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Action of the new H2-antagonist, DA 4577, on different in vitro and in vivo preparations.

The new H2-antagonist, 4(5)-(4- isopropylaminomethyleniminophenyl )-imidazole (compound marked DA 4577), was tested for its activity on different in vitro preparations and also in the conscious cat. Its effect was compared with that of some new H2 antagonists. Two sets of experiments were performed: in the first, concerning the specific H2-receptor antagonism, DA 4577 was found to be extremely potent on the guinea-pig papillary muscle and on the human atrium stimulated by histamine (pA2 = 8.24 and 8.60 respectively). Compound DA 4577 was also found very active in inhibiting histamine-induced acid secretion from the isolated rat fundus (pA2 = 7.37) and on the dimaprit-induced gastric secretion in conscious gastric fistula cats (ID50 = 0.39 mumol kg-1 h-1). In the second set of experiments, concerning effects independent of the H2-receptor blockade (side effects of the molecule), compound DA 4577 was found to be devoid of negative inotropic effect on the human atrium in the absence of histamine stimulation; in this respect it behaved like cimetidine or ranitidine but unlike oxmetidine which showed a constant negative inotropic effect even at concentration 10 times lower than those of DA 4577. Furthermore DA 4577 was ineffective in modifying gastrointestinal motility in vitro in concentrations up to 3 X 10(-4) M, conversely from ranitidine (which stimulated motility) and oxmetidine (which inhibited motility). On the whole DA 4577 appeared to be a very potent and selective H2 antagonist which, unlike other members of the family, is devoid of non-specific effect on human atrium and on motility of the gastrointestinal tract of different animal species.

Animals↗

[Clinicopharmacological study of gastrointestinal drugs from the viewpoint of postmarketing development].

Pharmaceutical development starts with the discovery of a new compound. Drugs become commercially available after non-clinical and clinical studies, but processes that take place after marketing are also important for pharmaceutical development. In recent years, use of the phrase "Ikuyaku" meaning postmarketing development has become more common. Sometimes, the proper usage, indications and harmful effects of a drug are discovered only after it becomes commercially available and is administered to many patients. Hence, pharmacists need to actively perform postmarketing studies to reveal the true nature of drugs. In the present clinicopharmacological study, we investigated the effects of histamine H(2) receptor antagonists (H(2)-RAs) on the plasma concentrations of gastrointestinal peptides from the viewpoint of postmarketing development. First we established an enzyme immunoassay for secretin, which is involved in gastrointestinal motility. Then we used this and existing peptide assays to investigate the above-mentioned issues. Ranitidine and nizatidine increased the plasma concentration of motilin. It is believed that the plasma concentration of Ach is elevated by ranitidine and nizatidine, which possesses an anti-AchE activity, and that the increased the plasma concentration of Ach facilitated release of motilin, elevating the plasma concentration of motilin. When compared to the placebo, lafutidine significantly increased the plasma concentration of CGRP (calcitonin gene-related peptide) and substance P. Furthermore, released CGRP stimulated CGRP1 receptors to facilitate secretion of somatostatin. Therefore, lafutidine appears to protect the gastric mucosa and regulate gastrointestinal motility. The same results were obtained with ranitidine and nizatidine. While H(2)-RAs have a common function in suppressing the secretion of gastric acid, they do not exhibit the same effects on factors related to recurrence of peptic ulcer, such as gastrointestinal motility and blood flow in the gastrointestinal mucosa. Hence, measuring the plasma concentration of gastrointestinal peptides can be used to estimate the effects of drugs on gastrointestinal motility. From the viewpoint of postmarketing development, we are in the process of establishing indicators for the proper usage of pharmaceutical drugs. Pharmacists need to closely follow and monitor adverse reactions. In order to further improve monitoring of drug therapy, it will be necessary to assess not only the blood concentrations of drugs, but also biological reactions to the drugs. Since the levels of peptides reflect the clinical efficacy of gastrointestinal drugs, measuring peptide levels appears to be useful for selecting appropriate drugs.

Adult↗

Gastric antrectomy with selective gastric vagotomy does not influence gallbladder motility during interdigestive and postprandial periods.

