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After the oral administration of mebeverine to animal or human, measurable concentrations of the drug have never been found in the plasma. The ex vivo hydrolysis of mebeverine can be blocked by esterase inhibitors. In the present study, human volunteers were pretreated with pyridostigmine to attempt to improve the bioavailability of the parent drug.Following a single-blind, random design, 12 normal human volunteers received orally either placebo or 60 mg pyridostigmine, followed 2 h later by 405 mg mebeverine. Blood samples were drawn intermittently for 4 h and were spiked immediately with neostigmine in order to block ex vivo hydrolysis.Even after pretreatment with pyridostigmine, the plasma samples failed to reveal detectable concentrations of mebeverine. Pyridostigmine pretreatment mediated a significantly higher peak concentration of veratric acid, the acid moiety resulting from hydrolysis of mebeverine.As mebeverine seemingly undergoes complete presystemic hydrolysis, it seems unlikely that the effects of the drug could be mediated centrally. Furthermore, as it is unlikely that sufficient mebeverine traverses the intestine to exert a local effect on the colon (i.e., the time-course of veratric acid plasma levels does not support such a conclusion), the therapeutic effect of the drug, if any, has to be ascribed to an active metabolite. However, the hydrolysis products of mebeverine are not known to be pharmacologically active.

A new, precise, simple and accurate HPLC method was developed for the first time to separate and determine mebeverine enantiomers. Enantiomeric resolution was achieved on a cellulose Tris (3,5-dimethylphenyl carbamate) column known as Chiralcel OD, with UV detection at 263 nm. The mobile phase consisted of n-hexane, isopropyl alcohol and triethylamine (90:9.9:0.1 v/v/v). Sample run time was 18 min. On using the chromatographic conditions described, mebeverine enantiomers were well resolved with mean retention times of about 11 and 14 min. A linear response (r>0.999) was observed over the concentration range 0.5-20 microg/mL racemic mebeverine. Precision, accuracy and stability were studied according to ICH guidelines. The limit of detection was found to be 0.05 microg/mL for each enantiomer of mebeverine. The proposed method was applied for analysis of mebeverine in commercially available tablets dosage formulations. Examples of application to biological samples are also given. Reanalysis of samples several weeks after the initial analysis showed no degradation of mebeverine.

SUMMARY Background Irritable bowel syndrome (IBS) is a functional disorder affecting the quality of life of patients. In the Nether-lands, mebeverine is currently the only medical treatment registered for IBS, although its efficacy is considered disputable.Objective To assess treatment patterns and associated health care cost in mebeverine users relative to matched controls.Methods A matched case-control study was performed using pharmacy data. Cases were mebeverine users as proxy forIBS patients. Controls were non-mebeverine users and matched to cases by age, gender and pharmacy. Prevalence and inci-dence of mebeverine use, concomitant drug use and hospitalizations were assessed in 3431 cases and 3431 controls. Con-comitant drug use and hospitalizations was also assessed in a subgroup of 1222 users of mebeverine and laxatives (proxy forconstipation-IBS) and their controls.Results Twelve per 1000 residents were ever-dispensed mebeverine in 1998. One-third of these mebeverine users usedlaxatives concomitantly. Concomitant drug use and hospitalizations were increased in mebeverine users. The odds ratiofor hospitalizations for gastrointestinal reasons was increased predominantly in mebeverine users with concomitant laxativeuse (OR:8.7; 95%CI [4.3–17.3]). Excess yearly costs for all concomitant medications were s94 [95%CI s79–s109] andfor hospital admissions s120 [s74–s166] per mebeverine user. In mebeverine users with concomitant laxative use thesecosts were s136 and s251 respectively.Conclusions In treated IBS patients, concomitant drug use and hospitalizations are increased relative to matched controls.Medical resource use and associated health care costs are particularly increased in mebeverine users using laxatives. Thetotal mean excess cost per patient per year is s482. Copyright # 2004 John Wiley & Sons, Ltd.key words—mebeverine; irritable bowel syndrome; matched case control study; incidence; laxatives; hospital morbidity;co-medication; health care costs

The Netherlands Pharmacovigilance Centre Lareb evaluates the reports as generated by the spontaneous adverse event reporting system in the Netherlands. This article describes the association between the adverse drug reactions (ADRs), headache and migraine and reported suspected drugs. In a case/non-case design, reporting odds ratios were calculated in order to analyse this association. Additionally the results of this analysis were compared with data from literature. Taken together, the ADRs headache and migraine are the second most reported ADR. The results of the analysis of the association between drugs and both ADRs in the Lareb data set are generally in accordance with literature data. Especially drugs causing vasodilative effects have often been associated with headache or migraine.

