What is the effect of cholecystokinin A antagonists (loxiglumide) on solid and liquid gastric emptying?
R.L. Brown, J Sarosiek, R.W. McCallum (Kansas City)
Cholecystokinin (CCK) is a hormone released from the enteric nervous system and entero-endocrine cells of the duodenum and small intestine in response to a meal. CCK and gastrin bind competitively at CCK A and CCK B receptors. Based on their binding affinity, CCK receptors are classified under three major groups [1]. CCK A (alimentary type) receptors are found in the pancreatic endocrine cells, gallbladder smooth muscle, gastrointestinal muscle and nerve cells, gastric D cells and various CNS locations. The affinity of these receptors for CCK over gastrin is significant (500 - 1000 fold). CCK B (brain type) receptors bind CCK over gastrin less significantly (10 fold). They are located throughout the cerebral cortex, in gastrointestinal cells and gallbladder smooth muscle. The third receptor is the gastrin receptor and is found in gastric parietal cells, and smooth muscle cells. Its binding affinity is similar to CCK B in that it only binds CCK mildly more avid than gastrin. In fact, CCK B and the gastrin receptors are often referred to together as CCK B-gastrin receptor due to a significant amount of genetic homology [2].
The potent CCK A antagonist, loxiglumide, has been used extensively to clearly define the major functions of CCK in gastrointestinal physiology which include: the initiation of gall bladder contraction, maintenance of fasting gall bladder tone, the regulation of gastric motility, and the stimulation of pancreatic secretion [3-7]. Based on its actions as a potent CCK A antagonist, loxiglumide has been suggested (but not studied significantly) as a possible therapeutic agent in pancreatitis, pancreatic carcinoma, "spastic" gall bladder conditions, and gastrointestinal motility disorders. Although its potential therapeutic role is limited, due to biliary stasis, loxiglumide has been instrumental in the more complete characterization of CCK and its vital function in human digestion.
Loxiglumide allowed investigators to specifically study the effect of CCK on gastric motility. In 1989, Meyer et al. used loxiglumide in human controls to test the effect of CCK on gastric emptying. The gastric emptying rate of radio-opaque markers was demonstrated to be significantly accelerated after loxiglumide infusion [3]. Although this was an imprecise method of measuring gastric motility, it provided the first objective evidence of loxiglumide's effect on gastric emptying in humans. In 1991, using more sophisticated techniques [4], Fried et al. found loxiglumide to accelerate liquid phase gastric emptying with a nutrient meal only (not a sham meal). The gastric emptying of the sham meal was not influenced by the infusion of loxiglumide, postulating that loxiglumide's effect on gastric motility was only realized when endogenous CCK release was stimulated by a nutrient meal. That same year, Schmidt et al. studied the effect of loxiglumide on pancreatic secretion, gall bladder contraction, and gastrointestinal motility after stimulation by exogenous CCK or a liquid test meal [5]. At a level sufficient to antagonize CCK, loxiglumide enhanced mouth to cecum transit time by twenty four percent. This provided further evidence that loxiglumide may block the gastroparetic effect of CCK on liquid phase gastric emptying [6]. Studies evaluating the effect of loxiglumide on solid phase gastric emptying are conflicting. Earlier studies indicated little to no effect of loxiglumide on solid phase gastric emptying [7, 8]. Recently, Borovicka et al. carefully measured the effect of loxiglumide on the gastric emptying of a solid meal (labeled sulfur colloid pancake). In this study, loxiglumide significantly accelerated gastric emptying of both liquid and solid meals [9].
The safety profile of CCK A antagonist has not been studied in a long-term fashion in humans. One study, which included a six-week course of loxiglumide for pancreatic carcinoma, demonstrated no adverse side effects or intolerance of the drug [10]. Gallstones or liver abnormalities were not mentioned specifically in this study. In all studies, loxiglumide antagonized the effects of CCK considerably. The most dramatic effect was complete arrest of gall bladder contraction within minutes and a significant increase in gall bladder volume over days [3, 5, 8]. Due to safer, and more effective promotility agents already in use and the high potential harm of bile stasis and stone formation during loxiglumide treatment, CCK A antagonists probably have no therapeutic future in the treatment of gastroparesis; however, they have been instrumental in more clearly defining the role of CCK in gastrointestinal physiology.
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