Ampicillin, an orally administered antibiotic, was microencapsulated with different viscosity grades of ethyl cellulose (10, 50 and 100 cps EC) and was orally administered to rabbits, beagle dogs and humans. A significant sustained release pattern was observed in rabbits. While a significant decrease in the area under the plasma concentration curve occurred, and the sustained release pattern was not obtained in beagle dogs. In humans, the extent of the sustained release was intermediate between the pattern observed in beagle dogs and rabbits. The treatment of data by log-log plots yielded a linear relation between half lives of dissolution of ampicillin from microcapsules in vitro (T₅₀) and the ratios of pharamacokinetic parameters of microcapsules to those of powder. In order to explain the difference in the sustained release pattern of rabbits, beagle dogs and humans, a pharmacokinetic model, considering gastric-emptying and intestinal-transit rates of drug formulations, was established and the pharmacokinetic consideration was done on the basis of the model. It seems that success in sustained release of a drug depended on the magnitude of the gastric-emptying and intestinal-transit rate constant (K_gi) of microcapsules, in the case of a drug with a small absorption rate constant (K_a) as observed with ampicillin. The magnitude of K_gi was thought to be in the order of beagle dogs, humans and finally rabbits.

抄録全体を表示

The protective effect of SKF 525-A on the suppression of cytochrome P-450 content and monooxygenase activities by treatment with CoCl₂ and polyriboinosinic acidpolyribocytidylic acid [poly (I.C)] was compared as a part of studies of suppression of drug metabolizing enzymes by interferon inducers. Induction of heme oxygenase activity by CoCl₂ and poly (I.C) was not altered by simultaneous treatment with SKF 525-A. Depression of cytochrome P-450 content and benzphetamine N-demethylase activity by treatment with CoCl₂ was prevented by co-treatment with SKF 525-A. This effect was explained by the prevention of release of heme from cytochrome P-450 by forming metabolic intermediate complexes with metabolites of SKF 525-A. On the other hand, poly (I.C) significantly suppressed P-450 content and benzphetamine N-demethylase and benzo [α] pyrene hydroxylase activities, even under simultaneous treatment with SKF 525-A. This inhibition by poly (I.C) was accompanied by weak staining of proteins corresponding to cytochrome P-450 in SDS gel electrophoresis. In addition, the activity of non-heme enzyme, 4-hydroxybiphenyl glucuronyltransferase, was suppressed by treatment with poly (I.C) but not by CoCl₂-treatment. These findings strongly suggested that, unlike CoCl₂, poly (I.C) suppressed cytochrome P-450 content and monooxygenase activities due to decreased synthesis or increased degradation of the apoprotein of cytochrome P-450 with slight contribution of the induced heme oxygenase.

抄録全体を表示

Intraperitoneal administration of neurotropin (NSP) did not modify the antibody response to sheep red blood cells (SRBC) in normal BALB/c mice. However, the suppressed antibody responses to SRBC in restraint-stressed mice were favorably restored to normal level by NSP at a dose of 10 or 25 mg/kg either before or even after the stress loading. The suppressed antibody responses in hydrocortisone-treated mice were restored by NSP when it was administered after cortisone. Moreover, NSP augmented the in vitro antibody response to a T cell-dependent antigen, SRBC, but not to T cell-independent antigens such as dinitrophenylated-Ficoll and trinitrophenylated-lipopolysaccharide.

抄録全体を表示

The properties of the interactions of anticancer quinone drugs, aclacinomycin A, adriamycin, carbazilquinone, and mitomycin C with nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P-450 reductase and xanthine oxidase under anaerobic and aerobic conditions were studied. K_m values of NADPH-cytochrome P-450 reductase for these drugs were in the range of 40-227 μM, and that of deflavo xanthine oxidase in the range of 39-over 200 μM. Under anaerobic conditions, when xanthine was used as an electron donor, deflavo xanthine oxidase catalyzed the reductive glycosidic cleavage reaction of anthracyclines and nicotinamide adenine dinucleotide was ineffective as an electron donor. In the electron spin resonance study, the formation of the semiquinone or free radical state of the quinone drugs in both enzyme systems were evidenced. A weak and symmetric signal was obtained from aclacinomycin A, and a symmetric signal from adriamycin was changed into an asymmetric and strong. The hyperfine structure was obtained from carbazilquinone in the oxidase system. In the studies of ultraviolet-visible spectra of the quinone drugs in the reductase system, the spectra of aclacinomycin A and adriamycin were changed to their 7-deoxylaglycones, and the formation of small amounts of the fully reduced form were observed after long incubations. The spectrum of carbazilquinone was changed to the hydroquinone form and mitomycin C was converted into mitosene analogues. Under aerobic conditions, superoxide radicals and hydrogen peroxide were effectively produced in the presence of anticancer quinone drugs in both enzyme systems. The superoxide-dependent hydroxyl radical production, which was measured by ethylene production from methional, was observed in the presence of aclacinomycin A and adriamycin in the deflavo xanthine oxidase system. From these results, the possible reactions in the interactions of anticancer quinone drugs with these enzymes and oxygen are discussed.