Previous investigators have shown significant benefit using CO(2) for bowel insufflation. Others have suggested that the long-acting smooth muscle relaxant, Mebeverine, may be of benefit. We subjected this to a randomised double-blind trial. A total of 181 outpatients were randomised to receive either Mebeverine or placebo as pre-medication, and either air or CO(2) for bowel insufflation, thus creating four treatment groups. Visual-analogue lines were used to record pain scores before, during, and up to 8 h following the enema. All groups showed increased pain scores during the enema, with peak pain scores at the end of the examination, falling to baseline scores by 8 h. Patients receiving the combination of C0(2) and placebo had significantly lower pain scores at 1 and 4 h ( P=0.00 and P=0.014, respectively; Kruskal-Wallis test) compared with all other groups. Having Mebeverine as a pre-medication did not significantly lower pain scores compared with placebo, and decreased the amount of benefit received from the CO(2). We confirm that CO(2) is of benefit in decreasing pain during barium enema, and we recommend its routine use to improve the comfort of patients. Mebeverine is not of benefit, and its use as a pre-medication for enemas is not recommended.

Mebeverine (Duspatal, MB), an antispasmodic drug, is the veratric acid ester of 4-[ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino]butan-1-ol (MB-OH), which is a N-substituted ethylamphetamine derivative. MB is metabolized via ester hydrolysis to MB alcohol (MB-OH) and veratric acid. N-Dehydroxybutylation leads to methoxyethylamphetamine (MO-EA) and, after O-demethylation, to hydroxy EA (HO-EA). N-Bisdealkylation leads to p-methoxyamphetamine (PMA). MO-EA and PMA are also known as designer drugs. Fluorescence polarization immunoassay (FPIA) and gas chromatographic-mass spectrometric studies on the toxicological analysis of MB after ingestion of a single 405-mg oral dose of MB were performed. We could show that intake of MB leads to positive FPIA results for amphetamine. The N-dehydroxybutyl metabolites of MB, MO-EA, HO-EA, and the bis-dealkyl metabolite PMA should be responsible for the positive immunoassay results. Using our systematic toxicological analysis procedure, every positive amphetamine immunoassay could be explained by detection of MO-EA, HO-EA, and/or PMA. Misinterpretation of the origin of MO-EA, HO-EA, or PMA can be avoided by detecting the specific (non-dehydroxybutylated) metabolites of MB, which are excreted for a much longer time after ingestion.

Irritable bowel syndrome (IBS) is a colonic function disorder. Both pinaverlum bromide (a selective calcium channel blocker) and mebeverine (an antispasmodic) are reported to be effective in the long-term (12-16 weeks) treatment of IBS patients. Their efficacy in the short-term treatment of IBS patients and colonic transit time is unclear. Furthermore, substance P and neuropeptide Y have either excitatory or inhibitory effects on colonic motility. Whether the efficacy of both drugs is mediated through these neuropeptides remains unknown.A clinical trial was conducted with 91 patients with diarrhoea-predominant IBS. After basal measurement of the total colonic transit time, IBS patients were randomized to receive either pinaverlum bromide (50 mg, t.i.d.) or mebeverine (100 mg, t.i.d.) for 2 weeks. The symptomatic scores regarding defaecation, total colonic transit time and serum levels of substance P and neuropeptide Y were measured before and after treatments. The daily defaecation frequency was markedly decreased after treatment (pinaverlum bromide, 2.9+/-1.2 vs 2.0+/-1.0, P0.05; mebeverine, 2.7+/-1.1 vs 2.1+/-1.0, P0.05). The stool consistency became well formed after both treatments (P0.05). Both drugs similarly improved the global well-being in these IBS patients (pinaverlum bromide vs mebeverine 73.4 vs 71.8%, P0.05). The total colonic transit time was significantly prolonged only after pinaverlum bromide treatment (21.4+/-15.5 vs 30.8+/-14.8 h, P0.01). Neither substance P nor neuropeptide Y serum level was significantly changed after either treatments.Pinaverlum bromide and mebeverine have similar therapeutic efficacies on diarrhoea-predominant IBS patients. Prolonged colonic transit time may be one of the factors responsible for the efficacy of pinaverlum bromide on the IBS patients. Substance P and neuropeptideY appear less important in the pathogenesis of diarrhoea-predominant IBS.

