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The effect of intravenous infusion of 5-hydroxytryptamine (5-HT) on gastrointestinal contractile activity was studied in conscious dogs during the digestive and interdigestive states. It was found that 30 to 300 μg/kg per hour of 5-HT induced phasic contractions mainly in the gastric antrum, duodenum, jejunum, and mid-intestine. However, when doses greater than 100 μg/kg per hour were used, a stimulatory effect was seen in the ileum and colon. The dose-dependent stimulatory effect of 5-HT on gastrointestinal motor activity was observed in both the frequency and amplitude of contractions. Atropine-resistant 5-HT-induced contractions in the stomach were completely inhibited by methysergide. This fact strongly suggests the existence of 5-HT receptor on the smooth muscle. The stimulatory effect of 5-HT given intravenously quickly disappeared with the cessation of infusion. No significant side effects such as nausea, vomiting, diarrhea, or other symptoms suggesting abdominal pain were observed during or after the intravenous infusion of 5-HT in doses between 10 and 300 μg/kg per hour in any of the dogs.

We studied the anticholinesterase activity of three H2-receptor antagonists (cimetidine, ranitidine, and famotidine) in vitro and in conscious dogs with chronically implanted strain-gauge force transducers. In vivo, acetylcholine (ACh) was infused intravenously at a dose of 0.05 mg/(kg · min) for 5 minutes with or without a background continuous intravenous infusion of H2-receptor antagonists or neostigmine during the quiescent period of the interdigestive state. Cimetidine and ranitidine enhanced the ACh-induced contractions in a dose-dependent manner in the gastric antrum, whereas famotidine did not. In vitro, the median inhibitory concentration (IC50) of the acetyl-cholinesterase activity of ranitidine was 3.5 × 10−6 M, and that of cimetidine 2.5 × 10−4 M, whereas famotidine had no effect on cholinesterase activity even at concentrations up to 10−3 M. The effects of a bolus intravenous injection of the three H2-receptor antagonists on gastric motor activity also were examined in the digestive state. Cimetidine at 10.0 mg/kg and ranitidine at 3.0 mg/kg significantly increased gastric motor activity. This dose of ranitidine, however, sometimes caused the dogs to collapse and significantly decreased blood pressure in the anesthetized dogs. In conclusion, the H2-receptor antagonists cimetidine and ranitidine enhanced gastric motor activity through the mechanism of their anticholinesterase activity, but further studies on gastric emptying and the circulatory system are needed.

Novel benzamide derivatives (19-24, 32a-c, 43d-f), each possessing a cycloaminoalkanecarboxylic acid side chain, were synthesized and their gastrointestinal prokinetic and dopamine D2 receptor antagonist activities were evaluated. 4-[(4-Amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetic acid (19) exhibited the most potent gastro- and colon-prokinetic activities, through intravenous administration to conscious dogs, and also showed the reduced dopamine D2 receptor antagonistic activity. However, 19 showed only weak gastrointestinal prokinetic activity after oral administration. Several ester prodrugs (44-62) of 19 were tested for pharmacological activities as well as physicochemical and metabolic stability; the butyl ester (46) was consequently selected as a promising gastrointestinal prokinetic agent with reduced side effects.

The novel benzamide derivative itopride was assayed for its effect on gastrointestinal motility in conscious dogs when it was administered intraduodenally (i.d.). Gastrointestinal motility was measured by means of chronically implanted force transducers, and itopride at a dose of 10 mg/kg, i.d. or more increased the gastric contractile force during the digestive state. Intraduodenal cisapride, domperidone and metoclopramide also stimulated gastric motility, and their threshold doses were 1, 3 and 1 mg/kg, respectively. Dopamine infusion (1 mg/kg/hr, i.v.) caused the postprandial gastric motility to disappear, but it was immediately restored by itopride at a dose of 3 mg/kg, i.d. With itopride at 1 and 3 mg/kg, i.d., acetylcholine (0.05 mg/kg/min)-induced contractions were greatly enhanced. In addition to its gastric stimulation, itopride at doses of 10–100 mg/kg, p.o. inhibited apomorphine (0.1 mg/kg, s.c.)-induced vomiting in dogs. In conclusion, intraduodenal itopride stimulates gastric motility through both anti-dopaminergic and anti-acetylcholinesterase actions. Its gastroprokinetic threshold dose was as large as 3–10 times those of cisapride, domperidone and metoclopramide. These findings suggest that itopride is an orally active gastroprokinetic with a moderate anti-emetic action.

