Aphthasol
Mechanism of action of an antiallergic agent, amlexanox (AA-673), in inhibiting histamine release from mast cells. Acceleration of cAMP generation and inhibition of phosphodiesterase.

Makino H, Saijo T, Ashida Y, Kuriki H, Maki Y.

Amlexanox markedly inhibits histamine release from rat mast cells. To clarify the mechanism of this inhibition, we investigated the effect of amlexanox on cAMP content, which, when increased, inhibits histamine release in rat peritoneal mast cells. At concentrations of 10(-8)-10(-6)M, amlexanox or isoproterenol increased the cAMP content of mast cells over that of control cells about 2-fold. When the mast cells were incubated with 10(-8), 10(-7) and 10(-6) M of amlexanox combined with 10(-7) M isoproterenol, the cAMP contents were synergistically increased 15-, 60- and 88-fold, respectively. 3-Isobutyl-1-methylxanthine (IBMX) at 10(-6)-10(-4) M increased the cAMP content 1.7-3.8-fold, and a combination of 10(-4) M IBMX and 10(-7) M isoproterenol synergistically increased the cAMP content 41-fold. A combination of amlexanox and IBMX synergistically increased the cAMP content 19-fold. The increase in cAMP content, when amlexanox and isoproterenol were combined, was transient; it peaked at 0.5 min after the drugs were administered, then decreased to 20-30% of the peak value about 2 min later. Pretreatment of mast cells with amlexanox reduced the effect of the combination of amlexanox and isoproterenol, indicating tachyphylaxis; pretreatment with IBMX had no such effect. The cAMP content of macrophages was also increased by amlexanox, but when combined with isoproterenol or PGE2, the effect was additive. Amlexanox inhibited cAMP phosphodiesterase in rat mast cells; its IC50 value was 1.4 X 10(-5) M, and its inhibitory activity was half that of IBMX.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2433225&dopt=Abstract amlexanox Aphthasol



Aphthasol
[Inhibitory effect of amlexanox (AA-673) on the immunological and non-immunological release of histamine or leukotrienes]

[Article in Japanese]

Kohno S, Shimizu T, Mizuta J, Ogino K, Yamamura H, Ohata K, Kawai M, Shindo T, Wada H, Hitomi S.

The effect of amlexanox on the non-immunological or immunological release of histamine or leukotrienes (LTs) from passively sensitized human lung fragments and atopic human leukocytes was investigated and compared with those of AA-861, tranilast, azelastine and disodium cromoglycate. 1) Amlexanox at concentrations of 10(-7)-10(-4) M showed an inhibition of histamine, LTB4, LTC4, LTD4 and LTE4 release from passively sensitized human lung fragments in a concentration-dependent fashion. A selective and competitive inhibitor of the 5-lipoxygenase activity, AA-861 modestly affected the histamine release and potently suppressed the any LT release at 10(-7) and 10(-6) M. Antiallergic drugs, tranilast and disodium cromoglycate also suppressed these chemical mediator release, but the inhibition potency was somewhat weaker than that of amlexanox. 2) Ca ionophore A23187-induced release of LTB4 and LTC4 from atopic human leukocytes was slightly enhanced up to 10(-6) M of amlexanox. However, 10(-4) M of the drug strongly diminished both of LT release. From these results, it is suggested that amlexanox is a clinically effective drug for atopic diseases, especially allergic asthma and rhinitis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2483310&dopt=Abstract amlexanox Aphthasol



Aphthasol
Effects of certain antiallergic drugs on experimental conjunctivitis in guinea pigs.

Kamei C, Izushi K, Nakamura S.

Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University, Japan.

Effects of certain antiallergic drugs on experimental conjunctivitis were studied with guinea pigs. Chlorpheniramine, ketotifen and levocabastine were effective in inhibiting histamine- and antigen-induced conjunctivitis in guinea pigs. By contrast, amlexanox was only effective in inhibiting antigen-induced conjunctivitis. Topical application of antigen released 46.5 +/- 3.8% of histamine from the conjunctiva in sensitized guinea pigs. Both levocabastine and amlexanox were effective in inhibiting conjunctival histamine release induced by antigen application. Lacrimal histamine contents were also increased after challenge. The increase in the histamine content of tears was inhibited by pretreatment with levocabastine and amlexanox, but no significant effect was observed with chlorpheniramine and ketotifen. From these findings, it is concluded that certain antiallergic drugs, but not amlexanox, exhibited potent inhibition on experimental conjunctivitis in guinea pigs. In addition, it has been established that measurement of histamine in the conjunctiva and tears as well as observation of conjunctivitis syndromes are useful for evaluating the effectiveness of antiallergic drugs on various kinds of allergic conjunctivitis in clinical situations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8593470&dopt=Abstract amlexanox Aphthasol