A dual stable isotope-based GC-MS method was developed for the simultaneous determination of two metabolites of mebeverine, mebeverine alcohol and desmethylmebeverine alcohol, in human plasma. Plasma samples were treated with beta-glucuronidase to cleave the glucuronide conjugates of both compounds prior to analysis. The treated plasma was prepared for analysis by solid-phase extraction using octadecylsilane cartridges. The isolated metabolites were derivatized and analyzed by GC-MS using selected-ion monitoring. Plots of peak-area ratio were linear with metabolite concentration from 2 to 200 ng/ml and the limit of detection for both metabolites was 0.5 ng/ml. The GC-MS methodology was applied to the analysis of plasma from human subjects following peroral administration of mebeverine. Pharmacokinetic parameters for both metabolites were determined and suggest that relative systemic mebeverine exposure may potentially be assessed using metabolite kinetics, if the latter subsequently are demonstrated to be linear with mebeverine dose.

The potential of on-line reversed-phase (RP) LC–GC–MS for the identification of impurities in pharmaceutical products has been investigated. The technical aspects of the system were studied using the potential drug eltoprazine as test compound. After LC separation on a 2 mm id RPLC column, using 5 mmol l–1 methanesulfonic acid in acetonitrile–water (84 + 16 v/v) as eluent, the eltoprazine-containing fraction of 200 µl was introduced on-line into the GC–MS, the mass spectrometer being a magnetic sector instrument. Before this introduction, the methanesulfonic acid was removed on-line from the LC eluent via an anion-exchange membrane. Most of the solvent introduced into the GC–MS was evaporated via a solvent vapour exit installed in front of the capillary GC column. As an application, impurity profiling was performed on the drug substance mebeverine which contained mebeverine amine as test impurity. The addition of acetonitrile was necessary before introduction into the GC; therefore only about 10% v/v of the mebeverine amine LC peak was transferred to the GC–MS. Nevertheless, electron impact and chemical ionization spectra of the impurity could be obtained at a level of 0.1% with respect to the drug.

A new simple, rapid and sensitive reversed-phase liquid chromatographic method was developed and validated for the simultaneous determination of sulpiride (SUL) and mebeverine Hydrochloride (MEB) in the presence of their impurities and degradation products. The separation of these compounds was achieved within 6 min on a 250 mm, 4.6 mm i.d., 5 m particle size Waters®-C18 column using isocractic mobile phase containing a mixture of acetonitrile and 0.01 M dihydrogenphosphate buffer (45:55) at pH = 4.0. The analysis was performed at a flow rate of 1.0 mL/min with fluorescence-detection at excitation 300 nm and emission at 365 nm. The concentration-response relationship was linear over a concentration range of 10- 100 ng/mL for both MEB and SUL with a limit of detection 0.73 ng/mL and 0.85 ng/mL for MEB and SUL respectively. The proposed method was successfully applied for the analysis of both MEB and SUL in bulk with average recoveries of 100.22 ± 0.757% and 99.96 ± 0.625% respectively, and in commercial tablets with average recoveries of 100.04 ± 0.93% and 100.03 ± 0.376% for MEB and SUL respectively. The proposed method was successfully applied to the determination of MEB metabolite (veratic acid) in real plasma simultaneously with SUL. The mean% recoveries (n = 3) for both MEB metabolite (veratic acid) and SUL were 100.36 ± 2.92 and 99.06 ± 2.11 for spiked human plasma respectively. For real human plasma, the mean% recoveries (n = 3) were and respectively.

