Shedding light on voltage-dependent gating

BACKGROUND: Erythromycin is a macrolide antibiotic that exhibits prokinetic effects. It has been shown to enhance antral contractility and accelerates gastric emptying rates, primarily by stimulating motilin receptors. AIM: To determine the optimal dosage form of erythromycin for use as a prokinetic agent. METHODS: Eight normal volunteers and three patients with documented gastroparesis ingested 250 mg erythromycin in tablet. suspension and intravenous forms. Serum erythromycin levels were determined at frequent intervals. These data were plotted vs. time and analysed for lag time, time to maximum concentration (tmax), maximum concentration (Cmax) and bioavailability (F). RESULTS: The absorption kinetics of the erythromycin suspension was notable for short lag times and early tmax, while lag times and tmax were delayed with the tablet form. Median lag time was 15 min for the suspension vs. 90 min for the tablet (P < 0.005). Median tmax for the suspension was 45 min vs. 180 min for the tablet (P < 0.005). A non-significant decrease in F was seen with the suspension compared to the tablet (P = 0.12). CONCLUSION: Based on the kinetic data from this study, erythromycin suspension is the ideal dosage form for administration of this drug as a prokinetic agent.     

Comparison of right ventricular outflow tract and apical lead permanent pacing on cardiac output

Interactions of gastrointestinal prokinetic benzamides with 5-hydroxytryptamine (5-HT)3 and 5-HT4 receptors and the relation to their effects on gastrointestinal propulsion were investigated. Renzapride and zacopride potently inhibited 5-HT3-receptor-mediated contractions in the guinea pig colon, whereas RS67506 (1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(2-methyl sulphonylamino)ethyl-4-piperidinyl]-1-propanone hydrochloride), a selective 5-HT4-receptor agonist, showed no inhibition. RS67506, renzapride and zacopride all exerted 5-HT4 receptor-mediated relaxation in the carbachol-precontracted rat oesophagus. In mice, RS67506 shortened the whole gut transit time, whereas renzapride and zacopride were reported to prolong it. Gastrointestinal prokinetic benzamides, which are selective for 5-HT4-receptor agonistic over 5-HT3-receptor antagonistic action, may be useful in treating gastrointestinal disorders associated with impaired lower intestinal propulsion such as constipation.     

Pathophysiology and pharmacology of migraine. Is there a place for antiemetics in future treatment strategies?

This article reviews the pathophysiology and pharmacology of emesis in relation to migraine pathogenesis. Also, the place of antiemetic and gastrointestinal prokinetic agents in current and future acute migraine treatment strategies is reviewed. The mechanisms of action of current and novel acute migraine therapies are considered with respect to the neurogenic and vascular hypothesis. Control of migraine-associated nausea and vomiting is often achieved with the benzamide dopamine D2 receptor antagonist metoclopramide. This drug also has 5HT3 receptor antagonist activity and reproducibly stimulates gastric motility to increase the availability of orally administered drugs. Other antiemetic and gastroprokinetic agents with potential value for the treatment of migraine-associated nausea and vomiting could speed absorption of oral antimigraine therapies without central nervous system side effects. Domperidone, a dopamine D2 receptor antagonist that does not cross the blood brain barrier is relatively free of the central side-effect liability of metoclopramide. Cisapride, a benzamide 5HT4 receptor agonist gastrointestinal prokinetic drug, lacks dopamine antagonist activity. A controlled comparison of these agents as migraine co-therapies could provide information on the importance of peripheral and central mechanisms in migraine-associated nausea and vomiting and improve antimigraine treatment options.     

Diabetes and the gastrointestinal tract

Gastrointestinal motility disorders are common in patients with diabetes. The entire gastrointestinal tract may be involved from the esophagus to the anal sphincter. Before instituting therapy, people with diabetes first require a careful diagnostic evaluation. Treatment includes tight glucose control and the use of antiemetics and prokinetic agents.     

Transdermal delivery of erythromycin lactobionate--implications for the therapy of gastroparesis

BACKGROUND: The treatment of many diseases may be complicated by abnormalities in gastric emptying. Gastric motor dysfunction may lead to unpredictable food and medication delivery to the small intestine, their site of absorption. Prokinetic agents improve gastric motility, but orally administered drugs are unreliably absorbed, thereby limiting their effectiveness. A method of delivering prokinetic agents which bypasses the gastrointestinal tract could lead to more effective treatment. METHODS: Skin samples from rat, hairless mouse and man were placed in an in vitro diffusion chamber. The epidermal side of the skin was exposed to erythromycin lactobionate and passage of the drug across the skin sample monitored and quantitated by high-performance liquid chromatography with UV detection. RESULTS: Erythromycin passes across all skin types tested. Steady-state flux across hairless mouse skin was greater than for rat, full thickness human skin and human epidermis. In the first 3 h following introduction of erythromycin lactobionate, 1.85 mg/cm2 crossed human epidermis. Given that a dose of 50 mg may exert prokinetic effects in vivo in man, increasing the patch size to approximately equal to 28 cm2 should provide therapeutic levels of drug within 3 h. CONCLUSIONS: Erythromycin lactobionate, when administered transdermally, can be delivered at levels sufficient to treat gastroparesis. This technique warrants in vivo investigation.     

