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AIM: To compare the impact of the right recumbent position with the sitting position on gastric emptying of water. METHODS: In eight healthy male volunteers, the 13C acetate breath test was performed twice to assess gastric emptying of 100 mL tap water. Subjects were seated in one test and lying on their right side in the other. In both positions, pulmonary (13)CO(2) exhalation curves were obtained by plotting breath data against time. Percent gastric retention curves were created by analyzing data using the Wagner-Nelson protocol. RESULTS: No significant posture effect was found in pulmonary (13)CO(2) output curves (P = 0.2150), whereas a significant effect was seen in gastric retention curves (P = 0.0315). The percent retention values at 10 min and 15 min were significantly smaller when subjects were in the right recumbent position compared with the seated position (P < 0.05). Our results verified the accelerating effect of the right recumbent position on gastric emptying of non-nutritive solutions. Concerning clinical implications, this study suggests that placing patients with acute pain on their right side after oral administration of analgesic drugs in solution is justified as an effective practice for rapid pain relief. For patients with gastrointestinal reflux symptoms, sleeping in the right recumbent position may reduce nocturnal symptoms, as delayed gastric emptying can cause reflux symptoms. CONCLUSION: Gastric emptying of water occurs more quickly when a subject lies on the right side compared with sitting.
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Pruebas Respiratorias/métodos , Vaciamiento Gástrico/fisiología , Postura/fisiología , Agua/metabolismo , Adulto , Análisis de Varianza , Isótopos de Carbono , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND/AIMS: In this pilot study, a new breath test system for gastric emptying study has been proposed. METHODOLOGY: The system involves 13C-uracil as a novel tracer and the Wagner-Nelson method for analyzing breath data. RESULTS: In three healthy volunteers, the new breath system allowed quantification of gastric emptying profiles as accurately as the scintigraphic technique. CONCLUSIONS: Further validation studies with a lager sample size are needed.
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Pruebas Respiratorias , Vaciamiento Gástrico , Estómago/diagnóstico por imagen , Estómago/fisiología , Uracilo , Adulto , Isótopos de Carbono , Ingestión de Alimentos , Humanos , Japón , Masculino , Persona de Mediana Edad , Proyectos Piloto , Cintigrafía , Factores de TiempoRESUMEN
Upper gastrointestinal hemorrhage (UGIH) is an urgent disease that is often encountered in daily medical practice. Endoscopic hemostasis is currently indispensable for the treatment of UGIH. Initially, when UGIH is suspected, a cause of UGIH is presumed from the medical interview and physical findings. After ample primary treatment, urgent endoscopy is performed. Many methods of endoscopic hemostasis are in wide use, including hemoclip, injection and thermo-coagulation methods. Although UGIH develops from a wide variety of diseases, such as esophageal varices and gastric and duodenal ulcer, hemostasis is almost always possible. Identification of the causative diseases, primary treatment and characteristic features of endoscopic hemostasis are needed to allow appropriate treatment.
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The proton pump inhibitor (PPI) is widely used for the treatment of gastroesophageal reflux disease, peptic ulcer diseases, and functional dyspepsia. The pathogenesis of these acid-related and/or functional upper gastrointestinal disorders is potentially associated with abnormal gastric emptying. To date, variable effects of PPIs on gastric emptying have been reported. Therefore, it is relevant to gather and analyze published information on this topic. A systematic literature search has been performed, showing that the delaying effect of PPIs on gastric emptying of solid meals is consistent, whereas the effect of PPIs on the emptying of liquids is inconsistent. The underlying mechanisms whereby PPIs may affect gastric emptying have been discussed, most of which still remain hypothetic. Gastric emptying of solids involves a process of peptic hydrolysis. PPIs impair the hydrolytic digestion by inhibiting acid-dependent peptic activity, thereby delaying the solid emptying. Gastric emptying of liquids largely depends on volume and energy density of intragastric contents. PPIs variably modify the volume and the energy density by reducing gastric fluid secretion, thereby modifying the liquid emptying in an unpredictable manner. Hypergastrinemia has been considered to delay gastric emptying, but it seems of minor importance in the regulation of gastric emptying during PPI use. The delayed emptying of solids due to PPI therapy may have clinical implications in the management of gastroesophageal reflux disease, functional dyspepsia, as well as diabetes.
