Identification of Drugs that Regulate Dermal Stem Cells and Enhance Skin Repair.

Here, we asked whether we could identify pharmacological agents that enhance endogenous stem cell function to promote skin repair, focusing on skin-derived precursors (SKPs), a dermal precursor cell population. Libraries of compounds already used in humans were screened for their ability to enhance the self-renewal of human and rodent SKPs. We identified and validated five such compounds, and showed that two of them, alprostadil and trimebutine maleate, enhanced the repair of full thickness skin wounds in middle-aged mice. Moreover, SKPs isolated from drug-treated skin displayed long-term increases in self-renewal when cultured in basal growth medium without drugs. Both alprostadil and trimebutine maleate likely mediated increases in SKP self-renewal by moderate hyperactivation of the MEK-ERK pathway. These findings identify candidates for potential clinical use in human skin repair, and provide support for the idea that pharmacological activation of endogenous tissue precursors represents a viable therapeutic strategy.

Effects of trimebutine maleate on colonic motility through Ca²+-activated K+ channels and L-type Ca²+ channels.

The effects of trimebutine maleate (TM) on spontaneous contractions of colonic longitudinal muscle were investigated in guinea pigs. The contractile responses of smooth muscle strips were recorded by an isometric force transducer. Membrane and action potentials were detected by an intracellular microelectrode technique. The whole-cell patch clamp recording technique was used to record the changes in large conductance Ca(2+)-activated K(+) (BK(ca)) and L-type Ca(2+) currents in colonic smooth muscle cells. At high concentrations (30, 100, and 300 µM), TM inhibited the amplitude of spontaneous contractions. At low concentrations (1 and 10 µM), TM attenuated the frequency and tone of smooth muscle strips, whereas TM had no influence on the amplitude of spontaneous contractions. TM depolarized the membrane potentials, but decreased the amplitude and frequency of action potentials at high concentrations. TM inhibited BK(ca) and L-type Ca(2+) currents in a dose-dependent manner. In the presence of the BK(ca) channel opener, NS1619, TM also inhibited BK(ca) currents. Bayk8644, a L-type Ca(2+) channel opener, increased L-type Ca(2+) currents. This augmentation was also attenuated by TM. These results suggest that TM attenuates intestinal motility through inhibition of L-type Ca(2+) currents, and depolarizes membrane potentials by reducing BK(ca) currents. Thus, TM may be a multiple-ion channel regulator in the gastrointestinal tract.

Comparação entre o sumatriptano, a trimebutina, o meloxicam e a associação dos três fármacos no tratamento agudo de enxaqueca / Comparison among sumatriptane, trimebutine, meloxicam and the association of those drugs in the acute treatment of migraine

