The objectives of the study were: 1. To show that a single dose of YF476 blocks gastrin receptors in healthy subjects 2. To show that YF476 retains its ability to block gastrin receptors after repeated dosing despite losing its ability to suppress gastric acidity.
The rationale for this study was as follows. On the basis of the pre-clinical studies, the original target disease for YF476 was gastro-oesophageal reflux disease (GORD), not only because of the excellent anti-secretory activity of YF476 but also because of its potential for increasing gastric emptying. But loss of the anti-secretory effect of YF476 in healthy subjects after repeated dosing excludes its use as an anti-secretory agent in patients with GORD. However, there is some evidence from within our repeated-dose studies in healthy subjects that gastrin receptors are blocked despite loss of the anti-secretory activity of YF476. Further evidence that repeated doses of YF476 cause sustained blockade of gastrin receptors comes from several types of study in animals. First, in the 13-week toxicology studies, all dose levels of YF476 reduced the ECL population, unlike other anti-secretory agents, histamine H2-antagonists and proton-pump inhibitors, which increase the ECL population. Second, YF476 at doses of 0.1 and 1.0 mg/kg subcutaneously twice daily for 14 days in rats abolished the increase in gastric output induced by pentagastrin on Days 1, 7 and 14. This protocol describes a study in healthy subjects using inhibition of pentagastrin-induced gastric acid output as a surrogate marker of efficacy of YF476. Pentagastrin has been used for many years to test gastric function in healthy subjects and patients. Intravenous infusion of 0.6 micrograms/kg/hour is a submaximal and well-tolerated dose.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
10
Hammersmith Medicines Research
London, United Kingdom
Safety of YF476
Assessed by by physical examinations, safety tests of blood and urine, ECG variables
Time frame: 4 weeks
Tolerability of YF476
Assessed by adverse events
Time frame: 4 weeks
Pharmacokinetic analysis of plasma YF476 concentrations
On Study Days 1 and 7, blood samples taken at 90 and 210 minutes after the start of gastric aspiration. On Study Day 14, a blood sample taken at 90 minutes only. Plasma separated and stored for subsequent assay of YF476, if deemed necessary.
Time frame: 4 weeks
Pharmacodynamic measurement for assay of volume, pH and total acidity of gastric aspirate
On Study Days 0, 1, 7 \& 14: volume, pH and total acidity of gastric aspirate measured at 15-min intervals from 0-30 \& 90-210 min after the start of gastric aspiration
Time frame: 4 weeks
Pharmacodynamic measurement for assay of pancreastatin and pancreatic polypeptides
On Study Days 0, 1, 7 \& 14: blood samples taken at about -30 min before the start of gastric aspiration, just before the introduction of nasogastric tube. Serum separated and stored for subsequent assay of pancreastatin, pancreatic polypeptide, and any other gastro-intestinal hormone (if necessary)
Time frame: 4 weeks
Pharmacodynamic measurement for assay of gastrin
On Study Days 0, 1, 7 \& 14: blood samples taken at 90 min after the start of gastric aspiration. Serum separated and stored for subsequent assay of gastrin, if necessary
Time frame: 4 weeks
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