In contrast the antral prokinetic effects of cisapride are partially reduced by granisetron (9) (a 5-HT3 receptor antagonist) suggesting a possible prokinetic component due to activation of 5-HT3 receptors.
Among the other 5-HT4 selective agonists, prucalopride (10) has also been shown to stimulate gastric emptying in humans (12). In patients with functional constipation associated with upper Gl symptoms, prucalopride at a daily dose of 4 mg during 7 days accelerates gastric emptying by 22% with improvement of the corresponding symptoms (12). Similarly renzapride consistently shorthens the oro-cecal transit time in patients with upper and lower Gl symptoms (13).
In agreement with the hypothesis that the prokinetic effect of cisapride is linked in part to activation of 5-HT3 receptors, selective 5-HT3 agonists have been proposed as new prokinetic agents. Indeed MKC-733, a selective 5-HT3 agonist, dose dependently accelerates both gastric emptying rate and oro-cecal transit time in healthy volunteers (14). This compound also relaxes gastric fundus and stimulates fasting human antral motility.
Cholecvstokinin antagonists - Cholecystokinin (CCK) is a logical target for pharmacotherapy of proximal gastrointestinal tract motility. CCK is released from intestinal cells in response to specific food components including fasty acids and amino acids. Its major effects are the stimulation of pancreatic enzyme secretion and gallbladder contraction. CCK slows gastric emptying by negative feedback and stimulates the perception of satiety. Conversely, the CCKA-receptor antagonist, loxiglumide, increases gastric emptying (15). CCKa antagonists have also been shown to block the effect of sham feeding on delaying the onset of phase III contractions (16). The role of CCKA antagonists in gastroparesis is currently being investigated. Moreover, it is known that selective CCKa receptor antagonists such as devazepide and loxiglumide reduce transient lower esophageal sphincter relaxating (TLESRs) in both dogs (17) and healthy volunteers (18). These TLESRs are not only responsible of gastro-esophageal reflux but also generate upper Gl symptoms associated with dyspepsia. CCKA antagonists such as dexloxiglumide and itriglumide, which is a selective CCKb antagonist, do not consistently affect gallbladder emptying and are not associated with an enhancement of gallstone formation. Clinical efficacy of CCKa antagonist in the treatment of functional dyspepsia has been demonstrated (19) as well as the role of fat and CCK in the genesis of symptoms (20).
Motilides - Motiiin, a 22-amino acid peptide, triggers phase III migrating myoelectric complex (MMC) activity in the stomach. During gastric phase III activity, strong antral contractions empty all residual (indigestible) chyme from the stomach. The motiiin receptor has been identified as a guanosine triphosphate-binding protein (G protein) (21). It is located throughout the enteric nervous system, with decreasing density from the stomach to the lower intestinal tract. Motiiin also stimulates cholinergic activity consistent with the observation that atropine reduces the motiiin effect. The stimulus for motiiin release is still unknown.
Erythromycin (11.) is a highly potent motiiin agonist that increases the amplitude and frequency of antral contractions and initiates gastric phase III contractions (22, 23). This effect is attributable to the 14-member ring structure of a family of compounds referred to as macrolides. Radionuclide studies verify that erythromycin accelerates gastric emptying. A brisk acceleration of solid-phase gastric emptying after intravenous erythromycin was reported (24). Patients with diabetic gastroparesis given erythromycin intravenously (200 mg) cleared approximately 95% of the test meal at 120 minutes compared with only 40% in the placebo-treated patients. Gastric emptying also improved after 4 weeks of continuous oral therapy with erythromycin at
250 mg three times a day. These findings have been consistently confirmed by other studies (25).
Research focusing on the optimal delivery and dose of erythromycin is continuing. Studies have shown that intravenous preparations are more effective, although the risk of cutaneous infection may ourweigh the benefits when compared with oral therapy (26). The optimal dose for the desired therapeutic effect is under debate. Although uncertain, there is a dose-dependent effect of erythromycin dependent on different subtypes of motilin receptors. In humans, erythromycin at a low dose (40 mg) generates a premature antral contractile front dependent on a cholinergic pathway, whereas a higher dose (200 mg) produces a more sustained contraction via a non-cholinergic pathway. Current recommendations are to begin at 250 mg/day and increase to 3 times per day as needed (5). Whether or not there is a down-regulation or tachyphylaxis, it still must be determined.
A retrospective analysis was conducted on patients receiving erythromycin for 1 -19 months and concluded that it may remain effective for at least this period (27).
Motilides and motilactides are macrolide derivatives being developed to promote motility in the gut. These new motilin agonists are intended to be devoid of antimicrobial activity and, thus, anticiotic-induced complications. Motilin agonists currently in development are: EM574 (12), KC-11458 and KW-5139 (13). EM574 has effects comparable with cisapride in improving gastric emptying in dogs (28). This agent is currently undergoing clinical trials. KW5139 is a peptide analogue of motilin in which there is a 1-amino acid substitution (leucine for methionine at position 13) (29). This agent has increased gastric motility in patients with early gastric stasis after pylorus-preserving pancreatoduodenectomy.
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