Gastroesophageal reflux in infants and children

Gastrooesophageal reflux is a common clinical condition in infancy and childhood. Evaluation and treatment are indicated if it is associated with complications such as failure to thrive, oesophagitis or pulmonary symptoms. Depending on the clinical symptoms, investigations may include pH-monitoring, upper gastrointestinal series and endoscopy. Gastrooesophageal reflux may be treated by parental reassurance, dietary advice, positional treatment, prokinetic agents and acid secretion inhibitors. Surgery is rarely indicated.     

Safety and long-term durability of completion gastrectomy in 81 patients with postsurgical gastroparesis syndrome

Postsurgical gastroparesis syndrome (PGS) is characterized by postcibal nausea and vomiting and is associated with functional gastric dysmotility. Patients frequently present with marked weight loss and malnutrition requiring hospitalization and prolonged parenteral nutrition. Typically, these patients fail to respond to prokinetic agents. Gastric reoperations are frequent and usually unsuccessful. Near-completion gastrectomy (NCG) has proved useful in small series of patients, but long-term follow-up has been lacking. The purpose of this study is to assess the safety and durability of NCG in a large group of patients with PGS. Eighty-one patients with documented PGS who failed to respond to prokinetic drug therapy were treated with NCG over an 11-year period. NCG was standardized with a 55-cm Roux-en-Y reconstruction. Patients were evaluated by a retrospective chart review and a prospective phone interview that compared pre- and postoperative health status based on a standardized severity of symptoms score. There were no operative deaths or complications related to the anastomosis. Average patient follow-up was 56.1 months (range, 2-142 months). Fifteen patients died of unrelated causes, and 14 patients were lost to follow-up. The remaining 52 patients showed a significant overall decrease in severity of symptoms score largely due to reduction in gastrointestinal symptoms and to a smaller but significant reduction in systemic symptoms. Nearly 80 per cent of patients reported long-term relief of symptoms. NCG is the procedure of choice for carefully selected patients with documented. Low morbidity and durable results can be anticipated in the majority of patients.     

Non-antibiotic effects of antibiotics: from side effects to therapeutic uses

Sometimes therapeutic needs to tap drugs side effects of a treatment to show new indications for those drugs. Antibiotics, which are somewhat some often-used drugs, are frequently prescribed in non-infectious pathologies. Some indications are reported in the literature: immunosuppressive or antiinflammatory (disulone, salazopyrine, cotrimoxazole, clofazimine, fusidique acid), small bowel prokinetic action (macrolides), endocrine effects (déméclocycline, kétoconazole), enzymatic effects (rifampicine, cyclines), sclerotherapy (cyclines), pro- or anti-tumoral effects. This incomplete list is growing up every days.     

Mice deficient in Mac-1 (CD11b/CD18) are less susceptible to cerebral ischemia/reperfusion injury

Many children with esophagitis demonstrate histological changes without gross evidence of esophagitis by esophagoscopy. The effect of omeprazole on the histological healing of esophagitis in children is unknown. Therefore, the aim of this study was to determine the effect of omeprazole on refractory histological esophagitis in pediatric patients. Eighteen patients with histological evidence of esophagitis and recurrent symptoms despite therapy with H2-receptor antagonists and prokinetic agents were prospectively treated with omeprazole. Dosing was adjusted by monitoring intragastric pH, and esophagoscopy was repeated after 8-12 weeks of omeprazole treatment. Two patients did not complete the study due to either worsening symptoms or hypergastrinemia. Of the remaining patients, 76% were asymptomatic with omeprazole treatment and 24% reported improvement in their symptoms. Approximately 40% demonstrated complete histological healing of their esophagitis. Three patients (17%) had persistent elevations in serum gastrin levels while on omeprazole treatment, which was associated with both younger patient age and higher omeprazole dosing; however, all elevated gastrin levels returned to normal after discontinuation of the medication. All patients had recurrence of their symptoms after completing a course of omeprazole, even patients with complete histological healing. Omeprazole is efficacious in treating children with esophagitis refractory to H2-receptor antagonist and prokinetic agents. However, none of the patients were able to discontinue acid suppressive therapy even after documented healing of their esophagitis.     

