Biomedical subjects

H Yuki

Publications and source records attributed to H Yuki.

At least 37 records · Page 2Linked to original sources

PubMed1995

Gastrin receptor antagonist YM022 prevents hypersecretion after long-term acid suppression.

Female rats were treated orally for 13 wk with YM022 (300 mumol.kg-1.day-1) and with omeprazole (400 mumol.kg-1.day-1) or famotidine (900 mumol.kg-1.day-1) with or without YM022. At 2 h after the last dose, YM022 and omeprazole markedly inhibited basal and pentagastrin-induced acid secretion. Famotidine was less potent than YM022 and omeprazole against both secretions. The degree of increase in plasma gastrin level in the three groups was parallel to the antisecretory potencies of the drugs. At 14 days after the cessation of omeprazole treatment, the secretory response to pentagastrin increased above that of the control. This hyperresponse lasted for > or = 56 days. In the famotidine-treated group, a small increase in secretory response to pentagastrin was observed but was not statistically significant. The increase in secretory response to pentagastrin was paralleled by an increase in mucosal cell mass. In contrast, YM022 not only exhibited a long-lasting inhibition of pentagastrin-induced acid secretion but also prevented the hyperresponse to pentagastrin caused by omeprazole. These results indicate that the hypergastrinemia caused by long-term administration of antisecretory drugs increases mucosal secretory response to pentagastrin through a gastrin/cholecystokinin B receptor-mediated pathway in rats.

Animals↗

PubMed1995

Antisecretory and antiulcer effects of YM020, a new H+,K(+)-ATPase inhibitor, in rats and dogs.

We examined the effects of YM020 (3-cyanomethyl-2-methyl-8-[(3-methyl-2-butenyl)oxy]-imidazo[1,2- a]pyridine), a novel H+,K(+)-ATPase inhibitor, on gastric acid secretion and experimental gastroduodenal lesions in rats and dogs. Intraduodenal, subcutaneous and oral YM020 inhibited basal gastric acid secretion in pylorus-ligated rats with ED50 values of 9.1, 9.1 and 9.5 mg/kg, respectively. Oral pretreatment with YM020 5 hr before ligation still suppressed acid secretion, with a potency a little less than that of omeprazole. In anesthetized dogs, intravenous YM020 inhibited histamine-, methacholine- and pentagastrin-induced gastric acid secretion with ED50 values of 0.05, 0.01 and 0.08 mg/kg, respectively. In Heidenhain pouch dogs, although oral YM020 (3 mg/kg) inhibited histamine-induced acid secretion, acid output returned to control levels faster than in dogs treated with omeprazole. Oral YM020 inhibited the formation of water-immersion restraint stress-, indomethacin-, absolute ethanol-, 0.7 N hydrochloric acid- and cysteamine-induced gastric or duodenal lesions with ED50 values of 2.9, 4.3, 2.0, 11.7 and 8.4 mg/kg, respectively. Moreover, subcutaneous YM020 also suppressed the formation of ethanol- and HCl-induced gastric lesions. These results suggest that YM020 has an antisecretory effect almost the same as or 2 to 3 times weaker than those of omeprazole and that its duration is not as long as that of omeprazole in rats and dogs. Furthermore, YM020 possesses a cytoprotective effect and the mechanism of YM020 may be different to that of omeprazole.

Administration, Oral↗

PubMed1995

Effects of rat bile-pancreatic juice on Fe2+ induced peroxidation of phospholipids.

The effects of rat bile-pancreatic juice (BPJ) on Fe2+ induced oxidation of soybean phosphatidylcholine (PC) was monitored to investigate the influence of this digestive juice on oxidative damage in the gastrointestinal tract. A large volume of BPJ (50% in the suspension of PC, v/v) suppressed the lipid peroxidation, but a smaller volume had the reverse effect. BPJ could decompose free fatty acid hydroperoxides (FFA-OOH) at a lower concentration (approximately 0.2 mM) completely, although its phospholipase activity liberated FFA-OOH from PC hydroperoxides. Sodium deoxycholate enhanced the Fe2+ induced oxidation of PC in a concentration-dependent manner when PC was suspended in the buffer. Boiled BPJ suppressed Fe2+ induced and peroxyl radical initiated oxidation of sodium deoxycholate micelles of soybean PC up to approximately 50% (v/v). It was strongly suggested that rat BPJ had a biphasic effect on Fe2+ induced oxidation of phospholipids depending on the enhancement by bile salts and the inhibition by antioxidant components with radical-scavenging activity and hydroperoxide-decomposing activity.

