Trimebutine suppresses Toll-like receptor 2/4/7/8/9 signaling pathways in macrophages.

Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1‒RAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1‒ERK1/2‒JNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling.

Repositioning Trimebutine Maleate as a Cancer Treatment Targeting Ovarian Cancer Stem Cells.

The overall five-year survival rate for late-stage patients of ovarian cancer is below 29% due to disease recurrence and drug resistance. Cancer stem cells (CSCs) are known as a major contributor to drug resistance and recurrence. Accordingly, therapies targeting ovarian CSCs are needed to overcome the limitations of present treatments. This study evaluated the effect of trimebutine maleate (TM) targeting ovarian CSCs, using A2780-SP cells acquired by a sphere culture of A2780 epithelial ovarian cancer cells. TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels. The GI50 of TM was approximately 0.4 µM in A2780-SP cells but over 100 µM in A2780 cells, demonstrating CSCs specific growth inhibition. TM induced G0/G1 arrest and increased the AV+/PI+ dead cell population in the A2780-SP samples. Furthermore, TM treatment significantly reduced tumor growth in A2780-SP xenograft mice. Voltage gated calcium channels (VGCC) and calcium-activated potassium channels (BKCa) were overexpressed on ovarian CSCs and targeted by TM; inhibition of both channels reduced A2780-SP cells viability. TM reduced stemness-related protein expression; this tendency was reproduced by the simultaneous inhibition of VGCC and BKCa compared to single channel inhibition. In addition, TM suppressed the Wnt/ß-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/ß-catenin pathway by simultaneous inhibition of BKCa and VGCC is necessary for the effective and selective action of TM. Taken together, TM is a potential therapeutic drug for preventing ovarian cancer recurrence and drug resistance.

Trimebutine attenuates high mobility group box 1-receptor for advanced glycation end-products inflammatory signaling pathways.

We previously identified papaverine as an inhibitor of receptor for advanced glycation end-products (RAGE) and showed its suppressive effect on high mobility group box 1 (HMGB1)-mediated responses to inflammation. Here, we found trimebutine to be a 3D pharmacophore mimetics of papaverine. Trimebutine was revealed to have more potent suppressive effects on HMGB1-induced production of pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α in macrophage-like RAW264.7 cells and mouse bone marrow primarily differentiated macrophages than did papaverine. However, the inhibitory effect of trimebutine on the interaction of HMGB1 and RAGE was weaker than that of papaverine. Importantly, mechanism-of-action analyses revealed that trimebutine strongly inhibited the activation of RAGE downstream inflammatory signaling pathways, especially the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), which are mediator/effector kinases recruited to the intracellular domain of RAGE. Consequently, the activation of Jun amino terminal kinase, which is an important effector kinase for the up-regulation of pro-inflammatory cytokines, was inhibited. Taken together, these results suggest that trimebutine may exert its suppressive effect on the HMGB1-RAGE inflammatory signal pathways by strongly blocking the recruitment of ERK1/2 to the intracellular tail domain of RAGE in addition to its weak inhibition of the extracellular interaction of HMGB1 with RAGE. Thus, trimebutine may provide a unique scaffold for the development of novel dual inhibitors of RAGE for inflammatory diseases.

Controversial effect on Erk activation of some cytotoxic drugs in human LOVO colon cancer cells.

UNLABELLED: The use of some classic antibiotics was recently shown to inhibit growth and to induce apoptosis in human LOVO colon cancer cells. In this study, we describe that ciprofloxacin (CI), trimebutine maleate (COL) and tiemonium methylsulfate (VIS) greatly inhibit cell proliferation in vitro. Proliferation inhibition reached its maximum at 10(-4 )M, 10(-3 )M and 10(-2 )M, respectively, for COL, CI and VIS. Moreover, phospho-extracellular-regulated kinase was totally abrogated in non-apoptotic cytotoxicity of VIS but decreases or increases in the apoptotic inhibition, respectively, of COL and CI treatments. ABBREVIATIONS: CI: ciprofloxacin; COL: trimebutine maleate; VIS: tiemonium methylsulfate; MAPK/Erk: mitogen-activated protein kinases/extracellular-regulated kinase.