Mebeverine hydrochloride is known to suffer from extensive first pass effect. In an attempt to improve its oral bioavailability and possibility to restrict its absorption only to the colon, mebeverine microspheres were prepared by emulsion solvent evaporation method. Four formulations were prepared with varying drug and polymer ratio. These formulations were subjected to various evaluation parameters like percent practical yield, entrapment efficiency, particle size, in vitro drug release, in vivo activity. Practical yield of the microspheres was up to 89.59% with encapsulation efficiency up to 79.4%. Scanning electron microscopy confirmed that the microsphere structures were smooth, spherical, and discrete and the particles were of the size range 200 to 300 I�m. In vitro release of the drug showed biphasic release pattern with non-Fickian diffusion release in 12 h. On the basis of drug content, particle size, in vitro release and in vivo studies, formulation F-3 was found to be optimal. Antiirritable bowel syndrome activity was performed in colorectal distention in rat, which is a model for constipation-induced irritable bowel syndrome. The formulations F-2 and F-3 showed significant effect in fecal output when compared to the control as well as the marketed preparation in the constipation-induced irritable bowel syndrome in rats.

The HPLC methods for the determination of plasma concentrations of the antispasmodic agent mebeverine (0.01-10 micrograms/mL) and its hydrolysis product veratric acid (0.1-50 micrograms/mL) are presented. Mebeverine was demonstrated to hydrolyze readily in fresh unbuffered human and rat plasma samples ex vivo. Hydrolysis in human plasma was completely inhibited in the presence of the esterase inhibitor physostigmine sulfate, at a concentration of 130 micrograms/mL. However, the inhibitor was only partially effective in blocking mebeverine hydrolysis in rat plasma. After oral administration of mebeverine.HCl (270 mg) to fasted human volunteers, measurable concentrations of the drug were not found in plasma. By contrast, the metabolite veratric acid achieved considerable concentrations (mean peak plasma concentration of 13.5 micrograms/mL at 40-80 min). After iv administration of mebeverine.HCl (2 mg) to rats, the drug was rapidly eliminated from plasma (mean half-life of 29 min) with simultaneous appearance of veratric acid (mean peak plasma concentration of 1.80 micrograms/mL at 15-30 min). However, after oral administration of the same dose, only traces of mebeverine were found in plasma, with the exception of one rat. Veratric acid again achieved considerable concentrations (mean peak plasma concentration of 0.90 micrograms/mL at 15 min-4 h). The results show that mebeverine undergoes rapid and extensive first-pass metabolism involving hydrolysis of the ester function, and that negligible circulating concentrations of the parent drug are found in humans.

Objective To assess the efficacy of cognitive behaviour therapy delivered in primary care for treating irritable bowel syndrome. Design Randomised controlled trial. Setting 10 general practices in London. Participants 149 patients with moderate or severe irritable bowel syndrome resistant to the antispasmodic mebeverine. Interventions Cognitive behaviour therapy delivered by trained primary care nurses plus 270 mg mebeverine taken thrice daily compared with mebeverine treatment alone. Main outcome measures Primary measures were patients' scores on the irritable bowel syndrome symptom severity scale. Secondary measures were scores on the work and social adjustment scale and the hospital anxiety and depression scale. Results Of 334 referred patients, 72 were randomised to mebeverine plus cognitive behaviour therapy and 77 to mebeverine alone. Cognitive behaviour therapy had considerable initial benefit on symptom severity compared with mebeverine alone, with a mean reduction in score of 68 points (95% confidence interval 103 to 33), with the benefit persisting at three months and six months after therapy (mean reductions 71 points (109 to 32) and 11 points (20 to 3)) but not later. Cognitive behaviour therapy also showed significant benefit on the work and social adjustment scale that was still present 12 months after therapy (mean reduction 2.8 points (5.2 to 0.4)), but had an inconsistent effect on the hospital anxiety and depression scale. Conclusion Cognitive behaviour therapy delivered by primary care nurses offered additional benefit over mebeverine alone up to six months, although the effect had waned by 12 months. Such therapy may be useful for certain patients with irritable bowel syndrome in primary care.

