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H Nagaya

Publications and source records attributed to H Nagaya.

At least 19 recordsLinked to original sources
PubMed1992

[Possible mechanisms for (H+ + K+)-ATPase inhibition by proton pump inhibitors, omeprazole, lansoprazole and SCH 28080].

Proton pump inhibitors are classified into two distinct types, and the mechanisms are reviewed. Substituted benzimidazole such as omeprazole and lansorrazole, inhibit (H+ + K+)-ATPase by reacting with SH groups of enzyme after the drugs are transformed into their active forms in the acidic environment of the intracellular canaliculi of parietal cells. This type of enzyme inhibition results in potent and long-lasting inhibition of gastric acid secretion. On the other hand, substituted imidazo pyridines, such as SCH 28080, inhibit (H+ + K+)-ATPase by competing with K+. This inhibition is reversible and the antisecretory effect is short-lived. Recent studies on DNA cloning and sequencing for (H+ + K+)-ATPase have led to a better understanding of enzyme structure and also the sites of action of the proton pump inhibitors.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1991

Effects of the enantiomers of lansoprazole (AG-1749) on (H+ + K+)-ATPase activity in canine gastric microsomes and acid formation in isolated canine parietal cells.

The effects of the enantiomers of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]-sulfinyl ]- 1H-benzimidazole (lansoprazole, AG-1749) on acid formation in isolated canine parietal cells and (H+ + K+)-ATPase activity in canine gastric microsomes were investigated. Both the (+)-and the (-)-enantiomer of lansoprazole inhibited the acid formation stimulated by dibutyryl cyclic AMP (db-cAMP) in isolated canine parietal cells in a concentration-dependent manner with IC50 values of 59 and 82 nM, respectively. The enantiomers showed concentration-dependent inhibition of (H+ + K+)-ATPase with IC50 values of 4.2 and 5.2 microM, respectively. On the other hand, the IC50 values of lansoprazole for db-cAMP-stimulated acid formation and (H+ + K+)-ATPase were 59 nM and 2.1 microM, respectively. These results suggest that the two enantiomers of lansoprazole have antisecretory action due to inhibition of (H+ + K+)-ATPase.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1991

Differences in the antisecretory actions of the proton pump inhibitor AG-1749 (lansoprazole) and the histamine H2-receptor antagonist famotidine in rats and dogs.

Antisecretory effects of a substituted benzimidazole, (+/-)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazole (AG-1749) were compared with those of a histamine H2-receptor antagonist, famotidine. AG-1749 inhibited acid formation regardless of the stimulant in isolated canine parietal cells, while famotidine inhibited the histamine-stimulated acid formation selectively. In pylorus-ligated rats, AG-1749 suppressed basal acid secretion, histamine-, bethanechol-, pentagastrin-, 2-deoxy-D-glucose- and stress (restraint and water-immersion)-induced acid secretion; ID50 values were 1.0-6.0 mg/kg. On the other hand, famotidine only partially inhibited the acid secretion induced by 2-deoxy-D-glucose or stress, although it suppressed the acid secretion stimulated by other secretagogues several times more potently than AG-1749. The antisecretory effect of AG-1749 lasted longer than that of famotidine, especially in the case of bethanechol-stimulated acid secretion. In Heidenhain pouch dogs, both AG-1749 and famotidine potently inhibited histamine-, bethanechol-, pentagastrin- and peptone meal-stimulated acid secretion, but the inhibitory effect of famotidine was short-lived in the case of bethanechol- and pentagastrin-stimulated acid secretion. These results suggest that AG-1749 persistently inhibits acid secretion induced by both peripheral and central stimuli and suggest that the antisecretory effect of famotidine depends on the nature of the stimuli.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1991

Effects of a proton pump inhibitor, AG-1749 (lansoprazole), on reflux esophagitis and experimental ulcers in rats.

