The safety of the injection therapy has to be secured including that of the injection itself as well as that of the equipment used for injection, i.e. i.v. fluid administration systems. The contamination of insoluble particulate matter ascribed to coating of silicone oil over disposable syringe is being solved by the development of syringe using fluoro-resin laminated rubber. In the case of blood administration set and blood bag system, there are some in which the solvent used for adhesion has been eluted. Further, the relationship between the quality of materials of administration set and the adsorption of drugs has become clear. As regards the plastic container for infusion, insoluble particulate matter and adsorption of drugs have become a problem in connection with the quality of materials used and yet the structure of plastic/rubber combined cap is related to the formation of core, thereby making the improvement. In the case of plastic bag, that made of polyethylene does not adsorb drugs so much and the formation of insoluble particulate matter is a little. For the measures of drug interaction of injection, i.v. fluid administration systems have been applied and the safe and effective method of administration of injection will be established along with the development of I.V. delivery system.
Anti-inflammatory activity of a hot water extract (A-ext) of Aconiti Tuber (Aconitum calmicaeli DEBX.) has been studied by using various experimental models. The succesive administration of A-ext from the day of injection of adjuvant agent or 5 d after the injection it significantly inhibited the adjuvant-induced arthritis developed in the primary and secondary lesions in rats. However, when A-ext was administered from 11 d after the injection of adjuvant, the arthritic paw edema was not reduced. A-ext did not inhibit an acetic acid-induced increase in vascular permeability in mice and carrageenin-induced paw edema in rats. A-ext inhibited cotton pellet-induced granuloma in rats, but did not suppress the weight of thymus and adrenal gland. In vitro experiment, A-ext contracted the isolated ileum of guinea pig, but the contractive activity was reduced by pretreatment of anti-histamine agent, diphenhydramine, but not by pretreatment of papaverine or atropine. A-ext did not release histamine from peritoneal mast cell. These results suggest that A-ext prevents the adjuvant-induced arthritis and bas a histamine-like effect.
Fresh lamprey oil (F-La) is known to contain a large amount of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. When F-La was deodorized with steam at 280°C and 1 mmHg for 1 h, the contents of EPA and DHA were reduced and unidentified peaks were detected by gas-liquid chromatography. In male ddY mice, one week feeding of the lamprey oil deodorized at 280°C (H-La) remarkably decreased the serum triglyceride level and increased the liver weight 2.0-fold. H-La also lowered the corrected phagocytic index (α), which is an indicator of activities of reticuloendothelial system, but suppressed relatively little the antibody production against sheep red blood cells. It is suggested that H-La contains biologically active substances, which have potent hepatotoxic and serum triglyceride-reducing effects. This biologically active substances appear to be derived from long-chain polyunsaturated fatty acids under thermal deodorization conditions.
The solubility parameters of cefalexin, α-lactose monohydrate, controlled pore glasses with various pore diameters (75 to 1000Å) and silanized controlled pore glasses were determined by the gas-solid chromatographic method. As partial solubility parameters, dispersion term δd and other specific interaction term δd were used. The partial solubility parameters of δd and δs of α-lactose monohydrate were calculated to be 8.9 and 15.4 cal1/2/cm3/2, respectively and these values were in close agreement with those reported by Kesselring et al. On the controlled pore glasses, it was observed that the solubility parameters decreased from 106 to 76.6 cal1/2/cm3/2 with an increase in diameter of controlled pore glass, and that this decrease resulted from the variations of δs values. To investigate the effects of surface hydrophilicity on solubility parameters of controlled pore glasses, silanol groups were inactivated by silanization. The solubility parameters could explain porous properties depending on the pore diameters of controlled pore glasses. The partial solubility parameters of δd and δs of cefalexin were determined to be 8.3, and 10.2 cal1/2/cm3/2 for the crystal and 9.6, and 15.6 cal1/2/cm3/2 for the amorphous, respectively. The solubility parameters were well correlated with the apparent saturated concentration of cefalexin.
In order to clarify the interspecies differences in the metabolism of emedastine difumarate (KG-2413), in vitro metabolism was studied with liver preparations of rats and guinea pigs. The activities of hydroxylase, N-oxidase and N-demethylase, of emedastine were evaluated with liver 9000×g supernatant and microsomes. As the results, the orders of activities were as follows ; 5-hydroxylase≨N-oxidase>6-hydroxylase>N-demethylase in rats, and N-oxidase»N-demethylase>6-hydroxylase>5-hydroxylase in guinea pigs. Emedastine N-oxide, little excreted into the urine of rats, was largely formed in vitro, so it was assumed that N-oxide reduction was important in vivo. The reductase activity of emedastine N-oxide was evaluated, and compared with N-oxidase activity of emedastine. In rats, the reductase activity was nearly equal to the N-oxidase activity, and relatively high even under aerobic conditions. On the other hand, in guinea pigs, the reductase activity was lower than the N-oxidase activity. It was considered that relative activities of the N-oxidation of tertiary amine in a 1, 4-diazepine ring of emedastine and the reduction of N-oxide once formed were one of the factors of interspecies differences of metabolism of emedastine in rats and guinea pigs.