Efectividad de la trimebutina como inductor de la motilidad intestinal durante el post-operatorio de cirugía abdominal de emergencia / Effectiveness of trimebutine as an intestinal motility inductor during abdominal post operative emergency surgery

Evaluar la efectividad de la trimebutina como inductor de la motilidad intestinal durante el período postoperatorio de cirugía abdominal de emergencia, en los pacientes que ingresan al servicio de cirugía general del Hospital Domingo Luciani, durante el período de junio del 2007 a junio del 2008. Estudio de tipo descriptivo, prospectivo y comparativo, con muestreo aleatorio para casos y controles. La muestra esta constituida por 158 pacientes: 79 casos y 79 controles, a quienes se les identificó signos y síntomas de la motilidad intestinal a través del interrogatorio y el examen físico. De las variables estudiadas, sólo la expulsión de flatos a las 24 horas (34,2 por ciento) casos vs el 13,9 por ciento controles); a las 48 horas (78,5 por ciento casos vs 36,7 por ciento controles), la presencia de ruidos hidroaéreos y evacuaciones fue mayor en el grupo de los casos, obteniéndose resultados significativamente estadísticos. El resto de las variables no fue estadísticamente significativo. La trimebutina actúa como un inductor de la motilidad intestinal, acortando el tiempo de duración del íleo postoperatorio de los pacientes a los cuales se le realiza laparotomía exploratoria de emergencia.

Antinociceptive effect of (S)-N-desmethyl trimebutine against a mechanical stimulus in a rat model of peripheral neuropathy.

Trimebutine (2-dimethylamino-2-phenylbutyl 3,4,5-trimethoxybenzoate, hydrogen maleate) relieves abdominal pain in humans. In the present study, the antinociceptive action of systemic (S)-N-desmethyl trimebutine, a stereoisomer of N-monodesmethyl trimebutine, the main metabolite of trimebutine in humans, was studied in a rat model of neuropathic pain produced by chronic constriction injury to the sciatic nerve. Mechanical (vocalization threshold to hindpaw pressure) stimulus was used. Experiments were performed two weeks after surgery when the pain-related behaviour has fully developed. (S)-N-desmethyl trimebutine (1, 3, 10 mg/kg s.c.) produced dose-dependent antinociceptive effects on the nerve-injured and the contralateral hindpaw. The effect of the lowest dose (1 mg/kg s.c.) of (S)-N-desmethyl trimebutine on the nerve-injured paw was equal to that seen after a ten time stronger dose on the contralateral paw. The effect of (S)-N-desmethyl trimebutine (1 mg/kg) was not naloxone reversible. The results suggest that systemic (S)-N-desmethyl trimebutine may be useful in the treatment of some aspects of neuropathic pain.

Motility of the Roux-en-Y hepaticojejunostomy in asymptomatic patients.

