Gastro-oesophageal reflux disease (GORD) occurs more frequently in Europe and North America than in Asia but its prevalence is now increasing in many Asian countries. Many reasons have been given for the lower prevalence of GORD in Asia. Low dietary fat and genetically determined factors, such as body mass index and maximal acid output, may be important. Other dietary factors appear to be less relevant. Increased intake of carbonated drinks or aggravating medicines may influence the increasing rates of GORD in some Asian countries but no strong evidence links other factors, such as the age of the population, smoking or alcohol consumption, to GORD. The management of GORD in Asia is similar to that in Europe and North America but the lower incidence of severe oesophagitis in Asia may alter the approach slightly. Also, because Asians tend to develop stomach cancer at an earlier age, endoscopy is used routinely at an earlier stage of investigation. Gastro-oesophageal reflux disease is essentially a motility disorder, so short-term management of the disease can usually be achieved using prokinetic agents (or histamine (H2)-receptor antagonists). More severe and recurrent GORD may require proton pump inhibitors (PPI) or a combination of prokinetic agents and PPI. The choice of long-term treatment may be influenced by the relative costs of prokinetic agents and PPI. 相似文献
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. 相似文献
This study examined the accumulation and metabolism of a number of drugs and commonly used probes for human cytochrome P450s (CYPs) in zebrafish larvae under conditions relevant to pharmacological and toxicological assays.
Studies with cisapride, chlorpromazine, verapamil, testosterone, and dextromethorphan showed that the zebrafish larvae catalyze a range of phase 1 (oxidation, N-demethylation, O-de-ethylation, and N-dealkylation) and phase 2 (sulfation and glucuronidation) reactions. Both similarities and differences in the metabolic pathways were observed in zebrafish larvae when compared to mammals.
Metabolism of phenacetin to paracetamol and dextromethorphan to dextrorphan (metabolic reactions catalyzed by CYP 1A2 and 2D6 in humans respectively) were observed in the zebrafish larvae. In addition the zebrafish larvae 7 days post fertilization (7 d.p.f.) hydroxylated diclofenac, bupropion, tacrine, and testosterone.
Although metabolites of several compounds were detected in zebrafish larvae, in the instances where the metabolite amounts were quantified, the amount of any specific metabolite formed was low, accounting for only a small percentage of the amount of parent compound added. Furthermore, when the concentrations of metabolite present in the zebrafish larvae were compared with the measured level of parent compound, the metabolite concentrations were always much lower than that of parent compound. Overall, for the compounds used in the current study it is unlikely that the quantified metabolites would significantly contribute to the outcome of safety pharmacology or toxicology studies conducted in zebrafish larvae under the paradigms typically used for such investigations.
The evaluation and management of gastric motor dysfunction continues to represent a significant clinical challenge. The very definition of what constitutes a clinically relevant disturbance of gastric motility remains unclear. The spectrum of gastroparesis extends from those with classical symptoms and severe delay of gastric emptying to those with dyspepsia and a mild delay in emptying rate. Indeed, for many patients with dyspepsia, the role of gastric emptying delay in the pathogenesis of symptoms, remains unclear. Any assessment of the efficacy of any therapeutic class in gastroparesis must be mindful, therefore, of these variations in definition. For those individuals with severe established gastroparesis, therapeutic success often remains elusive and iv. erythromycin and oral dopamine antagonists, or substituted benzamides, remain the best options for acute severe exacerbations and chronic maintenance therapy, respectively. Alternatives, currently under investigation, include a number of 5-HT4 agonists, macrolides devoid of antibiotic activity, CCK antagonists and gastric electrical stimulation. Other novel approaches include strategies to address some of the regional abnormalities in gastric motor function that have been identified in some patients with dyspepsia. 相似文献
Halter F, Miazza B, Bngnoli R. Cisapride or cimetidine in the treatment of functional dyspepsia. Results of a double-blind, randomized, Swiss multicentre study. Scand J Gastroenterol 1994;29:618-623Background: Functional dyspepsia is a major diagnostic and therapeutic challenge for the clinician. Several systems for the identification of 'high-risk' patients and classifications of dyspepsia subtypes and treatment schemes have been proposed in the past with limited experimental evidence to support the claims made. The present trial was designed to compare two different treatment modalities in a group of functional dyspepsia patients selected on the basis of a standardized diagnostic procedure as 'non-risk' for organic disease and to assess the result in the major symptom sub-groups of functional