Absorption, excretion and metabolism of tiquizium bromide in dogs, and relationship between pharmacological effect and plasma levels of unchanged drug

The disposition of 14C-tiquizium bromide was investigated in dogs after oral administration and i.v. administration. After oral administration, max. blood concn. of radioactivity were obtained from one to three hours after dosing. The half-lives of terminal phase were 7.1 h (i.v.) and 9.4-12.0 h (p.o.). The relative bioavailability was 26%. The urinary excretion in three days was 24% (i.v.) and 5-9% (p.o.). The most important mechanism of biotransformation was hydroxylation in the 5-position of the thiophene ring, and glucuronides of the isomeric hydroxylated products of tiquizium bromide were found in urine. The time-course of the inhibitory effect of tiquizium bromide on stomach contraction correlated well with the plasma levels of unchanged drug after intraduodenal administration.     

Absorption,excretion and metabolism of tiquizium bromide in dogs,and relationship between pharmacological effect and plasma levels of unchanged drug

1. The disposition of ¹⁴C-tiquizium bromide was investigated in dogs after oral administration and i.v. administration.

2. After oral administration, max. blood concn. of radioactivity were obtained from one to three hours after dosing. The half-lives of the terminal phase were 7.1?h (i.v.) and 9.4-12.0?h (p.o.). The relative bioavailability was 26%. The urinary excretion in three days was 24% (i.v.) and 5-9% (p.o.).

3. The most important mechanism of biotransformation was hydroxylation in the 5-position of the thiophene ring, and glucuronides of the isomeric hydroxylated products of tiquizium bromide were found in urine.

4. The time-course of the inhibitory effect of tiquizium bromide on stomach contraction correlated well with the plasma levels of unchanged drug after intraduodenal administration.     

Effect of increasing oral doses of loperamide on gallbladder motility in man.

1. Loperamide, a peripherally acting opiate receptor agonist with antidiarrhoeal action, inhibits ileal and colonic motor function. To determine the effect of loperamide on gallbladder motility, we have pretreated five healthy volunteers with 2 mg oral loperamide 24 h, 20, 12 and 2.5 h before; six healthy volunteers with 16 mg oral loperamide 2.5 h before; and eight healthy volunteers with 16 mg oral loperamide 12 and 2.5 h before intravenous infusion of a 'physiological dose' of 12.5 pmol kg-1 cholecystokinin (CCK) for 1 h to stimulate gallbladder contraction. All subjects served as their own controls. Gallbladder volume was measured by ultrasonography and plasma CCK by radioimmunoassay until 90 min after start of the CCK infusion. 2. Infusion of CCK resulted in plasma CCK concentrations similar to those after intraduodenal fat. Integrated gallbladder contraction after 4 X 2 mg loperamide (4600 +/- 891% min) was similar to that without pretreatment (5270 +/- 1037% min; NS). Integrated gallbladder contraction after 1 X 16 mg loperamide diminished from 5458 +/- 412% min without to 2632 +/- 816% min with loperamide (P less than 0.05), and was completely abolished to -596 +/- 762% min (P less than 0.0005 vs without loperamide) after 2 X 16 mg loperamide. 3. It is concluded that loperamide inhibits gallbladder contraction in response to a physiological dose of cholecystokinin in a dose-dependent manner.     

Effects of somatostatin and loxiglumide on gallbladder motility

Cholecystokinin (CCK) is the major hormonal stimulus of gallbladder contraction. Both somatostatin and CCK-A receptor antagonists inhibit stimulation of the gallbladder by CCK. The aim of this study was to compare the effect of somatostatin and the CCK-A receptor antagonist loxiglumide (CR 1505) on gallbladder volume at baseline and after feeding.In random order nine healthy subjects received somatostatin (IV loading dose 125 g, followed by IV infusion of 125 g · h^–1), loxiglumide (10 mg · kg^–1 · h^–1) and control saline. Gallbladder volumes and plasma CCK levels were measured basally and during stimulation by an intraduodenal infusion of fat using, respectively, ultrasound and a sensitive and specific radioimmunoassay.Mean basal gallbladder volume was similar prior to the saline control (28.5 ml), loxiglumide (28.7 ml) and somatostatin (23.4 ml) experiments. In the control experiment, intraduodenal fat led to a significant increase in plasma CCK from 2.6 to 4.8 pmol · l^–1, accompanied by contraction of the gallbladder to 2.0 ml. Loxiglumide induced dilatation of the gallbladder to 40 ml and prevented the any contraction in response to intraduodenal fat. During the somatostatin infusion, gallbladder volume remained the same both basally and during fat stimulation. The plasma CCK response to intraduodenal fat was exaggerated by loxiglumide and was abolished by somatostatin.We conclude that there are major differences between the effects of loxiglumide and somatostatin on gallbladder motility. Loxiglumide dilates the gallbladder, while somatostatin prevents its contraction during fat stimulation.     