The inhibitory effect of danazol, a synthetic androgen, on the hydroxylations of testosterone as a model for endogenous steroids and the dealkylations of aminopyrine and 7-ethoxycoumarin as models for xenobiotics in mouse hepatic microsomes in vitro was studied. Danazol inhibited these enzyme activities in a dose-dependent fashion. The inhibition constants (K1) of danazol for these enzyme activities were 1-4 orders of magnitude lower than those of cimetidine, while there was a great difference among the inhibitory potencies of danazol for each enzyme activity. Addition of danazol to microsomal preparation resulted in a reverse type I difference spectrum and the spectrophotometric analysis revealed that danazol had a high affinity for cytochrome P-450 with dissociation constants (K9) of 0.9 and 4.2 μM, which were 2 orders of magnitude lower than those of cimetidine. On the other hand, danazol did not significantly affect reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase activity and levels of cytochrome P-450 in the microsomes. These results suggest that danazol is a highly potent inhibitor for several cytochrome P-450-mediated metabolisms of testosterone and xenobiotics in mouse hepatic microsomes.
Active components contained in rhubarb (Rhei Rhizoma) that show a quenching effect of extra-weak chemiluminescence (CL) arising from Maillard reaction, had been studied. As the result of fractionation and purification of rhubarb, CL quenching activity was found to exist mainly in the fraction of quinone derivatives as emodin, aloeemodin or rhein. The authentic samples of these quinones showed high CL quenching activities.
The effect of 50% methanolic extract (U-ext) from Bearberry leaf on immuno-inflammation was studied by contact dermatitis caused by picryl chloride (PC-CD) in mice. The combined effect of U-ext and prednisolone was also investigated by using similar experimental model. When given orally twice immediately before and 16 h after the application of PC-CD, U-ext did not show an inhibitory effect on the swelling induced by PC-CD while it exhibited a significant therapeutic effect at a dose of 100 mg/kg or more once 24 h after the application. When U-ext (p.o.) and prednisolone (s.c.) in a given portion were simultaneously administered, the inhibitory effect was more potent than that of prednisolone alone in both administration immediately before and 16 h after or once 24 h after the application. Arbutin isolated from U-ext also increased the inhibitory effect of prednisolone similarly to that of U-ext. These results suggest that Bearberry leaf possesses a therapeutic effect against immuno-inflammation induced by PC-CD and also increases the inhibitory effect of prednisolone, and its active principle may be arbutin.
A study was carried out to examine the combined effect of arbutin isolated from the leaves of Arctostaphylos uva-ursi (L.) SPRENG. (Bearberry leaf) and prednisolone or dexamethazone on Type IV allergic reaction-induced immuno-inflammation. Contact dermatitis caused by picryl chloride (PC-CD) and sheep red cell delayed type hypersensitivity (SRBC-DTH) in mice was not inhibited by the oral application of arbutin at 2 divided doses immediately before and 16 h after the application, but arbutin at doses of 10, 50 mg/kg 24 h after the application speedily decreased the swelling of PC-CD and SRBC-DTH. Arbutin plus prednisolone or dexamethazone showed the inhibitory effect on the swelling of PC-CD and SRBC-DTH stronger than that of prednisolone or dexamethazone alone. Prednisolone and dexamethazone decreased the weight of thymus and spleen in intact, PC-CD and SRBC-DTH mice, but arbutin did not show these effects. These results suggest that arbutin may increase the inhibitory action of prednisolone and dexamethazone on PC-CD and SRBC-DTH, but further investigations are required to understand the mechanism involved.
The present study was carried out to elucidate the difference in the concentration of glycyrrhizin (G) in the rat plasma and in its absorption after oral administration of licorice extract and G. The concentration of G in the plasma was determined by high performance liquid chromatography. It was found that the time required for a maximum concentration (Tmax) of G was 8 h after administration of licorice extract. On the other hand, G reached a maximum plasma concentration at less than 6 h after administration of G. The plasma level of G fell slowly within 24 h after their oral administration, and it was still detected in the plasma even after 24 h. The maximum concentration (Cmax) of G in the plasma after oral administration of licorice extract was somewhat lower than that of G. On the other hand, the area under the plasma-time curve (AUC24h) of G after oral administration of licorice extract was almost the same as that of G. The effects of licorice extract and G on excretive urine volume was also investigated in rats. Licorice extract and G, at the dose used in this experiment, did not show any effect as compared with a control group.
For the purpose of evaluating Kijitsu, the content of synephrine in dried unripe citrus fruits was analyzed by high performance liquid chromatography after cleaning up the MeOH extract with an ion exchange cellulose column. Among them, Citrus unshiu had the highest amount of synerphrine. No difference was found between C. hassaku and C. aurantium. The synephrine content decreased corresponding with an increase in diameter of Kijitsu.