Physiological bases of the electrical phenomena in the heart were briefly reviewed, and our studies on the developmental changes in the electrical properties of chick embryonic hearts were described. We found that, as age advances, the potassium conductance increased, resulting in the increase in the resting potential. The rising phase of the action potential of the young heart was found to be formed by the slow Na+ channels, and that of the old heart by the fast Na+ channels. Slow Ca2+ channels were found to contribute to the formation of the plateau component increasingly with age. With respect to the drug actions on the electrical properties of the cardiac muscle, the effects of antiarrhythmic agents, catecholamines and histamine were mainly described. Four proposed mechanisms of action of antiarrhythmic agents were explained from the electrophysiological basis. The actions of Class I and II agents were mainly described, which we examined most extensively. Changes in the sensitivities to catecholamines and histamine during postnatal development were examined with rats and guinea pigs, respectively. Possible correlation between the sympathetic innervation and the catecholamine sensitivity was proposed, and it was suggested that the denervation supersensitivity was possibly of the postjunctional type. Lastly, cardiac slow channel system predominantly admitting the Ca2+ current and its relation to the cardiac mechanical activities were reviewed briefly. Results we obtained in relation to this slow Ca2+ channels were described. We found the lack of parallelism between the activities of the positive inotropic agents to elicit this slow channels in the depolarized myocardium and to increase the contractile force under the normal condition where the fast Na+ channels are functioning, and suggested that the positive inotropic effects of the drugs were not solely explained by their effects to increase the density of the slow channels.
1. Chronic administration of cortisone (12.5 mg/kg/day, s.c., 7 days) activated liver tryptophan pyrrolase (TP) and decreased 5-hydroxytryptamine (5-HT) content of the brain in adrenalectomized rats. In contrast, dl-pyridylalanine analogs (2-PA, 3-PA and 4-PA) decreased liver TP activity and increased brain 5-HT in both of adrenalectomized and intact rats. Simultaneous administration of 2-PA or 3-PA (100 mg/kg) with cortisone (12.5 mg/kg) clearly inhibited the induction of TP in the liver but also the decrease of brain 5-HT by cortisone. The inhibitory potency of 4-PA to the above actions of cortisone was weaker than that of the other PA analogs. Glycyrrhizin (GL, 100 mg/kg) also inhibited the actions of cortisone, while GL did not affect liver TP activity and brain 5-HT content when administered singly to rats. 2. Chronic administration of 2-PA or 3-PA increased liver tyrosine aminotransferase (TA) activity in both of adrenalectomized and intact rats. Liver TA activity in adrenalectomized rats was more potently activated by simultaneous administration of 2-PA or 3-PA (100 mg/kg) with cortisone (12.5 mg/kg) compared with any single administration of these compounds ; the effects were additive. 4-PA (150 mg/kg) decreased liver TA activity and slightly inhibited the induction of this enzyme by cortisone. A simultaneous administration of GL (100 mg/kg) with cortisone clearly inhibited the action of cortisone, but a single administration of GL hardly affected TA activity. Brain norepinephrine (NE) content in adrenalectomized and intact rats did not alter after single or simultaneous administration of these compounds. 3. These data suggest that alterations of liver TP activity can lead to changes in brain 5-HT content and that the altered liver TA activity is unrelated to brain NE content. The results indicate that PA analogs increase brain 5-HT content without affecting NE content in rats.
To examine interfacial transfer and absorption behaviors of drugs with the dissolution from compressed tablet, two reliable methods were preliminarily developed. One of the methods (S-Lw-Lo system) was constructed based upon an interfacial transfer of the drug from aqueous phase (Lw) to organic phase (Lo) with the dissolution in Lw. Another method (S-Lw-in situ system) was constructed based upon perfusing the drug solution in rat intestinal tract in situ with the dissolution of the drug in a reservior (Lw). The experiments were carried out by using benzoic acids and barbiturates as test compounds to survey the validity and reproducibility of the methods. The drug appearance in organic phase of S-Lw-Lo system (Co) was well correlated with the drug disappearance in the reservior of S-Lw-in situ system, following the first order kinetics. The Co value was found to be simply estimated from solubility and partition coefficient of drug. The results indicated that the methods developed here can afford a quantitative evaluation of drug absorption behavior with high precision and may extend to evaluation procedure of bioavailability.