Animals↗

PubMed1994

Alteration of asparagine-linked glycosylation in serum transferrin of patients with hepatocellular carcinoma.

The asparagine-linked sugar chains in serum transferrin purified from patients with hepatocellular carcinoma (n = 13), healthy individuals (n = 5) and patients with liver cirrhosis (n = 6) were compared. Sugar chains released with N-glycanase from desialylated and pepsin-digested transferrin were derivatized by reductive pyridylamination. Analysis of the sugar chains by high performance liquid chromatography in combination with exoglycosidase digestion revealed an increase of a biantennary complex-type sugar chain with a fucosylated trimannosyl core; Gal beta 1-4GlcNAc beta 1-2Man alpha 1-6(Gal beta 1-4GlcNAc beta 1-2Man alpha 1-3) Man beta 1-4GlcNAc beta 1-4(Fuc alpha 1-6)GlcNAc in 7 of 13 cancer patients and an increase of a sugar chain with a fucosylated trimannosyl core and bisecting N-acetylglucosamine; Gal beta 1-4GlcNAc beta 1-2Man alpha 1-6(GlcNAc beta 1-4) (Gal beta 1-4GlcNAc beta 1-2Man alpha 1-3)Man beta 1-4GlcNAc beta 1-4(Fuc alpha 1-6)GlcNAc in one of the 13 cancer patients. Further, the fucosylated alteration of the sugar chain was detected also in alpha 1-antitrypsin, hemopexin, alpha 1-acid glycoprotein and alpha 2-HS glycoprotein from one of the patients with increased fucosylated transferrin.

Asparagine↗

PubMed1994

Serotonin (5-HT)3-receptor antagonism of 4,5,6,7-tetrahydrobenzimidazole derivatives against 5-HT-induced bradycardia in anesthetized rats.

We investigated the mode of the 5-HT3-receptor antagonism of 4,5,6,7-tetrahydrobenzimidazole derivatives, YM060, YM114 (KAE-393), YM-26103-2 and YM-26308-2, against 5-HT-induced transient bradycardia in anesthetized rats. Results were compared with those of ondansetron and granisetron. YM060 (0.03-0.1 microgram/kg, i.v.), YM114 (0.03-0.3 microgram/kg, i.v.), YM-26103-2 (0.01-0.03 microgram/kg, i.v.), YM-26308-2 (0.01-0.03 microgram/kg, i.v.) and granisetron (0.3-3 micrograms/kg, i.v.) displaced the 5-HT dose-response curve to the right, with apparent DR2 values of 0.068, 0.068, 0.019, 0.011 and 0.69 microgram/kg, i.v., respectively. Higher doses of these compounds inhibited 5-HT-induced bradycardia with a reduced maximal response. In contrast, ondansetron displaced the 5-HT dose-response curve to the right without affecting the maximal response. Judged by the apparent DR2 values, YM060, YM114, YM-26103-2 and YM-26308-2 were approximately 13, 13, 50 and 79 times more potent than ondansetron, respectively, whereas granisetron was equipotent to ondansetron. Single i.v. doses of YM060 and granisetron inhibited 5-HT-induced bradycardia significantly longer than ondansetron. Moreover, inhibitory effects of p.o. doses of YM060 (3 micrograms/kg), YM114 (80 micrograms/kg), YM-26103-2 (12 micrograms/kg), YM-26308-2 (5 micrograms/kg) and granisetron (250 micrograms/kg) on the von Bezold-Jarisch reflex lasted for 3-6 hr, whereas ondansetron (700 micrograms/kg, p.o.) antagonized 5-HT3 receptors for only 1 hr. In isolated guinea pig colon, the inhibitory effect of YM-compounds on 5-HT-induced contraction persisted significantly longer than those of ondansetron and granisetron after washout of the bath containing compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Orally administered beraprost sodium inhibits pulmonary hypertension induced by monocrotaline in rats.

