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trimebutine maleate clinical pharmacology

Time:2015/9/30 7:22:04

Clinical data have confirmed the regulating effects of MODULON? (trimebutine maleate) on lower gastrointestinal tract. This data is based on intestinal electromyographic recordings or by stool transit time determinations in patients with postoperative paralytic ileus or in patients suffering from irritable bowel syndrome (IBS).

In addition, these regulating effects were also confirmed by sigmoid motor activity in patients with hypo- or hypersigmoid activity.Irritable Bowel Syndrome Trimebutine maleate has been extensively used in various clinical trials involving subjects with irritable bowel syndrome. A total of 18 studies were conducted on 744 patients to evaluate the effects of trimebutine maleate. Eleven of these 18 studies were double-blind controlled trials (363 patients) in which trimebutine maleate was compared with placebo. In three other controlled trials (130 patients), trimebutine maleate was compared with mebeverine, a papaverine-like drug, and the remaining four trials (251

patients) were of open design.

Among the controlled studies, three were short-term (3-day treatment) involving 197 patients and eight were medium-term (2-4 weeks treatment) studies with a total population of 166 patients. The doses used in these trials varied between 400-600 mg per day in divided doses with the 100 mg tablet formulation. Most of these studies used a single or double-blind cross-over design in order to reduce the bias of placebo effects.

Assessment of treatment efficacy was carried out by evaluating the severity of each of the symptoms before and during treatment (abdominal pain, constipation, diarrhea, etc). as

absent, mild, moderate or severe. Alternatively, the degree of symptom improvement was assessed. In addition, an overall evaluation of patients’ preference for any of the

study medications was also recorded.

A placebo effect was observed in most of these studies during the initial treatment period,i.e. there was no difference in the symptom improvement between the trimebutine and

placebo groups. On the subsequent treatment periods, however, trimebutine appeared to be more efficacious than placebo.

Short-Term Studies: In one of the three short-term cross-over studies (3-day treatment),trimebutine maleate was significantly superior to placebo regardless of whether it was

taken as the first or the second treatment. In the other two studies, patients receiving trimebutine maleate as the second treatment improved significantly more than those on

placebo.


Medium-Term Studies: Seven of eight studies were double-blind, cross-over whereas one was parallel design. The duration of the treatment varied from two to four weeks and

the dosage ranged between 300 to 600 mg daily. The following symptoms were evaluated: abdominal pain, constipation, diarrhea and distention/flatulence. Global evaluation and patients’ preference for a specific treatment were recorded at the end of the treatment period.

In three of these studies, the efficacy of trimebutine maleate was superior to placebo; the improvement was statistically significant. Also, analysis of single stool transit time (one study) showed a significant acceleration of transit in patients receiving trimebutine maleate, the median stool transit time being reduced from 52 to 25 hours(p<0.05).


Evaluation of data from the global assessment of symptom severity made by the patient and the physician further indicated that severity of symptoms ameliorated in more

patients on trimebutine maleate than on placebo. Furthermore, the patients with the most severe initial symptoms demonstrated improvement when given trimebutine maleate.

The results of one study indicated that the effect of trimebutine maleate became evident only after two weeks and persisted for one more week after the therapy was discontinued.

In this study, trimebutine maleate gave better improvement than placebo which was significant (p<0.01) with regard to alternating constipation and diarrhea. In other studies,

although subjects showed a statistically significant improvement during treatment compared to pre-treatment, there was no significant difference between trimebutine and

placebo.


In other controlled trials, trimebutine maleate was compared with mebeverine, a papaverine-like medication. A total of three studies involving 130 patients were conducted. Trimebutine maleate 100 or 200 mg t.i.d. and mebeverine 100 mg t.i.d. or q.i.d. was administered up to four weeks in patients suffering from irritable bowel syndrome. Both drugs provided statistically significant improvement (p<0.001) of the symptoms of irritable bowel syndrome after two and four weeks of treatment without any significant difference between the two groups. However, the improvement obtained with trimebutine maleate during third and fourth week of treatment was significantly superior (p<0.001) to that observed with mebeverine. The tolerance was excellent for both drugs.


In a recently published double-blind, placebo controlled study conducted by Shannon etal, trimebutine maleate (200 mg) was administered orally to 11 normal volunteers and

nine patients with constipation-predominant irritable bowel syndrome. The postprandial motor activity was measured manometrically in the sigmoid colon.

Results indicated that, although orally administered, trimebutine maleate had no effect on post prandial sigmoid motor activity in normal subjects. Nonetheless, it attenuated the increase observed in patient with constipation-predominant irritable bowel syndrome.  


In another, double-blind, cross-over study conducted by Schang et al, trimebutine maleate 200 mg daily was administered orally for one month to 24 patients suffering

from chronic idiopathic constipation. Results indicated that colonic transit time was significantly reduced (p<0.05) with trimebutine maleate in patients with “delayed” transit time (from 105 ± 9 to 60 ± 11 hours) while it did not change with placebo (from 103 ± 17 to 95 ± 10 hours). Electrical activity was not influenced by trimebutine maleate or placebo in constipated patients with “normal” transit time, neither before nor after meals.