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Digestión/efectos de los fármacos , Ácido Gástrico/metabolismo , Vaciamiento Gástrico/efectos de los fármacos , Enfermedades Gastrointestinales/tratamiento farmacológico , Inhibidores de la Bomba de Protones/efectos adversos , Estómago/efectos de los fármacos , Animales , Dispepsia/tratamiento farmacológico , Medicina Basada en la Evidencia , Reflujo Gastroesofágico/tratamiento farmacológico , Humanos , Hidrólisis , Plexo Mientérico/efectos de los fármacos , Plexo Mientérico/fisiopatología , Úlcera Péptica/tratamiento farmacológico , Estómago/inervación , Estómago/fisiopatologíaRESUMEN
A stable isotope ([(13)C]) breath test is a promising method for assessing gastric emptying, but it has not been pervasive yet in Japan. We think that there are some barriers to its popularization, including the uncertainty concerning its theoretical backgrounds, the ambiguity of analyzing and interpreting the data, and the lack of standard protocols for breath sampling. The aim of the present review is to break through these barriers. We hope this article could make the [(13)C]-gastric breath test more maneuverable for and more accessible to researchers and clinicians.
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Pruebas Respiratorias/métodos , Vaciamiento Gástrico/fisiología , Marcaje Isotópico/métodos , Isótopos de Carbono , Protocolos Clínicos/normas , Humanos , JapónRESUMEN
BACKGROUND/AIMS: Gastric bubble is present in approximately 70% of normal chest and abdominal radiograph. Most swallowed air is regurgitated and belching is a physiological phenomenon to expel ingested gas from the stomach and is a common symptom in normal adults. In the present study it was investigated whether gastric bubble detected on abdominal radiograph is associated with GERD symptoms. METHODOLOGY: All of the patients who first attend our hospital were asked to respond the F-scale questionnaire regardless of their chief complaints to diagnose GERD. Plain abdominal films in the erect position were used to measure the size of gastric bubble and to classify the form of gastric bubble into four groups: dome-type; irregular-type; stomach-type; and undetected-type. The quantity of gastric bubble (gastric bubble score) was determined as the pixel value on image collected from hospital's digital database. RESULTS: The gastric bubble score of irregular-type was significant lower than that of dome-type and stomach-type. GERD was most frequently detected in stomach-type group, followed by undetected-type, irregular-type, and dome-type. The mean score of F-scale was significantly higher in stomach-type than in dome-type. CONCLUSIONS: It is concluded that gastric bubble detected on plain abdominal films is an informative marker for evaluating the functional disorder of upper digestive tracts. Physicians have to recognize the importance of plain films of the abdomen in the diagnostic process of GERD.
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Reflujo Gastroesofágico/etiología , Radiografía Abdominal , Adolescente , Adulto , Anciano , Aire , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The patient with colonic obstruction may frequently have bacterial overgrowth and increased breath hydrogen (H2) levels because the bacterium can contact with food residues for longer time. We experienced two cases with intestinal obstruction whose breath H2 concentrations were measured continuously. CASE 1: A 70-year-old woman with small bowel obstruction was treated with a gastric tube. When small bowel gas decreased and colonic gas was demonstrated on the plain abdominal radiograph, the breath H2 concentration increased to 6 ppm and reduced again shortly. CASE 2: A 41-year-old man with functional small bowel obstruction after surgical treatment was treated with intravenous administration of erythromycin. Although the plain abdominal radiograph demonstrated a decrease of small-bowel gas, the breath H2 gas kept the low level. After a clear-liquid meal was supplied, fasting breath H2 concentration increased rapidly to 22 ppm and gradually decreased to 9 ppm despite the fact that the intestinal gas was unchanged on X-ray. A rapid increase of breath H2 concentration may reflect the movement of small bowel contents to the colon in patients with small-bowel pseudo-obstruction or malabsorption following diet progression. CONCLUSIONS: Change in breath H2 concentration had a close association with distribution and movement of intestinal gas.