The effects of (+/-)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy-2- pyridyl]methyl]sulfinyl]-1H-benzimidazole (lansoprazole, AG-1749) and famotidine on various experimental ulcers in rats were compared. AG-1749 inhibited reflux esophagitis; gastric lesions induced by water-immersion stress, aspirin or ethanol; and duodenal ulcers induced by cysteamine or mepirizole in a dose-dependent manner: the ID50 values were 0.7, 2.4, 0.7, 8.5, 1.1 and 0.3 mg/kg, p.o. or i.d., respectively. Famotidine inhibited reflux esophagitis with an ID50 value of 12.9 mg/kg, but did not cause 50% inhibition of ethanol-induced gastric lesions even at 100 mg/kg, although it showed almost the same or a little stronger potency on other experimental ulcers: ID50 values were 0.3-1.4 mg/kg. Significant aggravation of ethanol- or water-immersion stress-induced lesions was observed in rats given famotidine at 30 mg/kg twice daily for 4 days, but not in rats given AG-1749 at 10 mg/kg twice daily. Administration of AG-1749 for 14 consecutive days markedly accelerated the healing of acetic acid-induced gastric and duodenal ulcers, and the healing effect was significant at 10 and 30 mg/kg/day, p.o. Famotidine also accelerated the healing of ulcers, but its potency was less than that of AG-1749. The results of this study indicate that although AG-1749 is slightly less potent than famotidine in inhibiting acutely induced gastroduodenal lesions, this agent is superior to famotidine in promoting the healing of ulcers and in inhibiting reflux esophagitis and ethanol-induced gastric lesions.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1991

[Reappraisal of inhalant allergens available for allergy practice in Japan. A need to increase allergen extracts available for immunotherapy].

In an attempt to assess whether or not the availability of inhalant allergens for diagnosis and treatment of allergic diseases in Japan is adequate, we tested 21 Japanese patients with allergic rhinitis or bronchial asthma against 75 inhalant allergens commonly used in the United States of America. These 21 patients had never lived outside of Japan and came to the United States for the purpose of diagnosis and treatment of their allergic diseases. We determined the importance of each allergen by calculating an allergenicity index. Allergenicity index for a given allergen was defined as a sum of a multiple of each of 4 grades of prick test reactions to the allergen and a number of patients reacting to the allergen with each corresponding grade. Mite had the highest allergenicity index, followed by house dust. All 14 pollen allergens occupying the 3rd through 12th ranks including many grass and weed pollens are not available for immunotherapy in Japan. Japanese cedar pollen which is considered the most important pollen allergen in Japan ranked the 13th. Of a total 25 allergens occupying from the 1st through 13th ranks 22 allergens are not available for immunotherapy including the most important allergen, mite. These results suggest that we should expand the list of allergens available for diagnosis and treatment of allergic diseases in Japan.

Administration, Inhalation↗
PubMed1990

Possible mechanism for the inhibition of acid formation by the proton pump inhibitor AG-1749 in isolated canine parietal cells.

We have reported previously that 2-[[[3-methyl-4-(2,2,2-trifluorethoxy)-2-pyridyl]methyl] sulfinil]- 1H-benzimidazole (AG-1749) inhibits (H+ + K+)-adenosine triphosphatase after being transformed into its cyclic sulfenamide form (AG-2000) or disulfide form (AG-1812) under acidic conditions. In this study, mechanisms related to the inhibition of acid formation by AG-1749 were investigated in isolated canine parietal cells. AG-1749 suppressed the acid formation stimulated by histamine, carbachol or dibutyryl cyclic AMP with IC50 values of approximately 0.09 microM: AG-1749 being twice as potent as omeprazole. The inhibitory effect of AG-1749 was antagonized by dithiothreitol (1 mM). 2-Cyclo-hexen-1-one (3 mM) decreased cytosolic glutathione to less than 10% of control value, and caused a 3-fold increase in the inhibitory effect of AG-1749. Glutathione, however, when added exogenously, did not affect the action of AG-1749. The inhibition was reversed by removing AG-1749 from the medium or by adding dithiothreitol (1 mM). The reversal of inhibition by these two procedures was hardly affected by puromycin (100 microM) or cycloheximide (300 microM) but significantly prevented by 2-cyclo-hexen-1-one (1 mM). Exogenously added AG-2000 (10 microM) or AG-1812 (5 microM), active forms of AG-1749, did not inhibit acid formation.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1989

The role of the nigrotegmental GABAergic pathway in the propagation of pentylenetetrazol-induced seizures.

