The relationship between gastric emptying of semisolids and paracetamol absorption.

The relationship between gastric emptying rate of semisolid Tc-99m labelled Chelex-100 resin/oatmeal and paracetamol absorption was determined simultaneously in seven healthy volunteers. There was no significant correlation between the half-time of gastric emptying and the time of the peak serum paracetamol concentration. There was no significant correlation between the area under the serum paracetamol concentrations at 60 and 90 min and the % meal emptied in 60 and 90 min respectively. Three subjects showed a lag phase in gastric emptying pattern, while the other four showed the emptying curves without evidence of a delayed phase of emptying. Individual values of gastric emptying determined by the methods varied widely.     

Involvement of cholecystokinin receptor in the inhibition of gastrointestinal motility by oxytocin in ovariectomized rats

The effects of oxytocin on gastric emptying, gastrointestinal transit, and plasma levels of cholecystokinin (CCK) were studied in ovariectomized rats. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na₂⁵¹CrO₄. Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Blood samples were collected for CCK radioimmunoassay. After administration of oxytocin (0.2–0.8 mg/kg), gastric emptying and gastrointestinal transit were inhibited, whereas plasma concentration of CCK was increased in a dose-dependent manner. Atosiban, an oxytocin receptor antagonist, effectively attenuated the oxytocin-induced inhibition of gastric emptying and gastrointestinal transit. However, administration of atosiban alone had no effect on gastric emptying and gastrointestinal transit. The selective CCK₁ receptor antagonists, devazepide and lorglumide, effectively attenuated the oxytocin-induced inhibition of gastric emptying and gastrointestinal transit. L-365, 260, a selective CCK₂ receptor antagonist, did not alter the oxytocin-induced inhibition of gastric emptying and gastrointestinal transit. These results suggest that oxytocin inhibits gastric emptying and gastrointestinal transit in ovariectomized rats via a mechanism involving the stimulation of CCK release and CCK₁ receptor activation.     

An improved method of evaluation of drug-evoked changes in gastric emptying in mice

INTRODUCTION: The increased availability of transgenic mice prompts a need for the adaptation to mice of whole-animal assays traditionally performed in larger laboratory animals. Gastric emptying studies are frequently conducted in dogs and rats. Mouse-based gastric emptying models currently available often use inert, nonnutrient liquid meals containing nonabsorbable markers or radionuclides. We have developed a mouse gastric emptying assay that features a favorable throughput and the use of a semisolid, high-calorie meal. METHODS: A carbohydrate- and protein-rich semisolid test meal was prepared from common laboratory reagents. Gastric emptying was determined by subtracting the mass of test meal remaining in the stomach from the mass of test meal administered. A time-course study of basal emptying of a semisolid, paste-like test meal high in carbohydrate and protein from the stomachs of overnight-fasted mice was conducted. Agents known to either inhibit (propantheline, 0.3-10 mg/kg sc; corticotropin-releasing factor [CRF], 3-100 nmol/kg ip) or accelerate (metoclopramide, 1-10 mg/kg ip; bethanechol, 1-30 mg/kg ip) gastric emptying were tested. A single time-point variation of the assay can be used for quickly screening compounds for effects on gastric emptying. RESULTS: In time-course studies, the test meal emptied from the stomach with a half-emptying time of 30.6 min (95% CI: 27.3-34.7). The gastric emptying data were successfully modeled by a two-parameter exponential decay function. No lag phase was observed, indicating that the meal empties from the stomach as a liquid. The anticholinergic agent propantheline increased gastric half-emptying time (t(1/2)) approximately threefold, while metoclopramide decreased gastric half-emptying time approximately twofold compared to basal emptying. Single time-point screening studies correctly detected the gastrokinetic activity of bethanechol and the inhibitory effect of CRF. DISCUSSION: The mouse gastric emptying assay reported here is simple, inexpensive, and not labor-intensive. It is capable of detecting either stimulation or inhibition of gastric motor activity. This assay should prove useful for identifying drug-evoked changes in gastric emptying as well as for assessing the gastric motility effects of altered gene expression in genetically modified mice.     

The effect of phentolamine on basal and pethidine-induced inhibition of gastric emptying in healthy volunteers.

