RESPONSE TO REVIEWERS:
Title: The Potential Therapeutic Effect of Melatonin in Gastro-esophageal Reflux
Disease
Dear: (Editor-in-Chief):
Thanks for your help and advices. Please, find the revised manuscript entitled: "The
Potential Therapeutic Effect of Melatonin in Gastro-esophageal Reflux Disease" to be
published in the BMC gastroenterology Journal. The concerns of the reviewers were fully
addressed in the sent response and appropriate revisions were carried out. We do hope
that this work will be accepted for publication in your journal.
Please, accept my best personal regards.
RESPONSE TO REVIEWER 1
Reviewer's report
Title: The Potential Therapeutic Effect of Melatonin in Gastro-esophageal Reflux
Disease
Version: 3 Date: 29 September 2009
Reviewer: Stanisław Konturek
Reviewer's report:
Major Compulsory Revisions:
1 The data enclosed suggest that melatonin could inhibit gastric acid secretion in
humans with GERD but no secretory data have been included.
The Answer
Actually we depends on the clinical improvement of the patient treated by
melatonin or PPI either alone or in combination, also we depends on the
significant increase in the PH "measured by PH metry" in the treated patient
which reflect the decrease in HCL secretion.
2
Furthermore, the drop of pH could result in the rise in gastrin release due to
reduction in antral autoregulation of gastric acid secretion and the rise of gastrin
release. Again plasma gastrin level was not measured in this report.
The Answer
Actually, treatment with PPIs results in a degree of hypergastinemia but with no
detected deleterious effect in Human.
"Gastin levels are regulated by intragastric acidity. Acid suppression alters
feedback inhibition. So that, median gastrin level rises
1.5-2 folds in
patients receiving PPI. Although gastrin level remains within normal limits in
most patients, they exceed 500pg/ml (normal<100) in 3%. Upon stopping the
drug, the levels normalize within 4 weeks." "At present, routine monitoring
of serum gastrin levels is not recommended in patients receiving PPI
therapy."
Bertram G& Katzung G: drugs used in treatment of gastrointestinal
diseases. Basic and clinical pharmacology. 2007, 10th edition P1017
3
Most important it is not clear from this study whether functional improvement in
GERD was also accompanied by the adequate changes in histology of esophageal
mucosa. I would request the addition of the histological data of esophageal
mucosa in patients with GERD before and after treatment with melatonin.
The Answer
Yes, it has its clinical impact but it could be considered in further study about the
morphological changes.
We did not take endoscopic biopsies in this study and we hope in the future to re
evaluate the drug at wide scale with histological confirmation and long time follow
up to see if it has other beneficial effect or not, as its effect on the change of the
character of esophageal epith. And the decrease in the incidence of barrett's
disease.
Minor Essential Revisions:
Melatonin is a potent antioxidant acting, at least in part, via COX-prostaglandin
and NOS-nitic oxide systems (ref 27), that should be measured in esophageal
mucosa before and after melatonin therapy to determine the mechanism of
antiinflammatory action of this indole.
The answer
This could also be added in the future at wide scale and with the study of histological
changes
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being
Published
The manuscript was proof read by language specialist
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
I declare that I have no competing interests' below. If your reply is yes to any,
please give details below.
RESPONSE TO REVIEWER 2
Reviewer's report
Title: The Potential Therapeutic Effect of Melatonin in Gastro-esophageal Reflux
Disease
Version: 3 Date: 25 July 2009
Reviewer: Debasish Bandyopadhyay
Reviewer's report:
(A) Minor Essential Revisions:
Corrections of the following
(a)
1. Abstract; Line 1 (Page 2), changed from GERD is defined ….. to Gastro-Esophageal
Reflux Disease (GERD)is defined….
2.Abstract; Subjects and Methods; Line 2 (Page 2), changed from disease treated by
melatonin …. to disease treated with melatonin......
3. Results; line 2 (Page 3), changed from alone is better used in …. to alone is a
better.....