抄録全体を表示

The development of a sensitive and selective radioimmunoassay for determination of proscillaridin in plasma is described. Antiserum against proscillaridin was obtained from guinea pig immunized with an immunogen prepared by conjugating methylproscillaridin, 14β-hydroxy-3β-[(4-O-methyl-α-L-rhamnosyl) oxy] bufa-4, 20, 22-trienolide to bovine serum albumin. Methyl N-[3-[(14β-hydroxybufa-4, 20, 22-trienolid-3β-yl) oxy-carbonyl] propanoyl]-L-[3', 5'-¹²⁵I₂] diiodotyrosinate ([¹²⁵I] SST) was used as a radioactive ligand. [¹²⁵I] SST and antiserum were added to the recovered sample from plasma using a Bond Elut^[○!R] column. After overnight incubation, the antibody-bound and free [¹²⁵I] SST were separated using polyethylene glycol. The mean coefficients of variation of intra and interassay at four different plasma concentrations were 4.0 and 5.0%, respectively. The assay was able to determine as little as 125 pg/ml of proscillaridin in plasma by using 1.5 ml of sample. Beagle dogs were orally administered one tablet (Talusin^[○!R]) containing 0.25 mg of proscillaridin. Proscillaridin was rapidly absorbed, exhibiting plasma maximum concentration of 2.06 ng/ml at 20 min. Thereafter, the plasma level declined biphasically with half-lives of 0.6 and 25.4 h.

抄録全体を表示

E-64 isolated from a culture of Aspergillus japonicus is a specific inhibitor of cysteine proteinases. E-64-c, a synthetic analog of E-64, was effective in model animals of muscular dystrophy only when it was given intraperitoneally and by means of osmotic minipump. It showed no effects due to its low absorbability from intestine when it was administered orally. EST, the ethyl ester of E-64-c, was expected to be readily absorbed through intestinal membrane, since it is more lipophilic than E-64-c. Both EST and E-64-c have a high specificity to cysteine proteinase similar to E-64 but E-64-c was 100 to 1000 times stronger than EST in invitro cathepsin inhibition. However, EST was stronger than E-64-c in cathepsin inhibition when given orally. The cathepsin B&L activities (whole activities of cathepsins B and L) in the skeletal muscle, heart and liver of hamsters were strongly inhibited soon after oral administration of 100 mg/kg body weight of EST. The inhibition continued for at least 3 h and then disappeared gradually. E-64-c was found in plasma of hamster treated with EST, but unchanged EST was not found. These results suggested that EST was converted to E-64-c, a more active form, during the permeation through intestinal membrane. The conversion of EST to E-64-c was also indicated by the absorption experiment using in situ loop method. EST was thus shown to be useful as an oral drug and expected to be effective in therapeutic trials using model animals.

抄録全体を表示

The effects of restraint and water-immersion stress (RWIS) on the cardiovascular system (including blood pressure, heart rate, blood flow in the gastric region, and blood flow in the common carotid artery and descending aorta) and body temperature were studied in rats. The blood pressure of RWIS rats did not differ from that of restraint stress (RS) rats. The heart rate, blood flow in the gastric region, common carotid artery and descending aorta as well as body temperature were significantly decreased by RWIS, but not by RS. The decrease in heart rate in RWIS rats was not influenced by pretreatment with atropine, hexamethonium or vagotomy. The reduction of gastric regional blood flow was not influenced by pretreatment with atropine and phenoxybenzamine. The changes in these three parameters were closely correlated in all the RWIS rats tested. These results suggest that the decrease in gastric regional blood flow is due to a lowering of the body temperature via decreasing cardiac output.

抄録全体を表示

The antitumor activity of 5-fluorouracil (5-FU) in combination with ribothymidine was examined on some experimental murine carcinomas. The antitumor activity of 5-FU against Ehrlich ascites carcinoma was markedly enhanced by intraperitoneal coadministration of ribothymidine. The enhancement of the antitumor activity of 5-FU by ribothymidine was also observed against Ehrlich solid carcinoma both by oral and intraperitoneal administrations. Furthermore, the combination therapy of 5-FU and ribothymidine was effective even on 5-FU-resistant P388 leukemia. These results suggest that the combination of 5-FU and ribothymidine may be more effective than 5-FU monotherapy in clinical use.

抄録全体を表示

A series of twenty six 5'-substituted FdUMP (5-fluoro-2'-deoxyuridine 5'-monophosphate) have been evaluated for their inhibitory effects on the proliferation of murine lymphoma L5178Y cells sensitive or resistant to FUdR (5-fluoro-2'-deoxyuridine). 5'-Octylphenylene-FdUMP was the most active among these active derivatives against the parent cell line (L5178Y/P). Several other FdUMP derivatives also proved as potent as FUdR in their antiproliferating activity on the L5178Y/P cell line. Activity of these derivatives was decresed considerably by a substituent with a long aliphatic chain and the introduction of acyl groups on the C-3' position. Eicosyl-FdUMP was found to show no or low cross-resistance on the L5178Y/FUdR subline which was about 19000-fold resistant to FUdR compared with the parent cell line. This derivative might penetrate cell membrane in an intact form and be converted into FdUMP by a phosphodiesterase inside the cell, because an anabolic enzyme, deoxyuridine kinase, was defective in cells of the L5178Y/FUdR subline. The derivatives were promising as antitumor agents for the treatment of relapsed patients following 5-fluorouracil therapy.

抄録全体を表示

The effect of phenylbutazone (PBZ) on the in vivo serum protein binding of sulfadimethoxine (SDM) was examined in dogs, rabbits and rats. In dogs, PBZ itself was found to displace SDM from its protein binding sites. In rabbits, PBZ indirectly reduced the in vivo serum protein binding of SDM through the interaction of PBZ with N⁴-acetylsulfadimethoxine (N⁴-AcSDM), a major metabolite of SDM. In rats, however, PBZ had no effect on the in vivo serum protein binding of SDM. It is noteworthy that species differences were observed in the effect of PBZ on the in vivo serum protein binding of SDM.

抄録全体を表示