1. The effect of phentolamine 5 mg i.v. on basal and pethidine-induced inhibition of gastric emptying of semisolid TC-99m labelled Chelex-100 resin/oatmeal was studied in ten healthy volunteers. 2. Each volunteer acted as his/her own control. 3. Basal gastric emptying remained unchanged after administration of phentolamine. 4. Administration of phentolamine reversed the pethidine-induced inhibition of gastric emptying.     

Inter- and intrasubject variability of gastric emptying in healthy volunteers measured by scintigraphy and paracetamol absorption.

1. Inter- and intrasubject variability in the gastric emptying of semisolids and liquids was measured by scintigraphic emptying of radionuclide-labelled semisolid and from paracetamol absorption in ten healthy volunteers of both sexes. 2. The intrasubject variability was not statistically significant for any of scintigraphic or paracetamol absorption parameters. 3. The intersubject variation was significant for all scintigraphic and paracetamol absorption parameters. 4. In women, the gastric emptying rate of semisolid decreased linearly during the menstrual cycle. 5. The lag period and paracetamol absorption parameters were unrelated to the day of the menstrual cycle day. 6. There was no statistically significant relationship between scintigraphic and paracetamol absorption parameters.     

Pharmacological effects of oxytocin on gastric emptying and intestinal transit of a non-nutritive liquid meal in female rats

The effects of oxytocin (OT) on gastric emptying, gastrointestinal transit, and plasma levels of cholecystokinin (CCK) were studied in female rats. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na(2)(51)CrO(4). Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Blood samples were collected for CCK radioimmunoassay. After administration of OT (0.2-0.8 mg/kg), gastric emptying and gastrointestinal transit were inhibited, whereas the plasma concentration of CCK was increased in a dose-dependent manner. Atosiban, an oxytocin receptor antagonist, effectively attenuated the OT- induced inhibition of gastric emptying and gastrointestinal transit. However, administration of atosiban alone had no effect on gastric emptying and gastrointestinal transit. The selective CCK(1) receptor antagonists, devazepide and lorglumide, effectively attenuated the OT-induced inhibition of gastric emptying and gastrointestinal transit. L-365, 260, a selective CCK(2) receptor antagonist, did not alter the OT-induced inhibition of gastric emptying and gastrointestinal transit. These results suggest that OT inhibits gastric emptying and gastrointestinal transit in female rats via a mechanism involving CCK stimulation and CCK(1) receptor activation.     

五种不同基源石斛对小鼠肠推进及胃排空的影响

目的:观察叠鞘石斛、金钗石斛、铁皮石斛、马鞭石斛和鼓槌石斛对在体小鼠胃排空及肠推进的影响.方法:用营养性半固体糊灌胃法观察各实验组对在体小鼠小肠推进率和胃排空率的变化.结果:铁皮石斛可促进正常小鼠的胃排空,对正常小鼠的肠推进有双向调节作用;叠鞘石斛可促进正常小鼠的胃排空和肠推进;鼓槌石斛与马鞭石斛可抑制正常小鼠的胃排空及肠推进;而金钗石斛对小鼠胃排空和肠推进没有明显的作用.各石斛组对阿托品引起的胃肠运动迟缓作用不明显,能调节新斯的明引起的胃肠运动亢进,使其恢复正常水平.结论:不同基源石斛对小鼠胃排空和肠推进的作用不尽相同,将不同基源石斛作为同一味药物使用的合理性还有待进一步研究.     

Effect of metoclopramide, bethanechol and the cholecystokinin receptor antagonist, L-364,718, on gastric emptying in the rat

The prokinetic effects of metoclopramide, bethanechol and L-364,718 on a semisolid meal and solid pellet gastric emptying were evaluated and compared. Each compound increased the rate of meal emptying as measured 90 min post-dose. L-364,718, a non-peptide CCK antagonist, was the most potent of these three agents with statistically significant activity observed at 0.03, 0.1 and 0.3 mg/kg p.o. Only metoclopramide significantly enhanced pellet emptying in a dose-dependent manner (3-30 mg/kg p.o.). The effects of each test agent and the potential physiologic role of cholecystokinin in regulating gastric emptying are discussed.     

Lack of systematic effects of the 5-hydroxytryptamine 3 receptor antagonist ICS 205-930 on gastric emptying and antral motor activity in patients with primary anorexia nervosa.