4. Page 3; Line 3, changed from (GERD)… to GERD
5. Page3, Para 2, Line 1, changed from Knowledge to knowledge
6. Page 3, Line 3, changed from that melatonin synthesized … to that melatonin is
synthesized......
7. Page 3, Line 4, changed from, organs, special attention…… to, Organs. A special
attention......
8. Page 3, last but one line, HCl and not "HCL"
9. Page 3, changed from, Rather few … to Only a few studies on.....
10.Page 3, para 3, for treating (GERD). To, for treating GERD.
11. Page 4. Line 1, changed from, an informed concent … to consent......
12. Page 4, Line 20, changed from LES….. to Lower Esophageal Sphinctor (LES).......
13. Page 4, Line 21, changed from, and 27 subjects with… to and finally 27
subjects........
14, Page 5, Line 1, changed from and serum was frozen ….. to, and serum thus
obtained..................
15. Page 5, Lines 3-5, meaning is not clear. This portion should be re-written.
16. Page 5, Line 15, changed from stastical ….. to, statistical..........
17. Page 5, Result section; All the sub-headings shoul be in the bold, small caps.
18. Page 6, Line 18,........
19. Page 6, Line 19,
20. Page 6, Line 19,
Changed from, Significant increase in the tone of the LES in the form of increased LES
pressure. In addition, there is significant ….. to A significant increase in the tone of the
LES in the form of increased LES pressure was also noted. In addition, there is a
significant ….
21. Page 7, Line 6, Changed from showed significant increase in pH.........to, showed a
significant increase in pH….
22. Page 13, Discussion section, Line 6, changed from Melatonin have also been detected
in the…. To, Melatonin has also been detected in the ...........
23. Page 13, Line 8, G-protein coupled receptors [ Ref.? ], Ref no (30), sorry it was
missed
24, Page 13, Line 14, changed from, This came in agreement with…. To, This
observation is in agreement with.........
25Page 13, line 22, changed from, deficiency of indole …..to,
deficiency of the indole.
26. Page 14, Line 12, changed from, The current study evaluates......to, The current
study also evaluates.......
27. Page 14, Line 15, "and confirmed that it had few, if any, adverse effects" was
deleted.
28. Page 16, Line 5, changed from, However the pH, 5 cm above.......... to, However,
the pH, 5 cm above..........
(b) In the discussion section, Page 14, in between Lines 12 and 16, the authors
add one sentence as follows: It was also noted that Pharmacologically administered low
and high doses of melatonin have been found to be with very low or no toxicity (31)
(c)Page 5, Lines 3-5, the meaning is not clear. The authors may re-write these
lines to make it easily understandable.
Changed to the following to clarify the meaning, ….. An ambulatory digitrapper used to
perform 24 hours pH-metry measurement by UP S2020 Orion MMS Holland pH-metry.
The pH probe was positioned 5 cm above the position of the LES. The data were
collected using De-meester (DM) score; gastroesophageal reflux was considered as a
drop in esophageal PH below 4 and the percentage reflux in 24 hours was calculated for
each patient (9).
And the Ref No (9) was changed to….
9
Gad El-Hak N, Abo Zied M, Aboelenen A, Fouad A, Abd Alla T, ElShoubary M, Kandel T, Hamdy E, Abdel Wahab M, Fathy O, El-ebidy
G, Sultan A, Elfiky A, Elghwalby N, Ezzat F: Short gastric vessels division
in laparoscopic Nissen Fundoplication. Hepatogastro-enterology. 2005; 52
(66):1742-1747.
(d) The authors should mention in the manuscript which brand of melatonin they
have used. The same is also for omeprazole.
We use Losec 20 Mg caps (Astra) and melatonin as Viva max 3 Tablets.
(e)There should be an "acknowledgement" section in the manuscript which may
indicate the the authors funding sources, the people who might have helped
them in the current work in various manner etc.
it was added
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
'I declare that I have no competing interests'