Rats were fed on distilled water (DW) or DW containing beraprost sodium (BPS). BPS concentration was 1.5 or 3.0 mu/ml in DW for the low BPS groups and 6.0 or 10.0 mu/ml in DW for the high BPS group. Monocrotaline (MCT) was subcutaneously given (60 mg/kg), and saline was injected as control. Data were analyzed among the following groups; Groups (Saline + DW), (Saline + Low BPS), (MCT + DW), (MCT + Low BPS) and (MCT + High BPS). Three weeks later, pulmonary (Ppa) and systemic (Psa) arterial pressure were measured under anesthesia. MCT caused significant elevation of Ppa [18.3 +/- 0.6 cmH2O for Group (Saline + DW) vs. 27.2 +/- 1.2 cmH2O for Group (MCT + DW), p < 0.001, mean +/- S.E.] and Ppa was significantly and dose-dependently suppressed by BPS; Group (MCT + DW) vs. Groups (MCT + Low BPS), 23.4 +/- 0.7 cmH2O and (MCT + High BPS), 22.5 +/- 0.5 cmH2O, p < 0.05, mean +/- S.E.). Psa was not lowered dose-dependently by BPS. We conclude that oral beraprost sodium suppresses pulmonary hypertension produced by monocrotaline in rat.

Administration, Oral↗

PubMed1994

Pharmacological profile of (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo- 5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022), a new potent and selective gastrin/cholecystokinin-B receptor antagonist, in vitro and in vivo.

(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022) is an extremely potent and highly selective gastrin/cholecystokinin (CCK)-B receptor antagonist. We compared the gastrin/CCK-B receptor-blocking properties of this compound with those of the racemate (mixture of YM022 and its S-form), its enantiomer (S-form), L-365, 260 and Cl-988 in vitro and in vivo. YM022 replaced specific binding of [125I]CCK-8 to rat brain gastrin/CCK-B receptors in a stereoselective and competitive manner. The Ki value of YM022 for gastrin/CCK-B receptors in brain were estimated to be 0.068 nM. The racemate, the S-form of YM022, L-365,260 and Cl-988 also replaced gastrin/CCK-B receptor binding, with Ki values of 0.11, 140, 19 and 6.3 nM, respectively. The affinity of YM022 for gastrin/CCK-B receptor was more than 2 orders of magnitude higher than that for rat pancreatic CCK-A receptor and various other receptors, such as benzodiazepine. In vivo, intravenous (i.v.) administration of YM022 inhibited pentagastrin-induced gastric acid secretion in anesthetized rats, with an ED50 value of 0.0078 mumol/kg. Inhibition by the S-form of YM022 was only 33.8% even at the relatively high dose of 1 mumol/kg i.v. L-365,260 (1-10 mumol/kg i.v.) and Cl-988 (0.3-3 mumol/kg i.v.) also antagonized acid secretion induced by pentagastrin, with ED50 values of 4.23 and 1.01 mumol/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

YM022 [(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl- 1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea], a potent and selective gastrin/cholecystokinin-B receptor antagonist, prevents gastric and duodenal lesions in rats.