1. The 5-hydroxytryptamine 3 receptor antagonist, ICS 205-930, has been reported to have potent effects on gastric smooth muscle and to enhance gastric emptying in animals, but findings in man have been inconsistent. 2. This study investigated the effects of ICS 205-930 on gastric emptying of an isotopically labelled semisolid 1168 kJ meal and on antral contractility in patients with primary anorexia nervosa, a condition frequently associated with impaired gastric motor function. 3. Thirteen female patients (age 18-39 years, median 22 years; percentage of ideal body weight 52-90%, median 66%) participated each in two studies, in which 0.15-0.18 mg kg-1 ICS 205-930 or placebo were infused i.v. in crossover, double-blind fashion. Gastric emptying and antral contractility were recorded scintigraphically for 50 min. 4. ICS 205-930 did not affect gastric emptying: the mean percentage of meal remaining in the stomach after 50 min (69.6% +/- 3.2 s.e. mean) was nearly identical to that after placebo (70.7 +/- 3.3%). 5. Amplitude, frequency and propagation velocity of antral contractions differed only little after ICS 205-930 and placebo, respectively. 6. The results show that ICS 205-930 has no effect on the impaired gastric motor activity in primary anorexia nervosa and thus provide further evidence that the compound does not have prominent prokinetic effects in man.     

Effects of the 5-HT3 receptor antagonist ICS 205-930 on fat-delayed gastric emptying and antral motor activity.

1. The selective 5-HT3 receptor antagonist, ICS 205-930 (Sandoz), has been reported to have potent effects on gastric smooth muscle in vivo and to enhance gastric emptying in animals and in man. 2. This study investigated the effects of ICS 205-930 on fat-delayed gastric emptying of a semisolid meal and antral motor activity in humans. 3. Twelve healthy men participated in each of three studies in which 10 or 20 mg of ICS 205-930 or placebo were infused i.v. in a random double-blind fashion. Gastric emptying and antral motor activity were studied scintigraphically. 4. Gastric emptying was not altered after 10 mg but slower after 20 mg of ICS 205-930 than after placebo. Emptying after 20 mg of ICS 205-930 was significantly slower than after 10 mg of ICS 205-930. 5. Antral contraction amplitude was slightly lower after 20 mg of ICS 205-930 than after placebo, whereas the effects of 10 mg ICS 205-930 did not differ from those of placebo. 6. The results suggest that the investigated doses of ICS 205-930 have only slight effects on gastric motor activity of healthy young men, with 20 mg reducing the rate of emptying.     

Novel benzamides as selective and potent gastrokinetic agents. 2. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl] benzamide citrate (AS-4370) and related compounds

The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.     

Delta-9-tetrahydrocannabinol and gastric emptying.

The effects of delta-9-tetrahydrocannabinol (0.5 and 1 mg i.v.) on gastric emptying of liquid were investigated in seven normal volunteers and compared with placebo. Despite significant change in pulse rate and psychological parameters consistent with cannabis activity there was no significant effect on the pattern of gastric emptying. It is therefore suggested that an anti-emetic action of delta-9-tetrahydrocannabinol does not involve a change in gastric emptying.     

Histamine H2-antagonists modify gastric emptying in the rat.

1 Histamine H2-receptor antagonists were tested for their effect on gastric emptying in the rat. 2 At low doses all the compounds were inactive except for burimamide which delayed and ranitidine which accelerated gastric emptying. 3 At high doses burimamide, metiamide, cimetidine and oxmetidine delayed, whereas ranitidine accelerated gastric emptying; tiotidine remained ineffective. 4 Changes in emptying rate were not accompanied by changes in emptying pattern which, with all the compounds examined, proceeded, as in the controls, by apparent first order kinetics. 5 The mechanism of the ranitidine-induced acceleration of gastric emptying seemed to be connected with an interference with the cholinergic system, whereas the mechanism of cimetidine- and oxmetidine-induced slowing of gastric emptying was apparently related to cholinolytic and possibly also relaxant effects of the compounds. 6 These different effects of the various H2-blockers are consistent with the idea that changes in emptying rate are independent of H2-receptor blockade.     

Fat preload delays gastric emptying: reversal by cisapride.