Recent evidence suggests that the substantia nigra (SN) may be involved in the modification of various experimental epilepsy models. We determined the role of gamma-aminobutyric acid (GABA)ergic activity of the SN and the target sites of SN efferents, the pedunculopontine nucleus (PPN) and superior colliculus (SC), in pentylenetetrazol-induced seizures in rats. Bilateral administration of a GABA agonist (muscimol) into the SN significantly reduced seizure severity; its administration into the PPN significantly augmented seizure severity; administration into the SC did not alter the seizure severity. On the other hand, infusion of a GABA antagonist (bicuculline) into the PPN revealed a protective effect against seizures. Our findings indicate that the nigral GABAergic projections to the PPN play an important role in seizure propagation. Thus, PPN neurons may be a possible target site of nigral output modulating seizure propagation.

Animals↗
PubMed1989

Possible mechanism for the inhibition of gastric (H+ + K+)-adenosine triphosphatase by the proton pump inhibitor AG-1749.

Mechanisms related to the inhibition of (H+ + K+)-adenosine triphosphatase (ATPase) by 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazole (AG-1749) were studied using canine gastric microsomes. AG-1749 (1-100 microM) inhibited the K+-stimulated ATP hydrolysis and vesicular accumulation of H+. AG-1749 bound to the microsomes concentration-dependently and decreased the number of free SH groups; the binding correlating with the enzyme inhibition. Both the binding and inhibition were antagonized by dithiothreitol. N-ethylmaleimide inhibited the (H+ + K+)-ATPase and decreased the binding of [14C]AG-1749 to the microsomes. The inhibitory effect of AG-1749 gradually increased with incubation time, and was enhanced by lowering the pH. AG-2000 and AG-1812, acid-induced rearrangement products of AG-1749, inhibited (H+ + K+)-ATPase potently, rapidly and independently of pH; the inhibition was antagonized by dithiothreitol. We propose that AG-1749 is transformed into its active forms within the acidic compartment of the parietal cells and that the active compounds inhibit (H+ + K+)-ATPase activity by reacting with the SH groups of the enzyme.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1989

Antisecretory and antiulcer activities of a novel proton pump inhibitor AG-1749 in dogs and rats.

The antisecretory and antiulcer activities of 2[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazole (AG-1749) were investigated in dogs and rats. AG-1749 inhibited both the (H+ + K+)-adenosine triphosphatase activity in canine gastric microsomes and dibutyryl cyclic AMP-stimulated acid formation in isolated canine parietal cells and suppressed the acid secretion stimulated by histamine, pentagastrin, bethanechol or a peptone meal in Heidenhain pouch dogs; the ID50 values were between 0.2 and 0.7 mg/kg p.o. AG-1749 inhibited both the histamine-stimulated and the basal acid secretion in pylorusligated rats and prevented water immersion stress or aspirin-induced gastric lesions and mepirizole or cysteamine-induced duodenal ulcers in rats; the ID50 values were between 0.3 to 3.6 mg/kg p.o. or i.d. Furthermore, AG-1749 prevented gastric lesions induced by absolute ethanol or acidified aspirin, and accelerated the healing of acetic acid-induced gastric or duodenal ulcers in rats. The inhibitory potency of AG-1749 in dogs was much the same as that of omeprazole and about half that of ranitidine. However, it was about 2 to 10 times more potent than omeprazole and 4 to 34 times more potent than ranitidine in rats. These results suggest that AG-1749 exerts prominent antiulcer activities mainly by suppressing acid secretion via an inhibition of a proton pump in gastric parietal cells and partly by protecting the gastrointestinal mucosa against various ulcerative stimuli.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1987

Actions of antisecretory agents on proton transport in hog gastric microsomes.

