 21.0% of the administered cholesterol-4-¹⁴C, wheras the group treated with cholic acid (250 mg/kg p.o.) was found to have an increased value of 30.6% absorbed cholesterol. In comparison, the group treated with the same dose of ursodesoxycholic acid showed a decreased value of 12.1%, indicating an inhibitory effect on cholesterol absorption by the compound. This differential effect of the two compounds was also observed in a time-course study.

View full abstract

Afferent discharges were recorded in the nerve from the isolated muscle spindle of the m. extensor longus digiti IV of the bullfrog. Discharges of about 10 Hz generated by a sustained stretch were reduced concentration-dependently when Ca²⁺, Mg²⁺ or Mn²⁺ (1.0 ?? 8.0 mM) was added to normal Ringer's solution containing 2.0 mM Ca²⁺. In terms of the decrease of discharges following the addition of Ca²⁺ or Mn²⁺ (4.0 mM), abortive spikes were observed. With an excess of Mg²⁺ (4.0 mM), abortive spikes were not apparent. Removal of Ca²⁺ from the Ringer's solution caused an increase in the rate of discharges, and normal levels were restored by the addition of Ca²⁺ (2.0 mM), Mg²⁺ (2.3 mM) or Mn²⁺ (1.8 mM). Application of much higher concentrations of these ions to the nerve trunk produced no alterations in the conduction of afferent discharges. It appears that Ca²⁺ in the external medium contributes to the inhibition of the mechanism responsible for generating afferent discharges in the muscle spindle and that Ca²⁺ action is not specific since Mg²⁺ and Mn²⁺ can act as substitutes for Ca²⁺ to regulate afferent discharges.

View full abstract

Afferent discharges of about 10 Hz were recorded in the nerve from the isolated muscle spindle of the m. extensor longus digiti IV of the bullfrog subjected to a sustained stretch. When grayanotoxin-I, veratridine or aconitine was added to the Ringer's solution, the rate of discharges markedly increased and thereafter decreased. In these terms of decrease of discharges, abortive spikes were observed. The rate of discharges was markedly decreased by the application of procaine, diphenylhydantoin, chlorpromazine or tetrodotoxin. With the latter three drugs, abortive spikes were observed in the course of decrease of discharges. Increase of the discharge rate induced by grayanotoxin-I, veratridine and aconitine was antagonized by procaine. No alteration was evident in the conduction of afferent discharges, when test drugs were applied to the nerve trunk in concentrations sufficient to change the rate of discharges when applied to the muscle spindle. These results suggest that the rate of the muscle spindle discharges is closely related to sodium permeability of the membrane.

View full abstract

Hypotensive effect of dl-Mandelamidine (Olmidine, MA) in combination with some established antihypertensive drugs was studied in conscious normotensive rats. The mean blood pressure and heart rate were measured by means of a pressure transducer via a polyethylene tube inserted into the abdominal aorta of rat according to the method described by Weeks. The results obtained were as follows ; 1) The hypotensive effects of guanethidine and hydrochlorothiazide were enhanced in combination with MA. 2) The hypotensive effect of reserpine was reduced by MA. 3) The hypotensive effects of clonidine, C₆, propranolol and hydralazine were uneffected by MA. On the other hand, changes in heart rate induced by reserpine and C₆ were increased by MA, however, those induced by guanethidine, clonidine, propranolol and hydralazine were decreased by MA. The slight decrease in heart rate induced by hydrochlorothiazide was uneffected by MA. In view of our data, it is considered important that investigation of the interaction of antihypertensive drugs be done using conscious animals, as these drugs will be clinically prescribed.

View full abstract

Distribution of a new β-adrenergic blocking agent, ³H-carteolol in mice was studied by whole body autoradiography. The distribution of radioactivity was observed in all organs except the eyes and brain, with particularly high specific activities in the kidneys, liver, gall bladder and content in the intestines within a short time after either oral or intravenous administration. The radioactivity was then promptly eliminated from all tissues and organs, and excreted almost entirely in the urine and bile. Propranolol is known to be distributed at a high concentration in the brain, whereas the concentration of (³H-) carteolol detectable in the brain was slight. In the adrenal gland, the radioactivity was localized in the medulla. Radioactivity was detected also in the stomach contents after the intravenous administration. The distribution of radioactivity in the fetus through the placenta was less than that in the major organs of the mother mouse, and the elimination of the activity was more rapid in the fetus than in mother. These findi ngs indicate that carteolol and its metabolites do to some extent pass through the blood-brain barrier and placenta.

View full abstract

We attempted induction of the conflict behavior by the locus pattern, thumping and conditioning under hypothalamic stimulation in rabbits. Flight was classified as continuous and non-continuous. Thumping was elicited post stimulus. Conditioning responses were obtained during the autonomic-somatic responses, continuous run and non-continuous run. All drugs were administrated orally. Dosage of each drug used in this experiment was calculated by determining the dosage which caused the same degree of muscle relaxation and sedative action in mice (see, Fig. 1) or general behavior in rabbits. Diazepam 5 mg/kg, chlordiazepoxide 10 mg/kg and nitrazepam 1 mg/kg caused non-continuous flight in the smooth run, but chlorpromazine 5 mg/kg induced continuous run with snarling. Methamphethamine 5 mg/kg induced continuous run and autonomic-somatic tonus pattern, and phenobarbital-Na 30 mg/kg depressed the animal to the stage of flight. Diazepam, chlordiazepoxide and phenobarbital-Na inhibited thumping, while chlorpromazine, nitrazepam and methamphethamine increased the incidence of thumping. Chlorpromazine transformed the non-continuous run into autonomic-somatic responses of conditioning. Diazepam transformed the non-continuous run into a continuous one. Phenobarbital-Na transformed the non-continuous run into autonomic-somatic responses. Methamphethamine transformed the non-continuous run into a withdrawal response. It would thus appear that the non-continuous flight, thumping and the non-continuous run conditioning are forms of conflict in behavior which can be applied to study of emotional response with psychotropic drugs.

View full abstract

Effect of 3, 4-dihydroxyphenylserine (DOPS), a norepinephrine precursor, on harmaline tremor was investigated in mice to elucidate the role of norepinephrine in the genesis of tremor. 1) Spontaneous motor activity was inhibited by L-threo-DOPS (200 mg/kg i.p.). 2) Tremor induced by harmaline (5 and 7 mg/kg i.p.) was enhanced by α-methyl-p-tyrosine (200 mg/kg i.p.). 3) The development and duration of tremor induced by harmaline (10 mg/kg i.p.) were inhibited significantly in a dose dependent manner by L-threo-DOPS (50, 70, 100, 150 and 200 mg/kg i.p.), but neither by D-threo-DOPS (200 mg/kg i.p.) nor DL-erythroDOPS (200 mg/kg i.p.). 4) L-threo-DOPS (200 mg/kg i.p.) had no effect on the development of tremor induced by tremorine (5 and 10 mg/kg i.p.), while lacrimation and diarrhea caused by tremorine was markedly inhibited. 5) Administration of harmaline (10 mg/kg i.p.) produced an increase in brain 5-hydroxytryptamine content but not in that of norepinephrine. Administration of L-threo-DOPS (100 mg/kg i.p.) increased the norepinephrine content but not the 5-hydroxytryptamine content in the brain. Inhibition of harmaline tremor induced by L-threo-DOPS is attributed to the L-norepinephrine converted from L-threoDOPS and the involvement of a noradrenergic mechanism in harmaline tremor has to be considered.

View full abstract