1. Meals empty more slowly when they contain fat. 2. This study investigated whether an intragastric fat preload in comparison with a water preload affected gastric emptying of a semisolid meal and antral motor activity, and whether cisapride reversed such effects. 3. Twelve healthy subjects were studied under three conditions each: (A), preload of 50 ml water orally; (B) and (C), preload of 50 ml cream (20 g fat). After preloads, subjects reclined right sided for 20 min. Thereafter, placebo in conditions (A) and (B) and 10 mg cisapride in (C) were administered i.v. in a random double-blind fashion and subjects ingested a semisolid radiolabelled 1150 kJ meal. Gastric emptying and antral motor activity were recorded scintigraphically for 50 min using a dual-headed gamma camera. 4. Gastric emptying was significantly slower (P less than 0.005) after fat preload and placebo than after water preload and placebo. Cisapride administered after fat preload abolished the delaying effect of the fat preload (P less than 0.001). 5. Antral contraction amplitudes after fat preload and placebo were higher (P less than 0.01) than after water preload and placebo as well as fat preload and cisapride at the start of recording and decreased slightly thereafter, whereas slight increases occurred in the other conditions. Frequency and propagation velocity of contractions were not differently affected. 6 Gastric emptying is delayed after prior fat ingestion and this effect is abolished by cisapride.     

The influence of levodopa on gastric emptying in healthy elderly volunteers

Summary Paracetamol absorption and ⁹⁹Tc-DTPA measurements have been used to determine the influence of levodopa on gastric emptying in 8 healthy elderly volunteers.In the absence of levodopa 7 subjects showed a rapid gastric emptying pattern by gamma-camera and a single major peak in the plasma concentration-time curve of paracetamol. One subject showed two rapid phases of gastric emptying separated by a period of negligible emptying and had 2 separate peaks in the paracetamol plasma concentration-time curve.In the presence of levodopa, the gamma-camera data for 6 subjects showed a pattern of gastric emptying consisting of 2 rapid phases separated by a plateau. In each case secondary peaks in the plasma concentration-time curve of paracetamol occurred about 30 min after the end of the plateau. The time to 90% emptying on the gamma scan was increased significantly from 40 min to 65 min in the presence of levodopa.Comparison of the present data with those reported previously indicates that levodopa affects gastric emptying in the both elderly and young volunteers to a similar extent.     

The effects of domperidone on gastric emptying of liquid in man.

1 The effects of domperidone (20 mg) i.v. and saline i.v. on gastric emptying of 500 ml of fluid have been compared in a blind study in six normal male volunteers. 2 Gastric emptying was measured by real-time ultrasound. 3 Domperidone significantly reduced the volume in the stomach 5 min after the drink (domperidone 306 +/- 17 ml, saline 404 +/- 31 ml, P less than 0.02). 4 Domperidone had no significant effect on the half-life of gastric emptying measured between 5 and 60 min (T1/2 domperidone 21.2 +/- 1.17 min, T1/2 saline 21.3 +/- 1.58 min). 5 A similar pattern of gastric emptying to that produced by domperidone could be produced by giving a drink of a smaller volume.     

Novel benzamides as selective and potent gastric prokinetic agents. 1. Synthesis and structure-activity relationships of N-[(2-morpholinyl)alkyl]benzamides

With the purpose of obtaining more potent and selective gastric prokinetic than metoclopramide (1), a new series of N-[(2-morpholinyl)alkyl]benzamides (17-52) were synthesized and their gastric prokinetic activity was evaluated by determining effects on the gastric emptying of phenol red semisolid meal and of resin pellets solid meal in rats and mice. The morpholinyl moiety was newly designed after consideration of the side-chain structure of cisapride (2) and produced the desired activity when coupled with the 4-amino-5-chloro-2-methoxybenzoyl group of both metoclopramide and cisapride. Modification of the substituents of the benzoyl group markedly influenced the activity. In particular, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (17) and the 4-(dimethylamino) and 2-ethoxy analogues (25 and 29) of 17 showed potent and selective gastric prokinetic activity along with a weak dopamine D2 receptor antagonistic activity.     

