Trimebutine Maleate Research Articles

Novelty Stress Increases Fecal Pellet Output in Mongolian Gerbils: Effects of Several Drugs

Stress-induced colonic functional changes have been investigated mainly under conditions involving physical stress, like in the restraint stress model. In this study, we established a new stress-induced defecation model involving the placement of Mongolian gerbils in a novel environment (novelty stress) and determined the effects of several drugs on novelty stress-induced fecal pellet output. When animals kept in groups were placed individually in small cages, the fecal pellet output markedly increased, although the upper intestinal transit measured by charcoal method was not changed. The concentration of plasma adrenocorticotropic hormone was moderately but significantly increased by the novelty stress. Drugs reportedly effective for stress-induced defecation, like alosetron hydrochloride, atropine sulfate, and trimebutine maleate, inhibited both the novelty stress-induced increase in fecal pellet output and spontaneous defecation. In contrast, TAK-637, a tachykinin NK1-receptor antagonist, and diazepam inhibited the novelty stress induced defecation but did not inhibit spontaneous defecation. The present study indicated that novelty stress increases fecal pellet output without affecting the upper intestinal transit; this model may be useful for evaluating the effects of drugs on stress-stimulated colonic motility.

Beneficial effect of trimebutine and N-monodesmethyl trimebutine on trinitrobenzene sulfonic acid-induced colitis in rats

The use of local anesthetics, such as lidocaine, has been proposed in the treatment of distal ulcerative colitis. Trimebutine maleate (TMB) displays a local anesthetic activity higher than that of lidocaine in rabbit corneal reflex. TMB and nor-TMB its main metabolite in human show similar affinity to that of bupivacaine toward sodium channel labeled by [ 3H]batrachotoxin and block sodium currents in sensory neurons from rat dorsal root ganglia. The aim of this study was to evaluate the effects of TMB and nor-TMB in comparison to lidocaine and bupivacaine in a rat model of acute colonic inflammation induced by trinitrobenzene sulfonic acid (TNBS). A single intracolonic instillation of TNBS (50 mg/kg dissolved in ethanol 30%) led to early plasma extravasation then macroscopic damage (hyperemia and necrosis), increased colonic weight and tissular MPO, a marker of neutrophilic infiltration. Local administration of TMB at dose of 3 to 60 mg/kg, 30 min before, 24 and 48h after colitis induction, significantly reduced the severity of colitis. Nor-TMB (1, 3, 10, 30 mg/kg) as well as lidocaine (1, 3, 10 mg/kg) dose-dependently reduced colitis while bupivacaine at 10 mg/kg did not affect it significantly. In contrast systemic administration of TMB, nor-TMB and lidocaine at 10 mg/kg had no significant effect. Furthermore, local administration of TMB (30 mg/kg) and lidocaine (10 mg/kg) significantly reduced plasmatic extravasation. In conclusion, intracolonic treatment with TMB and nor-TMB improved acute experimental TNBS-induced colitis in rat and these effects could be explained by their local anesthetic activity.

Spectrophotometric and liquid chromatographic determination of trimebutine maleate in the presence of its degradation products

Three methods are presented for the determination of trimebutine maleate (TM) in the presence of its degradation products. The first method was based on a high performance liquid chromatographic (HPLC) separation of TM from its degradation products using an ODS column at ambient temperature with a mobile phase consisting of acetonitrile—5 mM heptane sulfonic acid disodium salt (45:55, v/v, pH 4) with UV detection at 215 nm. The second method depends on using first derivative spectrophotometry ( 1D) by measurement of the amplitude at 252.2 nm. The third method depends on using first derivative of the ratio spectrophotometry ( 1DD) by measurement of the amplitude at 282.4 nm where a normalized spectrum of 3,4,5-trimethoxy benzoic acid is used as divisor. The proposed HPLC and 1D methods were used to investigate the kinetics of acidic and alkaline degradation processes. The pH-rate profile of degradation of TM in Britton–Robinson buffer solutions within the pH range 2–11.9 was studied.