We evaluated the effect of YM022 [(R)-1-[2,3-dihydro-1-(2'- methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3- (3-methylphenyl)urea], a potent and selective gastrin/cholecystokinin-B receptor antagonist, on gastric acid secretion and gastric and duodenal lesions in rats. Oral YM022 (0.1-10 mumol/kg), famotidine (0.3-30 mumol/kg) and omeprazole (3-100 mumol/kg) dose-dependently suppressed acid secretion in pylorusligated rats with ED50 values of 0.83, 1.63 and 10.9 mumol/kg, respectively. YM022 (1-10 mumol/kg p.o.), famotidine (1-10 mumol/kg p.o.) and omeprazole (10-100 mumol/kg p.o.) prevented indomethacin-induced gastric lesions in a dose-related manner. The potency of YM022 was comparable to that of famotidine and was 8 times greater than that of omeprazole. YM022 and famotidine partially inhibited gastric damage induced by water-immersion and restraint stress, whereas omeprazole abolished these lesions. In an acidified ethanol-induced gastric injury model, all three drugs inhibited the formation of erosions. The YM022 dosage required in this model was much greater than that required in the inhibition of gastric acid. The inhibitory effect of YM022 was partially reversed by indomethacin, indicating the involvement of a prostaglandin-mediated pathway. YM022 (3-100 mumol/kg p.o.), famotidine (1-30 mumol/kg p.o.) and omeprazole (3-100 mumol/kg p.o.) inhibited mepirizole-induced duodenal ulcers. On the basis of ED50 values, YM022 was 5 times less potent than famotidine and as potent as omeprazole against mepirizole-induced duodenal ulcers. These results suggest that YM022 possesses antisecretory and antiulcer activities that are as potent as those of famotidine in rats and that YM022 represents a useful therapeutic agent in the treatment of peptic ulcer disease.

Animals↗

PubMed1993

Comparison of the effects of trimebutine and YM114 (KAE-393), a novel 5-HT3 receptor antagonist, on stress-induced defecation.

YM114 (KAE-393), (R)-5-[(2,3-dihydro-1-indolyl)carbonyl]-4,5,6,7- tetrahydro-1H-benzimidazole hydrochloride, is a derivative of YM060, a potent 5-HT3 receptor antagonist. We investigated the effects of YM114 on 5-HT3 receptors, both in vitro and in vivo, and on bowel dysfunction induced by restraint stress, 5-HT and thyrotropin-releasing hormone (TRH), and compared them with the effect of trimebutine. YM114 dose dependently inhibited the reduction in heart rate induced by 5-HT (30 micrograms/kg i.v.) in rats (ED50 = 0.31 micrograms/kg i.v.), and the potency of YM114 was almost the same as that of the racemate. The S-form of YM114 also inhibited 5-HT-induced bradycardia, but 1350 times less potent than the R-form. YM114 and its S-form inhibited [3H]GR65630 binding to N1E-115 cell membranes in a concentration-dependent manner with Ki values of 0.341 and 616 nM, respectively, showing the isomeric activity ratio (R-/S-form) of YM114 to be much greater (1800). YM114 antagonized 5-HT-induced depolarization of the nodose ganglion (EC50 = 1.39 nM). Trimebutine (1 mg/kg i.v.) failed to inhibit 5-HT-induced bradycardia, implying that it does not possess 5-HT3 receptor antagonistic activity. YM114 significantly and dose dependently prevented restraint stress-, 5-HT- and TRH-induced increases in fecal pellet output, and restraint stress- and 5-HT-induced diarrhea in rats and mice (ED50 = 6.9, 72.5, 154.6, 9.7 and 52.4 micrograms/kg p.o., respectively). Trimebutine significantly prevented stress- and 5-HT-induced diarrhea (ED50 = 29.4 and 87.3 mg/kg p.o., respectively), but only partially affected stress-, 5-HT- and TRH-induced increases in fecal pellet output. Thus, YM114 is a potent and stereoselective 5-HT3 receptor antagonist with much greater protective effects against stress-induced defecation than trimebutine.

Animals↗

PubMed1993

Mechanisms of cisplatin- and m-chlorophenylbiguanide-induced emesis in ferrets.