Use of electron scanning microscopy and technical mechanics methods for determination of prolonged usefulness of Polfix plates after clinical use]

BACKGROUND: The ability of gastroesophageal reflux disease to provoke asthma is controversial. Recent reports have suggested that reflux to the proximal esophagus may be especially likely to aggravate asthma, but the prevalence of proximal reflux in children and adolescents is poorly documented. It is also unclear how sensitive and specific the commonly used tests of reflux, barium swallow, and scintiscan are compared with pH probe studies in young patients. There is limited information on the effectiveness of the combination of H2 blockers and prokinetic agents in controlling reflux in children. OBJECTIVE: There were three objectives in this study: (1) to determine the prevalence of both proximal and distal gastroesophageal reflux in asthmatic children and adolescents; (2) to determine the sensitivity, specificity, positive and negative predictive values of barium swallow and scintiscan studies; and (3) to determine the effectiveness of standard antireflux pharmacotherapy. METHODS: A 24-hour, 2-channel pH probe study was carried out in 79 asthmatic children aged 2 to 17 years. The prevalence of abnormal proximal and distal gastroesophageal reflux was calculated from the findings. In 63 of these patients, barium swallow and Technetium99 scintiscan were carried out and the findings used to calculate the sensitivity, specificity, positive and negative predictive value of these studies relative to pH probe. In 11 subjects a follow-up, 24-hour pH probe was carried out after at least 3 weeks of therapy with an H2 blocker and prokinetic agent to determine the efficacy of therapy. RESULTS: There was abnormal proximal esophageal reflux in 64.5% of subjects and abnormal distal reflux in 73.4%. The sensitivity, specificity, positive and negative predictive values of barium swallow were 46.1%, 83.3%, 82% and 51%, respectively. Those of scintiscan were 15%, 72.7%, 50% and 32%, respectively. Of 11 subjects studied by repeat pH probe, 10 had persistent abnormal reflux. CONCLUSION: Abnormal reflux into the proximal esophagus occurs in the majority of asthmatic children with difficult-to-control disease. The barium swallow and scintiscan compare poorly with pH probe in diagnosing reflux. Treatment of reflux with recommended does of H2 blockers and prokinetic agents has a high failure rate, and follow-up studies are essential.     

Hashimoto''s thyroiditis in association with Tolosa Hunt syndrome: a case report

The effect of cisapride on constipation in para and tetraplegia is well known. We have investigated the effects of this prokinetic drug on anorectal activity and on the function of the lower urinary tract. One result of the anorectal study showed a significant increase in activity and a reduction in compliance of the ampulla. The urodynamic study demonstrated earlier and higher amplitude reflex contractions in hyperactive bladders; hypoactive bladders significantly reduced their compliance. No functional alterations of striated urethral sphincter were observed.     

Motilin and clinical application

Motilin is a regulatory polypeptide of 22 amino acid residues and orginates in motilin cells scattered in the duodenal epithelium of most mammals and chickens. Motilin is released into the general circulation at about 100-min intervals during the interdigestive state and is the most important factor in controlling the interdigestive migrating contractions. Recent studies have revealed that motilin stimulates endogenous release of the endocrine pancreas. Clinical application of motilin as a prokinetic has become possible since erythromycin and its derivatives were proved to be nonpeptide motilin agonists.     

Effect of bethanechol or erythromycin on gastric emptying in horses

OBJECTIVE: To investigate the prokinetic effect of bethanechol and erythromycin in the upper gastrointestinal tract of healthy horses by measuring the gastric emptying (GE) rate of a radioactive meal. ANIMALS: 4 healthy adult horses. PROCEDURE: After food was withheld for 12 hours, horses were given 370 MBq of 99mTc-labeled sulfur colloid incorporated into egg albumen and 37 MBq of 111In-labeled diethyltriaminepentaacetic acid in 120 ml of water via nasogastric intubation. Intravenously administered treatments were 0.9% NaCl solution, erythromycin (0.1 or 1.0 mg/kg of body weight), or bethanechol (0.25 mg/kg). All drugs were given in 10 ml of 0.9% NaCl solution. Dual-phase scintigraphic images were obtained by use of a gamma camera. The best-fit function was determined for each study, and the resultant curves were then analyzed by use of least squares nonlinear regression. Two variables, time to 50% emptying of the stomach (T-50) and slope of the emptying curve, were derived from the calculated power exponential equation. CONCLUSIONS: Treatment had a significant (P < 0.05) overall effect on T-50 of solid-phase GE. The T-50 of bethanechol (30.09 +/- 10.01 minutes), erythromycin at 0.1 mg/kg (59.08 +/- 10.01 minutes), and erythromycin at 1 mg/kg (60.50 +/- 10.01 minutes) were significantly shorter than T-50 after saline administration (89.97 +/- 10.01 minutes). There was a trend (P = 0.09) for the slope of solid-phase GE of bethanechol and erythromycin (0.1 mg/ kg; P = 0.37) to be steeper than that of saline solution. For liquid-phase GE, the T-50 and the slope of bethanechol differed significantly (P < or = 0.05) from those for saline solution. CLINICAL RELEVANCE: Bethanechol and erythromycin significantly increased solid-phase GE in healthy horses and may have value for use as prokinetic agents in certain gastrointestinal tract diseases.     

