Abstract
ABT-229 (8,9-anhydro-4"-deoxy-3′-N-desmethyl-3′-N-ethylerythromycin B-6,9-hemiacetal), a synthetic derivative of erythromycin (ERY) with no antibiotic activity, has been shown to bind to motilin receptors and stimulate contractile activity of the antrum and small intestine. The objective of this study was to determine the effect of ABT-229 on canine gastric emptying (GE) and contractile activity of the antrum and duodenum in response to a solid meal. Six beagles were used to determine GE of a solid meal and contractile activity in response to either vehicle, ABT-229 (0.17, 0.83, 2.5, or 5.0 μg/kg/min), ERY (33.3 μg/kg/min), or cisapride (CIS) (10 μg/kg/min). Lag (tlag), half-emptying (t1/2), and complete emptying (tfull) times were determined. Contractile data were analyzed for motility index and gastroduodenal coordination. Compared with vehicle, ABT-229 dose dependently accelerated GE,tlag was decreased at the two highest doses,t1/2 was decreased compared with vehicle at the three highest doses, and tfull was decreased at all doses compared with vehicle. ERY also decreasedt1/2 and tfull, whereas CIS decreased all GE parameters. The slopes of the linear phase of GE curves for all drugs and doses were greater than those for vehicle. ABT-229 dose dependently increased the motility index as well as gastroduodenal coordination. ABT-229 (two highest doses) and CIS accelerated GE of a solid meal by decreasing the lag phase and increasing the rate of GE, whereas ERY only increased the rate of GE. The data suggest that ABT-229 is 7- to 40-fold more potent than ERY in accelerating GE.
Footnotes
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Send reprint requests to: Dr. Verne Cowles, Depomed, Inc., 1360 O'Brien Dr., Menlo Park, CA 94025. E-mail:vcowles{at}depomedinc.com
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↵1 This work was presented in part at Digestive Disease Week in conjunction with the 100th annual meeting of the American Gastroenterological Association, May 16–19, Orlando, FL.
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↵2 Current address: Depomed, Inc., 1360 O'Brien Dr., Menlo Park, CA 94025.
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↵3 Current address: Pharmacia Corporation, 4901 Searle Pkwy., Rm. J322A, Skokie, IL 60077.
- Abbreviations:
- GE
- gastric emptying
- ERY
- erythromycin
- ABT-229
- 8,9-anhydro-4"-deoxy-3′-N-desmethyl-3′-N-ethylerythromycin B-6,9-hemiacetal
- CIS
- cisapride
- PEG
- polyethylene glycol
- Received November 15, 1999.
- Accepted February 2, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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