Focal points Little evidence is available on the benefit of many OTC medicines used for irritable bowel syndrome and more research is needed to enable community pharmacists and their support staff to make evidence-based recommendations It is feasible to conduct multi-centre community pharmacy-based studies on OTC medicine use Patients perceived significant relief of their symptoms when taking either OTC mebeverine or peppermint oil EC Patients who used mebeverine reported a slightly greater, though not statistically significant, improvement in symptoms than those who purchased peppermint oil-containing products

A series of semi-rigid analogs of phenethylamine was prepared as fixed transoid and cisoid analogs of mebeverine, and tested for spasmolytic activity in vitro. The fixed transoid analogs were more potent than the corresponding cisoid analogs. In this series, tetrahydro-2-napthylamine derivative (2a) which is presumed to take transoid conformation had the most potent activity, and tetrahydroisoquinoline derivatives (2g and 2h) which are presumed to take typical cisoid conformations were less active. These results suggested that the phenethylamine moiety of mebeverine takes the transoid conformation for the manifestation of the spasmolytic activity.

A rapid and specific reversed-phase high-performance liquid chromatographic method (RPHPLC) is described for the determination of mebeverine hydrochloride in tablets. Elution was performed on an octyl silane column with a methanol-water mixture (75-25), containing 0.05% hexylamine as silanol-blocking agent, adjusted to pH 5.0 with phosphoric acid. The method gave accurate, precise and reproducible results. The mean recovery of the drug from six synthetic tablet mixtures was 100.0% with a relative standard deviation (RSD) of 0.94%. In order to test the specificity of the method, the interference of the degradation compounds of mebeverine hydrochloride and of the intermediates from the synthesis was investigated. None of them did interfere. By means of mass spectrometry and UV-spectrophotometry, the degradation compounds of mebeverine were identified as veratric acid and as 4-|ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino| 1-butanol. The stability study proved that mebeverine hydrochloride is very stable in tablets; the tablets still contain more than 95% of the declared drug potency after storage for more than one year at 50°C.

N-[(Benzoyloxy)alkyl]-1,2,3,4-tetrahydro-2-naphthylamine derivatives were synthesized from 1,2,3,4-tetrahydro-2-naphthylamines and evaluated for their spasmolytic. Some of these compounds showed a nerve-selective effect on colon rather than stomach in anesthetized dogs and were found to be equal to or more active than the reference drug (mebeverine). The biological data have indicated some structure-activity relationships. Among these compounds, N-ethyl-N-[6-(3,4-dimethoxybenzoyl)oxy]hexyl]-1,2,3,4-tetrahydro-6-methoxy-2- napththylamine hydrochloride (63) was found to be the most active spasmolytic agent.

The chromatographic behaviour of mebeverine hydrochloride, a musculotropic spasmolytic agent, and some related compounds, i.e. degradation compounds and intermediates from the synthesis, on reversed-phase pre-coated high-performance thin-layer plates is described. The retention and selectivity on different commercially available layers are studied in connection with different eluent properties. The developed method is applied to the quantitative determination of mebevirine hydrochloride. Excellent selectivity and good reproducibility are obtained, and the method provides a combined test of assay, purity and stability.

Assay methods for measuring saliva levels of carbamazepine and its active metabolite, and of amidopyrine are developed using a standardized analysis strategy. Both assay methods include ion-pair extraction of the analytes with octylsulphate as the counter-ion and chromatography on a CN-bonded phase using a hexane—dichloromethane—acetonitrile—propylamine mixture as the mobile phase. Both methods are applied to patient samples.

A test was developed to quantify fecal output in rats. Narcotic analgesic (diphenoxylate, morphine), ganglionic blocking (mecamylamine) and anticholinergic drugs (atropine) decreased fecal output. Compounds with direct smooth muscle depressant properties (papaverine, mebeverine) did not alter fecal output. Several other drugs were also evaluated. The rat animal model is useful for assessing the effects of various drugs in altering fecal output.

