TITLE

L-ERYTHRO METHOXAMINE IS MORE POTENT AT INDUCING PORCINE INTERNAL ANAL SPHINCTER (IAS) CONTRACTION IN VITRO IMPARED WITH PHENYLEPHRINE: IMPLICATIONS FOR TOPICAL THERAPIES FOR FAECAL INCONTINENCE

AUTHOR(S)
Jones, O.M.; Thompson, J.; Brading, A.F.; Mortensen, N.J.M.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA93
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Introduction: Topical phenylephrine (an alpha-1 adrenoceptor agonist) increases resting anal canal pressure in normal and incontinent subjects, but requires high concentrations of gel, around 10-40%. This can cause local side effects, including perianal burning. This study examined if methoxamine might be a more potent alternative to phenylephrine. Methods: lAS tissue was cut into strips, suspended in a superfusion organ bath, and allowed to equilibrate. Strips were subjected to drugs under testing for 20 seconds, sufficient to obtain stable tone. Phenylephrine, methoxamine racemate, and its four stereoisomers were all evaluated, and concentration-response curves constructed. Results: In vitro, methoxamine racemate (1:1:1:1 ratio of its four isomers) and phenylephrine both caused contraction of lAS strips, blocked by phentolamine, an alpha-adrenoceptor antagonist. EC50 values for the two drugs were comparable (74.7±16.5 mM vs 58.3+13.4 mM, respectively; p > 0.05). However, when methoxamine racemate was separated into its four constituent isomers by chromatography, L-erythro methoxamine was significantly more potent than the other three isomers (EC50 17.6±3.7 mM; p < 0.01). Furthermore, this was also more potent than methoxamine racemate and phenylephrine (p < 0.01). This stereoisomer has been synthesised by a novel chemical synthetic pathway, which retains the potency of the chromatographically separated fraction (EC50 10.5±2.0 mM). Conclusion: L-erythro methoxamine is a possible treatment for incontinence and is four times more potent than phenylephrine. This compound has potential to produce more substantial rises in anal resting pressure with fewer local side effects. Further trials are underway examining the efficacy of berythro methoxamine in vivo.
ACCESSION #
9747913

 

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