一种治疗糖尿病餐后高甘油三酯血症的新策略:改善胃肠蠕动

糖尿病(DM)普遍存在餐后高甘油三酯(TG)血症和胃轻瘫，但是否胃轻瘫对餐后TG水平有一定影响缺乏相关的研究。本文通过四氧嘧啶诱导的DM小鼠调查了胃轻瘫、餐后高TG血症和它们之间可能的关系。结果显示：(1)DM小鼠出现了明显的胃肠功能障碍，表现为胃排空延迟，肠蠕动变缓；(2)饲喂橄榄油后，DM小鼠出现了延迟而恶化的高TG血症，吗叮啉缩短了TG峰时间；(3)腹腔和十二指肠给予橄榄油，DM小鼠没有延迟的TG峰时间出现。这些结果暗示DM胃轻瘫是导致DM餐后高TG血症的一个重要因素，改善胃肠蠕动也许将成为治疗DM餐后高TG血症的一种新的策略。     

Effect of cholinergic agonists and antagonists on gallbladder volume in fasting man

Summary The effect of direct cholinergic stimulation and blockade on gallbladder volume, determined by real-time ultrasonography (RUS), was evaluated in twenty normal, fasting subjects. Eleven subjects received atropine sulphate or placebo and 9 subjects a series of 3 injection of prostigmine, bethanechol or placebo, randomly assigned, at intervals of 24 h.RUS was performed under basal conditions after fasting for 12 h and every 5 min after drug injection up to 45 min in the atropine study and up to 60 min after prostigmine and bethanechol.There was no significant variation from fasting gallbladder volume after placebo in either group. After atropine sulphate gallbladder volume at first decreased and then significantly increased. With bethanechol and prostigmine, the volume fell significantly to a trough after 30 to 35 min, and then it returned to the basal value within 60 min. It is suggested that cholinergic mediation is involved in maintaining fasting tone in the gallbladder and that cholinergic stimulation causes contraction of the gallbladder by a direct effect.     

The effects of vapreotide, a somatostatin analogue, on gastric acidity, gallbladder emptying and hormone release after 1 week of continuous subcutaneous infusion in normal subjects

AIMS: Somatostatin analogues (e.g. vapreotide) are used for treatment of acromegaly, endocrine tumours and variceal bleeding. The pharmacodynamic effects of vapreotide have, however, not been documented in the gastrointestinal tract. The aim of this study was to investigate the effects of continuous vapreotide administration on gastric acidity, gallbladder contraction and hormone release. METHODS: Ten healthy males participated in this randomised, placebo-controlled, double-blind, crossover trial. A constant vapreotide (or placebo) infusion (1.5 mg day(-1) s.c.) was given for 7 days with a portable pump. Intragastric pH was monitored on days 2 and 7. Gallbladder volume was sonographically assessed and the maximal ejection fraction was calculated. In addition basal and postprandial plasma levels of gastrin and cholecystokinin (CCK) were measured. RESULTS: After an initial increase in the median 24 h intragastric pH to a value of 2.6 on day 2, vapreotide's effect on pH decreased: (day 7: median pH=1.9; respective placebo values were 1.7 and 1.5). On the same days with vapreotide treatment, gallbladder contraction and plasma levels of CCK were reduced; maximal ejection fractions after meal stimulation were 18% and 20% (respective placebo values were 57% and 62%). Plasma gastrin levels were not changed with vapreotide treatment. CONCLUSIONS: The short lasting effect of vapreotide on intragastric acidity suggests a down-regulation of somatostatin receptors during treatment. The lack of effect on gastrin indicates that the effects on gastric pH are not mediated by gastrin. Constant vapreotide infusion (but not placebo) reduced gallbladder contraction suggesting a long-lasting effect on biliary function.     

