Up to the earlier period of the war, undesirable reactions such as fever, chills, headache, general lassitude or fluctuation of white cell count following the intravenous injection of hypertonic or isotonic glucose-solutions were not so frequently witnessed. Consequently, these clinical reactions hardly presented any problem from the practical standpoint. Towards the end of the war, many commercial products of low quality were in wide circulation, some of which were revealed to be of substandard qualifications according to bacteriological or other routine investigative tests described in existing pharmacopoeia (J.P.V.). Thus we concede the fact that the flooding of those evidently inferior products in postwar markets is without doubt a factor which made worse the undesirable conditions of the therapeutic solution of glucose. Yet we could not ignore the fact that the officinal products which were apparently perfect and actually made to comform to the pharmacopoeial requirements occasionally yielded febrile reactions. As our animal, chemical and bacteriological examinations will show in detail in the next report, a high percentage of these apparently normal products in question contained pyrogens, it was detected, and we were convinced of the great role of “ pyrogens ” as the cause of thermal reactions in postwar Japan. Apart from the Billroth's experiment in 1865 as to the cause of febrile reaction due to the intravenous injection of distilled water, experiments by Wechselmann(1), Hort and Penfold(2)in 1911, Seibert(3)in 1923, Bourne and Seibert(4)in 1925, Rademaker(5) in 1930 and Co Tui and Schrift(6) in 1942 have disclosed the fact that some kinds of bacteria could produce pyrogenetic substances, the chemical and biological properties of which became clear to some extent through their efforts along with the recent research of Robinson and Flusser(7) in 1944. Co Tui and Schrift(6) have suggested the probability of pyrogenetic reaction due to mold contamination, but Wylie and Todd(8) in 1948 reported that only bacteria were capable of producing pyrogens. Until after our preliminary report(9) on pyrogen-producing molds in 1948 no scientific news was available as for pyrogens and molds. Of late it was a great joy to know about above mentioned researches by American and English scholars and especially the report on pyrogen-producing molds by Harkness, Loving and Hodges(10) in 1950. As our through bacteriological examinations failed to detect directly any microbe in most of the pyrogenous glucose-solution sealed in ampullae, we have been left in the dark as to whether the pyrogan which was found in the solutions in ampullae has any causal dependence to microbes or not. This is the reason why we have decided to concentrate on glucose powders as the second step in our present research. Several years ago we successfully isolated a certain pyrogenous mold at our pharmacological institute but lost it when Professor Miyake's mycological laboratory was bombed in 1944. But, the memory of this first discovery revived our hopes in the postwar period and hence, in the present attempt to detect pyrogens and their origin, our main attention was naturally turned to molds rather than bacteria.
Since the discovery of insulin, various new compounds having hypoglycemic action other than the pancreatic hormone have been reported. In 1922 Collip (1) reported Glucokinin and in 1927 Allen (2) Myrtillin, both of which are extracted from plants or yeast, and have hypoglycemic action. Best and Scott (1923) (3) stated that there are substances in the thyroid gland, liver and muscles that act in much the same way as insulin. Synthalin, a derivative of guanidin is effective but not in practical use, because of its marked side-action. That a kind of fatty acid containing seventeen C-atoms is effective against diabetes mellitus was reported by Kahn (1923) (4), but there was little evidence to support it. In 1945 Nath (6) reported he had succeeded in decreasing the acetone bodies in the blood of diabetics by using amellin. In Japan, proof has been found that there are substances which have hypogly-cemic action in seaweed, yeast and certain wild plants, but their chemical composition is totally unknown. In 1948 Kumagaya (5) reported he had discovered an acidic substance extracted from the Lathyrus Palustris L. var. Macranthus (white) Fernald and effective against diabetes mellitus. These findings so far reported led us to explore some unknown acidic compounds probably contained in plants, which might be efficacious in producing a marked decrease in the blood sugar level. This report deals with the hypoglycemic effect produced by the salts of meso-oxalic acid on the rabbit and dog having alloxap diabetes mellitus (10-18).