We investigated the involvement of peripheral and central serotonin (5-HT)3 receptors in cisplatin- and 5-HT3 receptor agonist-induced emesis in ferrets. Cisplatin (10 mg/kg i.v.)-induced emesis was inhibited by intravenous YM060 (0.003-0.1 microgram/kg). A highly selective and potent 5-HT3 receptor agonist, m-chlorophenylbiguanide (1-10 mg/kg i.p.), dose dependently elicited emesis an effect which was inhibited by YM060 (0.003-0.3 microgram/kg i.v.). Vagotomy markedly reduced this emesis, and the combination of abdominal vagotomy and greater splanchnicectomy abolished emesis. Lesion of greater splanchnic nerves alone did not markedly inhibit emesis. Intracerebroventricularly (4th ventricle) administered YM060 inhibited cisplatin- and m-chlorophenylbiguanide-induced emesis only at higher doses (0.01-0.1 and 0.01-0.03 microgram, respectively). Intracerebroventricularly (4th ventricle) administered m-chlorophenylbiguanide (30-100 micrograms) produced only a weak retching response. These results indicate that stimulation of abdominal vagal afferent nerves via peripheral 5-HT3 receptors is important for triggering cisplatin- and m-chlorophenylbiguanide-induced emesis in ferrets.

Animals↗

PubMed1993

Enzyme reactor for urinary acylcarnitines assay by reversed-phase high-performance liquid chromatography.

An immobilized enzyme reactor, made up acylcarnitine hydrolase, carnitine dehydrogenase and diaphorase in sequence, was developed for the sensitive and selective determination of urinary free and individual acylcarnitines by a reversed-phase high-performance liquid chromatography. A 100-microliter urine sample was directly injected onto the TSKgel ODS 80Ts column and eluted by a step-gradient procedure. The eluent was mixed with the substrate solution of beta-NAD+ (1.0 mmol/l), resazurin (25 mumol/l) and Tris acetate (0.2 mol/l, pH 9.0). The mixture was passed through the immobilized enzyme reactor at 40 degrees C. Acylcarnitines were hydrolyzed and the converted to rezorufin which was measured by monitoring the fluorescence intensity at lambda EX = 560 nm and lambda EM = 580 nm. Free, acetyl-, glutaryl-, propionyl-, butyryl-, isobutyryl-, valeryl- and isovalerylcarnitine were determined within 55 min with detection limits (< 1 mumol/l) and within-run and day-to-day imprecision (C.V. < 6%). Free, acetyl- and isobutyrylcarnitine were found in normal urine. On the other hand, propionylcarnitine was detected in the urine of children with propionic aciduria and methylmalonic aciduria and multiple acylcarnitines were found in the urine of children with glutaric aciduria (type II).

Acetylcarnitine↗

PubMed1993

Reduction of fatty acid hydroperoxides by human parotid saliva.

Arachidonic acid hydroperoxide (15-hydroperoxyeicosatetraenoic acid; 15-HPETE) was introduced into human parotid saliva and incubated at 37 degrees C. Straight phase high-performance liquid chromatography analysis of the reaction mixture showed that 15-HPETE was detoxified to its reduced form, 15-hydroxyeicosatetraenoic acid, in the presence of glutathione. Therefore, it is concluded that human parotid saliva possesses fatty acid hydroperoxide-reducing ability. However, its effectiveness was found to be lower than that of blood plasma.

Adult↗

PubMed1993

Antisecretory effects of a novel and long-lasting histamine H2-receptor antagonist, YM-14471, in rats and dogs.

We investigated some properties of YM-14471 (2-2(-[2-(diaminomethyleneamino)thiazol-4-yl]methylthio)ethy l-5-[3- (diethylamino)propyl]-6-methyl-pyrimidine-4-one trihydrochloride), a new H2-receptor antagonist, in comparison with those of famotidine, cimetidine and omeprazole. In guinea pig atria, famotidine and cimetidine produced a competitive dose-dependent displacement of histamine-induced tachycardia. In contrast, low concentrations of YM-14471 showed competitive inhibition of tachycardia, whereas high concentrations were irreversible or slowly dissociable. In pylorus-ligated rats, intravenous YM-14471, famotidine and cimetidine dose-dependently inhibited basal gastric secretion with ED50 values of 0.04, 0.43 and 31.2 mg/kg, respectively. ED50 values for oral YM-14471, famotidine, cimetidine and omeprazole were 0.81, 0.42, 28.9 and 7.7 mg/kg when given at 1 hr before ligation, and 5.7, 26.7, 1639.5 and 18.6 mg/kg at 5 hr before ligation. In anesthetized dogs, intravenous YM-14471, famotidine, cimetidine and omeprazole also dose-dependently inhibited histamine (160 micrograms/kg.hr)-induced acid secretion with ED50 values of 13.7, 8.7, 333.3 and 65.3 micrograms/kg, respectively. In Heidenhain pouch dogs, YM-14471 inhibited histamine (40 micrograms/kg.hr)-induced acid secretion by both intravenous (0.02 mg/kg) and oral administration (0.3 mg/kg). Moreover, the inhibitory effect of YM-14471 was more prolonged than those of famotidine and cimetidine by either route, and it was as long as that of omeprazole dosed orally. These results suggest that YM-14471 is an irreversible or slowly dissociable H2-receptor antagonist, and has long antisecretory effect.