Effect of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)phenyl] propionic acid hydrochloride on gastric mucosa directly from the lumen

The present experiments were designed to determine if the novel anti-ulcer drug 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)phenyl]propionic acid hydrochloride (TEI-5103, TG-51), acts on the gastric mucosa directly from the lumen when given orally. TEI-5103 given orally (50-400 mg/kg) prevented the lesion formation induced by 0.1N HCl + 60% ethanol, but when given intraperitoneally (50-200 mg/kg) or intravenously (40 mg/kg), it did not prevent the formation of lesions. Indomethacin-induced gastric lesions were inhibited by oral administration of TEI-5103, but not by intraduodenal administration. In pylorus-ligated rats, TEI-5103 given intragastrically also inhibited the development of gastric lesions induced by HCl + ethanol. These results suggest that the presence of TEI-5103 in the stomach is necessary to elicit its anti-ulcer effect. In microautoradiographic examination, silver grains corresponding to [14C]-TEI-5103 distributed in the upper part of the mucosa (luminal side) at 0.5 to 4 h after the oral administration. However, when given intraduodenally or intravenously, this high concentration of [14C]-TEI-5103 was not observed in the stomach tissue. When given orally, the content of [14C]-TEI-5103 in rat stomach tissue was about 100 times higher than that in plasma and the time course of distribution was different from that seen in the gastric content. From these results, it seems that TEI-5103 distributes in the gastric mucosa directly from the lumen. In conclusion, TEI-5103, when given orally, distributes in the gastric mucosa as a target issue directly from the lumen; and only the oral and gastric route of administration lead to the anti-ulcer effect.     

The effect of papaverine on the contraction of the human gallbladder

In a double-blind study, 40 mg of papaverine (Group I) or the same amount of placebo (1.0 ml of physiological saline, Group II)was injected intravenously in 19 patients to study the effect of papaverine on the contractility of the gallbladder in connection with routine oral cholecystography. In both groups a standard contraction meal (200 ml of cream) caused a significant contraction of the gallbladder (at 30 minutes). Thereafter, intravenously administered papaverine significantly inhibited further contraction caused by the fatty meal, but no significant dilatation was observed. This difference between the two groups lasted throughout the whole study period to 60 minutes after the drug administration. This time period mainly consisted of the distributional alpha-phase of the drug concentrations determined by gas chromatography in the serum. Because no dilation effect on the gallbladder was found, the clinical spasmolytic response to papaverine during an acute attack of pain in a patient with gallstones seems to be questionable.     

Pharmacokinetics of Levodopa and Carbidopa in Rats Following Different Routes of Administration

This study examined the pharmacokinetics of levodopa and carbidopa in the rat after different modes of administration. The drugs were given simultaneously by the intravenous, intraarterial, oral, duodenal, and intraperitoneal routes, as single doses. The ratio of levodopa to carbidopa given was always 4:1. Two iv doses (5 and 15 mg/kg of levodopa) were given to test for nonlinearity. Three ip doses of levodopa were given (5, 7.5, and 15 mg/kg), and the 15 mg/kg dose was given in three volumes (2, 4, and 20 mL/kg). One oral dose and two intraduodenal doses of 15 mg/kg were given. The drugs were dissolved in saline in one of the intraduodenal doses and suspended in 1.8% methylcellulose in the other. The elimination of levodopa was nonlinear. There was a comparatively high degree of interindividual variability in absorption with the oral route, but this was substantially reduced when levodopa was given intraduodenally. There was also much less variability with the intraperitoneal route compared to the oral, and the degree of absorption was generally high. There was a significantly higher extent and slower rate of absorption when levodopa was administered ip in a large volume of vehicle. These results suggest that the oral route may not be the optimal method of delivering levodopa to patients who have a fluctuating response and that a continuous delivery system via the intraperitoneal or intraduodenal routes might be a better alternative.     