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Alcohol is commonly consumed with, or soon after, a meal that affects gastric emptying and thus, absorption and metabolism of alcohol. The aim of this study is to evaluate the effect of liquid test meal ingested soon after, alcohol ingestion on alcohol metabolism, as is common in the social setting. First, a 100 mL of water containing of 80 mg of 13C-ethanol was administrated orally in 7 healthy subjects, and 200 mL of liquid meal (200 kcal) was administrated 5 min after alcohol ingestion. Breath samples were taken at baseline and at 10-min interval for 150 min. Next, 13C-ethanol breath test was performed without ingestion of liquid meal. Cmax was decreased after ingestion of liquid meal, whereas Tmax was unchanged. The descending gradient of 13CO2 excretion curves after ingestion of liquid meal is parallel to that without liquid meal, while the ascending gradient of 13CO2 excretion curves in the first 10 min had a tendency to be greater after ingestion of liquid meal than without ingestion of liquid meal. A significant delay in breath 13CO2 excretion after ingestion of liquid meal was found and the AUC values were lower after ingestion of liquid meal in each time point, indicating that liquid meal ingested soon after alcohol ingestion may not affect elimination but absorption and/or metabolism of a small amount of alcohol.
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Ingestión de Alimentos/fisiología , Etanol/farmacocinética , Adulto , Anciano , Bebidas Alcohólicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
BACKGROUND: Despite a close association between gastrointestinal motility and sex hormones, it has been unknown whether ovarian hormones affect absorption and metabolism of nutrients. The aim of this study is, therefore, to evaluate metabolism of acetate in rats with age and the influence of ovariectomy on its change. METHODS: Fourteen female rats of the F344 strain were used, and 13C-acetate breath test was performed at 2, 7 and 13 months of age. Seven rats were ovariectomized at three weeks of age (ovariectomy group) and the remaining seven rats were studied as control group. After 24-hr fasting, rats are orally administrated 1ml of water containing sodium (13)C-acetate (100mg/kg) and housed in an animal chamber. The expired air in the chamber is collected in a breath-sampling bag using a aspiration pump. The (13)CO(2) concentration is measured using an infrared spectrometer for 120 min and expressed as delta per mil. RESULTS: The breath (13)CO(2) excretion increased with time and peaked 30 min in control rats. In ovariectomized rats, thee peak time of (13)CO(2) excretion was prolonged to 40 min at 7 and 13 months of age. Cmax was significantly higher at 2 months of age but lower at 4 months of age in ovariectomized rats than in control rats. Those of two groups became equal at 7 months of age. CONCLUSIONS: From the viewpoint of acetate metabolism, removal of ovarian hormones might make rats to be precocious ones and accelerate ageing.
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BACKGROUND: During esophageal acid clearance, salivation plays an important role in defending the esophageal mucosa. Mosapride, an agent used in chronic, long-term therapy of gastro-esophageal reflux disease (GERD) was regarded as mediating its efficacy through prokinetic properties. Rebamipide is also widely used as an anti-gastritis and anti-ulcer agent in GERD patients with chronic gastritis. The aim of this study is to investigate the effects of rebamipide, mosapride, and risperidone on the salivation induced by pilocarpine. MATERIALS AND METHODS: The experiments were conducted on 4-week male SD rats (120-150g). The salivation was induced by intraperitoneally administrated pilocarpine and saliva was collected using preweighted small cotton balls inserted into the animal's mouth every 30 min for 180 min. Thirteen minutes before intraperitoneal administration of pilocarpine, rebamipide, mosapride, and risperidone were administered intraduodenally. Control rats were conducted by intraperitoneal administration of saline and intraduodenal administration of 0.5% methylcellulose solution. RESULTS: The saliva weight at 0-30 min was significantly (p<0.01) increased after administration of pilocarpine, compared to control rats. An additional administration of mosapride and rebamipide increased the saliva weight at 0-30 min. The total volume of saliva for 150 min after administration of pilocarpine was the highest after preadministration of rebamipide, followed by mosapride, and risperidone. CONCLUSIONS: Increase in salivation produced by i.p. pilocarpine was enhanced by preadministration of rebamipide and mosapride.
