Background-Stronger prokinetic agents which specifically enhance trans
it in different parts of the gut are required. R093877 is a novel 5-HT
4 agonist prokinetic compound which is chemically related to cisapride
but believed to have greater effect on colonic activity. Aims-To eval
uate the effects of R093877 on bowel function, upper and lower gut tra
nsit, visceral sensitivity, and sphincter function in healthy voluntee
rs in a double blind, placebo controlled, crossover study. Methods-The
study consisted of five consecutive one week periods: no drug treatme
nt; active drug treatment with either 1 or 2 mg daily or placebo; wash
out; active drug or placebo; no treatment. Seventeen male subjects mai
ntained a detailed diary of bowel function for the entire study. Oroca
ecal transit (breath hydrogen), whole gut transit (radio-opaque marker
s), and anorectal function were assessed at the end of each of the two
treatment periods. Blood testing was performed to confirm compliance
and for safety analysis. Results-One subject withdrew from the study d
ue to side effects while on placebo. Eight subjects completed the stud
y on 1 mg and a further eight on 2 mg. Blood testing showed non-compli
ance in one subject on the 2 mg dose, and he was excluded from analysi
s of all diary and physiological data. Treatment increased the number
of stools per week (placebo versus 1 mg, 7.8 versus 13.6, p=0.003; pla
cebo versus 2 mg, 8.9 versus 11.3, p=0.15) and the percentage of loose
or watery stools (24.2% versus 61.5%, p<0.04; 9.9% versus 40.0%, p<0.
02). Stool frequency and consistency reverted to normal immediately af
ter treatment. Treatment shortened orocaecal and whole gut transit in
all subjects on both doses. Treatment accelerated orocaecal (76 versus
51 minutes, p=0.007; 63 versus 47 minutes, p=0.07) and whole gut (38.
2 versus 27.0 hours, p=0.05; 44.8 versus 24.0 hours, p<0.04) transit,
and decreased the number of retained markers ingested 36 hours previou
sly (4.8 versus 1.8, p=0.016; 7.0 versus 4.3, p=0.033). Gut sensitivit
y to distension and electrical stimulation, and anal manometry, were u
nchanged. Transient headache occurred in seven subjects on R093877 and
one subject had mild elevation of liver aminotransferases which resol
ved on drug cessation. Conclusions-R093877 is well tolerated by health
y subjects and has a marked and consistent effect on stool frequency a
nd consistency, and upper gut and colonic transit. It does not affect
visceral sensitivity or sphincter function. It holds promise for patie
nts with large bowel symptoms or slow gut transit.