The properties of K+-stimulated ATP hydrolysis (K+-ATPase) and vesicular accumulation of H+ (H+ accumulation) in hog gastric microsomes were investigated. The microsomes consisted of smooth surfaced vesicular particles, 70-300 nm in diameter. Both the activities of ATPase and the vesicular accumulation of H+ were stimulated by K+ in the presence of Mg2+, and enhanced by the K+-ionophore, valinomycin. However, there were differences in regulation of K+-ATPase and H+ accumulation by K+ ions, i.e. K+ at concentrations higher than 10 mM decreased K+-ATPase activity but further enhanced H+ transport. This observation suggests that the two reactions are partly independent. The H+ accumulation was inhibited by omeprazole, fenoctimine, spermine, and NaSCN, but not by cimetidine, prostaglandin E2, and atropine. The inhibitory effect of omeprazole on H+ accumulation paralleled the inhibition of K+-ATPase, while fenoctimine, spermine, and NaSCN suppressed H+ accumulation, without inhibiting K+-ATPase, under appropriate concentrations. In addition, the spontaneous diffusion of H+ across the microsomal membrane was markedly enhanced by fenoctimine, but not by the other agents used. These results indicate that omeprazole inhibits H+ accumulation by inhibiting K+-ATPase, fenoctimine suppresses H+ accumulation mainly by increasing the loss of accumulated H+ from the microsomal vesicles, spermine and NaSCN reduce H+ accumulation by inhibiting the transport of H+ into microsomal vesicles.

Adenosine Triphosphatases↗
PubMed1986

Spizofurone, a new anti-ulcer agent, increases alkaline secretion in isolated bullfrog duodenal mucosa.

The effect of spizofurone, a new anti-ulcer agent, on alkaline secretion was studied in an isolated sheet of bullfrog (10(-4)-10(-3) M) as well as prostaglandin E2 (PGE2, 10(-8)-10(-5) M) added to the nutrient solution increased alkaline secretion, transmucosal potential difference (PD) and short-circuit current (Isc), in a concentration-dependent manner. The maximum increases in alkaline secretion stimulated by spizofurone and PGE2 were much the same. Spizofurone also showed this effect when added to the secretory solution while PGE2 did not. Treatment with indomethacin partly but significantly inhibited the effect of spizofurone, but did not affect that of PGE2. These results indicate that the increase in alkaline secretion in bullfrog duodenal mucosa seen in the presence of spizofurone is mediated, at least in part, by stimulation of endogenous PGs synthesis.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Gastric mucosal protection by spizofurone.

The protective effect of spizofurone (AG-629) on the rat gastric mucosa was studied in the presence of various stimuli. Spizofurone given orally markedly inhibited gastric lesions induced by ethanol (ED50 = 6.5 mg/kg). Spizofurone inhibited ethanol-induced gastric lesions even when administered intraperitoneally (i.p.), but the onset of action after oral administration was shorter. Spizofurone given orally or i.p. in a dose range of 25-200 mg/kg inhibited indomethacin-induced gastric antral ulcers in re-fed rats. Furthermore, spizofurone potentiated the inhibitory effect of prostaglandin E2 on indomethacin-induced gastric antral ulcers. Spizofurone given i.p. prevented a decrease in potential difference and the formation of gastric lesions induced by intragastric instillation of 30 mM aspirin in 0.1 N HCl. Spizofurone given i.p. inhibited the increase in net fluxes of H+ and Na+ caused by intragastric instillation of 15% ethanol in 0.1 N HCl. These findings indicate that spizofurone, like prostaglandin E2, exerts gastric mucosal protection and even potentiates the anti-ulcer effect of prostaglandin E2. The gastric mucosal protection by spizofurone is ascribed in part to preservation of the mucosal barrier.

