Possible Mechanisms of Action of the Antispasmodic Agent Tiropramide in the Isolated Detrusor from Rats.

Abstract

ABSTRACT-The effects of tiropramide hydrochloride on Ca 2+ induced contraction, cytoplasmic free Ca 2+ levels and tissue cyclic AMP concentrations were investigated to elucidate the mechanisms of its antispasmodic action in the isolated detrusor from rats. Tiropramide inhibited the Ca 2+ (3 mM) induced contractions of the isolated urinary bladder depolarized in a Ca2+free medium, and the IC50 value was 3.3 X 10-6 M. When tiropramide was added during the sustained phase of the K+ (60 mM) contracture, IC50 values of tiropramide for the contraction and the increased fluorescence were 1.9 X 10-5 M and 16.4 X 10-5 M, respectively. On the other hand, the IC50 values for the K=induced con traction and fluorescence after pretreatment of the isolated urinary bladder with tiropramide were 2.1 X 10-5 M and 2.6 X 10-5 M, respectively. Tissue cyclic AMP levels at 1 min after addition of 10-5 M tiropramide were significantly increased. Papaverine, IBMX or forskolin potentiated the inhibitory effect of tiropramide on carbachol-induced contraction and its cyclic AMP-elevating effect. However, a good correlation between the degrees of potentiation of the inhibitory effect and the increase in cyclic AMP levels was not observed. The present results suggest that the smooth muscle relaxant activity of tiropramide in the isolated detrusor from rats may be intimately associated with predominant inhibition of Ca2+ influx and, to a lesser extent, an increase in intracellular cyclic AMP levels.

Pharmacokinetics and Bioequivalence of Tiropramide in Healthy Volunteers

“…Tiropramide ((±)α-(benzoylamino)-4- [2-(diethylamino) ethoxy]-N,N-dipropyl-benzenepropanamide hydrochloride, CAS 55837-29-1) (see structure formula) has been known as a potent antispasmodic agent, and has been widely used for treatment of patients with disorders of the motility of the gastrointestinal, biliary and urinary tracts [1][2][3][4][5]. Its pharmacological effects have been reported to be potent on contractions provoked by chemical stimuli and less potent on vascular smooth muscle [5].…”

Efficacy and Safety of Tiropramide in the Treatment of Patients With Irritable Bowel Syndrome: A Multicenter, Randomized, Double-blind, Non-inferiority Trial, Compared With Octylonium

“…In an animal study using the isolated smooth muscle, tiropramide inhibited Ca 2+ influx for the most part and, to a lesser extent, increased the intracellular cyclic adenosine monophosphate (cAMP) levels 9. This study using rabbit also found that tiropamide increased Ca 2+ absorption into microvesicles and decreased the amount of Ca 2+ released to stimulate the contraction of the smooth muscle by increasing cAMP; as a consequence the smooth muscle relaxed 9. In terms of the distribution of tiropramide, a study showed that the radioactivity of tiropramide lasted longer in the colon than in other organs after intravenous or oral administration,17 indicating relative colonic selectivity.…”

“…One of the antispasmodics, tiropramide, is a derivative of tyrosine, and exerts a spasmolytic effect on the intestine through reducing Ca 2+ release into intestinal smooth muscle, rather than acting on the enteric nervous system 8,9. In a double-blind, placebo-controlled, randomized trial, tiropamide led to symptom improvement in terms of total symptom scores for 4 weeks, compared with 3 weeks in the placebo group; in addition, at week 4 abdominal pain was only improved in the tiropramide group 10.…”

New and Investigational Agents for Irritable Bowel Syndrome

“…Tiropramide exerts an antispasmodic effect on the intestine through reducing Ca 2+ release into the intestinal smooth muscle [61,62]. In a phase 4, double blind, randomized controlled trial of 245 patients, the mean change of visual analog scores for abdominal pain with tiropramide (100 mg thrice a day) was non-inferior to octylonium (20 mg thrice a day) [63].…”