The effect of food on the rate and extent of bioavailability of bromazepam was examined in seven normal volunteers following a single oral dose of 10 mg bromazepam with 200 ml of water in the fasting and non-fasting states. Plasma concentrations of bromazepam were measured by high pressure liquid chromatography. A t_max value in a non-fasting state was prolonged from 2.3±0.3 (mean ±S.E.M) to 2.8±0.6 h but not significantly different (p > 0.05) whereas a C_max value was significantly (p < 0.05) decreased from 259±12.7 (mean ±S.E.M.) to 169±13.9 ng/ml. The area under the plasma concentration-time curve in the non-fasting state was also significantly (p < 0.05) decreased from 1844±145 (mean ±S.E.M.) to 1233±98.1 ng·h/ml after oral administration of bromazepam.

抄録全体を表示

Effect of CV-3988, a specific antagonist against platelet activating factor (PAF), on homologous passive cutaneous anaphylaxis (PCA) elicited in the mouse ear was investigated. PAF caused a potent increase in vascular permeability in the mouse ear. The potency was slightly lower than that of serotonin but higher than those of histamine, leukotriene (LT) C₄, LTD₄, prostaglandin (PG) E₁ and PGE₂ on a weight basis. The increased vascular permeability caused by PAF was inhibited by CV-3988 in a dose-dependent manner. CV-3988 did not affect the increase in vasular permeability caused by histamine or serotonin. IgG1 antibody-mediated PCA in the mouse ear was inhibited by CV-3988, although it did not affect IgE antibody-mediated PCA. These results suggest a possibility that PAF might be involved in IgG1 antibody-mediated PCA in the mouse.

抄録全体を表示

Effects of hexachlorobenzene (HCB) and its sulfur-containing metabolites on the heme metabolic enzymes in rat liver were investigated. A single injection of HCB caused the increase in activities of δ-aminolevulinic acid (ALA) synthetase and heme oxygenase, and contents of cytochrome P-450 and total heme. After a single injection of pentachlorothioanisol (PCTA) or pentachlorophenyl methyl sulfore (PCPSO₂Me), ALA synthetase activity was enhanced. Heme oxygenase activity was increased by PCPSO₂ Me treatment. Cytochrome P-450 and total heme contents were increased by PCPSO₂Me or 1, 4-bis(methylthio)tetrachlorobenzene (MTTCB). When HCB was injected once daily for 5 weeks, a marked increase in ALA synthetase activity, a significant decrease in ALA dehydratase, almost complete inhibition of uroporphyrinogen decarboxylase activity, and an increased excretion of total porphyrin in the urine were shown. After chronic treatment with its sulfur-containing compounds, PCPSO₂ Me and MTTCB produced a significant increase in ALA synthetase activity. However, activities of ALA dehydratase and uroporphyrinogen decarboxylase, and excretion of total porphyrin in the urine were unaltered. At this time, the concentrations of the corresponding sulfur-containing compound and related metabolite(s) in blood, liver and kidney were nearly the same as those observed in HCB-treated rats. It is suggested that PCPSO₂ Me and MTTCB could induce the hepatic ALA synthetase, but these metabolites, and also PCTA, were not able to induce the porphyria in female rats, and the induction of porphyria by HCB is not attribuable to the action of its sulfur-containing compound.

抄録全体を表示

The uptake of manganese (Mn) induced by 100mM potassium (K), 10μM norepinephrine (NE) or 10 μM acetylcholine (ACh) was measured by atomic absorption spectroscopy in isolated vas deferens of the guinea pig. The agonists at these concentrations caused the maximal contraction of the vas deferens. The contents of Mn were increased with the repetitive treatments of Mn with K and were not significantly decreased after 1 h washing. The uptake of Mn was also stimulated by NE and ACh. The stimulation of uptake of Mn by K was the most potent while that by ACh was the smallest. The uptake of Mn was enhanced by elimination of Ca from the medium, while inhibited by the higher concentration of external Ca and by 2.1 μM diltiazem. The time course of K-induced Mn uptake was biphasic : an initial faster phase and a following slower phase of accumulation. The extents of increments of the Mn contents were dependent on the order of the applications of K and Mn : the increments became smaller in the following order, 1) when Mn was applied prior to K, 2) Mn was applied simultaneously with K, 3) Mn was applied after K. These results suggested that superficially bound Mn penetrates into the smooth muscle cells of vas deferens during the stimulation by agonists through the voltage-dependent calcium-channel (VDC) and that intracellular Mn was hardly extruded. It was also suggested that the degree of activation of VDC, through which Mn can enter the cells, was in the following order, K >NE > ACh. These results were consistent with our preious report about the dual effects of Mn : the inhibition and potentiation of contractions. It was also suggested that Mn may be a useful tool as a Ca analogue because Mn can penetrate into cells through VDC and, once taken up into the cells, Mn is not readily extruded and remains in the cells even after extracellular Mn is washed away.