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BACKGROUND: The usefulness of the typical direct methods involving duodenal intubation, such as the secretin and secretin-cholecystokinin tests, in the diagnosis of exocrine pancreatic dysfunction is widely accepted. However, these diagnostic tests tend to be avoided because of their technical complexity and the burden on patients. Recently, a simple breath test was developed for assessment of exocrine pancreatic function employing 13C-dipeptide [i.e., benzoyl-L-tyrosyl-[1-13C] alanine (Bz-Tyr-Ala)]. Although alcohol abuse causes pancreatic damage in humans, this has been unclear in rats. AIMS: The aim of the study is to evaluate the effect of ethanol exposure beginning at an early age on extra-pancreatic secretory function in rats. MATERIALS AND METHODS: Twelve female rats of the F344 strain aged 12 months were used. Seven rats were fed on a commercial mash food with 16% ethanol solution (Japanese Sake) as drinking-fluid since at 29 days of age (ethanol group). The remaining five rats were fed on a nutrient-matched isocaloric diet with water as drinking-fluid (control group). After 24-hr fasting, rats are orally administrated 1cc of water containing sodium 13C-dipeptide (5 mg/kg) and housed in an animal chamber. The expired air in the chamber is collected in a breath-sampling bag using a tube and aspiration pump. The 13CO2 concentration is measured using an infrared spectrometer at 10-min interval for 120 min and expressed as delta per mil. RESULTS: The breath 13CO2 level increased and peaked at 20 min in both two groups. In general, 13CO2 excretion peaked rapidly and also decreased sooner in ethanol rats than in control rats. The mean value of the maximal 13CO2 excretion is 34.7 per mil in ethanol rats, greater than in control rats (31.4 per mil), but the difference did not reach the statistically significance. CONCLUSION: Chronic ethanol feeding beginning at an early age does not affect extra-pancreatic secretory function in rats.
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BACKGROUND/AIMS: Gastric acid plays an important part in the prevention of bacterial colonization of the gastrointestinal tract. If these bacteria have an ability of hydrogen (H2) fermentation, intraluminal H2 gas might be detected. We attempted to measure the intraluminal H2 concentrations to determine the bacterial overgrowth in the gastrointestinal tract. METHODOLOGY: Studies were performed in 647 consecutive patients undergoing upper endoscopy. At the time of endoscopic examination, we intubated the stomach and the descending part of the duodenum without inflation by air, and 20 ml of intraluminal gas samples of both sites was collected through the biopsy channel. Intraluminal H2 concentrations were measured by gas chromatography. RESULTS: Over all, intragastric and intraduodenal H2 gas was detected in 566 (87.5%) and 524 (81.0%), respectively. The mean values of intragastric and intraduodenal H2 gas were 8.5 +/- 15.9 and 13.2 +/- 58.0 ppm, respectively. The intraduodenal H2 level was increased with the progression of atrophic gastritis, whereas the intragastric H2 level was the highest in patients without atrophic gastritis. CONCLUSIONS: The intraduodenal hydrogen levels were increased with the progression of atrophic gastritis. It is likely that the influence of hypochlorhydria on bacterial overgrowth in the proximal small intestine is more pronounced, compared to that in the stomach.
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Bacterias/crecimiento & desarrollo , Duodeno/metabolismo , Determinación de la Acidez Gástrica , Gastritis Atrófica/etiología , Adulto , Anciano , Anciano de 80 o más Años , Duodeno/microbiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estómago/microbiologíaRESUMEN
Accurate diagnosis of Helicobacter pylori infection is essential in today's clinical settings. Additionally, because of the widespread prevalence of this infection, noninvasive and convenient techniques are required for screening purposes. RAPIRUN H. pylori antibody detection kit (Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan) enables a diagnosis within 20 min using a random, single-voided urine specimen. Thus it is especially suited for use in point-of-care settings. The sensitivity and specificity are acceptable and comparable with other available methods. Here we provide an overview of the RAPIRUN kit.
