Neuropharmacological properties of Thalamonal were investigated and compared with those of Fentanyl, Droperidol and Morphine. The following results were obtained. 1. Muscle relaxation and the impairment of the posture maintenance, muscle coordination and placing, hopping and righting reflexes were observed following i. v. administration of 0.1ml/kg of Thalamonal in dogs and cats. In addition, threshold for eliciting the nociceptive reactions by natural stimulation was elevated without any noticeable central excitatory symptom. 2. No anti-cardiazol and strychnine convalsive effects or anti-electroshock activity were shown. Thiobarbital anesthesia was potentiated by Thalamonal in mice. Thalamonal was suppressive of apomorphine induced vomiting in dog and also had a slight hypothermic activity at 0.37ml/kg in rabbit. 3. The ED50s of analgesic activity in mice measured by Haffner's method were 0.32ml/kg, 0.087mg/kg for Thalamonal and Fentanyl, respectively, Fentanyl possessed an analgesic potency about 100 times as strong as that of Morphine. 4. In rabbit with chronically implanted electrodes “pain reactions” were induced by tooth pulp stimulation. Doses at which the threshold values were doubled were 0.6ml/kg, 0.03mg/kg, and 10mg/kg for Thalamonal, Fentanyl and Morphine, respectively. Droperidol was not effective at 1.5mg/kg. This threshold elevating effect was shortlasting. 5. By small doses of Thalamonal the EEG activity of both acute and chronic rabbits showed the tendency that the spindle burst waves became frequent, slow waves of high amplitude dominant in the cortex and the theta wave activity was abolished and slow wave became dominant in the hippocampus. Threshold for the EEG arousal response by brain stimulation became higher. 6. In the cat slowly developing potentials of the CM nucleus of the Thalamus evoked by the stimulation of the splanchnic nerve and the canine tooth pulp were abolished by 1.0ml/kg Thalamonal and 0.1mg/kg Fentanyl but rapidly developing evoked potentials of the cortical first and second somatosensory areas from the tooth pulp were not influenced. 7. The direct cortical response at the neocortex was almost uninfluenced even by 2.0ml/kg of Thalamonal.
Effects of Thalamonal, Fentanyl, Droperidol and Morphine upon the somato motor activity in the cat, endplate potential and membrane potential in the muscle fiber of the frog were studied and compared with each others. 1. Thalamonal (0.5ml/kg) and Fentanyl (0.04mg/kg) depressed the spinal polysynaptic reflex activity strikingly in the high spinal cat (Th1) leaving the monosynaptic reflex activity (MSR) uninfluenced even at a larger doses. 2. In the spinal cat, inhibition of the exensor MSR induced by the cutaneous nerve (sural, saphenous nerve) stimulation was abolished by Thalamonal, Fentanyl and Morphine, but not by Droperidol. 3. The tonic muscle activity of the neck in the decerebrate cat was depressed immediately after injection of Thalamonal (0.06ml/kg) Fentanyl (0.01mg/kg) and Droperidol (0.5mg/kg). Also the spontaneous efferent fusimotor activity recorded from split thin filament of L7 in the pentobarbitalized cat was abolished by 0.1ml/kg doses of Thalamonal. 4. Action potential of the sciatic nerve in the frog was reduced to 75.1±3.6% of the control size by 10-1v/v of Thalamonal and was depressed to 62.0±17.0% of the control by 2.5×10-5w/v of Droperidol. Fentanyl and Morphine at a concentration of 10-4w/v were not effective. 5. Twitch tension in the gastrocnemius muscle preparation and the end plate potential (E. P. P.) of the d-tubocurarine treated sartorius muscle of the frog were depressed by Thalmonal (10-2v/v) and Fentanyl (10-5w/v). 6. The resting membrane potential in the isolated frog sortorius muscle was not influenced by Fentanyl (10-2w/v) and Morphine (10-4w/v). By Droperidol (10-4w/v) the resting potential was slightly reduced. The spike potential evoked by intracellularly applied polarizing pulse became smaller in size by Thalamonal (2×10-3v/v) and Droperidol (1×10-5w/v). Fentanyl (1×10-4w/v) and Morphine (1×10-4w/v) had no significant effect.
Thiopental sleeping time and anesthetic dose of thiopental were examined in rats at 24 hours after administration of CCl4. It was found that CCl4 increased the sleeping time and reduced the anesthetic dose. Tissue distribution studies revealed that potentiation by CCl4 of thiopental anesthesia was attributed to an increased penetration of the barbiturate into the brain. Biochemical studies showed that plasma of CCl4-treated rats had relatively low quantities of albumin and did not have enough capacity for thiopental binding. Altered distribution of thiopental might be due to a hypoalbuminemia induced by CCl4. No changes in the sensitivity of central nervous system and in the permeability of blood-brain barrier were observed.