Quantitative determination of trimebutine maleate and its three metabolites in human plasma by liquid chromatography-tandem mass spectrometry

A sensitive and selective HPLC–MS–MS method was developed for the determination of trimebutine maleate (TM) and its major metabolites N-monodemethyltrimebutine (TM-MPB), N-didemethyltrimebutine (APB) and 3,4,5-trimethoxybenzoic acid (TMBA) in human plasma. The analytes were extracted from plasma samples by liquid–liquid extraction and chromatographed on a YMC J’sphere C 18 column. The mobile phase consisted of 2 m M ammonium acetate buffer (pH 6.5)–methanol (20:80, v/v), and at a flow-rate of 0.2 ml/min. Detection was carried out on a triple quadrupole tandem mass spectrometer in multiple reactions monitoring (MRM) mode using positive–negative switching electrospray ionization (ESI). The method was validated over the concentration range of 1–100 ng/ml for trimebutine maleate and APB, 1–500 ng/ml for MPB, and 50–10 000 ng/ml for TMBA. Inter- and intra-day precision (RSD%) for trimebutine maleate and its three metabolites were all within ±15% and the accuracy was within 85–115%. The limit of quantitation was 1 ng/ml for trimebutine maleate, TM-MPB and APB, and 50 ng/ml for TMBA. The extraction recovery was on average 58.2% for trimebutine maleate, 69.6% for MPB, 51.2% for APB and 62.5% for TMBA. The method was applied to the pharmacokinetic study of trimebutine maleate and its metabolites in healthy Chinese volunteers.

Effects of tachykinin NK1 receptor antagonists on the viscerosensory response caused by colorectal distention in rabbits.

Irritable bowel syndrome (IBS) is a common disorder mainly characterized by altered bowel habits and visceral pain. In this study, we investigated the role of tachykinin NK1 receptors in the visceral pain response (abdominal muscle contraction) caused by colorectal distention in rabbits previously subjected to colonic irritation, using the selective tachykinin NK1 receptor antagonists TAK-637 [(aR,9R)-7-[3,5-Bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4] diazocino[2,1-g][1,7]naphthyridine-6,13-dione] and (+/-)-CP-99,994 (+/-)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine. Intracolorectal administration of 0.8% acetic acid solution enhanced the nociceptive response to colorectal distention, producing a significant increase in the number of abdominal muscle contractions. Under these conditions, intraduodenal TAK-637 (0.1-3 mg/kg) dose dependently decreased the number of distention-induced abdominal contractions, and a significant inhibitory effect was observed with doses of 0.3 to 3 mg/kg. Another tachykinin NK1 antagonist, (+/-)-CP-99,994, also reduced the number of abdominal contractions. In contrast, the enantiomer of TAK-637 (which has very weak tachykinin NK1 receptor antagonistic activity), trimebutine maleate, ondansetron, and atropine sulfate did not inhibit the abdominal response. The main metabolite of TAK-637, which has more potent tachykinin NK1 receptor antagonistic activity but permeates the central nervous system less well than TAK-637, produced less inhibition of the viscerosensory response. When given intrathecally, TAK-637 and (+/-)-CP-99,994 markedly reduced the number of abdominal contractions. These results suggest that tachykinin NK1 receptors play an important role in mediating visceral pain and that TAK-637 inhibits the viscerosensory response to colorectal distention by antagonizing tachykinin NK1 receptors, mainly in the spinal cord. They also suggest that TAK-637 may be useful in treating functional bowel disorders such as IBS.

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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.

Duodenogastric reflux following cholecystectomy in the dog: role of antroduodenal motor function.

Duodenogastric reflux has been implicated in the pathogenesis of gastric ulcer and gastritis. Duodenogastric reflux after cholecystectomy is also a possible cause of post-cholecystectomy syndrome. To investigate the role of antroduodenal motor function in increased duodenogastric reflux following cholecystectomy and the effect of trimebutine maleate (trimebutine) on the duodenogastric reflux in conscious dogs. Antropyloric and duodenal motility and bile acids content in the gastric juice were measured for 3 h during the inter-digestive state in dogs with or without cholecystectomy. Bile acids content in the gastric juice of cholecystectomized dogs was significantly higher than that of non-cholecystectomized dogs. The frequency of pyloric relaxation during phase II of the migrating motor complex was significantly increased following cholecystectomy. Intravenous infusion of trimebutine inhibited both the increased duodenogastric reflux and the frequency of pyloric relaxation in the cholecystectomized dog. Duodenogastric reflux and frequency of pyloric relaxations were increased in cholecystectomized dogs and trimebutine suppressed both of them. These findings suggest that the increased frequency of pyloric relaxation contributes to the duodenogastric reflux following cholecystectomy.

Determination of trimebutine maleate in rat plasma and tissues by using capillary zone electrophoresis.