Many investigation were carried out in order to throw light on the mechanism of paralysis and intoxication in the case of ileus. Certain investigators believe that toxic proteoses formed in the obstructed intestine should be responsible for these phenomena, but nothing definite is known in these fields. From the pharmacological point of view Hirata (1) (1950) has observed that a little portion of the lower part of the small intestine of a rabbit, experimentally set apart by the double ligatures and laid in a blocked state for 24-48 hours, does not react on the various drugs examined, such as atropin, adrenalin, acetylcholin, etc., showing the paralyzed state of the obstructed, separated intestine. He could not find any pharmacological actions, such as histamine, in the inner fluid of the operated intestine, of which mucosa seemed to be somewhat necrotic and crumbled in some cases. Here rises a problem as to how the enzymatic activity of the intestine contents behaves in the small intestine loops laid aside by the double ligation. Very little is known about the enzymes in such a case. As the autolytic phenomena of the animal necrotic tissues are due to the activity of their proteolytic enzymes, it seems to be important to investigate these protease actions of the inner fluid of the intestinal loops, which were set aside by the ligatures. In these experiments the author has studied the activity of proteinase, peptonase, dipeptidase and acylase of the fluid contents of the small intestine loops set aside by the ligatures. The action of esterase on tributyrin was also examined in the experiments.
It is demonstrated in the previous report (1) (1951) that the activity of the proteinase of the fluid in the tied-off intestinal loops is negligiblly weak and that of the peptonase is also remarkably reduced in 48 hours after the operation, while only dipeptidase, halogenacylase and tributyrinase showed a notable activity in the fluid. Therefore it is concluded that there was neither increased activity of protease nor appearance of any strong protease, such as catheptase in the fluid contents of the tied-off intestinal loops of a rabbit. It seems that the proteinase and peptonase were found in a reduced states in the fluid of the ileus intestine of a rabbit. In these further experiments the activity of proteolytic enzymes in the fluid of the obstructed duodenum, which was tied off by the double upper and lower ligation, was investigated.
When a certain amount of contaminated distilled water was injected into the ear-vein of rabbit, there was often observed a double-peak fever curve, in which the increase of body temperture was plotted against time (1). D. W. Wylie and J. P. Todd (2) have recently discovered that there are several variations of the fever curves from the same culture when certain conditions are changed and also that the pyrogen from different bacterial sources differs in stability. They have suggested from these findings that certain bacteria probably produced two pyretic substances, one of which, in the medium and caused the single-peak fever curve of the immediate reaction type (extrinsic factor), and the other was contained mainly in the bacterial cell and caused the single-peak fever curve of the delayed reaction type (intrinsic factor), a mixture of both causing the double-peak fever curve. Now the scope of our experiment is to learn the connection between the patterns of this double-peak curve and the physiological responses of animals beside pyrexia, especially, the tolerance acquired by animals against pyrogen.