Animals↗
PubMed1985

Spizofurone (AG-629) increases gastric mucosal blood flow in dogs: a possible mechanism of its anti-ulcer effect.

The effect of spizofurone (AG-629), a new anti-ulcer agent, on gastric mucosal blood flow was investigated in anesthetized dogs and the effects were compared with those of prostaglandin E2. Intravenous administration of spizofurone in doses of 15 and 30 mg/kg caused a dose-related increase in gastric mucosal blood flow. Spizofurone (1-10 mg/ml) given intragastrically for 15 min produced a sustained increase in gastric mucosal blood flow in a concentration-dependent manner; with 3 mg/ml there was about a 50% increase in gastric mucosal blood flow at the peak and a 2 h duration of action. The mode of action of spizofurone was similar to that of prostaglandin E2. The reduction in the gastric mucosal blood flow as induced by indomethacin was markedly improved by spizofurone. The topical action of spizofurone was confirmed in an in situ experiment using a stomach flap fixed to a lucite chamber. These results indicate that spizofurone increases gastric mucosal blood flow after systemic and topical administration, and this increase in gastric mucosal blood flow would account for the anti-ulcer effects of this drug.

Aminopyrine↗
PubMed1985

Induction of antigen-specific suppressor cells in patients with hay fever receiving immunotherapy.

In order to evaluate the effect of immunotherapy on subpopulations of lymphocytes, peripheral blood mononuclear cells were fractionated into T and non-T cells by incubating in anti-immunoglobulin-coated plates. T cells were further fractionated into rye grass antigen-adherent and nonadherent fractions and human serum albumin (HSA)-adherent and nonadherent fractions by incubating in rye grass antigen-coated and HSA-coated plates, respectively. The mean rye antigen-stimulated proliferative response of rye antigen-adherent fraction was significantly lower than that of rye antigen-nonadherent fraction in patients with rye grass hay fever receiving immunotherapy. There was no difference in the rye antigen-stimulated proliferative response between the HSA-adherent and nonadherent fractions. Both the rye antigen-adherent and nonadherent fractions proliferated similarly when they were stimulated by an unrelated antigen, Candida albicans. The rye antigen-stimulated proliferative response of rye antigen-nonadherent cells could be suppressed by coculturing with rye antigen-adherent cells from patients receiving immunotherapy. Furthermore, the treatment of cocultures with monoclonal antibody against suppressor-cytotoxic T cell (OKT8) subpopulation and guinea pig serum complement reversed the suppression. In patients receiving no immunotherapy, there was no difference in the rye grass antigen-stimulated proliferative response between the rye antigen-adherent and nonadherent fractions. These results suggest that immunotherapy induces a subpopulation of T cells that are adherent to antigen-coated plates and are capable of suppressing T cell proliferation stimulated by the specific antigen.

Epitopes↗
PubMed1979

Relationship between antigen-specific IgE antibody (RAST) and total serum IgE levels.

Although the total serum IgE level is generally higher in atopic than in non-atopic individuals, high total serum IgE levels and atopic diseases are not invariably associated. In 42 atopic patients with the total serum IgE levels less than 100 U/ml, 27% of RAST against 14 allergens were positive whereas in 45 atopic patients with the total serum IgE levels greater than 500 U/ml, 57% of RAST against 14 allergens were positive. The mean RAST values against four grass antigens expressed as a percentage of antigen-disc bound radioactivities were significantly lower in the group with the lower total serum IgE levels. Low or normal total serum IgE levels are likely to be found in atopic patients who are allergic to a relatively few grass antigens.

Antibody Specificity↗
PubMed1979

Reappraisal of prick test to tree and weed antigens.

Although 3+ or 4+ prick test reactions to olive tree or Russian thistle are valid, the RAST values to these antigens are significantly lower than those in patients with similar reactions to grass antigens, suggesting that nonimmunologic factors are partially responsible for the skin test reactions to the tree and weed antigens.

Antigens↗