Novel therapies for secretory diarrhea

Hyperactivation of the enzyme guanylyl cyclase C (GC-C) followed by excessive
production of the signaling molecule cyclic GMP in the intestinal epithelium
plays a central role in the disease mechanism of secretory diarrhea (SD) and,
possibly, the irritable bowel syndrome (IBS-d). Newly developed inhibitors of
GC-C signaling, shown to exert an anti-secretory and pro-absorptive effect on
salt-and water transport in cultured enterocytes and in animal models, may
therefore be used to treat SD. Activation of GC-C and of the enzyme adenylyl
cyclase (AC) both result in the opening of CFTR, the major if not sole apical
chloride channel in intestinal epithelium, encoded by the cystic fibrosis gene.
Pharmacological inhibitors of CFTR are therefore expected to inhibit both GC-C
and AC-mediated SD, including cholera, but such an inhibition has not yet been
demonstrated convincingly in human intestine at the pre-clinical stage.

This study aims to assess the efficacy and potency of newly developed small
molecule inhibitors of the GC-C signaling pathway and of the CFTR chloride
channel in native human intestinal tissue.

Rectal biopsies will be obtained from healthy volunteers. The effect of the
inhibitor compounds on the GC-C-and AC-mediated fluid secretory response of the
intestinal mucosa will be studied ex vivo.
The test compounds have been selected on the basis of efficacy and potency in
cell models of GC-C- and AC- mediated pro-secretory signaling. In view of
subsequent structure-activity analysis, chemical diversity was also considered.
The ex vivo testing is performed by the intestinal current measurement (ICM)
technique in micro-Ussing chambers. These experiments will show whether the
GC-C- and CFTR-antagonistic action of our current selection of compounds,
established in cell and animal models, is retained in native human intestine.
Thus, they will also affirm, or refute, the validity of our preceding selection
procedure, and allow structure-activity analysis to aid further development of
novel anti-diarrheal drugs.

Biopsies will be sampled from the rectum with a suction biopsy device.

The procedure to obtain rectal biopsies can be completed within 15 minutes.
Including anamnesis, the whole procedure will take about 30 min. Tissue
sampling is virtually painless, although accompanied sporadically with the loss
of minute quantities of blood. The procedure is regularly performed for
screening and research purposes in the context of Hirschsprung*s disease and
cystic fibrosis. From this practice, it can be deduced that the risk of serious
adverse effects is negligible.
No benefits are associated with participation.