Fasting gastrointestinal motility and gallbladder motility during the interdigestive state and in the postprandial period was studied in eight patients who were operated for ulcer disease with an antrectomy and selective gastric vagotomy. Nocturnal motility recording revealed all three phases of the migrating motor complex (MMC) in all but one patient, where no phase III activity was recorded. In the rest of the patients 3-10 events with phase III activity were recorded. At scintigraphy ([75Se]HCAT) a cyclic gallbladder filling and emptying in relation to the MMC cycle was found. Episodes with emptying were confined to phase II and a total of 13 episodes with a median duration of 25 min (range 10-70 min) were observed. A median of 10.7% (6.1-17.7%) of the gallbladder contents was emptied. In a control group of eight healthy young men the values were 13.5 min (9-36 min) and 6.9% (3.7-31.1%), respectively. These differences were not significant. During the postprandial period, a lag period in gallbladder emptying of median 15 min (5-20 min) was observed when food ingestion took place during phase I of the MMC. Thereafter a gradual emptying occurred with a rate of 0.95% min (0.71-1.15%/min). In a control group of healthy young males, the lag period was 13.5 min (9-22.5 min) and the emptying rate 0.61%/min (0.08-0.77%/min). When food ingestion occurred during phase II of the MMC, the lag period of gallbladder emptying in the patient group was median 0 min (0-5 min) and the emptying rate was 0.77%/min (0.33-0.86%/min). The values in the control group were 0 min (-9 to 13.5 min) and 0.76%/min (0.54-2.25%/min), respectively. These differences between the patients and controls were not significant. In conclusion, antrectomy and selective gastric vagotomy do not influence fasting gastrointestinal motility or gallbladder motility during the interdigestive state or in the postprandial period.

Aged↗

Parent perceptions of the psychological functioning of their children diagnosed with pediatric motility disorders and that of family members.

The aim of our study was to characterize the parental perceptions of the behavioral and emotional functioning of their children and families coping with gastrointestinal motility disorders. The American Pseudo-obstruction and Hirschsprung's disease Society sponsored an educational meeting for parents of children afflicted with a variety of pediatric gastrointestinal motility disorders. During the conference, parents completed a questionnaire pertaining to the behavioral and emotional functioning of the afflicted child and other family members. Parents perceived that the child's illness was more difficult on the parents than on the affected child or their siblings. Also, parents perceived support from professionals, family, and friends increased after the children were diagnosed with pediatric gastrointestinal motility disorders. Parents worried most about the health and medical management of their afflicted child. The most common behavioral problem of the afflicted children was fear of separation, whereas the most common behavioral problem of their siblings was jealousy. The majority of referrals to mental health professionals resulted from parental emotional problems or marital discord.

Adaptation, Psychological↗

Interstitial cells of Cajal in dysmotility in intestinal ischemia and reperfusion injury in rats.

BACKGROUND: Intestinal ischemia and reperfusion (I/R) injury is an obligatory occurrence in small bowel transplantation. I/R may impair the normal gastrointestinal motility. Interstitial cells of Cajal (ICC) are known as pacemaker cells in the gastrointestinal tract. The aim of this study was to assess the role of ICC in the gastrointestinal motility in a rat model of I/R injury. MATERIALS AND METHODS: Wistar rats were subjected to 30- or 80-min intestinal ischemia by occluding the mesenteric vessels followed by reperfusion. Small intestinal segments were resected at 12 h or 4 days. The spontaneous mechanical activity was evaluated by organ bath technique. Immunopositivity of c-Kit and PGP9.5 at the level of the myenteric plexus was evaluated as markers of ICC and enteric nerves, respectively. RESULTS: In the bowel segment with 80-min ischemia followed by 12-h reperfusion, muscles showed a 25% reduction (P < 0.05) in the frequency of contractions compared to that with 30-min ischemia followed by 12-h reperfusion, whereas amplitude of contractions was not significantly different. This change was associated with a 70% decrease (P < 0.01) of c-Kit immunopositivity. These changes of intestinal motility pattern and distribution of c-Kit-positive cells were both recovered from 80-min ischemia followed by 4 days reperfusion. In contrast, the immunopositivity of PGP9.5 was not affected in any I/R injury group. CONCLUSIONS: Transient functional changes in ICC were induced by prolonged I/R injury but they recovered after 4 days, suggesting a central role of ICC in both disrupting and restoring the normal gastrointestinal motility in I/R injury.