Duration of anesthetic action of dibucaine in the presence of liposome was studied, by using intradermal wheal methods in guinea pigs. The intermolecular interaction of dibucaine and liposomes was also studied in vitro in order to investigate the mechanism of the duration effect. When dibucaine was entrapped into liposomes, the decay of anesthetic action of the drug was inhibited and the duration time of anesthesia was prolonged. In case of liposomes composed of phosphatidylcholine and cholesterol, the degree of anesthesia ran parallel with the percentage of apparent entrapped dibucaine. It was suggested that ionic interaction played an important role in the binding of dibucaine and liposome having a negative charge.
By allowing the sodium cephalothin (CET) injection to stand, it decomposed to be colored and declined to be acidic. The effect of the injection, kept under different storage conditions, on the experimental animals was discussed. The pain to mice was examined by writhing response, by the intraperitoneal administration of the CET injections stored at constant 4°and 37°temperatures. A more remarkable writhing response was observed with the injection stored at 37°than that at 4°. The major degradation products of the injection were identified as acetic acid, deacetylcephalothin, and deacetoxycephalothin by various chromatographic and GC-MS techniques. The higher the storage temperature is, the larger the amount of degradation product is. Rate of decomposition of CET injection stored at 37°for 24 hr was about 30%, calculated from the amount of acetic acid produced. Neutralization of the CET injection stored at 37°for 24 hr with sodium hydroxide solution decreased the pain in mice. Consequently, it is assumed that induced pain is mainly attributed to acetic acid produced by degradation.
The effect of magnesium stearate on the dissolution rate of rifampicin from a hard gelatin capsule was studied. The interesting phenomenon that the effect was influenced by the particle size of rifampicin was found. In the case of rifampicin (RFP 1) sieved into 42-80 mesh, magnesium stearate slowed down the dissolution rate of rifampicin. On the other hand, magnesium stearate accelerated the dissolution rate of rifampicin (RFP 3) passed through 200 mesh screen. These phenomena indicate that magnesium stearate is distributed over the surface of rifampicin particles to exhibit two different effects. The first is the inhibitory effect on the penetration of dissolution medium into the rifampicin powder bed. This effect is due to the formation of hydrophobic film of magnesium stearate over the surface of rifampicin particles. The second is the accelerating effect on the release of rifampicin from the powder bed to the dissolution medium. This effect is due to the reduction of cohesive force between rifampicin particles by magnesium stearate. In the case of RFP 1, the first effect appeared more remarkably than the second one because the particles were large and the cohesive force between the particles was weak. On the other hand, the second effect appeared more remarkably for RFP 3 because the particles were small and had strong cohesive force.
Effects of maltitol and mannitol on the gastrointestinal absorption of acetaminophen, sulfisoxazole and riboflavine in mice were investigated. When drugs were orally administered with maltitol or mannitol, and 2 hr after maltitol or mannitol was orally given in mice (in diarrhea), the blood levels of drugs became lower than that in the control, and drug absorption was inhibited. It was suggested that these results were not caused by molecular interaction between drugs and sugar alcohols, but by the action of maltitol and mannitol which accelerated small intestinal motility, secretion and vascular permeability in the intestinal membrane. These changes may be mediated by biogenic amine, serotonin, histamine and polyamines in the small intestine.
Analgesic-active N-alkyl-10-hydroxy-10, 5-(iminomethano)-5H, 10H-and-10-hydroxy-10, 5-(iminomethano)-5H, 10H-dibenzo [a, d] cyclohepten-11-one derivatives (V) were prepared from 5-acylaminomethyl-5H-dibenzo [a, d] cycloheptene via oxidative transannular reaction-lithium aluminium hydride reduction and the transannular reaction-hydrolysis. These derivatives (V) were easily converted by treatment with alkali, alumina and heating to very interesting ring contraction products such as 3, 8-(o-phenylene)-2, 3, 8, 9-tetrahydrobenzo [d] azepin-2-one derivatives. Moreover, an interesting ring opening reaction of the derivatives (V) with acetic anhydride-alkali was examined.
