The permselectivity to the small intestinal blood-lymph barrier for the exogenous macromolecules absorbed from the lumen was investigated using in situ rat closed loop experiment. We chose the fluorescein isothiocyanate-labelled dextran (FD) as macromolecule and lipid-surfactant mixed micelles as an absorption promoter. The mean molecular weights of FDs used were 1050O, 17500, 3900O and 64200 (abbreviated : FD10, 20, 40 and 70). The lymph/plasma ratios of FDs concentrations during 5 h post administration were 0.2 - 1.2 (FD10), 0.4-1.3 (FD20), 1.3-7.2 (FD40) and 2.6-11.9 (FD70), respecrively. The FD40 and FD70 levels in the lymph were significantly higher than those in the plasma. The cumulative amounts (% of the absorbed quaratity) of FDs in the lymph from the lumen of the small intestine for 5 h after administration were 0.46% (FD10), 0.51% (FD20), 1.17% (FD40) and 1.89% (FD70), respectively. These findings suggest that the threshold molecular weight of FD for the transfer into the lymphatics with higher level compared to the blood concentration from the lumen across the small intestinal blood-lymph barrier exists between 17500 and 39000.

View full abstract

Intravenous administration of 125 mg of griseofulvin to Gottingen minipigs showed biexponential elimination of the drug from plasma, in which the half lives of the initial and terminal phases were 0.2-0.6 h and 4.3-6.6 h, respectively. The bioavailability of four griseofulvin tablets used in a human bioavailability study was investigated in the pigs and compared with the human results. The differences of C_max and AUC between the standard product and the others were smaller in the pig than in humans, however, the correlations of C_max and AUC between humans and minipigs were high for the four products. The differences of T_max among the products were small, and the T_max of the standard product was large in the pigs compared with that in humans. In addition, delayed onset of drug absorption was observed in some of the pigs. The findings suggest slow gastric emptying of the drug in the pigs. The statistically small powers for the in vivo parameters observed in the pig, seem to indicate variable absorptxon of the drug in the animal.

View full abstract

The effect of cianidanol (KB-53) on the mouse cytotoxic-T-lymphocyte (CTL) activity of the splenic cells was investigated. The CTI, activity of the splenic cells prepared from C3H/He, DBA/2 and CBA strain mice which had been sensitized with EL-4 cells were recognized markedly 11 d after the sensitization. The CTL activity showed an antigen specificity. KB-53, in a dose range of 125-1000 mg/kg, augmented the mouse CTL activity in a dose-dependent manner by oral administration once daily for 5 d beginning immediately after the sensitization. This CTL activity disappeared with treatment of the splenic cell with anti-thy-l serum and normal guinea pig scrum, therefore, it was confirmed that the cytotoxic activity of the splenic cells which were prepared from the mice sensitized with EL-4 cells depended on the T-cell activity.

View full abstract

The effect of cianidanol (KB-53) on the mouse natural killer (NK) cell activity of the splenic cells was investigated using YAC-l cells as target cells. The oral administration of KB-53 at a dose of 500 mg/kg augmented significantly the NK cell activity. The activity was observed maximally 3 d after the administration, and significant difference from the control was observed even at 7 d after the administration of KB-53. The oral administration of KB-53, at a dose range of 125-500 mg/kg, augmented the NK cell activity in a dose dependent manner at 3d after the administration

View full abstract

The human urinary metabolites of diltiazem were analyzed by thin-layer chroma tography (TLC) and gas chromatography-mass spectrometry. Diltiazem was metabolized by deacetylation, N-demethylation, O-demethylation and conjugation. Metabolite M_A, N-monodemethyl-diltiazem, was identified as a new major metabolite in human urine, and four metabolites were identified as deacetyl-diltiazem (M₁), deacetyl-N-monodemethyl-diltiazem (M₂), deacetyl-O-demethyl-diltiazem (M₄), deacetyl-N, O-demethyl-diltiazem (M₆) which were known as rat urinary metabolites. Metabolite M₂, M₄ and M₆ were converted in part to glucuronides and/or sulfates. Unchanged diltiazem and metabolite M_A were determined in human plasma and urine by TLC-densitometry. Diltiazem and metabolite M_A excreted in 24-h urine were 44.4 and 48.5% of the total unconjugated form, rcspectively. The mean plasma level of metabolite M_A was approximately one-third of diltiazem level. On the basis of these findings, a probable metabolic pathway of diltiazem in man is presented.