Animals↗

PubMed1993

Histamine H2-receptor plays only a minor role in histamine-induced wheal response in the squirrel monkey and guinea pig.

We examined the contribution of the histamine H2-receptor to the histamine-induced wheal response in squirrel monkeys and guinea pigs. Intradermal injection of histamine, 2-pyridylethylamine (a selective H1-agonist), and dimaprit (a selective H2-agonist) dose-dependently induced the wheal response in squirrel monkeys and guinea pigs, although the reaction to dimaprit was much weaker than that to the other agonists. Chlorpheniramine dose-dependently depressed the wheal response in squirrel monkeys and guinea pigs at doses of 0.03-1 mg/kg and 0.03-3 mg/kg, p.o., respectively. However, famotidine, ranitidine and cimetidine had no effect at doses up to 30, 100 and 300 mg/kg, p.o. in guinea pigs and up to 1, 10 and 400 mg/kg, p.o. in squirrel monkeys, respectively. Cimetidine (3-300 mg/kg, p.o.) dose-dependently potentiated the inhibitory effects of chlorpheniramine (0.1 mg/kg, p.o.) in guinea pigs, but had no effects in squirrel monkeys. Famotidine and ranitidine did not alter the response to chlorpheniramine in either animal. These results suggest that the histamine H2-receptor plays only a minor role in the histamine-induced wheal response in squirrel monkeys and guinea pigs.

Animals↗

PubMed1992

L-365,260, a potent CCK-B/gastrin receptor antagonist, suppresses gastric acid secretion induced by histamine and bethanechol as well as pentagastrin in rats.

We evaluated the effects of a potent cholecystokinin (CCK)-B/gastrin receptor antagonist, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin - 3-yl)-N'-( 3-methylphenyl) urea); a selective CCK-A receptor antagonist, devazepide (L-364,718); and cimetidine on gastric acid secretion induced by pentagastrin, histamine and bethanechol in anesthetized rats. We also evaluated the effects of L-365,260 and cimetidine on acid secretion in pylorus-ligated rats. Intravenous administration of L-365,260, L-364,718 and cimetidine dose-dependently reduced acid secretion induced by pentagastrin (20 nmol/kg/hr), with ED50 values of 0.63, 19.1 and 2.5 mumol/kg, respectively. Of interest was the finding that L-365,260, like cimetidine, dose-dependently inhibited acid secretion induced by histamine (100 mumol/kg/hr) and bethanechol (5 mumol/kg/hr) with ED50 values of 5.9 and 4.3 mumol/kg, respectively. L-364,718, even at 30 mumol/kg, i.v., had only a slight effect on histamine- or bethanechol-induced acid secretion. Gastric acid secretion was suppressed by treatment with L-365,260 (3-100 mumol/kg, i.v.) and cimetidine (11.9-396.4 mumol/kg, i.v.) in pylorus-ligated rats, with ED50 values of 13.3 and 96.9 mumol/kg, respectively. These results indicate that L-365,260 suppresses acid secretion induced by histamine and bethanechol in rats and that the gastrin receptor plays an important role in acid secretion in pylorus-ligated rats.