dyspepsia as a means of identifying the potential for improving treatment outcome.Methods: The efficacy of the prokinetic drug cisapride (5 mg four times daily) and of the histamine H2-receptor antagonist cimetidine (200 mg four times daily) were evaluated after 1 month of treatment and after a further follow-up of 1 month. Patients were randomized to the trial if they fulfilled the following criteria: 1) 'low-risk' symptoms or negative endoscopy findings, and 2) 2 weeks of single-blind antacid treatment did not provide satisfactory relief. For analysis patients were stratified into dyspepsia subtypes.Results: One hundred and sixty-one patients entered the run-in period, and 137 patients were randomized to the study. At the end of 4 weeks' treatment a small but significant difference in favour of cisapride was found; this difference can mainly be accounted for by the significant difference found in the dysmotility-like subtype (83% improved with cisapride versus 59% with cimetidine). No significant differences could be detected between drugs in the other dyspepsia subtypes at the end of the treatment-or follow-up period.Conclusions: The study confirms the classification into dyspepsia-subtypes as a useful tool in selecting the most appropriate drug therapy. 相似文献
AIMS: To determine whether the pharmacokinetics of cisapride and its interaction with grapefruit juice are stereoselective. METHODS: The study was a randomized, two-phase cross over design with a washout period of 2 weeks. Ten healthy volunteers were pretreated with either water or 200 ml double strength grapefruit juice three times a day for 2 days. On the 3rd each subject ingested a single 10 mg dose of rac-cisapride tablet. Double strength grapefruit juice (200 ml) or water was administered during cisapride dosing and 0.5 and 1.5 h thereafter. Blood samples were collected before and for 32 h after cisapride administration. Plasma concentrations of cisapride enantiomers were measured by a chiral h.p.l.c. method. A standard 12-lead ECG was recorded before cisapride administration (baseline) and 2, 5, 8, and 12 h later. RESULTS: This study showed that cisapride pharmacokinetics are stereoselective. In control (water treated) subjects, the mean Cmax (30 +/- 13.6 ng ml-1; P = 0.0008) and AUC(0, infinity) (201 +/- 161 ng ml-1 h; P = 0.029) of (-)-cisapride were significantly higher than the Cmax (10.5 +/- 3.4 ng ml-1) and AUC(0, infinity) (70 +/- 51.5 ng ml-1 h) of (+)-cisapride. There was no marked difference in elimination half-life between (-)-cisapride (4.7 +/- 2.7 h) and (+)-cisapride (4.8 +/- 3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (-)-cisapride from 30 +/- 13.6-55.5 +/- 18 ng ml-1 (95% CI on mean difference, -33, -17; P = 0.00005) and of (+)-cisapride from 10.5 +/- 3.4 to 18.4 +/- 6.2 ng ml-1 (95% CI on mean difference, -11.8, -3.9, P = 0.00015). The mean AUC(0, infinity) of (-)-cisapride was increased from 201 +/- 161 to 521.6 +/- 303 ng ml-1 h (95% CI on mean difference, -439, -202; P = 0.0002) and that of (+)-cisapride from 70 +/- 51.5 to 170 +/- 91 ng ml-1 h (95% CI on mean difference, -143, -53; P = 0.0005). The tmax was also significantly increased for both enantiomers (from 1.35 to 2.8 h for (-)-cisapride and from 1.75 to 2.9 h for (+)-cisapride in the control and grapefruit juice group, respectively; P < 0.05). The t(1/2) of (-)-cisapride was significantly increased by grapefruit juice, while this change did not reach significant level for (+)-cisapride. The proportion of pharmacokinetic changes brought about by grapefruit juice was similar for both enantiomers, suggesting non-stereoselective interaction. We found no significant difference in mean QTc intervals between the water and grapefruit juice treated groups. CONCLUSIONS: The pharmacokinetics of cisapride is stereoselective. Grapefruit juice elevates plasma concentrations of both (-)- and (+)-cisapride, probably through inhibition of CYP3A in the intestine. At present, there are no data on whether the enantiomers exhibit stereoselective pharmacodynamic actions. If they do, determination of plasma concentrations of the individual enantiomers as opposed to those of racemic cisapride may better predict the degree of drug interaction, cardiac safety and prokinetic efficacy of cisapride. 相似文献
AIM—To assess the efficacy of cisapride in reducing ileus persisting to the tenth postoperative day after neonatal abdominal surgery.METHODS—A prospective, randomised, double blind trial comparing rectal cisapride (l.4-2.3 mg/kg/day) with placebo over seven days was undertaken in 33neonates.RESULTS—Seven of 12 (58%) patients receiving placebo and eight of 11 (73%) receiving cisapride achieved a first sustained feed during treatment. Of those receiving cisapride, the first sustained feed occurred at 2.3 days (SEM 0.6) compared with 4.7 days (SEM 0.8) with placebo. By the seventh day the mean daily net enteral balance was 69 (SEM 18) ml/kg in the cisapride subgroup and 17 (SEM 8) ml/kg for those receiving placebo. Stool was passed on 6.3 (SEM 0.4) treatment days in the cisapride subgroup compared with 4.1(SEM 1.0) treatment days in the placebo subgroup.CONCLUSION—Cisapride is effective in neonates with a prolonged ileus after abdominal surgery. 相似文献