The motilities of the isolated uterine strip, and longitudinal or circular muscle from the uterus of the rabbit, the guinea-pig and the rat were recorded, and the internal pressure of uterus was measured simultaneously. The behaviors on these strips have been examined for the following drugs: adrenaline, ephedrine, tyramine, acetylcholine, histamine, papaverine and magnesium chloride. Adrenaline, ephedrine, tyramine, acetylcholine and histamine caused the contraction of the isolated uterine strip of the rabbit, while sometimes caused the relaxation. But these drugs caused the contraction of longitudinal and circular muscle isolated from the uterus. Therefore, it seemed that the relaxation of the whole uterine strip caused by these drugs was due to more predominant contraction of the circular muscle than that of the longitudinal muscle. This curious phenomenon was not observed on the isolated uterine strips of the guinea-pig or the rat. Papaverine and magnesium chloride caused the relaxation of both the circular and longitudinal muscle. Above mentioned action of these drugs was observed on the isolated strip of the pregnant or non pregnant, and the confined or not confined rabbits. Dibenamine inhibited the relaxation of the isolated strip of the rabbit uterus caused by sympathetic amines, while did not inhibit the relaxation of that of the guinea-pig or the rat caused by these amines.
The urinary excretion of free santonin in rabbits was observed after administering santonin by 3 different methods: Subcutaneous injection of 10% solution of sodium santoninate, oral administration of santonin, and intramuscular injection of 2 % and 3 io santonin-propyleneglycol (PG). The dosages were all equivalent to 100 mg of santonin. The results obtained were as follows : The urinary excretion of santonin began at 5-15 min. after injection of sodium santoninate, at 10-15 min. after oral administration of santonin and at 15-50 min. after intramuscular injection of santonin-PG. The excretion of santonin continued for 16 hrs. after the injection of sodium santoninate, for 21 hrs. after the oral administration of santonin and for 24 and 59 hrs. respectively after the injection of 2% and 3% santonin-PG. Santonin recovered in urine amounted to 57.4% of the injection of sodium santoninate, to 19.9% of the orally administered santonin, and to 15.8% and 6.4% respectively of the injection of 2% and 3% santonin-PG.
In a series of chemical and chemotherapeutical researches on the nitrofurylacrylic acid derivatives it was proved that 5-nitro-furyl-acrylylaminoethanol (NFA) had a strong antibacterial activity against Grampositive as well as -negative bacteria. Result: NFA inhibits the growth of Shigella dysenteriae and Eberthella typhosa in a highly diluted concontration as much as 1:256000, while with 1:128000 of furacin Shigella dysenteriae are suppressed. NFA is a slightly yellowish crystal, which is melt at 151 ?? 152°C and dissolved in water to the dilution of 1:20 when boiled and to 1: 160 at 50%deg;C. At a very low temperature NFA is dissolved to 1:500, while furacin to 1: 5000. The penetrating capacity of NFA into an agar-medium is about 50 times as strong as that of furacin. MLD per 20 g body weight of mice is 20 mg by NFA and 5 mg by furacin respectively when applied orally.
In the preliminary experiment, it was recognized that the whole brain of the mouse, rabbit, rat, guinea-pig and frog contained only the specific cholinesterase (ChE). The ChE activity was determined by the titration method of Hall & Lucas. After the injection of various drugs and when toxic signs or death appeared, the mice were decapitated and their brain ChE activity was determined. DFP, eserine, prostigmine, camphor and evipan-Na decreased the brain ChE activity. Strychnine, caffein, picrotoxine, coramin, cardiazol, atropine, nicotine, methylpropamine, benadryl, 3015 R.P., cocaine, morphine, demerol, barbital sodium, tridione and urethane did not modify it. Fur thermore, the influence of various drugs on the mice was studied, of which brain ChE activity was decreased to 20 ?? 30% of normal value by the injection of DFP. Those mice tolerated to the lethal dose of strychnine and brucine, but did not tolerate to that of caffein, cardiazol and picrotoxine. And potentiated effect of DFP upon the analgesic action of morphine was found. The above results suggest that the relation between the convulsant or anticonvulsant agents and the activity of the brain ChE is not so intimate.
The value of potency of digitalis in frog method changed in accordance with temperature of the test chamber and health condition of frog, notably in winter, it was however, consistent practically when the healthy frogs were kept in thermoconstant chamber at 22±1°C within one or more days, not more than five days, prior to the onset of the assay. In the chamber at 22±1°C, the level of lactate in the blood of frogs which was exposed to winter air, increased remarkably within one or two days, indicating the optimal condition for the assay. The order of the potencies of cardiac glycosides and digitalis leaves which estimated in frog-method was similar to that which determined by cat or pigeon-method, except few principles, e .g. digitoxigenin and digicorin which affected cardiac actions very promptly. The order of the potencies of these drugs in pigeon method was the same as that in cat method. The standard error of the assay in the pigeon was less than that of assay in the cat.