Pharmacological studies of water extract of the Zizyphus seed and the Zizyphus seed containing drug

1. The pharmacological properties of a water extract of the Zizyphus seed (HO2) and that of the Zizyphus seed containing drug (HO1) were studied. 2. After oral or intraduodenal administration of 3 g/kg of HO1 or HO2, the hypnotic effects induced by hexobarbital-Na (38 mg/kg, i.p.) and diazepam-induced sleep in mice were potentiated. 3. After oral or intraduodenal administration of 3 g/kg of HO1 or HO2, gastric juice secretion and ulcers induced by water immersion stress, histamine and reserpine in rats were inhibited.     

Lipid peroxidation, glutathione and ascorbic acid concentrations in tissues of mice treated with oltipraz: influence of cysteine and olive oil pretreatments.

1. The effects of treatment with the antischistosomal drug oltipraz on reduced glutathione (GSH), lipid peroxide (LP) and ascorbic acid (AA) concentrations in the liver, kidney and brain were studied in mice 24 h after drug administration. 2. The influence of pretreatment with cysteine or olive oil on the above variables in oltipraz-treated mice was also investigated. 3. Oltipraz, at single oral doses of 25 and 125 mg/kg, did not affect significantly the concentrations of GSH, LP or AA in any of the tissues studied. 4. At a dose of 625 mg/kg, the drug produced significant increases in GSH concentration in the liver (about 34%), kidney (38%) and brain (24%). 5. AA concentrations were not significantly affected by the drug treatment in any of the organs studied. 6. However lipid peroxide formation in the liver of mice treated with oltipraz (625 mg/kg) was less than that in control animals by about 45% (P less than 0.05). 7. In other organs it was not significantly affected by the treatment. 8. Oltipraz (625 mg/kg) was given orally to mice which were pretreated with cysteine (25, 50 and 100 mg/kg for 7 days intramuscularly). 9. The cysteine pretreatments did not affect significantly the increases in GSH caused by oltipraz alone, although they were effective in significantly increasing GSH concentrations in saline-treated mice. 10. The oltipraz-induced increases in the concentrations of GSH in liver and kidney was enhanced (by about 16%) by olive oil (0.2, 02 and 0.4 ml/mouse) when given 1 h before oltipraz treatment. 11. Concentrations of LP and AA were not significantly affected by olive oil pretreatment.     

Gastrointestinal first-pass effect of YJA-20379-8, a new reversible proton pump inhibitor, in rats.

Since low bioavailability of YJA-20379-8 (3-butyryl-4-[5-R-(+)-methylbenzylamino]-8ethoxy-1,7-naph thy ridine), a new reversible proton pump inhibitor, has been reported after oral administration of the drug to rats, the first-pass organ of the drug was investigated in rats. YJA-20379-8, 50 mg kg(-1), was infused over 1 min via the jugular vein (n=5) or the portal vein (n=5), or was instilled directly into the stomach (n=5) or the duodenum (n=5). After intravenous or intraportal infusion of the drug, the total body clearance of YJA-20379-8 (18.1 and 19.7 mL min(-1) kg(- 1) based on plasma data) was considerably lower than the reported cardiac output (296 mL min(-1) kg(-1) based on blood data) in rats. This data indicated that the first-pass effect of YJA-20379-8 by the lung and heart was negligible. The areas under the plasma concentration-time curve from time zero to time infinity (AUC) after intravenous or intraportal administration of YJA-20379-8 (2760 and 2540 microg min mL(-1)) were not significantly different, indicating that the hepatic first-pass effect of the drug was also negligible in rats. After intragastric or intraduodenal instillation of YJA-20379-8, the extent of absolute oral bioavailability was 18.2 and 33.8%, respectively. Based on gastrointestinal recovery studies, approximately 86.5 and 91.2% of YJA-20379-8 was absorbed from rat gastrointestinal tract after intragastric or intraduodenal instillation, respectively. The data indicated that gastrointestinal and intestinal first-pass effects of YJA-20379-8 were approximately 68% (86.5-18.2) and 57% (91.2-33.8), respectively. The AUC(0-24h) values of YJA-20379-8 were significantly different between intragastric and intraduodenal instillation, indicating that the gastric first-pass effect of the drug was approximately 10% in rats. Therefore, it could be concluded that the low F value of YJA-20379-8 after oral administration of the drug could be due to a considerable (approx. 60%) intestinal first-pass effect in rats.     