OBJECTIVE: The aim of our study was to describe the motility in the limb, the duodenum, and the jejunum distal to the limb after Roux-en-Y hepaticojejunostomy in patients who remained asymptomatic postoperatively. Our objective was to obtain reference manometric recordings for interpretion of recordings in symptomatic patients. METHODS: Manometric recordings were obtained in the Roux-en-Y limb in 13 patients 15.6 +/- 1.1 days postoperatively, using a probe inserted into the limb during surgery and coming out through the abdominal wall. The recording openings were positioned in the limb itself in eight patients, and also in the jejunum immediately distal to the limb in five patients. In four of eight patients, limb manometry was combined with duodenal manometry using a second probe introduced nasally. RESULTS: Phase IIIs were recorded in all 13 patients, either spontaneously or after trimebutine stimulation (100 mg i.v.). Phase IIIs occurred spontaneously in 12 patients. They always migrated throughout the Roux-en-Y limb, and were also most often observed in the distal jejunum; migration stopped in the distal jejunum in three of five patients. Phase IIIs in the limb occurred independently from duodenal phase IIIs. In the limbs, the duration of phase IIIs was longer (p < 0.02), and the migration slower than in the duodenum (p < 0.001) and in controls (p < 0.02). In nine of 13 patients, injection of trimebutine (100 mg i.v.) initiated phase III in the Roux limb or in the distal jejunum within 2 min. During the combined recordings, trimebutine initiated phase III simultaneously in the duodenum and in the limb. The response to meals in the limb was poorer than in controls. Interruption of phase IIIs was shorter, and the area under the postprandial curve was smaller (p < 0.01) for each postprandial half-h. Postprandial motility was poorer in the limb than in the distal small bowel (p < 0.01). CONCLUSIONS: In asymptomatic patients, interdigestive motility is present in the hepaticojejunostomy Roux-en-Y limb, but it is abnormal because of slow migration of phase IIIs. The second abnormality observed in the limb is a response to meals that is both short and of low amplitude.

Short report: effect of two prokinetic drugs on the electrical and motor activity of the small bowel in dogs.

The effects of trimebutine and domperidone, on the electrical and motor activity of the upper small bowel in dogs, were studied simultaneously by means of a suction electrode and a manometric catheter. Trimebutine, given during phases I and II of the migratory motor complex, was followed by a period of regular spike potentials and contractions; the increased motor activity was significantly greater when the drug was given during phase II. Domperidone, when injected in phase I, was followed by an irregular pattern of spike potentials and contractions of low amplitude. By contrast, activity was not augmented when the drug was given during phase II. We conclude that the effects of drugs, such as trimebutine and domperidone, on the canine small bowel are influenced by the phase of the migratory motor complex.

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.

A comparison of metoclopramide and trimebutine on small bowel motility in humans.

Trimebutine meleate and metoclopramide increase small bowel motility. The present manometric study of the human normal interdigestive duodeno-jejunal motility demonstrated two different pharmacological effects in 15 healthy volunteers. Trimebutine constantly induced a premature phase 3 activity (0.81 +/- 0.4 min after a 100-mg intravenous injection) with patterns similar to spontaneous phase 3. Metoclopramide increased the motility index (contractile activity) during phase 2 without inducing a premature phase 3. No significant variations in plasma motilin concentration were noticed after either trimebutine or metoclopramide. The pancreatic polypeptide concentration rose significantly after metoclopramide injection.

[Effect of trimebutine on the plasma postprandial release of gastrointestinal hormones in the dog]. / Effet de la trimébutine sur la libération plasmatique postprandiale d'hormones gastrointestinales chez le chien.

The injection of trimebutine induces in the dog an increase of plasma motilin during the fasting period as well as after a meal. We studied the effect of trimebutine on several gastrointestinal hormones released into the circulation by the ingestion of a meal. The intravenous administration of trimebutine (10 mg/kg/h) in 4 dogs abolished the postprandial increase in plasma gastrin, pancreatic polypeptide, insulin, glucagon and GIP. Trimebutine could therefore, by its effects on various regulatory peptides, influence several digestive functions. Its mode of action could probably involves complex mechanisms, including paradoxical effects. The possibility that motilin is a mediator of the trimebutine effect on small bowel smooth muscle is discussed.

A normalizaçäo da motricidade digestiva / Gastrointestinal motility normalization

Descrevem-se, em revisäo rápida, os mecanismos reguladores da motricidade do tubo digestivo, passando-se em seguida a tecer consideraçöes sobre os medicamentos que agem neste terreno. Inicia-se por relembrar os medicamentos mais antigos, carminativos e eupépticos. Em seguida säo revistos os antispasmódicos, anticolinérgicos e antieméticos. Passando-se aos bloqueadores dopaminérgicos, säo revisados sucintamente os ortopramídicos (derivados da benzamida). Finalmente é focalizado o trimebutino, medicaçäo orginal, considerada como verdadeiro normalizador e harmonizador da motricidade digestiva