JUSTIFICATIVA E OBJETIVOS: A crise aguda de migrânea geralmente leva a grande incapacidade econômica e social para aqueles que sofrem deste transtorno. A fisiopatologia é complexa e envolve múltiplos mecanismos centrais e periféricos. O tratamento agudo tem como objetivo aliviar a dor e os fenômenos associados como a náusea e fotofobia, sem causar efeitos adversos importantes. Apesar do desenvolvimento de fármacos específicos como os triptanos, para o tratamento agudo, a sua eficácia ainda é baixa. O objetivo deste estudo foi comparar a eficácia e a tolerância da trimebutina, meloxicam, sumatriptano e a associação dos três fármacos no tratamento das crises agudas de migrânea de moderada a forte intensidade.MÉTODO: Após aprovação pelo Comitê de Ética das Instituições foram incluídos neste estudo prospectivo, duplamente encoberto e aleatório, 50 pacientes, sendo 43 mulheres e 7 homens, com idade entre 18 e 65 anos, portadores de migrânea com ou sem aura, que utilizavam medicação profilática, exceto anti-inflamatórios não esteroides (AINES). Foram tratadas quatro crises de migrânea de moderada a forte intensidade de cada paciente, com 200 mg de trimebutina, 50 mg de sumatriptano, 15 mg de meloxicam ou com a associação de 200 mg de trimebutina, 50 mg de sumatriptano e 15 mg de meloxicam. Os pacientes foram aleatorizados em 4 grupos de acordo com a ordem de chegada, de modo que o primeiro paciente incluído recebeu trimebutina para a primeira crise, sumatriptano para a segunda crise, meloxicam para a terceira crise e a associação entre os 3 fármacos para a quarta crise. O segundo paciente incluído recebeu sumatriptano para a primeira crise, meloxicam para a segunda superior a cada um desses fármacos isolados para controlar a dor, as náuseas e a fotofobia nas crises agudas de migrânea de moderada a forte intensidade. Além disso, a combinação dos fármacos apresentou maior incidência de efeitos adversos.crise, a associação para a terceira crise e a trimebutina para a quarta crise, e assim sucessivamente. A intensidade da crise de migrânea foi avaliada a partir da ingestão da cápsula com escala categorizada verbal na qual: 0 - sem dor, 1 - cefaleia leve, 2 - cefaleia moderada e 3 - cefaleia intensa. Cada paciente foi orientado para preencher o relatório de crise para cada crise tratada, na qual anotava a intensidade da cefaleia, a presença de náusea, fotofobia e dos efeitos adversos, e o uso da medicação de resgate, 100 mg de indometacina por via retal. RESULTADOS: Completaram o estudo 42 pacientes. Em uma hora 9,5% dos pacientes que utilizaram a associação dos fármacos estavam livres da dor, comparados com 14,2% com a trimebutina e sumatriptano e 2,4% com o meloxicam (p = 0,479). Em duas horas 21,4% dos pacientes que usaram a associação estavam livres da dor, comparados com 11,9% com a trimebutina, 26,1% com sumatriptano e 23,8% com o meloxicam (p = 0,555). Tanto a associação trimebutina, sumatriptano e meloxicam como os fármacos trimebutina, sumatriptano e meloxicam isolados foram efetivos para controlar a náusea e fotofobia após 1 e 2h para náusea (p = 0,157 e 0,587) e fotofobia (p = 0,671 e 0,929, embora sem diferença estatisticamente significativa entre eles. Dez pacientes em uso da associação dos fármacos, 6 em uso da trimebutina, 5 em uso do sumatriptano e 5 em uso do meloxicam relataram efeitos colaterais. CONCLUSÃO: Este estudo demonstrou que a associação sumatriptano, meloxicam e trimebutina não foi superior a cada um desses fármacos isolados para controlar a dor, as náuseas e a fotofobia nas crises agudas de migrânea de moderada a forte intensidade. Além disso, a combinação dos fármacos apresentou maior incidência de efeitos adversos.

BACKGROUND AND OBJECTIVES: Acute migraine crisis often leads to major economic and social disability for those suffering from such syndrome. Pathophysiology is complex involving several central and peripheral mechanisms. The acute treatment aims at evaluating pain and associated phenomena, such as nausea and photophobia, without causing major adverse effects. Notwithstanding the development of specific drugs for the acute treatment, such as triptanes, their efficacy is still low. This study aimed at comparing efficacy and tolerance of trimebutine, meloxicam, sumatriptane and the association of such drugs to treat moderate to severe acute migraine crises.METHOD: After the Institutions? Ethics Committee approval, participated in this prospective, double-blind and randomized study 50 patients, being 43 females and 7 males, aged between 18 and 65 years, with migraine with or without aura, under prophylactic medication, except non-steroid anti-inflammatory drugs (NSAIDS). Patients were treated for 4 moderate to severe migraine crises with 200 mg trimebutine, 50 mg sumatriptane, 15 mg meloxicam, or with the association of 200 mg trimebutine, 50 mg sumatriptane and 15 mg meloxicam. Patients were randomized in 4 groups according to their arrival, so that the first patient included received trimebutine for the first crisis, sumatriptane for the second crisis, meloxicam for the third crisis and the association of the three drugs for the fourth crisis. The second patient included received sumatriptane for the first crisis, meloxicam for the second crisis, the association for the third crisis and trimebutine for the fourth crisis, and so on and so forth. Migraine crisis intensity was evaluated as from the ingestion of the first tablet with verbal categorized scale where: 0 = no pain, 1 = mild headache, 2 = moderate headache, 3 = severe headache. All patients were oriented to fill a crisis report for each treated crisis, where they would record headache intensity, presence of nausea, photophobia and adverse effects and the use of rescue medication, 100 mg of rectal indometacin.RESULTS: Forty-two patients completed the study. In one hour 9.5% of patients using the association of drugs were free of pain, as compared to 14.2% with trimebutine and sumatriptane and 2.4% with meloxicam (p = 0.479). In two hours 21.4% of patients using the association were free of pain, as compared to 11.9% with trimebutine, 26.1% with sumatriptane and 23.6% with meloxicam (p = 0.555). Both the association of trimebutine, sumatriptane and meloxicam and trimebutine, sumatriptane and meloxicam alone were effective to control nausea and photophobia after 1 and 2 h for nausea (p = 0.157 and 0.587) and photophobia (p = 0.671 and 0.929) although without statistically significant difference among them. Ten patients under the association of drugs, 6 under trimebutine, 5 under sumatriptane and 5 under meloxicam have reported side effects. CONCLUSION: This study has shown that the association of sumatriptane, meloxicam and trimebutine was not better than each of those drugs alone to control pain, nausea and photophobia during moderate to severe migraine crises. In addition, the combination of drugs has shown a higher incidence of adverse effects.