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Anticuerpos Antibacterianos/inmunología , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/inmunología , Inmunoensayo/métodos , Juego de Reactivos para Diagnóstico , Humanos , Inmunoensayo/economía , Sistemas de Atención de PuntoRESUMEN
BACKGROUND AND OBJECTIVE: Recent studies have indicated that rabeprazole, a proton pump inhibitor, delays gastric emptying. However, the mechanism of action remains unclear. We conducted this study to clarify whether desacyl-ghrelin (the inactive form of the endogenous growth hormone secretagogue receptor ghrelin) is involved in rabeprazole-induced changes in gastric motor function. METHODS: Twelve healthy males underwent (13)C-acetate breath tests to evaluate gastric emptying of a liquid meal twice after administration of rabeprazole 20 mg/day for 3 days or no medication (control). Gastric emptying was evaluated by two parameters: half-emptying time and time to peak (13)CO(2) excretion. Plasma desacyl-ghrelin levels were measured in blood samples collected at three time points: immediately pre-test and 1 and 2 hours after ingestion of the test meal. RESULTS: Rabeprazole significantly delayed gastric emptying of the liquid meal. However, plasma desacyl-ghrelin levels after ingestion of the liquid meal showed little difference before or after rabeprazole administration. CONCLUSION: The results indicate that desacyl-ghrelin was not associated with changes in gastric emptying caused by rabeprazole.
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2-Piridinilmetilsulfinilbencimidazoles/farmacocinética , Vaciamiento Gástrico/efectos de los fármacos , Ghrelina/sangre , 2-Piridinilmetilsulfinilbencimidazoles/administración & dosificación , 2-Piridinilmetilsulfinilbencimidazoles/sangre , Administración Oral , Adulto , Pruebas Respiratorias/métodos , Dióxido de Carbono/análisis , Dióxido de Carbono/metabolismo , Isótopos de Carbono , Vaciamiento Gástrico/fisiología , Gastrinas/sangre , Gastrinas/química , Ghrelina/química , Semivida , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/sangre , Inhibidores de la Bomba de Protones/farmacocinética , Rabeprazol , Estadísticas no ParamétricasRESUMEN
A [13C]-breath test is a promising method for measuring gastric emptying. The methodological relevance is based on a close correspondence between gastric emptying of [13C]-acetate/octanoate (input) and pulmonary excretion of [13CO2] (output). Despite the close input-output correspondence, the pulmonary output is quite remote from the gastric input: the pulmonary output is delayed compared to the gastric input, and the total recovery of [13CO2] in the breath is incomplete. This review focuses on the kinetics of [13C]-acetate/octanoate in the body and suggests that (1) the delayed pulmonary output results from temporal retention of [13CO2] in the well-perfused tissues (heart, brain, etc.), (2) the incomplete recovery results from incorporation of the label into metabolic products (ketone bodies, amino acids, etc.) or from fixation of [13CO2] in the low-perfused tissues (bone, skeletal muscle, etc.), and (3) knowledge on the retention is the key to appropriate interpretations of breath test results. Recognition of these kinetic aspects is essential for appropriate interpretations of these breath test results.
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Pruebas Respiratorias/métodos , Vaciamiento Gástrico , Acetatos/metabolismo , Caprilatos/metabolismo , Isótopos de Carbono/metabolismo , Humanos , Intercambio Gaseoso PulmonarRESUMEN
UNLABELLED: During esophageal acid clearance, salivation plays an important role in defending the esophageal mucosa. Nizatidine, a histamine H2 receptor antagonist, inhibits acetylcholine esterase, with a resultant increase in acetylcholine. We experienced a patient with gastroesophageal reflux disease (GERD) and impaired salivary secretion who has been successfully treated with nizatidine. CASE REPORT: A 63-year-old female visited our hospital with complaints of heartburn and continuous laryngeal discomfort. Saliva scintigraphy was performed to evaluate the salivary function. Washout ratio was decreased to be 25%-40% in individual salivary gland. After the treatment with nizatidine, salivary scintigraphy demonstrated the increased washout ratios. The values of both parotid glands increased up to 90%, whereas those of submandibular glands improved to be around a normal range. GERD symptoms disappeared completely after treatment. In conclusion, nizatidine may be one of therapeutic options for low salivary excretion.