Mebeverine hydrochloride (Duspatalin†), synthesized during the course of a study on a series of reserpine derivatives, was found to be an active smooth muscle relaxant.

A previous therapeutic trial of factorial design showed that a combination of a psychotropic drug, a smooth-muscle relaxant, and a bulk former (lorazepam, hyoscine hydrobromide, and ispaghula husk) relieved symptoms of the irritable bowel syndrome more effectively than the same agents given singly. Another trial of similar design was undertaken to compare each of these three agents with another having the equivalent clinical actions--namely, Motival (fluphenazine/nortriptylene mixture), mebeverine, and bran. Ninety-six patients took part; all received three agents, one from each of the three pairs being compared, and no placebos were used. Fifty-six patients reported a sustained symptomatic improvement, which was a significantly higher incidence than in the previous trial, when placebos were used. Ispaghula was significantly more effective than bran. The combination of ispaghula, Motival, and mebeverine improved 11 out of 12 patients--significantly more than bran, Motival, and hyoscine (five improved), or bran, lorazepam, and mebeverine (four improved). Mebeverine was significantly more effective when combined with Motival (18 out of 24 improved) than with lorazepam (10 improved). These results confirm the value of a combined therapeutic approach to the relief of the irritable bowel syndrome and suggest the possibility of synergism between agents.

The effect of mebeverine, mebeverine-alcohol and veratric acid on voltage-operated ion channels and on sodium pump activity were studied. The amplitude and duration of the compound action potential evoked in the vagus nerve were decreased by mebeverine but not by the metabolites. The amplitude of the post-tetanic hyperpolarization was decreased by mebeverine while the time constant of decay, representing sodium-potassium pump activity, was not affected by the compounds tested. These results show that mebeverine exerts a local anaesthetic action by blocking voltage-operated sodium channels.

SummaryThree controlled trials were carried out in patients with irritable bowel syndrome to assess the effectiveness of trimebutine in controlling the symptoms of abdominal distension, pain, flatulence, constipation, diarrhoea and dyspepsia. In the first two trials, it was shown that 200 mg trimebutine 3-times daily for 3 days produced rapid relief of symptoms and was significantly (p < 0.001) more effective than placebo, but not significantly so when the dosage level was halved. In the third trial, the results showed that 200 mg trimebutine 3-times daily for 2 weeks was as effective as 100 mg mebeverine 4-times daily in relieving the major symptoms and in improving motility. No serious side-effects were reported with trimebutine at the dosages used.

Changes in the potential and contractility of smooth muscle cells of guinea-pig taenia caeci were measured (22°C) in order to investigate the effect of mebeverine, a derivative of β-phenylethylamine, on α1-receptor-operated ion channels in particular. Mebeverine (6×10−6 M showed atropine-like properties by shifting to the right the concentration-response curve obtained with carbachol. Hyperpolarization and cessation of spike activity of the muscle cells, accompanied by an increase amplitude of the electronic potential were observed in the presence of mebeverine (6 × 10−5) after block of the α2-, β- and muscarinic receptors. This effect of mebeverine was not observed in low-sodium solution (23.8 mM), suggesting that mebeverine decreased sodium permeability. The α1-receptor-induced hyperpolarization caused by adrenaline (3 × 10−6 M) in the presence of mebeverine declined after reaching an initial maximum. The hyperpolarization induced by a second addition of adrenaline to the preparation was decreased and sustained in the presence of mebeverine, while the decrease of the electronic potential evoked during the α1 response was less pronounced. The transient hyperpolarization representing the α1 response in the absence of extracellular calcium developed more slowly in the presence of mebeverine, the area of the response being constant. When the experiment was continued in calcium-free solution after a short exposure to calcium-containing Krebs solution still in the presence of mebeverine, the α1-receptor-induced hyperpolarization was suppressed. Depolarization of the muscle cells was observed on addition of adrenaline to the preparation in calcium-free conditions and in the presence of apamin (3 × 10−7 M). Mebeverine affected this reversed α1 response similarly to the hyperpolarization observed without apamin. The results show that mebeverine inhibited the α1 action by limiting the amount of available calcium mobilized on receptor stimulation of the smooth muscle cells of guinea-pig taenia caeci