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.

Rizatriptan vs. rizatriptan plus trimebutine for the acute treatment of migraine: a double-blind, randomized, cross-over, placebo-controlled study.

Gastroparesis frequently happens during migraine attacks, postponing the onset of action of orally administered drugs. Furthermore, triptans seem to work better in the earlier phases of the migraine attacks. Therefore, associating a gastrokinetic drug with a triptan may translate into better efficacy and higher consistency of response. Trimebutine is an opioid derivative with exclusive action on receptors of the Meissner and Auerbach plexus throughout the digestive tube. It has no absorption or central penetration. Herein we contrast the combination of rizatriptan plus trimebutine with rizatriptan alone in the acute treatment of migraine. Forty patients with migraine consecutively seen in our clinic were randomized to treat two consecutive moderate or severe attacks with one tablet of 10 mg rizatriptan plus one capsule of 200 mg trimebutine and two attacks with the same triptan and placebo, in counterbalanced order. We collected information on the severity of the attack, as well as presence of nausea and photophobia at the time of drug intake, and after 1, 2 and 4 h. Recurrence and adverse events were also contrasted. Sixty-four attacks were treated with each drug regimen. At 1 h postdose, 30 (46.8%) of 64 attacks treated with the combination resolved completely, vs. eight (12.5%) of the rizatriptan-treated attacks, a difference of 34% (P < 0.01). At 2 h postdose, 47 (73.4%) attacks treated with the combination vs. 20 (31.2%) of those treated with rizatriptan alone resolved completely, a difference of 42% (95% confidence interval 26, 58, P < 0.001). Regarding nausea and photophobia, the combination was also associated with significantly better response. Recurrence was similar among the two drug regimens, as well as adverse events. The combination rizatriptan and trimebutine is more effective than rizatriptan alone. The combination does not increase adverse events or recurrence of pain.

Pharmacokinetic study of trimebutine maleate in rabbit blood using in vivo microdialysis coupled to capillary electrophoresis.

In vivo microdialysis was used together with capillary electrophoresis (CE) to monitor the concentration of trimebutine maleate (TM) in rabbit blood. Dialysis probe was perfused at 3 microl/min resulting in relative recovery of 26.6+/-3.1% (n=3). After a one step sample preparation the samples were injected directly into the capillary. TM was detected on-column using UV detector at 214 nm. Separation of TM from other components in the dialysate was achieved within 15 min. Evaluation was based on the relative collected peak height (TM/IS). The response for TM in the blood dialysate was linear over the range of 0.5-100 microg/ml. The detection limit of TM in the blood dialysate was 0.1 microg/ml (S/N=3). This method has been successfully applied to the pharmacokinetic study of trimebutine maleate in rabbit blood following oral administration of 200 mg/kg. It provides a fast and simple technique for the pharmacokinetic study of TM in vivo.

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 48 h 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.

[Pharmacokinetics and bioequivalence of trimebutine dispersive tablet in healthy subjects].

