Title: The insoluble excretion of multi-matrix system mesalazine preparations in patients with
ulcerative colitis
Version: 3 Date: 18 May 2022
Reviewer's report:
In the paper „the insoluble excretion of multi-matrix system mesalazine preparations in patients
with ulcerative colitis“ the authors estimate the bioavailability of Multi-Matrix mesalazine
tablets by visual control.
It is well known that patients affected by ulcerative colitis are suffering from diarrhea in their
active phase. This implicates high frequencies and less firmness of their stool. Therefore the
transit time through the gastrointestinal tract often is accelerated and it is highly interesting, if
the medication prescribed reaches the targeted organ in these patients. But it is doubtful, if this
can be achieved satisfactory in a retrospectively investigated survey based on interviews and
visual control of the stool.
In the methodical part it seems not fully clear if only the disease type were investigated
retrospectively by examining the medical record as written in the abstract, or if the authors
investigated retrospectively defecation frequency at the start of treatment, stool consistency,
disease type and the presence or absence of insoluble excretion of the administered medication
within nearly two years as described in ‘methods’.
Herein specification is necessary. Because retrospective evaluation about frequency and
consistency of the stools is obviously not reliable enough, just as the retrospective survey of
visible excreted medication.
On one hand, visual stool analysis with different consistencies naturally carries the risk that
larger tablets can be overlooked in the more solid stool, whereas in more liquid stool solid
components such as tablet residues and undigested food, e.g. corn grains, are easier to detect.
It is not discussed whether the patients were instructed to specifically examine their stool for
tablets, e.g. by rinsing it with water, as is required when recovering the capsule camera after
performing a capsule endoscopy (depending on the manufacturer). And even if there seems to
be visible apparently complete tablets or parts of tablets in the stool, no statement can be made
whether effective active substances have been released after all.
And there I see the main limitation of this publication: in the lack of pharmacological control
as an objective parameter.
Because of the topical mode of action of mesalazine [5-aminosylicylate(5-ASA)], the
medication must reach the inflamed mucosa from the luminal side of the bowel. This can be
achieved via oral administration of delayed release formulations which deliver 5-ASA at the
appropriate location in the bowel, or by rectal application of mesalazine in the form of enemas,
foams of suppositories.
However, long-term rectal therapy is not preferred by some patients because it causes discomfort
and therfore subsequently poor adherence. Especially for patients with a distal location of their
disease it is desirable to offer a medication that, given orally, has a similarly good effect.
Therefore it is highly relevant to make sure that the medication reaches its target.
Since visual methods are rather unreliable in providing information about the true bioavailability
of mesalazine, a more objective method of measurement is desired, which does exist. Salicylate
measurement in plasma or urine can be a reliable method. It is commonly used in scientific
works, e.g. to demonstrate compliance [1].
And this works although the basic idea ist that the effect of meslazine should be predominantly
topical. There are several studies demonstrating  MMX formulation also achieves relevant
plasma and urine levels, both in children and adolescents [2], as well as adults.
[1] Am J Gastroenterol. 2013 Feb; 108(2):249-55 A. Gifford et al: A random urine test can
identify patients at ris of mesalamine non-adherence: a prospective study
[2] Drug Ded Devel Ther. 2016; 10:593-607 C. Cuffari et al: Randomized clinical trial:
pharmcokinetics and safety of mutimatrix mesalamine für treatment of pediatric ulcerative
colitis
Title: The insoluble excretion of multi-matrix system mesalazine preparations in patients with
ulcerative colitis
Version: 3 Date: 18 May 2022
Reviewer's report:
In the paper „the insoluble excretion of multi-matrix system mesalazine preparations in patients
with ulcerative colitis“ the authors estimate the bioavailability of Multi-Matrix mesalazine
tablets by visual control.
It is well known that patients affected by ulcerative colitis are suffering from diarrhea in their
active phase. This implicates high frequencies and less firmness of their stool. Therefore the
transit time through the gastrointestinal tract often is accelerated and it is highly interesting, if
the medication prescribed reaches the targeted organ in these patients. But it is doubtful, if this
can be achieved satisfactory in a retrospectively investigated survey based on interviews and
visual control of the stool.
In the methodical part it seems not fully clear if only the disease type were investigated
retrospectively by examining the medical record as written in the abstract, or if the authors
investigated retrospectively defecation frequency at the start of treatment, stool consistency,
disease type and the presence or absence of insoluble excretion of the administered medication
within nearly two years as described in ‘methods’.
Herein specification is necessary. Because retrospective evaluation about frequency and
consistency of the stools is obviously not reliable enough, just as the retrospective survey of
visible excreted medication.
On one hand, visual stool analysis with different consistencies naturally carries the risk that
larger tablets can be overlooked in the more solid stool, whereas in more liquid stool solid
components such as tablet residues and undigested food, e.g. corn grains, are easier to detect.
It is not discussed whether the patients were instructed to specifically examine their stool for
tablets, e.g. by rinsing it with water, as is required when recovering the capsule camera after
performing a capsule endoscopy (depending on the manufacturer). And even if there seems to
be visible apparently complete tablets or parts of tablets in the stool, no statement can be made
whether effective active substances have been released after all.