Itopride is a gastroprokinetic benzamide derivative. This agent inhibited both electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE). The IC50 of itopride with AChE (2.04 +/- 0.27 microM) was, however, 100-fold less than that with BuChE, whereas in the case of neostigmine with AChE (11.3 +/- 3.4 nM), it was 10-fold less. The recovery of AChE activity inhibited by 10(-7) M neostigmine was partial, but that inhibited by up to 3 x 10(-5) M itopride was complete when the reaction mixture was subjected to ultrafiltration. Double reciprocal plots of the experimental data showed that both Km and Vmax were affected by itopride, suggesting that the inhibition is a "mixed" type, although primarily being an uncompetitive one. The inhibitory effect of itopride on cholinesterase (ChE) activity in guinea pig gastrointestine was much weaker than that on pure AChE. However, in the presence of a low dose of diisopropyl fluorophosphate, just enough to inhibit BuChE but not AChE, the IC50s of itopride against ChE activities were found to be about 0.5 microM. In conclusion, itopride exerts reversible and a "mixed" type of inhibition preferably against AChE. The IC50 of itopride for electric eel and guinea pig gastrointestinal AChE inhibition was 200 times and 50 times as large as that of neostigmine, respectively.

Since particle size of deadman coke greatly affects the permeability of gas and liquid in the lower part of a blast turnace, elucidation of the behavior of the replacement of deadman coke is an important subject. This paper describes the degradation of deadman coke by t he reaction with molten FeO. With use of a one-dimensional reaction model in which two kinetic parameters were determined from a fundamental experiment, the degradation of the deadman coke in an actual blast furnace was simulated. The effect of FeO in molten slag on the degradation of deadman coke concerns reduction ratio on the melting down of ore, temperature, and productivity. It takes about 2 weeks that vertical size distribution of degrading deadman coke becomes stationary pattern.

Stimulatory effects of HSR-803 on intestinal motor activity in vitro were studied in guinea pig ileum. HSR-803 (1 x 10(-6)-1 x 10(-4) M) increased the amplitude of longitudinal muscle contractions and increased the frequency of peristalsis in isolated segments of guinea pig ileum. The stimulatory effect in amplitude and not frequency was abolished by 1 x 10(-6) M atropine. In the Magnus method with ileal segments, HSR-803 (1 x 10(-7) - 1 x 10(-4) M) produced contractions concentration-dependently, which were inhibited by atropine (1 x 10(-8) and 3 x 10(-8) M) and 3 x 10(-7) M tetrodotoxin (TTX). In the [3H]-quinuclidinyl benzilate (QNB) binding experiment with ileal smooth muscle, HSR-803 had low affinity for acetylcholine (ACh) receptors (pKi = 4.47 +/- 0.04). In addition, HSR-803 failed to increase the spontaneous release and the electrical stimulation-induced [3H]ACh release in ileal smooth muscle. On the other hand, HSR-803 (1 x 10(-5) M) enhanced contractions induced by ACh, but had no effect on contractions induced by carbachol, which is not hydrolyzed by acetylcholinesterase (AChE). In conclusion, HSR-803 stimulated ileal motor activity. However, HSR-803 had low affinity for ACh receptors and had no influence on ACh release. It is likely that HSR-803 stimulated motor activity mainly due to prevention of ACh hydrolysis.

Novel benzamide derivatives (19-24, 32a-c, 43d-f), each possessing a cycloaminoalkanecarboxylic acid side chain, were synthesized and their gastrointestinal prokinetic and dopamine D2 receptor antagonist activities were evaluated. 4-[(4-Amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetic acid (19) exhibited the most potent gastro- and colon-prokinetic activities, through intravenous administration to conscious dogs, and also showed the reduced dopamine D2 receptor antagonistic activity. However, 19 showed only weak gastrointestinal prokinetic activity after oral administration. Several ester prodrugs (44-62) of 19 were tested for pharmacological activities as well as physicochemical and metabolic stability; the butyl ester (46) was consequently selected as a promising gastrointestinal prokinetic agent with reduced side effects.

Villous tumor of the colon is rare in Japan compared to that in the USA or Europe, but is an interesting disease in terms of its carcinogenesis and surgical treatment. Twenty legions of villous tumors in the colon treated at our hospital from January 1983 to December 1988 were examined clinically and pathologically. The average age was 61.3 years and the male-to-female ratio was equivalent. The frequent first onset of symptom was anal bleeding. It was most frequently found in the sigmoid colon and rectum. About 55% of the patients were associated with cancer. There was no relationship in the size of tumors between benign adenomas and cancers in adenoma. There was also no relationship in the macroscopical types of tumors between them. Histologically the cancers were more frequently associated with villous adenomas compared with tubulo-villous adenomas. In the treatment, the benign adenomas and cancers invading the muscle layer were polypectomized through endoscopes or with trans anal surgical resections. On the other hand, large benign adenomas and cancers with under the invasion depth of submucosa were treated by radical colectomy with dessection of the regional lymphnodes. In a final analysis, we assume that the cancers from villous tumors of the colon predominantly involve cancers from villous adenomas. Moreover, it is important that the villous tumor of the lower rectum should be resected first of all.

