Biomedical subjects
Publications and source records attributed to T Nishihata.
Experimental insulin suppositories regulated postprandial hyperglycaemia in diabetic patients. The insulin suppositories seemed also to avoid hyperinsulinaemia. The formulation with more rapid dissolution of insulin, which contained a solid dispersed form of insulin, effectively reduced the insulin dose required.
Oral administration of ethanol to rats at a dose of 3 g/kg decreased alcohol dehydrogenase (ADH) activity and metabolism of lactate to pyruvate in the liver. The effects of water extracts of Aloe and some other herbs on blood ethanol concentration and on ADH activity in liver cytosol were examined. The water extracts of these herbs caused a faster elimination of ethanol from blood of normal rats when administered orally 30 min before oral administration of ethanol. The rapid elimination of ethanol seems to be due to a protection of ADH activity and the supply of nicotinamide dinucleotide, both of which are reduced by high ethanol concentration. The effects of ethanol in decreasing the enzyme activities relating to its own metabolism occur when high concentrations of ethanol pass through the liver, and thus may primarily appear during the absorption of alcohol from the gastrointestinal tract, when portal concentration of ethanol are very high.
Some of the Zingiberaceae herbs are known to be useful as stomachics. Water extracts and methanol extracts of eight such herbs were examined in intact unanesthetized rabbits for their effect on gastric secretion. Oral administration of either water extracts or methanol extracts caused a significant decrease in gastric secretion. A significant effect of these extracts appeared at 3 h after administration. The effect of water extracts on gastric secretion was very similar to that of cimetidine, with a significant decrease in acid output. The effect of the methanol extracts was primarily observed as decreased pepsin output.
Studies on the mechanism of chemically induced intestinal epithelial injury were carried out using isolated, rat small intestinal epithelial cells. Compounds such as 2,4-dinitrophenol (DNP) and diethyl maleate (DEM), caused NADH loss, an increase in cytosolic Ca2+ concentration and protein thiol loss. Further, these compounds accelerated cell aggregation and decreased cell viability. Calmodulin antagonists inhibited protein thiol loss induced by either of the compound, inhibited cell aggregation and prolonged cell viability, but did not influence NADH loss. It has been reported that the calmodulin-binding protein may regulate cytoskeletal activity. Therefore, the inhibition of protein thiol loss by calmodulin antagonist may be due to a dissociation of calmodulin-binding proteins from cytoskeletal elements. Salicylate also inhibited protein thiol loss induced by DNP and DEM, and inhibited cell aggregation. However, salicylate may have a direct effect in reducing the cytosolic free Ca2+ concentration by complexation and subsequent facilitated release of Ca2+ from cells. Further, in the present study, the induction of cell aggregation may be caused by the appearance of specific sites on the cell membrane surface to which arsenazo III could adsorb, since adsorption of arsenazo III to the isolated epithelial cells seemed to correlate with increased cell aggregation.
The penetration of diclofenac through excised rat dorsal skin was found to be poor. Treatment of the skin with a reductant such as dithiothreitol or ascorbate increased the permeability of the skin to diclofenac, along with an increase in the protein thiol content of the stripped skin surface tissue. An increase in protein thiol content may increase the hydration capability of the stratum corneum.
The relationship between chemically induced glycogenolysis and decreased thiol content in the rat isolated, perfused liver has been examined. Chemicals such as 2,4-dinitrophenol (DNP), diethyl maleate, alcohols and anti-inflammatory agents (except for sodium salicylate) accelerated glycogenolysis. Protein thiol loss correlated well with a marked increased rate of glucose release. Non-protein thiol loss, without significant loss of protein thiol, caused by a slight increase in the rate of glycogenolysis compared with controls. Since it has been reported that protein thiol loss rather than non-protein thiol loss is correlated to liver cell injury, a marked glucose release from the perfused liver may be a convenient measure of hepatic toxicity for a variety of chemicals.
