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Aldioxa improves delayed gastric emptying and impaired gastric compliance, pathophysiologic mechanisms of functional dyspepsia.

Asano T, Aida S, Suemasu S, Tahara K, Tanaka K, Mizushima T - Sci Rep (2015)

Bottom Line: Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying.Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity.We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.

View Article: PubMed Central - PubMed

Affiliation: Department of Drug Discovery and Development, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan.

ABSTRACT
Delayed gastric emptying and impaired gastric accommodation (decreased gastric compliance) play important roles in functional dyspepsia (FD). Here we screen for a clinically used drug with an ability to improve delayed gastric emptying in rats. Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying. Administration of allantoin, but not aluminium hydroxide, restored the gastric emptying. Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity. Aldioxa or aluminium hydroxide but not allantoin restored gastric compliance with restraint stress, suggesting that aluminium hydroxide moiety is involved in this restoration. We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.

No MeSH data available.


Related in: MedlinePlus

Stimulatory effect of aldioxa on gastric emptying was independent of 5-HT4 and D2 receptors.Mice fasted for 18 h were orally administered aldioxa (200 mg kg−1) (a,b), cisapride (5 mg kg−1) (a), itopride (200 mg kg−1) (b) or vehicle (1% methylcellulose) (a,b). GR113808 (10 mg kg−1), a selective 5-HT4 antagonist, was administered 5 min before each drug administration (a). Forty-five (a) or thirty (b) minutes after each drug administration, delayed gastric emptying was induced by administration of clonidine (100 μg kg−1) (a) or apomorphine (5 mg kg−1) (b) and examined using the phenol red method as described in the legend of Fig. 1. Values are mean ± s.e.m. *P < 0.05; **P < 0.01 (Tukey test). n.s., not significant. Experiments were replicated at least two times.
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f5: Stimulatory effect of aldioxa on gastric emptying was independent of 5-HT4 and D2 receptors.Mice fasted for 18 h were orally administered aldioxa (200 mg kg−1) (a,b), cisapride (5 mg kg−1) (a), itopride (200 mg kg−1) (b) or vehicle (1% methylcellulose) (a,b). GR113808 (10 mg kg−1), a selective 5-HT4 antagonist, was administered 5 min before each drug administration (a). Forty-five (a) or thirty (b) minutes after each drug administration, delayed gastric emptying was induced by administration of clonidine (100 μg kg−1) (a) or apomorphine (5 mg kg−1) (b) and examined using the phenol red method as described in the legend of Fig. 1. Values are mean ± s.e.m. *P < 0.05; **P < 0.01 (Tukey test). n.s., not significant. Experiments were replicated at least two times.

Mentions: As described in the introduction, a number of molecular targets of drugs that could restore gastric emptying have been proposed, particularly those involving the α-2 adrenergic, D2 and 5-HT4 receptor types. We examined here the involvement of these receptors in the stimulatory effect of aldioxa on gastric emptying. To test the involvement of the 5-HT4 receptor, we examined the effect of a selective 5-HT4 receptor antagonist (GR113808)30 on the stimulatory effect of aldioxa on gastric emptying. As shown in Fig. 5a, aldioxa suppressed clonidine-induced delayed gastric emptying even in the presence of GR113808. On the other hand, cisapride (a 5-HT4 agonist) did not affect clonidine-induced delayed gastric emptying in the presence of GR113808 (Fig. 5a).


Aldioxa improves delayed gastric emptying and impaired gastric compliance, pathophysiologic mechanisms of functional dyspepsia.

Asano T, Aida S, Suemasu S, Tahara K, Tanaka K, Mizushima T - Sci Rep (2015)

Stimulatory effect of aldioxa on gastric emptying was independent of 5-HT4 and D2 receptors.Mice fasted for 18 h were orally administered aldioxa (200 mg kg−1) (a,b), cisapride (5 mg kg−1) (a), itopride (200 mg kg−1) (b) or vehicle (1% methylcellulose) (a,b). GR113808 (10 mg kg−1), a selective 5-HT4 antagonist, was administered 5 min before each drug administration (a). Forty-five (a) or thirty (b) minutes after each drug administration, delayed gastric emptying was induced by administration of clonidine (100 μg kg−1) (a) or apomorphine (5 mg kg−1) (b) and examined using the phenol red method as described in the legend of Fig. 1. Values are mean ± s.e.m. *P < 0.05; **P < 0.01 (Tukey test). n.s., not significant. Experiments were replicated at least two times.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664916&req=5

f5: Stimulatory effect of aldioxa on gastric emptying was independent of 5-HT4 and D2 receptors.Mice fasted for 18 h were orally administered aldioxa (200 mg kg−1) (a,b), cisapride (5 mg kg−1) (a), itopride (200 mg kg−1) (b) or vehicle (1% methylcellulose) (a,b). GR113808 (10 mg kg−1), a selective 5-HT4 antagonist, was administered 5 min before each drug administration (a). Forty-five (a) or thirty (b) minutes after each drug administration, delayed gastric emptying was induced by administration of clonidine (100 μg kg−1) (a) or apomorphine (5 mg kg−1) (b) and examined using the phenol red method as described in the legend of Fig. 1. Values are mean ± s.e.m. *P < 0.05; **P < 0.01 (Tukey test). n.s., not significant. Experiments were replicated at least two times.
Mentions: As described in the introduction, a number of molecular targets of drugs that could restore gastric emptying have been proposed, particularly those involving the α-2 adrenergic, D2 and 5-HT4 receptor types. We examined here the involvement of these receptors in the stimulatory effect of aldioxa on gastric emptying. To test the involvement of the 5-HT4 receptor, we examined the effect of a selective 5-HT4 receptor antagonist (GR113808)30 on the stimulatory effect of aldioxa on gastric emptying. As shown in Fig. 5a, aldioxa suppressed clonidine-induced delayed gastric emptying even in the presence of GR113808. On the other hand, cisapride (a 5-HT4 agonist) did not affect clonidine-induced delayed gastric emptying in the presence of GR113808 (Fig. 5a).

Bottom Line: Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying.Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity.We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.

View Article: PubMed Central - PubMed

Affiliation: Department of Drug Discovery and Development, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan.

ABSTRACT
Delayed gastric emptying and impaired gastric accommodation (decreased gastric compliance) play important roles in functional dyspepsia (FD). Here we screen for a clinically used drug with an ability to improve delayed gastric emptying in rats. Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying. Administration of allantoin, but not aluminium hydroxide, restored the gastric emptying. Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity. Aldioxa or aluminium hydroxide but not allantoin restored gastric compliance with restraint stress, suggesting that aluminium hydroxide moiety is involved in this restoration. We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.

No MeSH data available.


Related in: MedlinePlus