The effects of IV injection of 5-hydroxytryptamine 3 receptor antagonists (BRL 43694 and GR38032F) on gastrointestinal contractile activity were studied in dogs with vagally denervated fundic pouch in the conscious state by means of chronically implanted force transducers in the gastrointestinal tract and the pouch. In the interdigestive state, 5-hydroxytryptamine 3 receptor antagonists (0.01-0.1 mg/kg), if given during phase III contractions, instantly and dose-dependently inhibited the spontaneous and motilin-induced phase III contractions in the intact stomach and altered the duodenal phase III contractions to a pattern of continuous contractions, the contractile force which was 65% of the spontaneous phase III contractions in the duodenum and caused immediate caudad migration of phase III contractions along the small intestine. However, the spontaneous and motilin-induced phase III-like contractions in the denervated pouch were not affected at all by 5-hydroxytryptamine 3 receptor antagonists. When 5-hydroxytryptamine 3 receptor antagonists (0.1-3.0 mg/kg) were given during the phase I period, they did not directly stimulate gastrointestinal contractions. The cyclic fluctuation of the plasma motilin concentration with phase III activity in the stomach was also not influenced by 5-hydroxytryptamine 3 receptor antagonists, but the next phase III contractions in the stomach were inhibited. During the digestive state, however, 5-hydroxytryptamine 3 receptor antagonists (0.1-3.0 mg/kg) did not influence contractile activity in the gastrointestinal tract and in the vagally denervated fundic pouch. On the basis of recent pharmacological studies showing that the distribution of 5-hydroxytryptamine 3 receptors is recognized in the area postrema, peripheral neurons of vagal afferents, and the enteric nervous system, the results of the current study provide a basis for a hypothesis that 5-hydroxytryptamine 3 receptor antagonists are most likely to block motilin-induced signals at 5-hydroxytryptamine 3 receptors on the vagal afferents. In conclusion, the present findings suggest the possible involvement of 5-hydroxytryptamine 3 receptors on vagal afferents especially in terms of endogenous release of acetylcholine in the control of interdigestive phase III activity in the stomach by motilin.

In order to clarify the combustion reaction when PC (Pulverized Coal) is blown into the tuyeres of a blast furnace and the effects of resultant unburnt PC on reactions, in the furnace, some fundamental experiments were carried out. The main results obtained are as follows:(1) Most of PC blown through the tuyeres rapidly burns in the raceway.(2) Unburnt PC tends to adhere to the softened and fused ore bed.(3) Unburnt PC adhering to the ore bed is consumed by the direct reduction of FeO and improves the softening and melting-down properties of ores effectively.In this way, PC entering inside the blast furnace without burning was found to be consumed effectively.

In order to elucidate the behavior of coke fines in blast furnace, fundamental experiments were carried out on the disintegration of coke during gasification reaction accompanied by mechanical impact.The following results were obtained:(1) Coke fines of high ash content are generated with the progress of gasification, which suggests the close correlation between generation of coke fines and gasification.(2) Coke fines generate increasingly when the mechanical impact strength is beyond a critical value.(3) Reaction temperature, gas composition and coke size also affect the generation of coke fines causing a different rate of gasification.A mathematical model was introduced using the rate equation of coke fine generation based on the experimental results. The calculation results by this model agree very well with the experimental results. The model, therefore, is supposed to be applied for the investigation of the behavior of coke fines in blast furnaces.

We investigated the effects of itopride hydrochloride (itopride, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride), a gastroprokinetic agent, on the colonic motor activity in vitro and in vivo, in comparison with benzamides, cisapride hydrate (cisapride), and mosapride citrate (mosapride). Itopride stimulated both peristaltic and segmental motility induced by applying intraluminal pressure to the isolated guinea pig colon. Although cisapride and mosapride enhanced the segmental motility, they markedly reduced the peristaltic motility. In conscious dogs with implanted strain gauge force transducers, itopride stimulated contractile activity in the gastrointestinal tract from the stomach to the colon. Cisapride stimulated contractile activity in the gastric antrum, ileum, and ascending colon. Mosapride stimulated contractile activity only in the gastric antrum and ileum. In guinea pigs and rats, itopride accelerated colonic luminal transit. On the other hand, cisapride and mosapride failed to enhance colonic transit. These results demonstrate that itopride has a stimulatory action on colonic peristalsis, propelling colonic luminal contents, different from that of cisapride and mosapride. Therefore, itopride may be a useful drug for the treatment of functional bowel disorders such as functional constipation.