N-[(Benzoyloxy)alkyl]-1,2,3,4-tetrahydro-2-naphthylamine derivatives were synthesized from 1,2,3,4-tetrahydro-2-naphthylamines and evaluated for their spasmolytic. Some of these compounds showed a nerve-selective effect on colon rather than stomach in anesthetized dogs and were found to be equal to or more active than the reference drug (mebeverine). The biological data have indicated some structure-activity relationships. Among these compounds, N-ethyl-N-[6-(3,4-dimethoxybenzoyl)oxy]hexyl]-1,2,3,4-tetrahydro-6-methoxy-2- napththylamine hydrochloride (63) was found to be the most active spasmolytic agent.

Eight spasmolytic drugs commonly used in the treatment of the irritable bowel syndrome were compared to verapamil with respect to their effects (all drugs injected i.v.) on the contraction of duodenum, ileum and colon induced by high K+ topical application in the anaesthetized rat. Verapamil greater than rociverine greater than papaverine greater than mebeverine greater than dicyclomine antagonized dose-dependently the contraction of duodenum and colon, the activity on duodenum being from 2 (rociverine) to 10 (verapamil) fold higher. Verapamil and rociverine, but not the other drugs mentioned above, were also active on ileum. N-Butylscopolammonium bromide, phloroglucinol and trimebutine were inactive against the contraction of the three intestinal tracts and prifinium bromide was inactive on duodenum and ileum, while it had remarkable activity on colon, unrelated to its antimuscarinic activity. The results are discussed briefly with reference to the pharmacological therapy of the irritable bowel syndrome.

There is no generally accepted treatment in the irritable bowel syndrome (IBS), probably because of a lack of convincing therapeutic trials. In the present study, 120 outpatients with IBS participated in a prospective randomized therapeutic trial. According to a double-blind design, 40 patients received 400 mg/day mebeverine and 40 patients received a placebo. In an open branch of the trial, 40 patients were treated with 15 g/day wheat bran. The effects of treatment on symptoms were noted after 4, 8, 12 and 16 weeks of therapy. A significantly superior symptomatic effect of bran in comparison to mebeverine and placebo was demonstrated after 12 weeks, but could not be confirmed at the end of the study. There was no significant difference between the symptomatic effect of mebeverine and placebo. The compliance with the therapy was about 80% for 4 weeks, but dropped to about 50% at the end of the trial. This points to a particular difficulty in the management of patients with IBS. The results of this trial suggest that bran and mebeverine are no ideal therapy for patients with IBS but they support the therapeutic use of bran in patients with IBS.

Summary: In a single blind clinical trial, a significant preference emerged for mebeverine against the placebo tablet, when patients compared the efficacy of the two agents in relieving the symptoms of the irritable colon syndrome. This result confirms a previous study and indicates that mebeverine deserves a place in the management of the irritable colon syndrome in those patients who require drug therapy.

1. The spontaneous contraction of the isolated colon was inhibited by mebeverine at doses greater than 1×10-7g/ml. The effect of mebeverine was stronger than that of papaverine or buscopan. Two kinds of movement occur in the rabbit colon, peristaltic movement and the local tonic wave. The local tonic wave is produced mainly by the ring muscle. Papaverine mainly inhibited the peristaltic contractions but the effect of mebeverine and that of buscopan were the inhibition of tonic contractions. These drugs showed greater inhibitory effects on the colonic activity than on the small intestinal one.2. The antispasmodic properties of mebeverine against the evoked contractures yb acetylcholine 10-5 g/ml or BaCl2 10-3g/ml were stronger than those of papaverine and buscopan.3. When mebeverine 10-5g/ml was applied on the isolated colon the spontaneous contractions were enhanced about 50% of the cases. The phasic and tonic contractions were enhanced with the increase of spike discharge. The mechanisn of this phenomenon is obscure.4. When 5mg/kg mebeverine was induced intravenously, the movement of the colon was slightly inhibited. But sometimes colonic movement enhanced, tachycardia appeared, respiration became irregular, tonic convulsion appeared and the animal died. But when mebeverine was given orally no significant alteration of colonic motility was observed.