AIM: To develop an HPLC-ESI-MS assay for determination of trimebutine in human plasma and to investigate the pharmacokinetics and bioequivalence of two trimebutine tablets in human. METHODS: After being made alkaline with saturated sodium bicarbonate, plasma was extracted by cyclohexane and separated by HPLC on a reversed-phase C18 column with a mobile phase of 10 mmol x L(-1) ammonium acetate buffer solution (pH 3.5)-methanol (18:82). HPLC-ESI-MS was performed in the selected ion monitoring (SIM) mode using target ions at m/z 388 for trimebutine and m/z 280 for the internal standard (sibutramine, IS). The fragmentor voltage was 50 V. A randomized cross-over design was performed in 20 healthy volunteers. In the two study periods, a single 100 mg dose of each tablet was administered to each volunteer. RESULTS: Calibration curve was linear over the range of 0.3 - 150 microg x L(-1). The main pharmacokinetic parameters of T1/2, Tmax and Cmax were (9.2 +/- 2.8) h, (1.0 +/- 0.3) h and (40 +/- 20) microg x L(-1) for the reference tablet; (9.2 +/- 2.3) h, (0.9 +/- 0.4) h and (41 +/- 20) microg x L(-1) for the test tablet. The relative bioavalability of the test tablet was (97 +/- 13)%. The results of variance analysis and two one-sided t-test showed that there was no significant difference between the two formulations in the AUC and Cmax. CONCLUSION: The assay was proved to be sensitive, accurate and convenient. The two formulations were bioequivalent.

Preparation, characterization and taste-masking properties of polyvinylacetal diethylaminoacetate microspheres containing trimebutine.

The objectives of this study were to produce acid soluble, polyvinylacetal diethylaminoacetate (AEA) microspheres containing trimebutine (as maleate), using a water-in-oil-in-water (w/o/w) emulsion solvent evaporation method, to characterize their in-vitro release properties, and to evaluate the taste-masking potential of this formulation in human volunteers. The pH of the external aqueous phase was the critical factor in achieving a high loading efficiency for trimebutine in the microencapsulation process; nearly 90% (w/w) loading efficiency was obtained at above pH 10. Trimebutine was completely released from AEA microspheres within 10 min in a dissolution test at pH 1.2, simulating conditions in the stomach, whereas at pH 6.8, the pH in the mouth, only small quantities of trimebutine were released in the initial 1-2 min. The results of a gustatory sensation test in healthy volunteers confirmed the taste-masking effects of the AEA microspheres. Finally, an attempt was made to encapsulate the salts of other basic drugs (lidocaine, imipramine, desipramine, amitriptyline, promethazine and chlorpheniramine) into AEA microspheres using the w/o/w emulsion evaporation method. The loading efficiencies were ranked in almost inverse proportion with the solubility of the drugs in the external aqueous phase. This study demonstrated the possibility of masking the taste of salts of basic drugs by microencapsulation with AEA using a w/o/w emulsion solvent evaporation method.

The role of remote gut inflammation in duodenojejunal dysmotility.

The aim of this prospective study was to determine the role of remote inflammation of the gut on duodenojejunal motor status by comparing patients with acute cholecystitis (AC) to those with biliary colic (BC). Thirty-six gallstone patients (11 AC and 25 BC) were explored. Manometric recordings were performed during fasting and after a 750-kcal meal and ended by an intravenous injection of 100 mg trimebutine. Patient data were compared to those of 20 healthy controls. Phases III were more frequently absent in AC patients than in BC patients (P < 0.01) and controls (P < 0.05). When phase III characteristics were similar between the AC and BC group, the phase III amplitude was lower in both groups than in controls (P < 0.0001). After the meal, the mean motor index in the jejunum expressed by the area under the curve (AUC) per 30-min period was higher in the AC group than in BC group and controls (P < 0.05). Specific motor phenomena were observed after the meal. In particular, propagating clusters of contractions (PCCs) were more frequent in AC patients than in BC (P < 0.05) and controls (P < 0.01). A lack of the expected decrease in the AUC during recording occurred with the same frequency in the AC and BC groups but was more frequent in patients than in controls (P < 0.05). In 8/11 patients in the AC group with duodenojejunal tracings before and 3 months after surgery, preoperative motor disturbances disappeared in 5/8 patients and improved in 3/8 patients. The higher frequency of duodenojejunal motor disturbances especially after a meal in patients with AC and their disappearance in most of the patients after removal of the infected gallbladder suggest that remote inflammation of the gut affects duodenojejunal motility.

The effect of trimebutine maleate on gastric emptying in patients with non-ulcer dyspepsia.