Effect of inhibition of gastric acid secretion on antropyloroduodenal motor activity and duodenal acid hypersensitivity in functional dyspepsia

BACKGROUND: Heightened visceroperception and a decreased duodenal motor response to intraduodenal acid infusion have been reported in functional dyspepsia. AIM: To investigate the effect of treatment with a proton pump inhibitor on sensorimotor impairment in 19 patients with functional dyspepsia. METHODS: Patients were assigned double-blind to pantoprazole (n=10) or placebo (n=9) treatment for 2 weeks. Antropyloroduodenal manometry was performed before and after treatment, using a 21-channel catheter, and the responses to intraduodenal infusion of 5 mL of saline and acid were assessed. Nausea, fullness and epigastric pain were scored before and after each infusion. RESULTS: Acid induced a modest duodenal motor response and suppression of antral pressure waves, not altered by either treatment. However, acid evoked isolated pyloric pressure waves after pantoprazole treatment (P < 0.02), and not after placebo. Saline induced no motor response. Acid (not saline) induced nausea, both before and after treatment in both groups (all P < 0.05). Subgroup analysis of the seven acid-hypersensitive patients (37%) showed a tendency towards a decrease in nausea in all four pantoprazole-treated patients (P=0.07), in contrast to the three placebo-treated patients (P=1.0). CONCLUSIONS: In functional dyspepsia, pantoprazole influenced the acid-induced duodenogastric feedback mechanism, but not the impaired duodenal motor response. Duodenal acid hypersensitivity was decreased to some extent.     

Pharmacokinetics, bioavailability and absorption of flumequine in the rat.

The study demonstrates that the oral extent of bioavailability of flumequine in the rat, relative to the intravenous injection, is complete (0.94 +/- 0.04) and not significantly different from that found by the intraduodenal route (0.95 +/- 0.04). The rate of oral bioavailability, however, is slow (ka = 1.20 +/- 0.07 h-1; Tmax = 2.0 h), but enough to maintain plasma levels above the minimal inhibitory concentration of the most common pathogens for an extended period of time (about 10 h). The reason for the oral absorption slowness could be a slow gastric emptying, an adsorption to the gastric mucosae, a precipitation in the gastric medium or any other feature concerning the stomach as the intraduodenal administration is very quick (kid = 38.1 +/- 4.7 h-1; Tmax = 0.05 h). A possible precipitation of flumequine cannot be discarded as the solubility of flumequine is very low in the pH range of 3 to 6 (mean pH values for rat stomach and rat intestine, respectively; T.T. Kararli, Biopharm. Drug Dispos. 16 (1995) 351-380). Flumequine was shown to be not substantially excreted in bile (2-3% of the dose). Surprisingly, plasma levels and AUC values found for animals with interrupted bile flow always surpass those found for animals with enterohepatic circulation. This could be due to experimental model features, which might bias plasmatic flumequine concentrations if the homeostatic equilibrium of the animal is not completely restored due to the volume reduction induced by biliary extraction.     

Oral or intravenous erythromycin has no effect on human distal colonic motility

Erythromycin is a prokinetic agent for the lower oesophageal sphincter, the stomach, the gallbladder and the small bowel, acting directly on motilin receptors. Its effect on pressure activity of the human colon has not been investigated. Eight healthy volunteers were studied on 2 occasions and given intravenous or oral erythromycin, or placebo in a single-blind, randomized crossover study. Sigmoid pressure activity was measured using a 4-lumen water perfused system placed sigmoidoscopically at 50, 45, 30 and 15 cm from the anal verge. The pressures were analysed for activity index (mmHg.min) for the 35 cm colonic study segment using dedicated software. No significant difference was found in the activity index following oral erythromycin (500 mg) or placebo, or following intravenous erythromycin 1.8 mg/kg or placebo. A further 8 subjects were studied in a single-blind crossover study to determine the effect of oral erythromycin (500 mg) b.d. on colonic transit, measured with radio-opaque markers and a single abdominal X-ray. Mean or segmental colonic transit times were not statistically significantly different (Student's paired t-test) in the subjects on placebo or erythromycin. This lack of effect of erythromycin on the distal large intestine may indicate the absence of receptors for motilin in that part of the gut.     