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Although there have been many studies that showed a close association between gastroesophageal reflux disease (GERD) symptoms and chronic cough, it has been unknown whether acute cough is also associated with GERD. The aim of this study was to evaluate the relationship between GERD and respiratory symptoms in general practice. 1725 consecutive patients who first attended our hospital were enrolled in the present study. They were asked to respond the F-scale questionnaire regardless of their chief complaints. Over all, 656 (38%) patients were diagnosed as GERD and 226 (13%) had respiratory symptoms. Patients with respiratory symptoms had GERD symptoms more frequently than patients without respiratory symptoms (p < 0.05). Forty-three (37%) of 115 patients with acute cough and 48 (43%) of 111 with nonacute cough had GERD symptoms, suggesting that development of GERD is not associated with the period of respiratory symptoms. Patients with respiratory symptoms are at a significantly increased risk of developing GERD. Whether or not treatment for GERD or respiratory diseases is useful for the prevention of respiratory symptoms and GERD, respectively, should not be driving management decisions in primary care.
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In the [(13)C]-octanoate breath test, two popular parameters have been used to quantify gastric emptying rates, namely the time to the maximal [(13)CO(2)] excretion (T(max)) and the time to the half-[(13)CO(2)] recovery (T(1/2b)). Although each of T(max) and T(1/2b) is closely correlated with the scintigraphic half-emptying time, the two parameters occasionally indicate different judgments on a gastric emptying rate. In this study, to clarify which of the two parameters is more reliable, T(max) and T(1/2b) were compared to the "reference" parameters calculated using the Wagner-Nelson method, which allows accurate estimation of a time-course of gastric emptying from breath data. Ten healthy male volunteers underwent the breath test after ingestion of a muffin meal (320 kcal) containing 100 mg [(13)C]-octanoate. Breath samples were collected at 15-min intervals for 6 h. According to the conventional analytical algorithm, T(max) and T(1/2b) were mathematically calculated. By applying Wagner-Nelson analysis to the breath test, the time-percent gastric retention curve was generated and the half-emptying time (T(1/2WN)) was determined. T(1/2WN) was more closely correlated with T(max) (r=0.954, P<0.0001) than with T(1/2b) (r=0.782, P=0.008). T(max) was significantly correlated with the percent gastric retention value in the early (t=0.25 and 0.5 h), the middle (t=1.0 and 1.5 h), and the late (t=2.0 h) postprandial phase. T(1/2b) was significantly correlated with the gastric retention value in the middle and the late phase, but not with the gastric retention value in the early phase. The present results show that T(1/2b) has limited capability to reflect gastric emptying in the early postprandial period, suggesting that T(max) is more reliable than T(1/2b) as a gastric emptying parameter.
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Pruebas Respiratorias , Dióxido de Carbono/análisis , Vaciamiento Gástrico/fisiología , Estómago/fisiología , Adulto , Caprilatos/administración & dosificación , Isótopos de Carbono/análisis , Humanos , Masculino , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: It is generally considered that gastric acid suppression delays gastric emptying of solid meals because gastric hypoacidity impairs peptic digestion and antral triturition. Rabeprazole is one of the most potent acid suppressants. We conducted this cross-over study to investigate if rabeprazole delays gastric emptying of liquid nutrients, for which peptic digestion is unnecessary. METHODS: On two randomized occasions, 13 healthy male volunteers underwent the (13)C-acetate breath test following ingestion of a 300 kcal-liquid meal. On one occasion, they had received 20 mg rabeprazole for the preceding 2 days and 1 h before the test. On another, they took no pretreatment. Based on 4 h breath samples, the half (13)CO(2) excretion time (t(1/2b)) and the time of maximal excretion (t(max)) were calculated as overall measures of gastric emptying. In addition, time profiles of gastric emptying were generated using the Wagner-Nelson analytical method, which creates the gastric emptying curve as accurately as the scintigraphy. RESULTS: Rabeprazole significantly prolonged t(max) but unchanged t(1/2b). The gastric emptying profiles showed that rabeprazole evoked a segmental slowing of gastric emptying during 0.5-1.25 h of post-meal ingestion. CONCLUSIONS: Rabeprazole suppresses gastric emptying of a liquid nutrient 0.5 h after meal ingestion. We have speculated that: (i) rabeprazole delays gastric emptying via a mechanism other than acid-pepsin maldigestion; and (ii) rabeprazole may intensify the post-gastric feedback regulation system (>0.5 h of post-meal).