Lower GI 05

Abstract

Background: Nitric oxide is the main inhibitory neurotransmitter in the internal anal sphincter. UK 357,903 (an inhibitor of type-5 phosphodiesterase (PDE)) prevents hydrolysis of cyclic guanosine monophosphate, enhancing the effect of nitric oxide. We investigated the effect of a single oral dose of UK 357,903 on maximal anal resting pressures (MARP) in healthy subjects. Methods: This was a double-blind, placebo-controlled, three-way cross-over study with four treatment arms. Twelve male subjects were randomized to receive three of four treatments: single oral dose of UK 357,903 (10 and 100 mg), single dose (0.5 g) of topical 0.2 per cent glyceryl tri-nitrate (GTN) paste applied perianally or oral placebo. For each study period, MARP was recorded prior to dosing and for 2.5 h postdose. Squeeze pressures were recorded 1.25 and 2.5 h postdose. Results: One subject withdrew consent and was excluded. The maximum change from baseline MARP was 28.7, −71.6, 3.92 and −37.6 per cent for placebo, 100 mg UK 357,903, 10 mg UK 357,903 and GTN, respectively. The difference between placebo and 100 mg UK 357,903 was significant (P = 0.001). Squeeze pressures were unchanged. High-dose UK 357,903 caused facial flushing in two subjects, headaches in four subjects and penile erections in two subjects. GTN caused headaches in four subjects. Conclusions: This study shows that the 100 mg UK 357,903 causes a significant reduction in MARP compared to placebo and GTN. PDE-5 inhibitors may benefit patients with internal anal sphincter hypertonia, including anal fissures.