The hemostatic effect of Menaquinone-4 (K2) on bleeding at partially incised tail vein of rats pretreated with Dicumarol, Urokinase or Carbon Tetrachloride to prolong definitely bleeding time was studied. The effect of K2 on the bleeding was compared with the effects of Phytonadion (K1), Etamsylate, Tranexamic Acid (AMCHA), Epsilone Aminocaproic Acid (EACA) and Carbazochrome (CA-17). Intramuscularly administered K2, K1 and AMCHA showed statistically significant effect on shortening bleeding time on the rats given Dicumarol but K2 was the most potent. The bleeding time on K2-administered rats pretreated with Carbon Tetrachloride was significantly shortened, but K1 showed no effect. The bleeding time on the rats given Urokinase was apparently reduced by AMCHA, while K2 and K1 were not significantly effective.
Normal rabbits with 2.5-3.0kg body weight were intramuscularly injected 50mg/kg of K2 which was correspond to 100-300 fold of clinical dosage for human, and then, prothrombin time and thrombelastogram on blood of the rabbits were observed daily for 7 days. During this term, the prothrombin time and the thrombelastogram were little changed. Serum bilirubin of the rabbits showed normal level under this condition.
Influence of morphine on the fine structure of mitochondria in zona fasciculata in rat adrenal cortices electronmicroscopically were studied. The results obtained are as follows: Administering morphine in a dose of 20mg/kg to rats, the honeycomlike structures of inner membranes of mitochondria in adrenocortical cells were observed to be altered either tubulo-vesicular or lamellar ones, while the deformed structure gradually became to diminish during repeated administration of the drug. However, the withdrawal of morphine extensively caused such the deformed changes in the mitochondrial structures again, but in case of the reinjection of the drug, the changes promptly restored to pre-treated structure.
Anti-inflammatory assay by carboxymethyl cellulose pouch method, 2, 5) which is suitable for assaying leucocyte infiltration in the inflammatory reaction induced by CMC solution, was applied to test the action of clonixin, indomethacin, phenylbutazone and hydrocortisone acetate. These drugs were given locally together with 1.5% CMC solution on the dorsum of rats. Clonixin in a high dose (130mg/kg) gave 91.3% inhibition and 47.3% inhibition in a low dose (16.0mg/kg). Indomethacin and phenylbutazone showed significant inhibitory effect without giving clear dose-response relationship. Inhibition by these two drugs did not exceed a maximum of 50%. Hydrocortisone acetate (10mg/kg) gave 81.8% inhibition.
Inhibitory action of Clonixin, 2-(2'-methyl-3'-chloro)-anilinonicotinic acid, on the carrageenin edema and acetic acid edema of the rat paw was tested. It was somewhat more potent than aspirin. Analgesic action was tested on pressure pain on the mouse tail, writhing movements of mice treated with diluted acetic acid and pressure pain on carrageenin-inflamed rat's paw. It was proved 1.5 to 3 times more potent than aspirin. It had an inhibitory action on capillary permeability of mice peritoneal cavity and antipyretic action. Clonixin aggravated acetic acid ulcer produced on the rat stomach. It produced musculotropic contraction of isolated ileum of the guinea pig and at the same time weak papaverine-like non-competitive antispasmodic action.
Spectrophotofluorometric determination of catecholamine in aqueous humor was made. It was demonstrated that the mucosaccharide in aqueous humor did not affect the recovery of catecholamine, at the same time it was shown that vitamin C co-existing with catecholamine did not interfere with the intensity of fluorescence of THI formed in the eluate unless vitamin C content in aqueous humor exceeds of 0.8mg. Catecholamine in aqueous humor was only determinable at concentrations higher than 5μg/L. It was noted that the concentration of catecholamine in aqueous humor was much higher than that of serum and that it was not affected by changes in blood level provided that sympathetic nerve control was maintained in the eyes.
1) The contraction of 5-HT is due to the direct stimulation of D-receptor in the muscle and not due to the release of ACh. 2) The contraction of nicotine is due to the release of ACh and 5-HT. No evidence was found suggesting the pharmacological responses of autonomic ganglia. 3) Scopolamine was highly superior to atropine in the selective block of cholinergic receptor. 4) As regards the receptors inducing relaxation, the β-adrenergic and the dopaminergic are present, but not the α-adrenergic. 5) The relaxation of transmural stimulation is due to the release of dopamine. 6) The tyramine relaxation is due to the stimulation of β-adrenergic receptor. 7) Tyramine produces contraction by the release of ACh from parasympathetic nerve endings after the occurrence of tachyphylaxis to its relaxing action.