A simple and rapid capillary zone electrophoresis method was developed for the determination of trimebutine maleate in rat plasma and tissues. Rat plasma and tissue homogenates were mixed with acetonitrile containing internal standard, ephedrine hydrochloride, and then centrifuged. The supernatant was dried under a stream of nitrogen, and the residue was reconstituted in methanol-water (1:1). The electrophoresis was performed in uncoated capillary with 30 mmol/L phosphate buffer of pH 6.0 as the separation electrolyte. The applied voltage was 10 kV and the UV detection was set at 214 nm. The peak height ratio vs concentration in plasma or homogenates was linear over the range of 5-500 ng/mL and the limit of quantitation was 5 ng/mL. The intra- and inter-day precision was RSD < 14% and <15%. The accuracy was relative error (RE) within +/- 14%. This method was applied to studying the pharmacokinetics and tissue distribution after a single dose of trimebutine maleate was administrated to the rats. The T(max), AUC, C(max) and t(1/2) were 30 min, 7.8 x 10(2) (ng/mL) min, 39 ng/mL and 1.7 x 10(2) min. The drug distribution was found in a decreasing order of liver, kidney, spleen, lung and heart.

Effect of trimebutine maleate on experimental colitis in rats

Effect of trimebutine maleate on experimental colitis in rats

Ion-pair formation of Bi(III)–iodide with some nitrogenous drugs and its application to pharmaceutical preparations

A systematic spectrophotometric study on the ion-pair formation of Bi(III)–iodide with amineptine hydrochloride, piribedil and trimebutine maleate is carried out. The optimal experimental conditions pH, concentration of Bi(III) nitrate, potassium iodide; and the nature and amount of organic solvent have been studied. The ion pairs are soluble in 1,2-dichloroethane and the optimum pH range is 2.0–2.8. By application of the methods of Sommer and Job involving non-equimolar solutions, the conditional stability constant (log K′) of the Bi(III)–piridedil ion pair (1:1) at the optimum pH of 2.4 and an ionic strength ( μ) 0.1 M, was found to be 5.436. The validity of Beer's law has been tested in the concentration range 5–50 μg ml −1 in the organic layer, the relative standard deviation is less than 1%. The method is applied to the determination of these drugs in tablets without interference.

Effect of trimebutine maleate on the contractile response of the isolated ileum from diabetic rats

1. 1. Tension of the isolated ileum from diabetic rats induced by streptozotocin was measured isometrically to study the mode of action of trimebutine maleate (TMB). 2. 2. The hyperreactivity of contractile response to KCl was observed in the isolated ileum from diabetic rats. TMB inhibited the contraction induced by KCl and acetylcholine (ACh) in normal solution. 3. 3. In Ca 2+ free solution, the hyperreactivity of contractile response to KCl was attenuated, and TMB did not inhibit the contraction induced by KCl. In contrast, TMB inhibited the contraction induced by ACh even in Ca 2+ free solution. 4. 4. These results suggest that the hyperreactivity of contractile response to KCl in the ileum from diabetic rats is due to the enhancement of Ca 2+ influx through voltage-dependent Ca 2+ channel and that TMB inhibits the hyperreactivity of contractile response through the inhibition of Ca 2+ movement by the cell.

Effect of trimebutine maleate on emptying of stomach and gallbladder and release of gut peptide following a solid meal in man

We investigated the effect of orally administered trimebutine maleate on gastric and gallbladder emptying and on the release of gut peptide, pancreatic polypeptide (PP), and gastrin in humans for 120 min after ingestion of a solid meal. Gastric emptying was measured by a radionuclide technique. Gallbladder emptying was estimated by real-time ultrasonography. The oral administration of 200 mg of trimebutine maleate significantly shortened the lag time in starting gastric emptying (P < 0.05). Considering gallbladder emptying, trimebutine significantly inhibited the fasting emptying induced by neural reflex. Postprandially, there was a tendency toward an accelerated gallbladder emptying in the early phase. Neither the maximal percentage of gallbladder emptying nor the time of peak gallbladder emptying were affected. Trimebutine significantly blunted the post-prandial PP response in the cephalic and gastric phases, reflecting a vagal-cholinergic activity (P < 0.05). The PP response in the intestinal phase was also blunted. Gastrin release was significantly augmented only during the period of fasting after drug administration (P < 0.05). The major effect of trimebutine maleate appears to be a shortening of the lag time at the start of gastric emptying probably via its anticholinergic activity.

P-60 - Effect of trimebutine maleate on hyperreactivity in isolated ileum from diabetic rats.

P-60 - Effect of trimebutine maleate on hyperreactivity in isolated ileum from diabetic rats.