We investigated the laxative and anti-diarrheal activity of polycarbophil, an insoluble hydrophilic polymer, in comparison with other agents used for treating functional bowel disorder (FBD). In naive rats, polycarbophil (500 mg/kg) increased fecal weight and water contents without producing diarrhea. Carboxymethylcellulose (CMC) did not produce evident changes in bowel movement. Picosulfate markedly produced diarrhea. Loperamide, trimebutine and granisetron decreased stool output dose-dependently. Constipation, indicated by decrease in fecal weight, was produced by loperamide and clonidine in rats. Polycarbophil (500 mg/kg) and CMC increased fecal weight without diarrhea. Conversely trimebutine further decreased fecal weight in constipated rats. Polycarbophil (500 mg/kg) suppressed diarrhea induced by castor oil, and at 250 – 500 mg/kg, it produced shaped stools in animals with stools loosened by prostaglandin E 2, serotonin or carbachol in mice. Polycarbophil (500 mg/kg) also reduced stools in rats with stool output increased by wrap restraint stress (WRS). CMC had no effect in the diarrhea models, except for carbachol-induced diarrhea, and WRS-induced evacuation. Loperamide, trimebutine and granisetron inhibited diarrhea production and WRS-induced evacuation, except for carbachol-induced diarrhea. The results show that polycarbophil prevents constipation and diarrhea without inducing diarrhea or constipation, which is different from the other agents. Hydrophilic polymers such as polycarbophil will be promising agents for the treatment of FBD.

Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain or discomfort and abnormal defecation. Polycarbophil calcium, a water-absorbing polymer, is expected to improve stool consistency. Polycarbophil calcium decalcified under the acidic condition and then absorbed 70 times its weight of water under the neutral condition. In in situ experiments using rat jejunum and colon, polycarbophil decreased water absorption by the intestine without affecting water secretion. Polycarbophil inhibited prostaglandin E2-, 5-hydroxy-L-tryptophan- and castor oil-induced diarrhea in mice or rats. Polycarbophil calcium also inhibited sennoside-induced diarrhea in dogs. Polycarbophil increased the weight of feces in naive or low-fiber diet feeding rats. In naive dogs, polycarbophil calcium increased stool frequency, stool weight and moisture. Polycarbophil was not absorbed from the gastrointestine, not metabolized and eliminated into feces in rats and dogs. Polycarbophil calcium did not affect the absorption of coadministered drugs in dogs. In the dose-finding clinical study for IBS, polycarbophil calcium was effective both in diarrhea and constipation. In the Phase III study, polycarbophil calcium was superior to trimebutine maleate in efficacy and equal in safety. Emesis/vomiting and thirst were observed, but episodes of diarrhea or constipation by excessive action were few. Polycarbophil calcium seems promising as an anti-IBS agent.

The effects of calcium polycarbophil (CP), a water-absorbing polymer, on bowel movement were examined in comparison with known laxatives and anti-diarrheal agents in dogs, a species that resembles humans for stool output. CP increased stool frequency, fecal water content and fecal weight in a dose-dependent manner, but did not induce diarrhea. Sennoside and carboxymethylcellulose sodium (CMC-Na) increased fecal water content and induced diarrhea at lower doses than that which enhanced stool frequency. Trimebutine decreased stool frequency, fecal weight and fecal water content, resulting in inhibition rather than stimulation of defecation. In sennoside-induced diarrhea, loperamide and CP improved stool consistency and this was accompanied by reduced fecal moisture and frequency of diarrhea. In contrast, CMC-Na aggravated stool consistency with increased fecal water content and frequency of diarrhea, and trimebutine had little noticeable effect apart from reducing fecal weight. Our results show that CP has both laxative and anti-diarrheal effects in dogs and differed from conventional laxatives and anti-diarrheal agents. CP may be a suitable agent for treatment of idiopathic constipation, secretory diarrhea and irritable bowel syndrome with alternating constipation and diarrhea and with either predominating in terms of less side effects such as diarrhea or constipation.