Animals↗

PubMed1992

Role of the serotonin3 receptor in stress-induced defecation.

The possibility that 5-hydroxytryptamine (serotonin; 5-HT) mediates bowel dysfunction caused by stress was evaluated in rats and mice treated with 5-HT or thyrotropin-releasing hormone (TRH) injection and in rats subjected to stress. Restraint stress at room temperature (23 degrees C) significantly increased fecal pellet output without the formation of gastrointestinal mucosal lesions in free-feeding rats, and caused diarrhea in 90 to 100% of animals within 3 hr in food-deprived rats. Oral YM060, ondansetron, granisetron, atropine and diazepam and s.c. tetrodotoxin inhibited these stress-induced changes in bowel function in fed and fasted rats. ED50 values were 1.1 (0.2-6.6) and 2.5 (1.1-5.7) micrograms/kg for YM060, 483 (338-691) and 354 (262-477) micrograms/kg for ondansetron, 208 (111-393) and 142 (48.9-414) micrograms/kg for granisetron, 811 (639-1,030) and 847 (641-1,118) micrograms/kg for atropine, 3,099 (1,499-6,405) and 5,396 (4,768-6,106) micrograms/kg for diazepam and 1.9 (1.7-2.1) and 3.3 (1.6-6.5) micrograms/kg for tetrodotoxin, respectively. Methysergide inhibited stress-induced diarrhea with an ED50 value of 724 (384-1,366) micrograms/kg s.c., whereas it had partial effect on stress-induced increases in fecal pellet output. Exogenous 5-HT increased fecal pellet output in rats and caused diarrhea in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Determination of platelet-activating factor by a chemiluminescence method and its application to stimulated guinea pig neutrophils.

A simple, rapid and sensitive chemiluminescence method has been developed to measure platelet-activating factor (PAF). Hydrogen peroxide generated from PAF, upon phospholipase D cleavage, by choline oxidase is determined as chemiluminescence by a luminol-microperoxidase system. The detection limit of PAF by this method is 5 pmol/tube. The method is reproducible with a 5.5% coefficient of variation at 10 pmol of PAF (n = 5). Lipids were extracted from guinea pig neutrophils after stimulation with cytochalasin B and N-formyl-methionyl-leucyl-phenylalanine, and PAF was isolated by high-performance liquid chromatography and determined by chemiluminescence measurements. The amount of PAF detected was 96.1 +/- 39.7 (mean +/- SD, n = 7) pmol/10(8) cells. This highly sensitive method could be useful for the determination of PAF generated under pathophysiological conditions.

Animals↗

PubMed1991

Antiemetic effects of YM060, a potent and selective serotonin (5HT)3-receptor antagonist, in ferrets and dogs.

YM060, (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride, is a new serotonin (5HT)3-receptor antagonist. We examined the effects of YM060 on chemotherapeutic agent-, apomorphine- and copper sulfate-induced emesis. Intravenous YM060 potently prevented cisplatin (10 mg/kg, i.v.)-induced emesis with ED50 values of 0.06 (0.05-0.07) micrograms/kg, i.v. in ferrets. Based on the ED50 values, YM060 was 300, 20 and 100 times more potent than ondansetron, granisetron and the S-isomer of YM060, respectively. The relative potencies of these drugs described above were similar to those in the previously reported 5HT3-receptor antagonism. YM060 given orally also potently inhibited cisplatin (10 mg/kg, i.p.)- and cyclophosphamide (200 mg/kg, i.p.)-induced emesis in ferrets with ED50 values of 0.1 (0.09-0.11) and 0.02 (0.16-0.27) micrograms/kg, p.o., respectively. All tested 5HT3-receptor antagonists including YM060 failed to prevent apomorphine (0.1 mg/kg, s.c.)-induced emesis in dogs and copper sulfate (1%, 10 ml, p.o.)-induced emesis in ferrets. Our data indicate that YM060 is a highly potent inhibitor of chemotherapeutic agent-induced emesis and that the antiemetic effect of YM060 may be depend on 5HT3-receptor antagonism.

Administration, Oral↗