抄録全体を表示

The mechanism of intestinal absorption of an antimicrobial agent, fosfomycin (FOM), was investigated in rats using small intestinal brush-border membrane vesicles (BBMV). The uptake of [³H]FOM by BBMV was osmolarity- and temperature-sensitive and showed apparently saturable uptake kinetics consistent with the Michaelis-Menten equation, having K_t=15.3 mM and J_max=7.78 nmol/30 s/mg protein at 37°C. An overshoot uptake of FOM was observed in the presence of an inwardly directed Na⁺ gradient. The replacement of extravesicular Na⁺ with choline or mannitol significantly reduced the uptake. An addition of a protonophore, FCCP, significantly decreased the intial uptake of FOM in the absence of Na⁺ gradient but in the presence of a H⁺ gradient (pH_in=7.5, pH_out=6.0), whereas in the absence of a H⁺ gradient no significant difference was observed between the uptakes at an acidic pH (pH_in=pH_out=6.0) and a neutral pH (pH_in=pH<out>=7.5). An inside negative potassium diffusion potential induced by valinomycin enhanced significantly the uptake of FOM. The uptake of FOM in the presence of both Na⁺- and H⁺- gradients was significantly inhibited by phosphate, arsenate and phosphonoformic acid (PFA), which are specific inhibitors of phoshate transport, but not by D-glucose. Based on these results, it is concluded that FOM transport in the small intestine is partially shared with the Na⁺-phosphate cotransport system and in part occurs via a H⁺- gradient dependent carrier-mediated system.

抄録全体を表示

The intestinal transport of [<14>^C]nicotinic acid was investigated at 27°C by using brush-border membrane vesicles (BBMV) isolated from the rat small intestine. The osmolarity sensitive uptake by BBMV showed a remarkable overshoot phenomenon in the presence of an inward-directed H⁺ gradient (pH_in=7.5, pH_out=6.0). In contrast, the imposition of a Na⁺ gradient ([Na⁺]_in=0 mM, [Na⁺]_out=100 mM) had no stimulatory effect on the uptake of [<14>^C]nicotinic acid. The remarkable pH-dependence of the initial uptake showing an increase of the uptake rate with decreasing the extravesicular pH disappeared completely in the presence of a structural analogue, isonicotinic acid, at pH below 6.5. In the presence of a H⁺ gradient, the initial uptake of [¹⁴C] nicotinic acid was saturable with the apparent K_t of 4.43 mM and J_max of 2.55 nmol/mg protein/15 s. The uptake was increased by the imposition of an inside-positive membrane potential and was significantly inhibited by monocarboxylic acids such as benzoic acid, salicylic acid, acetic acid, propionic acid, valproic acid and L-lactic acids as well as two isomers (isonicotinic acid and picolinic acid). The uptake was not inhibited by nicotinamide, nicotinyl alcohol, D-glucose, p-aminohippuric acid, glycyl-L-proline, succinic acid and an exchange transport inhibitor. From these results it was concluded that nicotinic acid is transported through the intestinal brush-borde membrane by a carrier-mediated system and the system can recognize some acidic drugs with a monocarboxylic group. The pH dependent intestinal uptake of nicotinic acid can be ascribed to the proton-coupled and active carrier-mediated transport mechanism rather than a simple diffusion of the undissociated nicotinic acid to follow a pH-partition hypothesis.

抄録全体を表示

The delayed-type hypersensitivity (DTH) reactions for penams or cephems of beta-lactam antibiotics were investigated by intrademal skin test and leucocyte migration test (LMT) in guinea pigs. The animals were immunized with ampicillin (ABPC) or cephalexin (CEX) using Freund's complete adjuvant. The cross-reactivities among ABPC, penicillin G (PCG) and cloxacillin as penam and CEX, cephalothin (CET) and cephalosporin C (CEPC) as cephem and phenylglycine (PhGly), which is the amino acyl side chain of ABPC and CEX, were examined. By intradermal reaction, ABPC-sensitized animals showed a cross-reaction with CEX, PCG and CET, but CEX-sensitized animals did not cause cross-reaction with ABPC. The CEX-sensitized group exhibited slight cross-reactions to CET and PhGly. PhGly exhibited low immunogenicity only in maximzation test of guinea pig. The above results indicate that there is the difference in cross-reactivity between penams and cephems in skin test. In LMT, all the ABPC-sensitized animals reacted with ABPC and showed cross-reactions with all drugs tested. The CEX-sensitized group reacted with 4 out of 7 animals with CEX and exhibited cross-reactivities to ABPC, PCG, CET, CEPC and PhGly. The cross-reactivity between intradermal skin reaction and LMT elicited some different results.

抄録全体を表示

Photobiological activities of pinacyanol chloride (PC), which is known as a non-intercalating dye, were investigated. Irradiation of PC-sensitized yeast cells in the dark brought about marked decrease of survival and induction of "petites" which are respiration-deficient mutants caused by partial loss of mitochondrial deoxyribonucleic acid. Nuclear mutation represented by reversion from Try-to Trp⁺ was also induced by photodynamic action of PC. This fact suggested photoactive dyes are not necessarily intercalated for inducing mitochondrial and nuclear mutation. Singlet oxygen production was determined in the photoirradiated PC solution by electron spin resonance spectrometry. Photobiological effects of PC might be brought about mainly by a type II photodynamic mechanism.

抄録全体を表示

Zn²⁺ at the concentration of 10 μM inhibited the depolarization-induced [³H] glutamate release from the preloaded rat hippocampal slices both in the presence and absence of Ca²⁺ without affecting [³H] GABA and [³H] Ach release. Of divalent cations tested, Zn²⁺ and Fe<2+> had an inhibitory effect on the release of glutamate.

抄録全体を表示