The C-A curves of acetylcholine, pilocarpine and BaCl2 suited best with the formula Kxn = y/y max-y (x : drug conc., y : intensity of action measured by tonus rise, ymax : maximum action, K, n : constants) among other formulae under the experimental condition : ordinary Locke-solution of pH 7.2-7.4 used as the bathing fluid at 30°C. The change of temperature (10°-30°C) and of pH (5.8-8.0) and the increase in K·, Ca·· and Mg·· conc. of the fluid, modified the values of K and/or ymax of the above formula in various ways, but not of n. The change of the values of K and ymax usually went in the same direction, but occasionally in the opposite ; in the latter case a crossing of the C-A curves in different experimental conditions was produced in the plot (log x, y).
Using excised intestine and seminal vesicle of rabbits and abdominal rectus muscle of frogs, the modification of the C-A curves. of the active drugs : acetylcholine, pilocarpine, adrenaline and BaCl2, by the presence of their respective synergists was compared. Results : 1) The formula Kxn=y/ymax-y (x : drug conc., y : intensity of action measured by tonus rise, ymax : maximum action, K, n : constants) suited best with the C-A curves of the active drugs in the absence and presence of the synergists among other formulae. The synergists modified the values of K and/or ymax in various ways, but not the value of n. 2) Based on the pattern of modification of the values of K and/or ymax, 5 different types of synergism have been classified and exemplified, and further, an assumption has been made of the existence of two factors, “susceptibility” and “reactivity” for the drug “sensìtivity” of the tissue.
1) Adopon was observed to have marked paralyzing action, anti-acetyl-cholinic and anti-histaminic action on the isolated intestine of rabbit and guinea pig. However, it is inferior to Banthine in anti-acetylcholinic action, but superior in anti-barium action. The action on the intestine in situ was fluctuating and uncertain. 2) Adopon exhibits inhibitory action on the isolated heart of the frog, but lesser degree. On the blood vessel it has dilatatory action and anti-adrenaline and anti-barium actions were also observed. 3) In the blood pressure and respiration tests with rabbit, the intravenous injection of less than 0.2 mg/kg Adopon did not show any appreciable effects, but the intravenous injection of 3.0-5.0 mg/kg showed marked fall of blood pressure and inhibitory action on respiration after transient stimulation. 4) It has paralyzing action on skeletal muscle of frog, but to a lesser degree as compared with its action on smooth muscle. 5) Adopon did not have any marked influence on the size of pupil of the rabbit eye or of the isolated eye of the frog. 6) The toxicity of Adopon in mice is relatively low; especially with the subcutaneous injection, the toxicity was observed to be much lower than with the intravenous injection.
1) The parenterally administered Adopon was observed to be distributed in the body rapidly. However, without being retained in various organs, it disappears rapidly. 2) Adopon incorporated into body was observed to be excreted in the urine only in a small amount. 3) Adopon may be split rapidly by the enzymes included in various organs. Isoamylalcohol was confirmed as a metabolite, therefore, α- [N- (β-diethylaminoethyl)] -aminophenyl acetic acid may also be considered to be produced. 4) Pharmacological activities of isoamylalcohol andα- [N- (β-diethylaminoethyl] -aminophenylacetic acid, which may be considered as the decomposed products of Adopon, were observed to be much weaker thanthat of Adopon. 5) Adopon-splitting esterase may be widely distributed among organs of various animals, especially rich in liver and little in intestine. 6) The reason why the action of Adopon in vivo is temporary or fluctuating may be due to the fact that this agents is rapidly split by this esterase.
The administration of less than 5.0 mg of atropine or scopolamine exerts no remarkable influence on the general development of chick embryo, but has some influence on the excretions of in organic substance and nitrogen into the allantoic fluid. In the histological examination, it was found that atropine and scopolamine induce the slight hepatic disturbance in chick embryo, and this effect is stronger in the case with scopolamine
The actions of laurifoline chloride, a quaternary ammonium base isolated from Cocculus laurifolius DC., were investigated in detail. Laurifoline showed predominant vasodepressive and very weak curarelike action. It was further proved that this alkaloid had marked nicotinolytic but no atropine-like, no muscarine-like, no histamine liberating, nor adrenolytic actions. It is worth noting that laurifoline is a natural alkaloid belonging to groups of drugs which exert the typical action of ganglion blocking agents.
To study the influence of hyaluronidase on the permeability of eggs, the time until onset of the effects of the dyes on the heart-rate were measured after exposure to the Ringer's solutions containing basic, acid dyes or toxic protein. At 22°C, after 3-24 hours treatment by 2000 U/cc of hyaluronidase, the stable state of permeability can be maintained for 24 hours; irrespective from molecular weight and electric change, that is, drug can reach the heart as fast as that of larvae just hatched out. But 48 hours after hyaluronidase treatment, such state of permeability begins to decrease and after 72 hours, recovers to a certain level, a little higher than the state existing before the hyaluronidase treatment. This fact would show the recovery of vitelline membrane, not cholion.
Eggs treated with hyaluronidase were exposed to the Ringer·solution of digitoxigenin, lanatoside C, g-strophanthin, or digitoxin. The percentage or the time until onset of A-V block and percentage mortality 24 hours after exposure to the solution were observed to determine : 1) the relation between stages of development (myogenic and innervated), 2) influence of temperature (22°C, and 30°C), 3) interrelation of glycosides, 4) linear relation between the time until onset of A-V block and log concentration of digitalis, and 5) influence of ethanol and eserine on the action of digitalis glycosides. A-V block occurs faster and in higher percentage in innervated stage, at higher temperature, and in the order of digitalis preparations described above. By the linearity of the time concentration curve of digitalis, 10-10 g/cc concentration can be detected, and 1/2×10-9 g/cc determined quantitatively, using 0.02 cc of sample solution (containing 1 or 0.1% of ethanol) on each eserinized (10-9, 30 min) egg at 30°C.
Cholinesterase activity was determined with manometric techniques on tissues of cats which had succumbed to poisoning of digitoxin, g-stropharithin and convallatoxin. Results obtained were as follows : Digitoxin inhibits cholinesterase of serum, auricle, ventricle and medulla oblongata. g-Strophanthin and convallatoxin reduce cholinesterase of ventricle markedly and that of auricle slightly, but have no effect on cholinesterase in medulla oblongata. The 3 glycosides have no influence on cholinesterase of brain cortex. In cats from which liver has been blockaded from blood circulation, digitoxin produces more prominent inhibitory action on cholinesterases of serum and tissues than in normal cats.