The in vitro metabolism of dehydroepiandrosterone sulfate (DHAS) was investigated in placentas at term from human subjects and monkeys (Macaca fascicularis). In each case DHAS was easily hydrolyzed to unconjugated metabolites and dehydroepiandrosterone (DHA), androst-4-ene-3, 17-dione (Δ4-A-dione), androst-5-ene-3β, 17β-diol (Δ5-A-diol), testosterone (T), estrone (E1) and estradiol-17β (E2) were identified as metabolites by two dimensional thin layer chromatography and reverse isotope dilution technique. DHAS was rapidly converted to E1 and E2 which were already main metabolites after incubation for 20 min with human placentas in the presence of NADPH as coenzyme. The conversion of the substrate to E1 and E2 after incubation for 2 hr was in the range of 45 to 67% and 7 to 16%, respectively After the incubation with monkey placentas, DHA was a main metabolite and the activity to convert the substrate to E1 and E2 was considerably lower than that observed in human placental preparations.
Pharmacological effect of crude extracts CS-2, -3, -5 and-6, obtained from the chinese crude drug"Shoma"(the rhizome of Cimicifuga simplex WORMSK.) was examined in small animals. CS 2 prolonged significantly the sleeping time induced by thiopental and inhibited the convulsion induced by strychnine in mice. CS 3 also had sedative and anticonvulsive effects, but toxicity of CS 3 may be involved in these effects. CS 5 was highly effective in the suppressing contraction induced by norepinephrine in the isolated guinea pig vas deferens and relaxation induced by isoproterenol against contraction induced by acetylcholine in the isolated rat anorectum. Antagonistic effect of CS 6 was observed against contraction induced by serotonin in the isolated guinea pig ileum. Any remarkable effects of CS 5 and CS 6 were observed in the isolated guinea pig tracheal strips and rat uterus.
Bis (haloalkyl) piperidine (CAP) derivatives were studied with respect to the relationship among their mode of hydrolysis in a bicarbonate buffered solution, their reactivity with Na2S2O3 or 4-(p-nitrobenzyl) pyridine, and their antitumor activity on Ehrlich ascites carcinoma and rat ascites hepatoma AH-13. It was deduced that CAP derivatives rapidly formed intramolucular cyclic intermediates, an ethylene imine from the secondary amines and an ethylene imonium ion from the tertiary amines, in the process of hydrolysis. Moreover, the reactivity of these compounds was in the order of 1-methyl-2, 6-bis (halomethyl) piperidines>1-(β-haloethyl)-2-halomethylpiperidines>1-(γ-halopropyl)-2-halomethylpiperidines>2, 6-bis (halomethyl) piperidines, but there was no parallelism between the chemical reactivity and the antitumor activity. However, a significant correlation was observed between the cytotoxicity of the tertiary amine type CAP derivatives proceeded by a similar mechanism of reaction, EC50 against Ehrlich ascites carcinoma cells or IC50 against AH-13 cells, and the ratio of the rate constant of halogen ion release, k1', to the rate constant of disapperance of alkylating active compounds, -k", from these amines, -k1'/k", which seemed to be a durability of alkylating activity. On the other hand, 1-(γ-halopropyl)-2-halomethylpiperidines which showed a monofunctional chemical reaction only provided with a high therapeutic index, LD50/ED50, on AH-13 bearing rats, which was equal to those of cyclophosphamide and nitrogen mustard N-oxide.
On preliminary examination of the constituents and antitumor study on Agrimonia pilosa LEDEB. by using HeLa cells, Ehrlich acsites carcinoma, and whole blood of rat, the acidic fraction soluble in n-hexane showed strong cytocidal effect, hemo-agglutinability, and hemolytic action in the absence of protein.