Animals↗

Oral neurotensin increases gastrointestinal transit in suckling rats.

Several neuropeptides known to alter gastrointestinal motility are present in milk. We investigated the effect of gastric administration of neurotensin, bombesin, somatostatin, and vasoactive intestinal polypeptide on gastrointestinal motility in suckling rats. We gavage fed 7- to 10-day-old rats with a meal consisting of 10 microliters/g of body weight of 0.9% NaCl with 51Cr tracer and one of the peptides (0, 0.1, 10, and 1,000 ng/ml). We estimated the rates of gastric emptying and the small intestinal transit from the distribution of the radioactivity in the gut. Approximately one-half of the counts emptied from the stomach in 15 min. Both gastric emptying and small intestinal transit were time dependent and were accelerated by metoclopramide and inhibited by butylscopolamine. Neurotensin 1 micrograms/ml accelerated the gastric emptying by 35% (p less than 0.02). Small intestinal transit was also accelerated (p less than 0.05). The other neuropeptides had no effect on gastric emptying and small intestinal transit. Neurotensin did not change either the gastric emptying or small intestinal transit in weaned rats, 40-50 days old, studied in the same manner. These data suggest that the intraluminal administration of neurotensin may increase gastrointestinal motility in suckling animals.

Administration, Oral↗

Effect of anthraquinone derivatives on canine and rat intestinal motility.

The effects on gastrointestinal motility of 3 senna preparations containing 18% oxidized Ca-sennosides, 60% Ca-sennosides, or pure sennosides A + B were tested in dogs and rats as measured by electromyography. Oral administration of the oxidized products in the fasted animal increased the activity of the small intestine within 2 h and reduced both caecal and colonic contractions for 24 h. Severe diarrhoea was present 4-6 h after administration and lasted for at least 1 day. Ca-sennosides had a similar, but weaker effect while pure sennosides affected motility only 6-10 h after oral administration. The intracolonic administration of the oxidized products resulted in an immediate reduction of colon motility for 7-8 h and diarrhoea was present within 40 min. Intracolonic Ca-sennosides and sennosides A + B induced only small changes in the intestinal motility, but diarrhoea also appeared. The results confirm that pure sennosides act predominantly on large intestine motility after their degradation by colonic microorganisms. Oxidized products are already effective in the upper gastrointestinal tract. The early action of Ca-sennosides requires further investigation. Side effects after oral senna treatment such as griping or nausea may be caused by motility changes induced by the presence of small amounts of oxidized products in the drug.

Animals↗

[An experimental study on the remnant gastric motilities and gastrointestinal hormones after various types of gastrectomies].

Using adult mongrel dogs, remnant gastric motility in relation to the changes of gastrointestinal hormone (gastrin and motilin) levels were measured under conscious states before and after distal partial gastrectomy in the Billroth I (BI) or II (BII) reconstruction and proximal partial gastrectomy with or without pyloroplasty. Remnant gastric motility was studied during the digestive and interdigestive states by chronically implanted strain gage transducer (S.G.T.) along the gastrointestinal tract. Gastrointestinal hormone levels were determined by radioimmunoassay. Results were summarized as follows: 1. Remnant gastric motility after BI was different from BII, that is, digestive patterns after BII were more shorter than BI, as a result, gastric emptying times were shortened. 2. Gastrin release by the meal intake in the dogs with BI was greater than that in BII. On the other hand, motilin release in the dogs with BII was higher level than that in BI during the digestive and interdigestive states. Gastrointestinal hormone levels after BI were approximately as same responses as controls. These findings suggested that BI reconstruction for distal partial gastrectomy was more physiological surgical procedure than BII reconstruction. 3. Remnant gastric motility during the digestive state after proximal gastrectomy showed the excitatory pattern and gastric emptying time was remarkably shortened than in controls. 4. In gastrin and motilin levels stimulated by the meal in the dogs with proximal gastrectomy, the peak of gastrin and the depression of motilin were observed more early in relation to remnant gastric emptying time. These findings suggested that the pyloroplasty for the proximal gastrectomy was necessary to prevent an increased motility of the remnant stomach during the digestive states.

Animals↗

Gastrointestinal manometry: a practical tool or a research technique?