Impaired absorption of oral levodopa: a major cause for response fluctuations in Parkinson's disease

Most patients with Parkinson's disease develop response fluctuations after several years of chronic treatment with levodopa. Accumulating evidence suggest that pharmacokinetic mechanisms are the cause of some subtypes of response fluctuations, especially the "delayed-on" and "no-on" phenomena. Evaluation of gastric emptying in Parkinson patients with and without response fluctuations revealed that those with fluctuations had a significant delay in gastric emptying compared to patients without fluctuations. Treatment with cisapride, a prokinetic drug, causes amelioration of these fluctuations. The optimal solution is to bypass the stomach completely and deliver levodopa parenterally. This was done by levodopa ethylester injections, which reduced latency to "on" and prolonged "on" duration in patients with severe response fluctuations. These data emphasize the role of the stomach as one of the causes for deterioration in Parkinson's disease.     

Effect of the introduction of a financial incentive for fee-paying A&E attenders to consult their general practitioner before attending the A&E department

Gastric stasis in pancreatic cancer without mechanical obstruction is distressing and difficult to manage. We describe two patients who were treated by percutaneous endoscopic gastroenterostomy (PEG) combined with a jejunal extension. Both patients had pancreatic cancer and gastric stasis, with recurrent vomiting and no evidence of distal duodenal obstruction. They were unresponsive to high-dose prokinetic agents. In both cases a Bower-PEG feeding tube with jejunal extension was inserted endoscopically, with clinical improvement. The technique has the advantages of permitting enteral feeding and allowing aspiration of upper gastrointestinal secretions between feeds, which produces symptomatic relief from nausea and vomiting. This manoeuvre can produce effective palliation, perhaps following the patient to be managed at home during the terminal phase of their illness.     

Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis

Patients with gastroparesis frequently present challenging clinical, diagnostic, and therapeutic problems. Data from 146 gastroparesis patients seen over six years were analyzed. Patients were evaluated at the time of initial diagnosis and at the most recent follow-up in terms of gastric emptying and gastrointestinal symptomatology. The psychological status and physical and sexual abuse history in female idiopathic gastroparesis patients were ascertained and an association between those factors and gastrointestinal symptomatology was sought. Eighty-two percent of patients were females (mean age: 45 years old). The mean age for onset of gastroparesis was 33.7 years. The etiologies in 146 patients are: 36% idiopathic, 29% diabetic, 13% postgastric surgery, 7.5% Parkinson's disease, 4.8% collagen vascular disorders, 4.1% intestinal pseudoobstruction, and 6% miscellaneous causes. Subgroups were identified within the idiopathic group: 12 patients (23%) had a presentation consistent with a viral etiology, 48% had very prominent abdominal pain. Other subgroups were gastroesophageal reflux disease and nonulcer dyspepsia (19%), depression (23%), and onset of symptoms immediately after cholecystectomy (8%). Sixty-two percent of women with idiopathic gastroparesis reported a history of physical or sexual abuse, and physical abuse was significantly associated with abdominal pain, somatization, depression, and lifetime surgeries. At the end of the follow-up period, 74% required continuous prokinetic therapy, 22% were able to stop prokinetics, 5% had undergone gastrectomy, 6.2% went onto gastric electrical stimulation (pacing), and 7% had died. At some point 21% had required nutrition support with a feeding jejunostomy tube or periods of parenteral nutrition. A good response to pharmacological agents can be expected in the viral and dyspeptic subgroups of idiopathics, Parkinson's disease, and the majority of diabetics, whereas a poorer outcome to prokinetics can be expected in postgastrectomy patients, those with connective tissue disease, a subgroup of diabetics, and the subset of idiopathic gastroparesis dominated by abdominal pain and history of physical and sexual abuse. Appreciation of the different etiologies and psychological status of the patients may help predict response to prokinetic therapy.     