Among a series of highly effective alkylchlororesorcinols against Ascaris luinbricoidgs, effects of which were discovered in our laboratory in 1948/49 (1, 2, 3) as a result of systematic studies with the co-operation of Dr. Tomita and Dr. Uyeo (4, 5, 6) of the Pharmaceutical Institute of Kyoto University in the synthesis of these compounds, a member that proved lowest in toxicity as well as in local irritant action was 4-n-octyl-6-chlororesorcinol. Ashikaga (1) of our laboratory first studied clinical effects of this compound in 1949 and obtained satisfactory results, which, in due time, were confirmed by Hattori and his co-workers (7). For about a year after this there came forth no significant report on clinical studies of this compound. But, last year, reports by Hattori et al. (8) and by Inouye et al. (9) came out, and according to these reports, the efficacy of the compound seems to have suffered rather a severe diminution. Not only that but also, we too have discovered, after having examined two kinds of tablets of this compound prepared by a pharmaceutical Co., that, to our surprise, there occurred a great deal of deterioration in its efficacy compared to earlier data. Whereupon, we again examined the efficacy of three samples of crystalline octylchlororesorcinol that were synthetized since its first trial and found every one of them to be unsatisfactory. In order to know to what causes this change could be ascribed, we decided to launch our researches in the following two directions: Firstly, to find out if any drug-resistance against this compound had been developed on the part of Ascaris under the recent circumstances in which hexylresorcinol became so popular and widely used, and secondly, to re-investigate the problems concerned with the purity of the compound. On the first point, however, recent Mannami's investigations (10) of actual cases revealed no convincing evidence of manifestations of drug-resistance that would explain the above-mentioned change in the efficacy. In respect to the second point, however, the analysis performed by Tomita et al. of Kyoto University showed, oddly enough, that the one lower in efficacy to be the purer. Puzzled by these findings, we finally asked there for a new sample of this drug to be prepared under the same condition as when we received it for the first time. The newly prepared crystals, when tested, proved to be much more efficacious than the other low-efficacy crystals, though the former had lower melting point than the latter. Confronted with these facts, it became necessary for the authors to clarify as to what difference or differences in the properties of these two samples, which are supposed to be alike, the distinct difference in the behavior of these samples could be attributed. In this paper, the authors tried to solve the problem by studying if there is any difference in the physical and chemical properties of all samples of octylchlororesorcinol that have been used in the clinical investigations and by comparing pharmacologic properties of the low-efficacy crystals with those of the newly prepared efficacious crystals.
It is led to the effect that it makes a correlation between physiological change of function and intermediary substance of metabolism, such as acetonuria in case of hunger, increase of pyruvic acid and lactic acid in blood of diabetics as well as avitaminostic stage, and such, which had been made public in effect. Acute chloroform poisoning (1) and that of many narcotics injure the function of liver and kidney and it was shown by many academic reports of the past that it produces considerable changes in intermediary metabolism. While, Quastel and Wheatly (2) have explained that narcotics inhibit the cerebral cells' oxidation by which a special effect brings about on the various functions. Such being the case, narcotics of each kind are considered to be much correlated in point of the intermediary run of metabolism. I tried, therefore, to examine the amount of lactic acid, an intermediate of carbohydrate metabolism, together with acetone, acetoacetic acid and β-hydroxybutyric acid in blood of rabbits, those of fat metabolim, in order to let me know the physiological change of function by giving morphine hydrochloride and soluble phenobarbital.
It is well known that some of the antihistaminic drug such as diphenhydramine has marked hypnotic action. The mechanism of this action is, however, remained obscure for it acts in experimental animal not as a central depressant but rather as a central stimulant. An attempt was made, therefore, to compare the effect of this drug upon the electroencephalogram (EEG) of man with that of rabbit.
It is widely known that cocaine potentiates the responses of sympathetically innervated organs to adrenaline, sympathin, and to sympathetic nerve stimulation. Adrenaline potentiating action of cocaine was first observed by Froehlich and Loewi (1) in 1910. But the mode of this action has not yet been clearly established, though many experiments have since been carried out in order to account for the phenomenon. It has been suggested that cocaine enhances the sensitivity of adrenergic effector systems, or protects the autoxidation of adrenaline or increases the permeability of sympathetically innervated cells, thus favoring the entrance of stimulating agents. Recently, with the advance in the study of metabolism of adrenaline, it has been suggested that the potentiating action of cocaine is due to inhibition of the enzymatic systems