THE CLINICAL-PHARMACOLOGY OF SINGLE DOSES OF OTILONIUM BROMIDE IN HEALTHY-VOLUNTEERS

Objective: Otilonium is a smooth muscle spasmolytic with greater affin ity for receptors in the smooth muscle of distal than proximal gut in rats. This study was the first to compare distal and proximal GI trans it effects in human subjects. Methods: Using an increasing dose design for the safe exploration of clinical and supraclinical single dose le vels, two groups of eight volunteers received either 40, 120 and 200 m g or 80, 160 and 240 mg otilonium. Gastric emptying of 400 mi 10% gluc ose solution was assessed by epigastric impedance (EI), orocaecal tran sit time (OCTT) by the lactulose breath-hydrogen method and whole gut transit time (WGTT) by the method of Hinton et al. [1]. Potential anti cholinergic effects were assessed via visual accommodation using the R AF rule and saliva flow in response to sucking a sweet. Results: Media n WGTT after 120 mg significantly increased by 4.1 h relative to place bo, but at higher doses median changes relative to placebo were not si gnificant due to wide increases in group variance. The EI t50% was del ayed by 1.4 min when results from the two highest doses were combined and compared with placebo; this small difference was statistically sig nificant but seems unlikely to achieve physiological or clinical signi ficance. OCTT, visual accommodation and saliva flow were unaltered. Ot ilonium bromide was well tolerated at all doses, due mainly to low sys temic absorption.