Experimental studies on the mode of cardiac action of cardiac glycosides, as well as digitalis leaves, notably digicorin, were carried out, employing the pigeon and cat. The duration of action was significantly varied among them, finding the longest in digitoxin. This was followed by digoxin, lanatosid C, some of digitalis leaves, digicorin, ouabain and digitoxigenin in the order herewith given. The onset of the action was proved most rapid with digitoxigenin, followed by digicorin, ouabain, lanatosid C, digoxin, some of digitalis leaves and digitoxin, the last of them showing very much slower than the others. Some differences of mode of action of these glycosides were shown in the experiments in which the activities on the papillary muscle and the changes on the electrocardiogram of them were observed. On the papillary muscle performed by means of Cattell's method, the slight decrease of the threshold of the muscle to the electrical stimulation was followed by the increase of that of the same to it prior to the significant increase of the contraction of the muscle in all drugs tested except digitoxin, while the changes took place in the reversed order in only digitoxin: In comparison with the concentration of those drugs indicating the efficacy and also the toxicity on the papillary muscle digitoxigenin was fairly superior to its parent compound, digitoxin. In view of the fact that the former has been by no means satisfactory in its cardiotonic activities tested in the intact animal, this discrepancy must be interpreted by the evidences that digitoxigenin is much more rapidly metabolized than its parent compound; digitoxigenin is hardly maintained for a certain interval in the concentration enough to bring about its remarkable cardiac actions. The electrocardiogram of the cat revealed that a toxic dose of these drugs except digitoxin caused the depression of the conduction prior to affecting the S-T segment, whereas digitoxin showed the initial change of the S-T segment in the early stage.
Toxic symptoms of several preparations were fully observed and their lethal doses were determined. LD50 of sulfamin (J.P.) for mice was 3.0g/ kg by mouth and was less than two thirds of it when used subcutaneously, and that of pyridinine was 2.1g/kg by mouth. Disulfamin and sulfathia ole were both too weak to obtain LD50 orally. 4 : 4'-Dinitrodiphenylsulfoxide and sulfone were both about one half toxic as compared with sulfamin. With 4:4'-diaminodiphenylsulfone an ataxic symptom was unfailingly manifest and hence the 50 per cent ataxic dose proved available for judging its toxicity along with the lethal dose; LD50 per kg for mice were 375 mg by mouth, 329 mg subcutaneously, and 313 mg intraperitoneally, and its 50 per cent ataxic dose 228 mg, 221 mg and 110 mg respectively and the repeated administrations with various intervals revealed that there was a close and simple relation between the toxic effects and the actual doses, as indicating a high rate of its absorption and excretion.
Our experiments corroborated that when sodium or calcium salt of mesooxalic acid was given orally to alloxan-diabetic rabbit for several days, daily amount of sugar in the urine decreased or disappeared totally, the non-protein nitrogen in the urine decreased markedly and the level of sugar and acetone bodies in the blood fell, resulting the increase of the body weight of rabbit affected. If the administration of the drug was sustained, glycosuria reappeared from the selfsame day and the body weight, blood sugar content and other findings returned to their respective level prior to the drug was given. The more serious the diabetes in rabbit, the less the effect of the drug. From the histological studies on the pancreas of rabbit tested it was proved that the intensive and typical change of the islet of Langerhans induced by alloxan was found in all of our experiments to which the drug was not or less effective.
The salts of meso-oxalic acid showed the remarkable effect against the alloxan diabetes in dog as it had been proved in rabbit. In the diabetic dog the abnormal value observed in the blood and urine was restored to the normal level during the oral administration of drug and often for a few days after giving up the administration in less the dose than in rabbit. The anticipated effect was proved by giving and adequate amount of insulin prior to the administration of meso-oxalic acid to dog when the drug alone was not effective for the very severe diabetic animal. It was also revealed that there was no effect for the depancreatized dog in any doses of the drug.
With the first sample of promin prepared in this country, examinations were carried out by the author during the war-time. Toxic symptoms observed in mice and rats were indicative of a close resemblance of the compound in its toxicity to the mother compound, 4 : 4'-diaminodiphenylsulfone. LD50 for mice were 3.93 g. per kg of body-weight by mouth, 6.5 g subcutaneously and 45.25 g. intravenously, and for rats almost the same readings in the respective potencies were obtained. It was revealed that the oral toxicity of promin exceeded the parenteral one, not only in a single dose but also when given repeatedly for a certain period. Kymographic examinations for respiratory and cardiovascular responses were conducted in rabbits and frogs. The fall in blood-pressure in rabbits, the presence of temporary cyanosis and the local irritation or edematous swelling of skin in rats were the noticeable findings observed by the author. Examinations on the bronchial instillation were given to rule out some possible but untoward reactions of the drug ingested through the tracheal puncture.