which inactivate adrenaline in vivo. On the other hand, the fate of adrenaline is still unknown, in spite of many experiments that have been done on this problem. Hynal (2) and many others reported that liver destroys adrenaline in vivo, while Markowitz (3) and others obtained the negative results. Even in vitro experiments, Embden (4) and others observed the destruction of adrenaline in blood but Machii (5) and others observed the fact that adrenaline is inactivated by perfusion through the isolated liver or other organs, or by addition of various tissue extracts. On the contrary, Oliver and Schaefer (6) found that small amount of suprarenal extract or adrenaline retained its activity much longer in blood than in aqueous solution, and this observation has many times been confirmed by Wiltshire (7) and many other investigators who suggested that in blood and tissues is present an inhibitor of autoxidation of adrenaline such as protein, amino acids, ascorbic acid or glutathion. More recently, various enzymes inactivating adrenaline were discovered from animal and plant tissues and one of them is called amine oxidase. It is considered that amine oxidase is contained abundantly in liver and intestine, the inactivating power of which is much stronger than that in other organs. It is not yet clear, however, how much important part these enzymes play in the inactivation of adrenaline in the animal body. Richter (8) reported that the rapid inactivation of adrenaline in vivo is rather due to sulfoconjugation than to amine oxidase. Bacq (9) has also expressed doubts on the deamination of adrenaline due to amine oxidase in vivo. Okamura (10) described that the rapid disappearance of the biological action of adrenaline in vivo is mainly due to the adsorption of adrenaline by red blood-corpuscles but not due to the oxidative destruction. Since Gaddum (11) has explained the ephedrine potentiation to adrenaline by inhibition of amine oxidase, MacGregor (12), Tripot (13) and Philpot (14) have extended Gaddum's hypothesis, and have proved that not only ephedrine but also cocaine and other local anesthetics inhibit the action of enzymes which inactivate adrenaline. Philpot (14) pointed out that amine oxidase is much more strongly affected by these local anesthetics than other enzymes, but Bain et al. (15) described that cocaine cannot diminish the adrenaline inactivating power of liver in vitro. As above mentioned, the fate of adrenaline in vivo is very complicated, and the experimental evidences are not yet sufficient to show how cocaine prevents adrenaline from inactivation. It was, therefore, intended to study the effects of cocaine and other local anesthetics on the action or adrenaline, on the detoxication of adrenaline in liver in vivo and in vitro and also the correlation between blood and tissues (especially liver extract) which may possibly be connected with the inactivation of adrenaline. Furthermore, the influence of local anesthetics (especially cocaine) on the adrenaline inactivation in vitro was investigated.
Recently methylalcohol is attracting the attention of medical circle, because of many cases of its intoxication, but a lot of questions are still left unanswered as of its pharmacological action. About the distribution of methylalcohol in body and its ways of excretion, there are not so many reports as yet. As far as we know, S. Ueno (1) analysed the methylalcohol contents of various organs of corpses by its intoxication and found that most methylalcohol was contained in blood, and then came out in order of urine, bile, brain and stomach contents. A.Benedicenti (2) let the cats inhale methylalcohol of 3, 4 vol.% eight hours long, and recovered it in the organs as follows: blood, 0, 562g%; liver 0.207; brain 0.19; urine 0.528. According to M. Nicloux (3) and M. Neymark (4), methylalcohol remains in body longer than ethylalcohol. We made the same analysis systematically on more organs than they did.
At the present time, ascariasis is to be considered as one of the serious medical problems in the oriental countries including Japan. In many human experiments in our country, it is found that both santonin and hexylresorcinol are reliable in their anthelminthic action (1). From the result of comparable studies on the pharmacological as well as clinical benefits of both drugs, it is confirmed that santonin is markedly superior to the other in view of its negligible side action. Effective doses of santonin never induce ill effects except a slight and temporary disturbance in vision, while oral administration of hexylresorcinol induced some local irritations on the mucous membrane of the digestive organ, even when it was administered under a perfect condition of coating on it. After taking santonin, ascaris are expelled alive and active. Some authorities, therefore, assume that santonin is not directly toxic to the parasites, but that rather they are irritated by the drug and migrate from the small intestine to the colon to be expelled (2-6). According to others, the drug is excreted in the intestine as an unknown compound, possibly an oxidation product, on which the ascaricidal properties may depend (7-12). But there has been no positive evidence to support both of the views until recently. We have now been able to find out a characteristic locomotion of ascaris in a glass tube which is made to imitate the shape of the bowel, and have good reasons to connect this movement of the worm closely with the anthelminthic activity of santonin (13).