Gastrointestinal motility disorders constitute a major segment of digestive illness. Therefore, measurement of gut motor activity should be a desired goal. However the practical usefulness of gastrointestinal manometry is controversial. In this report we review the theoretical, technical, and practical problems posed by gastrointestinal manometry in health and in disease. Special emphasis is put on aspects pertaining to the indications and clinical applicability of the technique. New methodological developments that allow measurement of motor functions of the proximal stomach and the antroduodenal junction are also examined. Gastrointestinal manometry is potentially helpful in the diagnostic evaluation of patients presenting with upper gastrointestinal symptoms without demonstrable anatomic alteration as evidence by conventional diagnostic evaluation. It may help to localize the affected region of the gut as well as to monitor the evolution of the motor disorder and to determine the effect of pharmacological treatment. For a complete evaluation of upper gastrointestinal motility it is important to record gastric activity at the same time as in the intestine, during fasting and also postprandially. Manometry may help to determine the type of abnormal motor pattern that occurs in a given motor disorder. However, at the present time no specific abnormalities for specific diseases have been described. Thus, alterations in upper gut motility due to lesions at different levels of the brain-gut axis (central nervous system, autonomic nervous system or myenteric plexus) may produce a similarly deranged manometric pattern. Moreover, relations between a particular motor abnormality and the symptoms that the patient complains of may be quite variable. Still, we conclude that measurement of gastrointestinal motility has matured and proven its value to an extent that its application to clinical gastroenterology in carefully selected instances is appropriate and timely.

Gastric Emptying↗

Randomised controlled trial of cisapride in preterm infants.

AIM: To determine the effect of cisapride on gastrointestinal motility in preterm infants. METHODS: Cisapride (0.2 mg/kg, 8 hourly ) or placebo was given first for seven days in a double blind randomised crossover study of 10 preterm infants. Gastrointestinal motility was assessed on day 3 of each treatment. The half gastric emptying time (GET1/2) was determined by using ultrasonography to measure the decrease in the gastric antral cross sectional area after a feed. The whole gastrointestinal transit time (WGTT) was assessed by timing the transit of carmine red through the gut. Treatments were compared using the Wilcoxon matched pairs signed ranks test. RESULTS: Median (range) birthweight was 1200 (620, 1450) g and postconceptional age 33 (29, 34) weeks at recruitment. GET1/2 was significantly longer during cisapride treatment than during placebo; the median of the differences (95% confidence interval) was 19.2 (11, 30 minutes, p=0.008). WGTT was also longer during cisapride treatment, but the difference was not significant; the median of the differences was 11(-18, 52 hours, p=0.1). CONCLUSIONS: Cisapride delays gastric emptying and may delay WGTT in preterm infants. Its use to promote gastrointestinal motility in this group cannot be recommended.

Cisapride↗

Erythromycin as a prokinetic agent in preterm infants.

BACKGROUND: The macrolide antibiotic erythromycin is a prokinetic agent that stimulates gastrointestinal motility. The aim of the study was to determine the effect of erythromycin on the gastrointestinal motility of preterm infants. METHODS: Erythromycin 10 mg/kg, 8 hourly or a placebo, was given orally for 7 days in a double-blind randomized, crossover study of 20 preterm infants with a median gestational age of 32 weeks (range, 26-34 weeks). Antral contractility was determined by using ultrasonography to measure the decrease in the gastric antral cross-sectional area after a feed. The whole gut transit time was assessed by timing the transit of carmine red through the gut. RESULTS: Antral contractility lasted for a shorter period of time during erythromycin treatment than during placebo treatment (mean [standard deviation], 31 minutes [9.9 minutes] vs. 70 minutes [13 minutes]; P < 0.01). Whole gut transit time was also shorter during erythromycin treatment (mean, 23.1 hours [12.9 hours] vs. 49.3 hours [29 hours]; P < 0.01). All infants tolerated the drug well. CONCLUSIONS: Oral erythromycin in food-intolerant preterm infants enhances both antral contractility and whole gut transit time.

Administration, Oral↗

Effect of enterokinetic prucalopride on intestinal motility in fast rats.