P-171 - Effects of trimebutine maleate on K+ currents in rabbit ileal smooth muscle cells

P-171 - Effects of trimebutine maleate on K+ currents in rabbit ileal smooth muscle cells

O-228 - Effect of trimebutine maleate on gastric motility in rats

O-228 - Effect of trimebutine maleate on gastric motility in rats

Effects of trimebutine on cytosolic Ca 2+ and force transitions in intestinal smooth muscle

The effects of trimebutine maleate on cytosolic free Ca 2+ and force transitions in the guinea-pig taenia cecum were studied by fura-2 fluorometry and tension recording. The addition of 80 mM K + induced a transient increase in cytosolic free Ca 2+ concentration ([Ca 2+] i) and tension, followed by a sustained increase. Trimebutine (10 μM) suppressed both [Ca 2+] i elevation and tension development. The tonic responses were more potently inhibited than the phasic responses. Phasic components gradually increased as the added K + increased (10–40 mM). The relationship between the peak increases in [Ca +] i and tension was not affected by trimebutine (10 μM). This means that trimebutine dose not affect the Ca 2+ sensitivity of contractile elements. In a high K + and Ca 2+-free medium, carbachol (10 μM) or caffeine (30 mM) caused transient [Ca 2+] i elevation and tension development in the smooth muscle. Trimebutine (10 μM) decreased the amplitude of both responses. Trimebutine (10 μM) inhibited the spontaneous fluctuations in [Ca 2+] i and motility of taenia cecum in the presence of tetrodotoxin (TTX; 0.3 μM). These results suggest that trimebutine has two types of inhibitory actions on intestinal smooth muscle; one, the inhibition of Ca 2+ influx through voltage-dependent calcium channels, and the other, the inhibition of Ca 2+ release from intracellular storage sites.

Effect of Trimebutine Maleate on Diabetic Diarrhea

Effect of Trimebutine Maleate on Diabetic Diarrhea

O-201 - Inhibitory actions of trimebutine maleate on cytosolic Ca2+ and force transitions in intestinal smooth mucle.

O-201 - Inhibitory actions of trimebutine maleate on cytosolic Ca2+ and force transitions in intestinal smooth mucle.

Trimebutine maleate has inhibitory effects on the voltage-dependent Ca2+ inward current and other membrane currents in intestinal smooth muscle cells

We examined effects of trimebutine maleate on the membrane currents of the intestinal smooth muscle cells by using the tight-seal whole cell clamp technique. Trimebutine suppressed the Ba2+ inward current through voltage-dependent Ca2+ channels in a dose-dependent manner. The inhibitory effect of trimebutine on the Ba2+ inward current was not use-dependent. It shifted the steady-state inactivation curve to the left along the voltage axis. Trimebutine also had inhibitory effects on the other membrane currents of the cells, such as the voltage-dependent K+ current, the Ca2(+)-activated oscillating K+ current and the acetylcholine-induced inward current. These relatively non-specific inhibitory effects of trimebutine on the membrane currents may explain, at least in part, the dual actions of the drug on the intestinal smooth muscle contractility, i.e. inhibitory as well as excitatory.

Allosteric interaction of trimebutine maleate with dihydropyridine binding sites

The effects of trimebutine maleate on [ 3H]nitrendipine binding to guinea-pig ileal smooth muscle membranes and Ca 2+-induced contraction of the taenia cecam were studied. Specific binding of [ 3H]nitrendipine to smooth muscle membranes was saturable, with a K D value and maximum number of binding sites (B max) of 0.16 nM and 1070 fmol/mg protein, respectively. Trimebutine inhibited [ 3H]nitrendipine binding in a concentration-dependent manner with a K i value of 9.3 μM. In the presence of trimebutine (10 μM). Scatchard analysis indicated a competitive-like inhibition with a decrease in the binding affinity (0.31 nM) without a chane in B max(1059 fmol/mg protein). However, a dissociation experiment using trimebutine (10 or 100 μM) showed that the decreased affinity was due to an increase of the dissociation rate constant of [ 3H]nitrendipine binding to the membrane. In mechanical experiments using the taenia cecum, trimebutine (3–30 μM) caused a parallel rightward shift of the dose-response curve for the contractile response to a higher concentration range of Ca 2+ under high-K + conditions in a noncompetitive manner. These results suggest that trimebutine has negative allosteric interactions with 1,4-dihydropyridine binding sites on voltage-dependent Ca 2+ channels and antagonizes Ca 2+ influx, consequently inhibiting contractions of intestinal smooth muscle.