Tu1407 Extracorporeal Magnetic Stimulation for Sacral Nerve is as Effective as Biofeedback Therapy in Patients With Rectal Hyposensitivity

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Background: Asimadoline, a peripherally-restricted highly selective kappa-opioid receptor (KOR) agonist, has been shown to be efficacious in relieving pain or discomfort, urgency, stool frequency and other symptoms in diarrhea-predominant-IBS (D-IBS) patients with at least moderate pain (Mangel et al 2008). The mechanism of action for this therapeutic effect is thought to involve activation of up-regulated KORs on visceral afferent terminals in the gut wall. KOR activation in the central nervous system (CNS) can lead to aquaresis, dysphoria, and sedation. Penetration of asimadoline into the CNS is poor due to its amphiphilic structure and because it is a substrate for P-glycoprotein (P-gp), thus, there is no evidence for CNS effects of asimadoline in the IBS dose range (1-2 mg/day). Aim: The potential for drug interaction-induced CNS effects with ketoconazole, an inhibitor of P-gp and cytochrome P450 3A4 (CYP3A4), which plays a role in the metabolism of asimadoline, was assessed in this study. Methods: This was a single center, double-blind, placebo-controlled, randomized, two-period, crossover drug interaction study. Twelve healthy male subjects (Caucasian, 1840 years) received ketoconazole 200 mg bid for 3 days followed by a combination of ketoconazole 200 mg and asimadoline 1.5 mg bid (3 fold higher than the 0.5 mg bid clinical dose for IBS) from Days 4 to 9 and a single morning dose on Day 10 in one period and the same treatments but with ketoconazole placebo in a second period, with a 14 day washout between treatments. Pharmacodynamic tests aimed at detecting activity of asimadoline in the CNS included plasma antidiuretic hormone concentrations, the Critical Flicker Fusion test, the Profile of Mood State and the Bond & Lader visual analogue scale of mood and alertness, performed on Days 1, 4, 7 and 10. Primary pharmacokinetic variables were plasma asimadoline Cmax and AUC0-τ after a single dose on Day 4 and after multiple doses on Day 10. Results: The Cmax of asimadoline was approximately doubled with ketoconazole compared to placebo co-administration (from 46.2 to 98.9 ng/mL on Day 4 and from 50.7 to 112.1 ng/mL on Day 10). Mean AUCτ values were 3-fold higher during ketoconazole compared to placebo treatment. Although co-administration of ketoconazole led to a 2to 3-fold increase in asimadoline Cmax and AUC, no effects were observed on any of the CNS pharmacodynamic endpoints. Conclusions: There were no CNS pharmacodynamic effects even at plasma asimadoline levels 8-fold higher than those achieved at the IBS dose. These data provide further evidence for the peripheral restriction of asimadoline and suggest that dose adjustment when co-administered with ketoconazole or other CYP3A4 / P-gp inhibitors is not required.