Diagnosis and management of gastroesophageal reflux in infants and children

Use of histamine blockers, proton pump inhibitors, and prokinetic drugs, along with traditional antacids, has become standard therapy for gastroesophageal reflux (GER) in symptomatic adults. Response to this therapy is assessed to confirm the diagnosis of GER, and is often advocated as the best way to establish the causes and effects of the disease. It is well documented that reflux occurs throughout the life span. However, the incidence in children is difficult to estimate, requiring interpretation of behavior and symptoms in nonverbal and atypical presentations. Unfortunately, the diagnosis of GER in children is often made after the development of complications such as aspiration pneumonia, esophagitis, or ulcers. Early recognition and intervention by primary care providers is necessary to prevent such serious complications of untreated GER. This article presents the pathophysiology and clinical manifestations of GER. Diagnosis in children is discussed, and recommendations for empiric therapy, including conservative measures and drug therapies, are presented.     

Clinical characteristics of chronic idiopathic intestinal pseudo-obstruction in adults

BACKGROUND: Chronic idiopathic intestinal pseudo-obstruction, a syndrome of ineffectual motility due to a primary disorder of enteric nerve or muscle, is rare. AIMS: To determine the clinical spectrum, underlying pathologies, response to treatments, and prognosis in a consecutive unselected group of patients. METHODS: Cross sectional study of all patients with clinical and radiological features of intestinal obstruction in the absence of organic obstruction, associated with dilated small intestine (with or without dilated large intestine), being actively managed in one tertiary referral centre at one time. RESULTS: Twenty patients (11 men and nine women, median age 43 years, range 22-67) fulfilled the diagnostic criteria. Median age at onset of symptoms was 17 years (range two weeks to 59 years). Two patients had an autosomally dominant inherited visceral myopathy. Major presenting symptoms were pain (80%), vomiting (75%), constipation (40%), and diarrhoea (20%). Eighteen patients required abdominal surgery, and a further patient had a full thickness rectal biopsy. The mean time interval from symptom onset to first operation was 5.8 years. Histology showed visceral myopathy in 13, visceral neuropathy in three, and was indeterminate in three. In the one other patient small bowel motility studies were suggestive of neuropathy. Two patients died within two years of symptom onset, one from generalised thrombosis and the other from an inflammatory myopathy. Of the remaining 18 patients, eight were nutritionally independent of supplements, two had gastrostomy or jejunostomy feeds, and eight were receiving home parenteral nutrition. Five patients were opiate dependent, only one patient had benefited from prokinetic drug therapy, and five patients required formal psychological intervention and support. CONCLUSIONS: In a referral setting visceral myopathy is the most common diagnosis in this heterogeneous syndrome, the course of the illness is usually prolonged, and prokinetic drug therapies are not usually helpful. Ongoing management problems include pain relief and nutritional support.     

The hypotensive effect of cisapride in rat

1. Cisapride is a prokinetic agent believed to facilitate acetylcholine release from the myenteric plexus of the gut. The aim of the present study was to investigate the effect of cisapride on blood pressure and the effects of muscarinic receptor antagonists on the cisapride-induced blood pressure changes. 2. Cisapride was given i.v. alone or 10 min after muscarinic receptor antagonists. Cisapride given i.v. produced a significant decrease in blood pressure in a dose-related manner. Atropine, AF-DX 116 and 4-DAMP given 10 min before cisapride injection, partially inhibited the hypotensive response to cisapride. In pithed rat, the effect of cisapride on blood pressure remained unaltered. 3. This study indicates that the action of cisapride is not through central mechanisms and part of cisapride's effect is through the cholinergic system.     

Extracorporeal photopheresis in therapy-refractory disseminated discoid lupus erythematosus

BACKGROUND: The place of acid pump inhibitors at the top of the efficacy table in the league of reflux therapies, and their eager patient acceptance, has aroused debate on their role. OBJECTIVE: To understand the role of gastric acid and its inhibition in the pathogenesis and treatment of gastroesophageal reflux disease. DISCUSSION: Gastroesophageal reflux disease results from excessive exposure of the oesophagus to acidic contents. Acid pump inhibitors provide the most effective medical control of gastric acid throughout day and night, returning oesophageal pH to normal levels. They provide fast symptom relief and rapidly restore quality of life in all reflux patients more effectively than H2 receptor antagonists or prokinetic drugs. APIs heal oesophagitis of all grades of severity and provide safe, effective maintenance of healing with prevention of complications in longer term use.