苯环喹溴铵对豚鼠鼻超敏反应的影响

目的:观察苯环喹溴铵对豚鼠超敏性鼻炎的治疗效果。方法:(1)以10%的2,4-二异氰酸甲苯酯(TDI)橄榄油溶液行豚鼠双侧鼻腔给药,建立豚鼠超敏性鼻炎的模型;另设溶媒对照组,以橄榄油溶液代替10%TDI橄榄油溶液行豚鼠双侧鼻腔给药。(2)将模型成功的豚鼠随机分模型对照组,苯环喹溴铵大、中、小剂量组和硫酸阿托品组;与溶媒对照组一起合计共6组。治疗2周后,观察各组豚鼠的症状、鼻分泌物、鼻黏膜组胺含量以及光镜下鼻黏膜组织形态学的变化。结果:模型组出现鼻痒、喷嚏、清涕、鼻黏膜组胺含量增高、嗜酸性粒细胞增多等变化。苯环喹溴铵治疗组上述变化明显减轻。结论:经鼻给予苯环喹溴铵,对于豚鼠鼻超敏性鼻炎有明显的治疗作用。     

Cyclosporine A preparations and their vehicles induce contraction of the guinea pig gallbladder in vitro: the role of cyclooxygenase metabolites.

The aim of this study was to establish whether prostanoids play a role in the contraction induced by cyclosporine A (CyA) preparations in the guinea pig isolated gallbladder strips. It was also aimed to study the effects of the preparations and their solvents on the acetylcholine-evoked rhythmic contractions of the guinea pig isolated sphincter of Oddi (SO). Isometric contractions were recorded. CyA parenteral and oral preparations and their vehicles, Cremophor-EL and Labrafil caused concentration-dependent and sustained contractions (74.2 +/- 6.2, 58.4 +/- 6.3, 88.9 +/- 4.9 and 47.5 +/- 6.2% of maximum KCl contraction, respectively) of gallbladder strips, but not of SO. Quinacrine, indometacin and ridogrel inhibited the contraction induced by CyA preparations and their vehicles in gallbladder strips (for CyA parenteral preparation, 34.7 +/- 6.7, 1.4 +/- 0.9, 19.0 +/- 6.4% of maximum KCl contraction, respectively). The drug and its vehicles changed neither the initial contraction nor the amplitude and frequency of the phasic contractions induced by acetylcholine in SO preparations. The results indicate that the drug is able to contract the gallbladder strips and the vehicles contribute to the contracting effect of CyA. Prostanoids may be responsible for the CyA-induced contraction of the gallbladder.     

Effect of cisapride on human fasting gallbladder volume: A real-time ultrasonographic study

Summary The effect of cisapride, a new non-antidopaminergic agent, on human gallbladder volume has been studied in nine normal subjects. In a double-blind crossover fashion, each subject was given a slow i.v. injection of cisapride and placebo after 12-h fasting. Gallbladder volume was monitored every 15 min for 90 min by real-time ultrasonography. After cisapride, gallbladder volume significantly diminished, with a mean reduction of 22.9±5%, observed 30 min after injection, whereas no significant changes were noted after placebo. A cholinergic mechanism is proposed to explain the effect of cisapride on gallbladder volume.     

In Vivo Model for Ciclosporin Intestinal Absorption in Lipid Vehicles

The influence of lipid vehicles on the intestinal absorption of Ciclosporin was studied in vivo. The model takes into account the effect of the intestinal lipid digestion on the absorption after intraduodenal administration of [³H]Ciclosporin in olive oil or middle-chain triglyceride (MCT) to the bile duct-cannulated rat. Digested vehicles significantly promoted the absorption compared to nondigested vehicles. In the nondigested state, olive oil was a significantly better vehicle than MCT, whereas the difference between both lipids was only a trend in the digested state. Further studies with variants of this in vivo model should determine the influence of abnormalities of fat digestion and absorption on the pharmacokinetics and pharmacodynamics of a drug with a low therapeutical index.