AIM: To evaluate the effects of prucalopride on intestinal prokinetic activity in fast rats and to provide experimental basis for clinical treatment of gastrointestinal motility diseases. METHODS: Gastrointestinal propulsion rate was measured by the migration rate of activated charcoal, which reflexes gastrointestinal motility function. 120 Spraque-Dawley rats were randomly divided into four groups and received an intravenous injection of physiological saline (served as control), prucalopride 1 mg/kg, prucalopride 2 mg/kg and cisapride 1 mg/kg, respectively. The gastrointestinal propulsion rate was measured 1, 2 or 4 hours after intravenous injection of the drugs. RESULTS: Significant accelerations of gastrointestinal propulsion rate in prucalopride 1 mg/kg and 2 mg/kg groups were found compared with control group at 2 and 4 hours(83.2 %+/-5.5 %, 81.7 %+/-8.5 % vs 70.5 %+/-9.2 %, P<0.01; 91.2 %+/-2.2 %, 91.3 %+/-3.9 % vs 86.8 %+/-2.6 %, P<0.01). The gastrointestinal propulsion rates at 1, 2 or 4 hours were faster in prucalopride 1 mg/kg and 2 mg/kg groups than in cisapride group (84.0 %+/-11.7 %, 77.1 %+/-11.9 % vs 66.3 %+/-13.6 %, P<0.01, P<0.05; 83.2 %+/-5.5 %, 81.7 %+/- 8.5 % vs 75.4 %+/-5.9 %, P<0.01, P<0.05; 91.2 %+/-2.2 %, 91.3 %+/-3.9 % vs 88.6 %+/-3.5 %,P<0.05, P<0.05). No difference of gastrointestinal propulsion rate was found between prucalopride 1 mg/kg group and prucalopride 2 mg/kg group (P>0.05). CONCLUSION: Prucalopride accelerates intestinal motility in fast rats, and has no dose dependent effect.

Animals↗

Analysis of fasting antroduodenal manometry in children.

Antroduodenal manometry has been used to determine the pathophysiology associated with signs and symptoms of gastrointestinal motility disorders. The diagnostic value of antroduodenal manomentry has been limited by the paucity of data from normal children. In this study, we compared antroduodenal manometry findings from 95 patients with symptoms suggesting a gastrointestinal motility disorder to 20 control children. Phase III of the migrating motor complex (MMC) was less frequent in patients (P < 0.05), especially in those who required total parenteral nutrition (P < 0.001), than in controls. Abnormal migration of phase III and short intervals between phase IIIs were more frequent in patients than in controls (P < 0.01 and P < 0.05, respectively). During phase II, persistent low-amplitude contractions and sustained tonic-phasic contraction were found only in parenteral-nutrition-dependent children. Short or prolonged duration of phase III, absence of phase I following phase III, tonic contractions during phase III, low amplitude of phase III contractions in a single recording site and clusters of contractions or prolonged propagating contractions during phase II were not more frequent in patients than in controls. We conclude that there are five manometric features having a clear association with pediatric gastrointestinal motility disorders: (1) absence of phase III of the MMC, (2) abnormal migration of phase III, (3) short intervals between phase III episodes, (4) persistent low-amplitude contractions, and (5) sustained tonic-phasic contractions.

Adolescent↗

Catabolic outcome from non-gastrointestinal malignancy-related malabsorption leading to malnutrition and weight loss.

PURPOSE OF REVIEW: Malnutrition of cancer patients is a significant cause of mortality and morbidity. RECENT FINDINGS: The contributory factors in cancers anatomically involving the gastrointestinal tract are self-evident. However, how non-gastrointestinal malignancies affect gastrointestinal structure and function is not clear. The aim of this paper is to review the relationship between non-gastrointestinal malignancies and malabsorption, which leads to malnutrition, weight loss and increased mortality. In non-gastrointestinal cancer patients, intestinal morphological atrophy occurs, whereas in the jejunum absorption is impaired. Cytokines including IL-1 and TNF-alpha primarily induce delayed gastric emptying and also act directly on intestinal mucosa to induce malabsorption. These cytokines also directly act on several gastrointestinal hormones including cholecystokinin, neuropeptides including corticotropin-releasing factor, and via the vagus to decrease gastrointestinal motility. SUMMARY: The combination of small intestine atrophy and delayed gastrointestinal motility are some of the reasons for malabsorption in cancer patients with non-gastrointestinal malignancies that contribute to the catabolic process.

Cytokines↗