And there I see the main limitation of this publication: in the lack of pharmacological control
as an objective parameter.
Because of the topical mode of action of mesalazine [5-aminosylicylate(5-ASA)], the
medication must reach the inflamed mucosa from the luminal side of the bowel. This can be
achieved via oral administration of delayed release formulations which deliver 5-ASA at the
appropriate location in the bowel, or by rectal application of mesalazine in the form of enemas,
foams of suppositories.
However, long-term rectal therapy is not preferred by some patients because it causes discomfort
and therfore subsequently poor adherence. Especially for patients with a distal location of their
disease it is desirable to offer a medication that, given orally, has a similarly good effect.
Therefore it is highly relevant to make sure that the medication reaches its target.
Since visual methods are rather unreliable in providing information about the true bioavailability
of mesalazine, a more objective method of measurement is desired, which does exist. Salicylate
measurement in plasma or urine can be a reliable method. It is commonly used in scientific
works, e.g. to demonstrate compliance [1].
And this works although the basic idea ist that the effect of meslazine should be predominantly
topical. There are several studies demonstrating  MMX formulation also achieves relevant
plasma and urine levels, both in children and adolescents [2], as well as adults.
[1] Am J Gastroenterol. 2013 Feb; 108(2):249-55 A. Gifford et al: A random urine test can
identify patients at ris of mesalamine non-adherence: a prospective study
[2] Drug Ded Devel Ther. 2016; 10:593-607 C. Cuffari et al: Randomized clinical trial:
pharmcokinetics and safety of mutimatrix mesalamine für treatment of pediatric ulcerative
colitis
Please review this paper.
user
Title: The insoluble excretion of multi-matrix system mesalazine preparations in patients with
ulcerative colitis
Version: 3 Date: 18 May 2022
Reviewer's report:
In the paper „the insoluble excretion of multi-matrix system mesalazine preparations in patients
with ulcerative colitis“ the authors estimate the bioavailability of Multi-Matrix mesalazine
tablets by visual control.
It is well known that patients affected by ulcerative colitis are suffering from diarrhea in their
active phase. This implicates high frequencies and less firmness of their stool. Therefore the
transit time through the gastrointestinal tract often is accelerated and it is highly interesting, if
the medication prescribed reaches the targeted organ in these patients. But it is doubtful, if this
can be achieved satisfactory in a retrospectively investigated survey based on interviews and
visual control of the stool.
In the methodical part it seems not fully clear if only the disease type were investigated
retrospectively by examining the medical record as written in the abstract, or if the authors
investigated retrospectively defecation frequency at the start of treatment, stool consistency,
disease type and the presence or absence of insoluble excretion of the administered medication
within nearly two years as described in ‘methods’.
Herein specification is necessary. Because retrospective evaluation about frequency and
consistency of the stools is obviously not reliable enough, just as the retrospective survey of
visible excreted medication.
On one hand, visual stool analysis with different consistencies naturally carries the risk that
larger tablets can be overlooked in the more solid stool, whereas in more liquid stool solid
components such as tablet residues and undigested food, e.g. corn grains, are easier to detect.
It is not discussed whether the patients were instructed to specifically examine their stool for
tablets, e.g. by rinsing it with water, as is required when recovering the capsule camera after
performing a capsule endoscopy (depending on the manufacturer). And even if there seems to
be visible apparently complete tablets or parts of tablets in the stool, no statement can be made
whether effective active substances have been released after all.
And there I see the main limitation of this publication: in the lack of pharmacological control
as an objective parameter.
Because of the topical mode of action of mesalazine [5-aminosylicylate(5-ASA)], the
medication must reach the inflamed mucosa from the luminal side of the bowel. This can be
achieved via oral administration of delayed release formulations which deliver 5-ASA at the
appropriate location in the bowel, or by rectal application of mesalazine in the form of enemas,
foams of suppositories.
However, long-term rectal therapy is not preferred by some patients because it causes discomfort
and therfore subsequently poor adherence. Especially for patients with a distal location of their
disease it is desirable to offer a medication that, given orally, has a similarly good effect.
Therefore it is highly relevant to make sure that the medication reaches its target.
Since visual methods are rather unreliable in providing information about the true bioavailability
of mesalazine, a more objective method of measurement is desired, which does exist. Salicylate
measurement in plasma or urine can be a reliable method. It is commonly used in scientific
works, e.g. to demonstrate compliance [1].
And this works although the basic idea ist that the effect of meslazine should be predominantly
topical. There are several studies demonstrating  MMX formulation also achieves relevant
plasma and urine levels, both in children and adolescents [2], as well as adults.
[1] Am J Gastroenterol. 2013 Feb; 108(2):249-55 A. Gifford et al: A random urine test can
identify patients at ris of mesalamine non-adherence: a prospective study
[2] Drug Ded Devel Ther. 2016; 10:593-607 C. Cuffari et al: Randomized clinical trial:
pharmcokinetics and safety of mutimatrix mesalamine für treatment of pediatric ulcerative
colitis
assistant