The study was designed to investigate the effect of trimebutine maleate, a drug used in both hyperkinetic and hypokinetic motility disorders, on gastric emptying in patients with non-ulcer dyspepsia having prolonged gastric emptying rates and to compare the parameters used for the determination of the lag period observed during the emptying of solid foods from the stomach. Gastric emptying was measured by the radionuclide technique. Twenty normal volunteers and 43 patients with non-ulcer dyspepsia participated in the study. Radionuclide imaging was performed by using a solid meal labeled with 99mTc-tin colloid. Of the patients with non-ulcer dyspepsia, 20 had prolonged gastric emptying. They were given three weeks of oral treatment with trimebutine maleate and had their radionuclide gastric emptying study repeated. Treatment with trimebutine maleate resulted in reduction in duration of the lag period and less retention of food at 100 minutes (p < 0.0005). After treatment with trimebutine maleate, no significant difference has been observed in the mean symptom score of patients with prolonged gastric emptying. Among the parameters used for the determination of the lag period, lag period determined by a mathematical equation (TLAG) has been found to be longer than the lag period determined by visual inspection of the images (VLAG) and there was correlation between the two parameters when the lag time was short.

Effects of trimebutine maleate on gastric motility in patients with gastric ulcer.

The effects of trimebutine maleate (TM), a prokinetic drug, on gastrointestinal motility in patients with gastric ulcer were investigated. Twenty patients with active gastric ulcers were allocated to two groups; 10 patients received a proton pump inhibitor alone (PPI group), given orally, and 10 patients received oral TM in combination with a PPI (PPI + TM group), each for a period of 8 weeks. Electrogastrography (EGG) and gastric emptying were measured before and after the treatment period. During the active ulcer stage, tachygastria (more than 0.06 Hz) or bradygastria (less than 0.04 Hz) in the EGG frequency were observed in 9 patients either before or after meals. During the healed ulcer stage, tachygastria or bradygastria was observed in 4 of 10 patients in the PPI group, while in the PPI + TM group, 1 patient had tachygastria and none had bradygastria. Postprandial dip (PD) was observed in 3 of the 20 patients during the active stage, while after treatment, PD was observed in 3 patients in the PPI group and in 6 patients in the PPI + TM group, respectively. Gastric emptying in the PPI group did not show any change between before and after treatment, while that in the PPI + TM group improved significantly after treatment. These results suggest that TM may have an ameliorative effect on abnormal gastric motility in patients with gastric ulcer.

Influence of trimebutine on inflammation- and stress-induced hyperalgesia to rectal distension in rats.

The effects of trimebutine and its major metabolite, N-desmethyltrimebutine on inflammation- and stress-induced rectal hyperalgesia have been evaluated in rats fitted with electrodes implanted in the longitudinal striated muscle of the abdomen. Intermittent rectal distension was performed before and 3 days after induction of rectal inflammation by local infusion of trinitrobenzenesulphonic acid (in ethanol). Stress consisted of 2h partial restraint and rectal distension was performed before and 30min after the end of the partial restraint session. The animals were treated intraperitoneally with trimebutine or desmethyltrimebutine (5, 10 or 20mgkg(-1)) or vehicle 15min before rectal distension. Naloxone (1mgkg(-1)) or saline was injected subcutaneously before trimebutine and desmethyltrimebutine. Before treatment trimebutine at the highest dose (20mgkg(-1)) reduced the abdominal response to rectal distension for the highest volume of distension (1.6mL) whereas desmethyltrimebutine was inactive. After rectocolitis the abdominal response to rectal distension was enhanced and trimebutine at 5mgkg(-1) reduced and at 10 mgkg(-1) suppressed inflammation-induced hyperalgesia, an effect reversed by naloxone. Desmethyltrimebutine was inactive. Stress-induced hypersensitivity was attenuated or suppressed, or both, by trimebutine and desmethyltrimebutine at doses of 5, 10 or 20mgkg(-l); greater efficacy was observed for desmethyltrimebutine and the effects were not reversed by naloxone. It was concluded that trimebutine and desmethyltrimebutine are active against inflammation- and stress-induced rectal hyperalgesia but act differently. The effect of trimebutine on inflammation-induced hyperalgesia is mediated through opioid receptors.

Effects of trimebutine on sphincter of Oddi motility in patients with post-cholecystectomy pain.