Influences of morphine on the alteration of inner membranes of mitochondria in zona fasciculata in rat adrenal cortices and the degree of adrenal corticosteroid biosynthesis electron microscopically and biochemically were studied. The results obtained are as follows: Administering morphine at a dosage of 20mg/kg to rats, the decrease of corticosteroid biosynthesis in the adrenal cortex was observed to be parallel in time to the onset of transformation of mitochondria, while the withdrawal of morphine after repeated administration of the drug, also resulted in the similiar alterations. However, re-injection of the drug to withdrawn rats, alteration above-mentioned promptly recovered to the normal states within a few hours.
Beat-to-beat blood pressure in a free ranging dog within laboratory has been measured by a simple F. M. monolithic transmitter with chronic intra-arterial cannulation. The oscillator was modulated directly by semiconductor pressure transducer changing E base. Center of irradiated frequency was 78MHz. A conventional F. M. radio was used as signal receiver and also as demodulator, since DC signal output could be taken between center of AFC switch and common base. The calibrated DC output was 76.4mV per 100mmHg and linear up to ±300mmHg. Maximum telemetered distance of the system was 30 meters in an ideal condition. Single battery, H-2D, 2.6V survived 130 hours without changing DC output.
1. Homotaurine (HT) and hexamethonium (C6) showed remarkable inhibitory effects on the pressor responses following electrical stimulations of the splanchnic nerves in dogs. 2. HT and C6 showed remarkable inhibitory effects on the rise of inferior mesenteric arterial perfusion pressure following preganglionic stimulation (P. S.) of the inferior mesenteric ganglion (I. M. G.), but no effects on the rise of perfusion pressure by post ganglionic stimulation, in dogs. 3. The contractile force of the nictitating membrane following P. S. of the superior cervical ganglion was not inhibited by HT, but inhibited by C6, in dogs. 4. In cats, the ganglionic potential following P. S. of I. M. G. was not inhibited by HT, but inhibited remarkably by C6. In Dogs, the postganglionic action potential following P. S. of I. M. G. was inhibited remarkably by HT.
In the anesthetized dog, intravenously given capsaicin caused a transient apnoea, bradycardia and hypotension. Blood flows in the mesenteric, renal and femoral arteries were decreased, however, that of of carotid artery was increased even in a small dose causing no changes in the respiration, heart rate and blood pressure. Cardiac muscle contractility was depressed principally whilst capsaicin increased contractility of isolated guinea pig atrium. There were considerable shortening of apnoetic phase and complete vanishment of bradycardia after vagii cut. On the other hand, capsaicin caused a drastic increase of blood pressure and characteristic behavioral changes in the unanesthetized dog.
2-Methylaminomethyl 2, 3-dihydrobenzofuran (EPS-4032) revealed relatively potent analgesic effect on various method in mice. Its effect was roughly equivalent to codein and as 5 times potent as aminopyrine. Morphine analgesia was apparently antagonized by levallorphan, while EPS-4032 analgesia was markedly potentiated by it, as well as aminopyrine. In the animals pretreated with reserpine or tetrabenazine, EPS-4032 and morphine failed to produced analgesic action. However, this antagonism was disappeared by administration of 1-DOPA after tetrabenazine. Analgesic effect of EPS-4030 was significantly intencified with pretreatment of nialamide and SKF-525A, but apparently reduced by pretreatment of phenobarbital. Also slight developement of tolerance was observed by repeated administration of EPS-4032 on mice.
Subcellular fractions of neutrophilic leucocytes collected from rabbit peritoneal exudates were separated by differential centrifugation. The effects of each fractions on pyrogenicity of bacterial lipopoly saccharide were examined. The fever-suppressing activity was found in two fractions, 7, 000g 10m pellet (neutrophilic B granules fraction) and 14, 000g 10m pellet (neutrophilic A glanules fraction). The fever-suppressing factor in 7, 000g pellet was inactivated by the 60°C 30m heat treatment or freezing-and-thawing. The fever-suppressing factor in 14, 000g pellet was inactivated by the 60°C 30m heat treatment, but they were activated with freezing-and-thawing or sonication. Then A granules were sonicated and centrifuged 78, 000g 120m. The fever-suppressing activity was found in 78, 000g pellet of A glanules. Supernatant was fractionated with ammonium sulfate. The activity was appeared in 80% saturated supernatant. Paper-electrophoretical data showed that active substance might be cationic or basic polypeptide. The physiological significancy of this fever-suppressing factors are discussed.