Objectives To determine whether cognitive behavioural therapy (CBT) in addition to antispasmodic treatment offers a cost-effective benefit to primary care patients with irritable bowel syndrome (IBS) and to identify predictors of outcome. Design This was a randomised controlled trial in primary care of the addition of CBT to standard general practice management of IBS, using the antispasmodic agent mebeverine hydrochloride. The study set out to compare the addition of a standardised package of IBS-specific CBT to treatment with mebeverine hydrochloride. Setting Ten general practices, serving a population of around 45,000 patients, located principally in south London, with some patients resident in north London. Participants Patients identified as having IBS by their GPs, aged between 17 and 54 (mean 34) years and predominantly white; 82% were female and half had had IBS for more than 5 years. Interventions Practice nurses delivered CBT in a randomised trial of the addition of CBT to mebeverine in patients who had IBS of moderate or greater severity after 2 weeks of GP care and 4 weeks of mebeverine. The Symptom Severity Scale (SSS) was used to identify patients with moderate or severe IBS. Patients who continued to report moderate or severe IBS after 4 weeks of mebeverine at a dose of 270 mg three times a day were randomised to receive six sessions of CBT in addition to mebeverine (72 patients) or mebeverine alone (77 patients). These patients were followed at 3, 6 and 12 months after treatment. As part of the baseline evaluation, blood tests for antiendomysial and antigliadin antibodies were carried out on 141 patients to determine the prevalence of coeliac disease in this population. Main outcome measures The principal outcome measure was the SSS. Others included the Hospital Anxiety and Depression Scale, psychopathology, the Work and Social Adjustment Scale (WASA, disability), a modified version of the Illness Perception Questionnaire (illness perceptions), the Beliefs about Medicine Questionnaire (attitudes to medication), the Reported Adherence to Medication Scale (adherence to prescribed medication), the Client Service Receipt Inventory (economic analysis), the Cognitive Scale for Functional Bowel Disorders (illness cognitions) and the Behaviour Scale for IBS (IBS coping behaviour). Results The addition of CBT produced a significant benefit compared with the mebeverine-only group at 3 months after treatment on all outcome measures, except for the adherence to medication scales. The difference between the groups was 107.8 points on the SSS, 24.5 points on question 4 of the SSS and 6.3 points on the WASA, representing therapeutic gains of approximately 20%, 28% and 40%, respectively. However, there was also evidence that these improvements began to wane, so that at 6 and 12 months follow-up significant therapeutic benefit of the addition of CBT could only be detected on question 4 of the SSS and on the WASA. The behaviour scale for IBS detected significant, positive changes in coping behaviours at up to 6 months after treatment. Three factors predicting a poor outcome were identified: male gender, believing that IBS had serious consequences and belief in an external aetiology, all of which were associated with greater than average disability at follow-up. The addition of CBT to mebeverine did not reduce overall treatment or social costs. The nested study on testing for coeliac disease provides cautious support for the inclusion of antiendomysial and antigliadin antibody testing in the investigation of patients thought to have IBS. Conclusions Specially trained practice nurses can provide effective CBT to primary care patients with a clinical diagnosis of IBS, which although effective does not reduce service or social costs. Using a variety of measures the beneficial therapeutic effects of the addition of CBT to antispasmodic therapy persist for up to 6 months. Future research might include studies of the long-term follow-up of IBS patients treated with CBT, cost-benefit analyses comparing CBT with other therapeutic approaches to IBS, and evaluating means of training both non-specialist health professionals and GPs to deliver CBT.

A double blind controlled trial to determine the effect of mebeverine (Colofac) pre-medication on the incidence of spasm, pain and discomfort during examination of the colon by double contrast barium enema was carried out. There was a significant reduction in spasm on fluoroscopy and reported pain and discomfort in the mebeverine group. The number of segments of spasm on the radiographs was not significantly reduced.