BACKGROUND: Trimebutine is an opiate modulator of the gastrointestinal motility that interacts with enkephalinergic receptors. AIM: To evaluate the effects of trimebutine (50 mg intravenous injection) on the motility of the sphincter of Oddi (SO) as assessed by endoscopic manometry. METHODS: Endoscopic manometry was performed on 15 cholecystectomized patients who presented with symptoms suggestive of SO dysfunction. Prior to the endoscopic manometry, endoscopic ultrasonography was performed in order to rule out the possible presence of a bile duct stone. RESULTS: Injecting trimebutine resulted in a significant increase in the SO antegrade phasic contraction rate (P = 0.02). Trimebutine decreased the basal pressure of the SO (32.5 vs. 27.5 mmHg), but the difference is not statistically significant (P = 0.11). The effects of trimebutine differed depending on the basal SO motility anomalies involved, but the period of latency was similar (mean 89 s: range 30-240 s). The basal anomalies were an increased basal SO pressure of > 40 mmHg in three patients, a tachyoddia (frequency of phasic contractions (PC) > 10/min) in six patients, prolonged PC (> 10 s) in two patients and an absence of phasic contraction in one patient. The basal pressure of the SO decreased in the three patients presenting with SO hyperpressure, but returned to a normal value in one case. The frequency of the PC decreased to normal in three out of the six patients with tachyoddia. The duration of the PC returned to normal in the two patients with prolonged PC whereas their frequencies increased. Prolonged PC developed in the patient without any detectable phasic contraction. CONCLUSIONS: Trimebutine modulates SO motility in various ways depending on the basal SO motility anomaly observed after cholecystectomy. This regulatory effect suggests the existence of encephalinergic control of SO motility.

Randomized controlled trial of trimebutine (anal sphincter relaxant) for pain after haemorrhoidectomy.

BACKGROUND: Anal sphincter spasm may aggravate pain after haemorrhoidectomy. The aims of this study were to investigate whether a trimebutine suppository (Proctolog) reduced anal resting pressure and, subsequently, to test its efficacy in relieving pain after haemorrhoidectomy. METHODS: Ten patients underwent anal manometry before and 4 h after Proctolog application. A controlled randomized trial was then conducted on 160 consecutive patients. A standard haemorrhoidectomy was performed. Eighty patients were then randomized to receive an application of Proctolog immediately after the procedure (group 1). The remaining 80 did not receive a suppository (controls, group 2). An independent, blinded observer determined the pain scores. RESULTS: Proctolog resulted in a mean 35 per cent reduction in resting anal pressure (P < 0.001). However, there were no differences in the pain score at 4 h after haemorrhoidectomy, maximum pain during the first 24 h, maximum pain during the second postoperative day, ketoprofen requirement or need for intramuscular pethidine injections between groups 1 and 2. CONCLUSION: Although Proctolog reduced mean resting anal pressure at 4 h after application, this did not affect pain after haemorrhoidectomy.

Effect of Y-25130, a selective 5-hydroxytryptamine3 receptor antagonist, on gastric emptying in mice.

The effect of Y-25130 on gastric emptying of nutrient test meals (solid chow) was examined in mice. In a dose range of 0.01-1 mg/kg, p.o., Y-25130 significantly accelerated gastric emptying of solid meals in a dose-dependent manner, at an ED30 of 0.021 mg/kg. Other 5-hydroxytryptamine3 receptor antagonists and prokinetic agents having 5-hydroxytryptamine3 receptor antagonistic properties accelerated the emptying of solid meals in the following rank order of potency: Y-25130 = granisetron > or = tropisetron > ondansetron > cisapride > metoclopramide. The acceleration of the gastric emptying showed a good correlation with the antagonistic potencies of these compounds on 5-hydroxytryptamine3 receptors, determined by the inhibition test of the von Bezold-Jarisch reflex in anesthetized rats (r2 = 0.99). Domperidone (1 and 10 mg/kg, p.o.) and trimebutine (10 and 100 mg/kg, p.o.) failed to increase the rate of emptying from the stomach. Cisplatin (30 mg/kg, i.p.), a chemotherapeutic agent, significantly delayed the gastric emptying of solid meals, and Y-25130 (0.1-1 mg/kg, p.o.) prevented such a delay in emptying in a dose-dependent manner. These results suggest that Y-25130 accelerates the gastric emptying in mice by antagonism of the 5-hydroxytryptamine3 receptor.