This study was undertaken to ascertain the difference between serratiopeptidase, a new anti-inflammatory-enzymatic drug, and aminopyrine, a time-honoured anti-inflammatory drug, in the mechanism of changes of the vascular permiability and the cellular infiltration that is a factor of inflammation in early stage. Results: 1. A macroscopic swelling induced by the dextran injection in the hind paws of rat was apparently inhibited due to the oral administration of serratiopeptidase (500mg/kg) or aminopyrine (100mg/kg); those were administrated 3 hours before the dextran injection or at the same time of this injection. And this swelling was slightly inhibited due to aminopyrine that was injected 3 hours after the dextran injection, too. 2. As for the influences on changes of vascular permiability induced by evans blue in the abdominal skin of rat, both serratiopeptidase and aminopyrine administrtaed orally 3 hours before the concentration of pigmentation by evans blue. When both drugs were adminstrated at the same time or 3 hours after the dextran injection, they could not inhibit the enlargement of the area of pigmentation, but as for the concentration serratiopeptidase inhibited it apparently and aminopyrine did it slightly. 3. In any time of the administration of the drugs, serratiopeptidase apparently inhibited the histo-pathological edema, but weakly the cellulal infiltration. On the contrary, aminopyrine apparently inhibited the cellular infiltration, but weakly the histopathological edema. From the above results, the difference of the inhibitory effects on the inflammation in early stage was ascertained clearly between serratiopeptidase and aminopyrine.
The effect of 1-phenyl-1-hydroxy-n-pentane (PHP) on the pancreatic secretion was investigated on the urethane anestheized rat and the pentobarbital anesthetized canine. In rats, the secretory volume of pancreatic juice and the output of protein in it were appearently increased by peroral and intraduodenal administration of PHP (50_??_200mg/kg), but not by perrectal administration (100mg/kg). However, these effects of PHP were not so marked in intraperitoneal (50_??_200mg/kg) or intravenous (5_??_10mg/kg) injection. While biliary secretion was considerably increased in either route of administration of PHP. PHP administerd intraduodenaly (25_??_200mg/kg) revealed the stimulatory effects of pancreatic secretion in the canine.
1. Intraduodenal administration of 1-phenyl-1-hydroxy-n-pentane (PHP) 200mg/kg body weight diluted with cocoanut oil produced significant increased in amount of amylase in the “flushed-out” solution. Intraduodenal administration of cocoanut oil 400mg/kg body weight failed to produce amylase secretion. 2. Perfusing the superior mesenteric artery with Tyrode solution containing PHP produced increase in amylase secretion in the isolated rat pancreas. The higher the concentration of the drug was given (ranging 0.5 to 2.5mg/ml) the larger amount of amylase was secreted. The enhancement of secretion due to PHP disappeared when calcium concentration in the perfusing solution was removed. 3. On these results, it is concluded that PHP acts on the pancreatic cells to secrete amylase. The mechanism of the action of PHP on the pancreas was discussed.
1. The hypotensive activities of the synthetic colistin derivatives in which the amino groups were substituted for N-alkyl and N-alkylidene in the position of colistin base were studied in dogs, cats and guinea pigs. The hypotensive activity of colistin derivatives was proportional, both in intensity and duration, to the number of carbon atoms in N-alkyl and N-alkylidene groups. The decreasing order of hypotensive activity of colistin derivatives is as follows: N-amyl>N-butyl>N-propyl>N-ethyl>N-methyl and N-benzyl>N-butylidene>N-propylidene>N-ethylidene>N-methylidene. 2. Except for N-amyl colistin, N-alkyl and N-alkylidene produced negative inotropic and chronotropic effect on the toad's isolated heart. The decreasing order of the negative inotropic action of colistin derivatives is as follows: N-benzyl>N-butylidene>N-propylidene>N-ethylidene>N-methylidene and N-butyl>N-propyl>N-ethyl>N-methyl. 3. N-alkyl and N-alkylidene had vasoconstrictor effect on the toad's perfused hind limbs. The decreasing order of the vasoconstriction intensity of these derivatives is as follows: N-butyl>N-butylidene>N-propylidene>N-ethylidene>N-methylidene.
The abilities of both CG-315 and morphine inducing the deformed changes of fine structures of mitochondrial inner membranes in rat adrenocortical cells electron-microscopically were studied. The ability of CG-315 was observed to he much weaker than that of morphine.
Influences of codeine on the fine structure of zona fasciculata of rat adrenal cortex electron microscopically were studied. The results obtained are as follows. Administering codeine at a dosage of 40mg/kg to normal rats, the honeycombed structures of inner membranes of mitochondria in adrenocortical cells gradually disappeared and the matrix of mitochondria became to less dense. While the deformed structures above-mentioned gradually diminished during the chronic administration of the drug. However, the deformation of inner membranes in mitochondria were produced again in tolerant rats after withdrawal of codeine or treatment of levallorphan, but after the reinjection of codeine, the changes disappeared to the normal state.