The objective of the present study was to determine the action duration of tulobuterol tape within a 24-hr period in conscious guinea pigs. The bronchoconstriction induced by histamine-inhalation was significantly inhibited by tulobuterol tape in comparison with its placebo tape 8 and 12 hr after binding, and the inhibitory rate was 50±11% and 35±13%, respectively. Twenty-four hours after binding, the inhibitory effect of tulobuterol tape gradually diminished, but the inhibitory rate was maintained at 30±14%. These results suggest that tulobuterol tape has a long lasting bronchodilatory action.

Scintigraphic techniques can measure sequentially gastric emptying, small bowel transit, and colonic transit in humans, and comparable methods for experimental studies in animals would be useful. We developed such a method in dogs and examined the effects of prokinetic drugs on regional transit. Two isotopes were given to fasting dogs. Polystyrene pellets labeled with99mTc were mixed in a can of dog food and111In- labeled pellets were given in a gelatin capsule coated with a pH-sensitive polymer, designed to dissolve in the distal bowel. Gamma camera images were obtained for up to 24 h. Prokinetic drugs were given by intravenous injection. Duplicate baseline studies showed good agreement in seven dogs. In a second group ( n = 4), intra- and interanimal variabilities were established. Two novel prokinetic drugs (AU-116 and AU-130) accelerated small bowel and colonic transit. A simple noninvasive method for measuring whole gut transit in dogs was developed and validated. Two new prokinetics accelerated small bowel and colonic transit.

A new method has been developed that is suitable for physiological studies of urethral motility in the conscious state with a strain-gauge force transducer (force transducer). In anesthetized dogs, the contractile or relaxing responses of the urethral smooth muscle in the direction of the circular layers measured with the force transducer, elicited by either phenylephrine or isoproterenol, were significantly correlated to the increase or decrease in the intra-urethral pressure (r = 0.998 and 0.780, respectively). In conscious dogs, the fluctuation in the urethral tone was observed to be less than in the intra-urethral pressure, and a dose-dependent response to phenylephrine (1-30 micrograms./kg. i.v.) and isoproterenol (0.1-3 micrograms./kg. i.v.) was clearly recognized. Moreover, this conscious model provided a fairly reproducible pattern with the urethral contraction or relaxation related to the filling or voiding phase of the cystometrogram, which was abolished by anesthetization. These results indicate that the present force transducer method makes it possible to evaluate the further physiological characteristics of urethral motility in conscious dogs.

SHIBATA, C., SASAKI, I., NAITO, H., OHTANI, N., MATSUNO, S., MIZUMOTO, A., IWANAGA, Y. and ITOH, Z. Effects of Substance P on Gastric Motility Differ Depending on the Sites and Vagal Inneruation in Conscious Dogs. Tohoku J. Exp. Med., 1994, 174 (2), 119-128-The effect of substance P on gastric motility was studied in conscious dogs by means of strain gauge force transducers chronically implanted on the gastric body, antrum, and a vagally-denervated fundic pouch. Intravenous infusion of substance P in the interdigestive state induced phasic contractions in the pouch and antrum. Atropine inhibited these contractions in the pouch and antrum. Hexamethonium enhanced substance P-induced contractions in the gastric antrum, but reduced those in the pouch. Pretreatment with phentolamine, propranolol, or naloxone did not affect substance P-induced contractions in the pouch and antrum. The intact gastric body scarcely reacted to substance P. Mean systemic blood pressure was lowered by substance P-infusion, but there was no dose-dependency in the reduction of the blood pressure, nor was it affected by the pretreatment with atropine or hexamethonium. These results suggest that 1) the vagal innervation influences the effect of substance P on motility in the gastric body, and that 2) substance P may stimulate postsynaptic excitatory cholinergic and presynaptic inhibitory neurons simultaneously in the gastric antrum.

We report herein a rare case of primary esophageal malignant melanoma in a 49-year-old Japanese woman who presented with a 3-week history of dysphagia. Esophagogram and esophagoscopy demonstrated a polypoid tumor in the upper to mid-thoracic portion of the esophagus, and a radical subtotal esophagectomy was performed through a right thoracotomy. Histological and immunohistochemical studies proved this tumor to be a primary esophageal malignant melanoma. She received no postoperative adjuvant therapy and no signs of recurrence have been clinically observed for the 22 months since her operation.

Nobel N-[[2-(dialkylamino)ethoxy]benzyl]benzamide derivatives (II-1-51), derived form the structural modification of metoclopramide (i), were synthesized and examined for their pharmacological activities. Among them, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3, 4-dimethoxybenzamide (II-34) which exhibited well balanced gastrointestinal prokinetic and antiemetic activities was selected as a new type of gastrointestinal prokinetic agent.