View full abstract

Pharmacokinetics of dicloxacillin and ampicillin dosed individually and in combination were investigated by means of moment analyses of urinary excretions of intact forms and metabolic products of parent penicillins. Comparison of excretion profiles between individual and combined doses to human subjects indacated that the transformation of ampicillin to penicilloic acid and subsequent conversion to secondary metabolite are suppressed by the simultaneous dose of dicloxacillin, while the total excretion ratio to dose and the mean residence times in the body remain almost unchanged. The excretion profiles of dicloxacillin and metabolites are not significantly affected by the combined dose.

View full abstract

Drug binding to rat skeletal muscle homogenate was studied using quinidine and quinine as basic drugs, and furosemide and phenylbutazone as anionic drugs. Characteristically different binding fashions were observed among basic and anionic drugs. Quinidine and quinine which are stereoisomers bound to muscle not depending on drug concenttation and showed similar binding ratios, while furosemide and phenylbutazone bound to muscle depending on drug concentration. Quinidine and quinine bound mainly to 1000×g precipitates of muscle homogenate while furosemide and phenylbutazone bound exclusively to cytosol fraction. Binding to 1000× g precipitates was not explained by binding to actin and myosin alone, while the second protein fraction eluted from cytosol by Sephadex G-75 gel filtration was found to have binding properties for furosemide.

View full abstract

when using laboratory animals (e.g., mice) for phencyclidine (PCP) tolerance studies, an essential part of the procedure is to administer the PCP in such a way that the animals received adequate doses of the drug at frequent enough intervals to reach and main train the desired levels of tolerance or employ a osmotic minipump which is either suitable or convenient to develop a high degree of tolerance to PCP in a large number of animals in a short period. However, these methods are unfit for routine work because of repeated daily injections consume too much time and osmotic minipump comes expensive. Therefore, in this paper we attemped to develop PCP pellet suitable for tolerance development The s.c. implantation of a 10 or 20 mg PCP pellet in the back of a conscious mouse resulted in a much more rapid development of tolerance to PCP than that produced in mice receiving daily i.p. injection of, 10 or 20 mg/kg, PCP-HCL. Assessment of and degree of tolerance to PCP by PCP peller implantation and daily injection of PCP-HCL were evidenced by a degree of decrease in the duration of motor incoordination after the challenge with, 20 mg/kg, PCP-HCL 24 h after removal of PCP pellets or a last injection of PCP-HCL. These studies may demonstrate a substantial methodological improvement in producing a high degree of tolerance to PCP in a short period of time by means of the s.c. pellet implantation technique.

View full abstract

The potentiated absorption of human fibroblast interferon (HuIFN-β) with the aid of lipid-surfactant mixed micelles from the rat large intestine and lymphatic delivery were studied. The administration of HuIFN-β with saline solution alone into the lumen of the large intestine indicated no detectable HuIFN-β in the serum or the lymph for 5 h. Neither lipid (linoleic acid) nor surfactant (HCO60, polyoxyethylene hardened castor oil derivative) could promote the absorption of HuIFN-β. However, the administration with linoleic acid-HCO60 mixed micelles enabled the great absorption of HuIFN-β from the large intestine, and HuIFN-β was delivered into the lymphacics with an extremely high selectivity

View full abstract

The myocardial ATP level in guinea pig ventricular muscles was determined during hypoxia and reoxygenation and compared with the cardiac electrical and mechanical function. The action potential duration (APD), contractile force (CF) and tissue ATP level were depressed gradually depending on the N₂ concentration in the medium. Time course studies recealed that the membrane electrical activity and the ATP content did not show parallel evolution although changes in CF coincided with changes in ATP level.

View full abstract

The antitumor activity of 5-fluoro-2'-deoxyuridne (FUdR) against P388 leukemia was markedly enhanced by addition of guanosine-5'-monophosphate (GMP). With daily i.p. treatment for 5 d, the combination of FUdR at 100 mg/kg/d and GMP at 30O mg/kg/d showed the highest antitumor effect (more than 290% ILS), while maximum ILS of FUdR alone (100 mg/kg/d) was 94%.

View full abstract

Effect of vitamin E (α-tocopheryl acetate and α-tocopheryl nicotinate) on IgE antibody formation in mice was investigated. Female BALB/c mice were immunized with dinitrophenylated ascaris protein (DNP-As) and aluminium hydroxide gel (alum). Supplementation of vitamun E in diets or oral administration of vitamin E mixed with sesame oil resulted in a suppression of IgE antibody formation. On the contrary to IgE antibody formation, IgM or IgG (hemagglutinin; HA) formation was sngnifucantly enhanced. These results indicate that vitamin E is capable of suppressing IgE antibody formation and enhancing nonIgE antibody formation.

View full abstract