The uptake of salicylate into rat isolated small intestinal epithelial cells reached an equilibrium within 15 min, but that of cefmetazole alone did not. The presence of salicylate at concentrations greater than 50 mM accelerated the uptake of cefmetazole, which reached equilibrium within 5 min. At equilibrium, the uptake clearance of salicylate (mumol (g protein)-1 M-1 initial salicylate concn) was greater than that of cefmetazole. The uptake clearance of salicylate during the first several minutes was concentration-dependent, and a 'super-uptake' clearance of salicylate, greater than equilibrium values, was observed when 100 mM salicylate was present. This indicates that some mechanism, other than a simple diffusion process, may be involved in salicylate uptake into these cells.
The effect of the content of protein thiols and non-protein thiols in the tissue of the rat small intestinal loop on the absorption of cefmetazole has been investigated. 2,4-Dinitrophenol (DNP), at a concentration of 500 microM, caused rapid protein thiol loss, followed by non-protein thiol loss, along with a decrease of cefmetazole absorption by the intestine. The coadministration of 75 mM salicylate with DNP inhibited the effect of DNP on protein thiols and cefmetazole absorption but not on non-protein thiol loss by DNP.
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Coadministration of trilaurin or monolaurin with sodium cefoxitin increased its absorption from the small intestine of the rat. Its absorption from the rectum was effected to a lesser extent except when lipase was present. Lipase, a natural constituent of the small intestine fluid, may therefore be essential for the adjuvant action of trilaurin on cefoxitin absorption across the intestinal membrane. Among the triglycerides used, trilaurin and tricaprin were the most effective enhancers of cefoxitin absorption. Both the rate of degradation of triglyceride to its fatty acid component and subsequently the rate of fatty acid absorption were factors influencing the enhancing action. Maintenance of fatty acid concentration at the small intestinal absorption site was shown to be necessary to obtain a cefoxitin bioavailability of up to 70%.
Plasma levels of cefoxitin, as enhanced by rectal coadministration of sodium salicylate, were reduced by concurrent administration of less than 0.5 mg mL-1 N-ethylmaleimide (NEM) or p-chloromercuriphenylsulphonic acid, sodium salt (p-CMP). Concentrations of these inhibitors above 1 mg mL-1 resulted in enhanced peak plasma values of cefoxitin. This did not occur after coadministration with either ethylenediaminetetraacetic acid (EDTA) or polyoxyethylene-23 lauryl ether (POE). Ouabain and 2,4-dinitrophenol (DNP) suppressed plasma cefoxitin levels in the presence of salicylate and the enhancing effects of EDTA and POE when EDTA and POE were administered at low doses. At higher concentrations of EDTA and POE, DNP had little effect, while ouabain had little effect on POE and only partially suppressed the effects of EDTA. Plasma concentrations of cefoxitin after coadministration with salicylate and POE together, or with EDTA and POE together, were about the same as expected from summing the plasma levels resulting from coadministration of each adjuvant individually at the same concentrations. However, combined administration of salicylate and EDTA with cefoxitin yielded plasma cefoxitin concentrations which were much higher than expected from the sum of their individual actions.
An in vitro rat colonic sac method developed in this study was found to be suitable for frequent collection of samples and determination of transport of compounds from serosal and mucosal medium, since the volume of both was large. Under no a treatment condition, both cefmetazole and inulin penetrated the intestinal mucosa via the paracellular route, but did so very poorly. Phenothiazines as well as disodium ethylenediaminetetraacetic acid increased the transport of cefmetazole and inulin, probably via the paracellular route, while diethyl maleate increased the transport of only cefmetazole, probably via the intracellular route. The effect of phenothiazines in increasing the clearance rate for both cefmetazole and inulin showed dependency on their initial concentrations in the mucosal medium with maximum action at a concentration of 30 microM for trifluoperazine, 20 microM for perphenazine, 75 microM for profenemine and 50 microM for propericiazine.
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