Wagner-Nelson method for analysing the atypical double-peaked [13CO2] excretion curve in the [13C]-octanoate gastric emptying breath test in humans

1. In the [(13)C]-octanoic acid breath test, the time versus pulmonary [(13)CO(2)] excretion rate curve is analysed using mathematical curve-fitting techniques to calculate gastric emptying parameters. Thus, the goodness-of-fit highly influences the accuracy of the breath test. However, a double-peaked [(13)CO(2)] excretion curve, which occasionally develops owing to the presence of an interval of quiescent gastric emptying (the plateau phase), is likely to be fitted poorly. 2. In pharmacokinetics, the Wagner-Nelson method has been used to describe precisely the absorption kinetics of orally administered drugs and its reliability is independent of the nature of gastric emptying. A recent study has shown the potential of the Wagner-Nelson method to generate a realistic gastric emptying flow curve from [(13)CO(2)] excretion data. In the present report, we have demonstrated that the Wagner-Nelson method can visualize the plateau emptying phase responsible for the cases of double peaks. 3. Wagner-Nelson analysis applied to the breath test described precisely the characteristic emptying pattern of the two emptying phases being interrupted by the plateau phase. Conventional analysis for the breath test failed to detect the plateau phase. 4. The Wagner-Nelson method is a useful tool for analysing atypical double-peaking [(13)CO(2)] excretion curves.     

The effect of cold-restraint stress on gastric emptying in rats

The effects of drug treatment and of cold-restraint stress (a method used to produce experimental stomach ulcers) on gastric emptying of a resin (colestipol-phenol red complex) were investigated in rats. Gastric emptying was decreased by intraperitoneal treatment with atropine (0.3 mg/kg) or verapamil (4 mg/kg), and enhanced by bethanechol (1.2 mg/kg). Stress by restraint at 4 degrees C for 2 hr markedly reduced gastric emptying; the pattern of effects of drug pretreatment in these stressed rats was similar to that seen in their nonstressed controls. Further experiments, with stress for 3 hr, revealed that the gastric emptying rate was triphasic; increasing in the first hr, returning to normal and then slowing in the third hr of stress. Initial increase in emptying rate was probably due to predominant vagal overactivity. Hypothermia and possibly other factors induced by cold-restraint stress could have subsequently depressed gastric motility.     

Oral mitemcinal (GM-611), an erythromycin-derived prokinetic, accelerates normal and experimentally delayed gastric emptying in conscious dogs

1. We examined effects of orally administered mitemcinal, an erythromycin-derived motilin agonist, on gastric emptying and antroduodenal motility in conscious normal dogs and conscious dogs with experimentally delayed gastric emptying. For comparison, we also examined the effects of orally administered cisapride. 2. Gastric emptying was assessed by adding paracetamol to the test meal and determining three of its pharmacokinetic parameters as indices of gastric emptying. Antroduodenal motility was assessed from the output of force transducers chronically implanted in the gastric antrum and duodenum. 3. In normal dogs, mitemcinal (0.25, 0.5 and 1 mg/kg) dose-dependently accelerated gastric emptying, significantly increasing all three indices at doses of 0.5 and 1 mg/kg; cisapride (1, 3 and 10 mg/kg) had no significant effect. Mitemcinal also dose-dependently stimulated antroduodenal motility in the interdigestive and digestive states. Cisapride, at 100-fold the dose, produced similar effects in the interdigestive state, but mixed results in the digestive state. 4. In dogs with delayed gastric emptying induced by subcutaneous clonidine (0.03 mg/kg), mitemcinal (0.25, 0.5 and 1 mg/kg) dose-dependently improved delayed gastric emptying, significantly increasing two of three indices at a dose of 1 mg/kg. Cisapride (1, 3 and 10 mg/kg) caused non-significant increases in the indices of gastric emptying, with roughly bell-shaped dose-response curves. The highest dose of mitemcinal (1 mg/kg) also stimulated antroduodenal motility. 5. In dogs with delayed gastric emptying induced by vagotomy, mitemcinal (0.125, 0.25 and 0.5 mg/kg) dose-dependently improved delayed gastric emptying, significantly increasing all three indices at doses of 0.25 and 0.5 mg/kg. Cisapride (3 mg/kg) restored the indices to roughly prevagotomy levels, but none of the increases was significant. Mitemcinal, at a dose of 0.25 mg/kg, also stimulated antroduodenal motility. 6. Because delayed gastric emptying is the basic characteristic of gastroparesis, the fact that mitemcinal accelerated gastric emptying in dogs with normal and delayed gastric emptying much more robustly than cisapride adds to the evidence that mitemcinal is likely to be useful for the treatment of patients with gastroparesis.