December 18th , 2009
Scott Edmunds PhD
The BioMed Central Editorial Team
BioMed Central, Middlesex House, 34-42 Cleveland St., London, W1T 4LB, UK
Tel: +44 (0) 20 3192 2013
E-mail: editorial@biomedcentral.com
Web: http://www.biomedcentral.com/
Dear Dr. Scott Edmunds,
Thank you for reviewing our manuscript (MS: 1648542833003838), entitled: " Sodium Pentosan
Polysulfate Resulted in Cartilage Improvement In Knee Osteoarthritis - An open clinical trial".
We corrected our manuscript according to your comments and questions those of the two reviewers.
We are grateful for your very helpful comments and guidance.
We hope that with these changes will make our manuscript suitable for publication in BMC Clinical
Pharmacology.
Following is a point by point response to the reviewers’ comments.
To the editor, Prof. Scott Edmunds
We recommend that you copy-edit the paper to improve the style of written English.
Response : We corrected our manuscript and we also had the manuscript corrected by a native
English translator who was an English professor in Japan.
Please also ensure that your revised manuscript conforms to the journal style
Response : We formatted our manuscript according to your journal guidelines and template from
your HP.
For the competing interest section, if you do not have any competing interests then just state "We do
not have any competing interests".
Response : We added the sentence "We do not have any competing interests".
We would like you to confirm that your prospective controlled trial is in a publicly accessible
registry, and for the number to be included in the abstract of the article.
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Once you know your trial registration number, please include it with the revised version of your
manuscript with the number included in the abstract.
Response : We added this information in the last section of the abstract: “Trial Registration: UMIN
Clinical Trials Registry (UMIN-CTR) UMIN000002790".
To the Reviewer1, Prof. Daniel Uebelhart, MD
The English wording should be carefully checked again by the authors or the Editor.
Response : We corrected our manuscript and we also had the manuscript corrected by a native
English translator who was an English professor in Japan.
Materials and Methods:
The presentation should follow the regular order usually used for the presentation of clinical
trials...for instance:
4. Practice of the Study is certainly not the usual way to describe the section which follows...the
authors must clearly state if they performed an of synovial fluid or not as the description is not clear.
Response : We changed the presentation order in the materials and methods and described clearly
that there was no aspiration.
Discussion: this part of the text kis？ definitively too long with a total of 6 pages !
It should be shortened to maximum 3 pages and focused on the results.
Response : We shortened the discussion to 3 pages.
The study performed by the authors concerned exclusively pentosan polysulfate and not any other
drug used for the treatment of knee OA. In addition, trying to make a detailed review of the whole
literature on OA treatment and omitting to list and drugs like chondroitin sulfate and
avocado-soybean insaponifiables is not acceptable !
Instead of insisting on Diacerhein, it would have been very appreciated to mention these other
substances which are documented as well in knee OA treatment.
Response : We assembled literature on OA treatment drugs. We removed sentences about diacerein
and added information about chondroitin sulfate and avocado-soybean unsaponifiables. Accordingly,
the references were changed.
Conclusions: The authors are very optimistic regarding the future clinical use of pentosan
polysulfate in Japanese knee OA patients, but I am not sure that all the safety issues linked with the
product are really going into this direction ? I would therefore recommend the authors to be
significantly less categorical.
2
Response : We agree that, because the scale of this research was small, assertive expressions should
be avoided. We changed the conclusion based on the results.
References: incomplete regarding the available literature on used drugs for knee OA treatment.
Response : We changed the references according to the discussion.
Figures: The Figures should be organized according to 1st outcome and 2nd outcomes and not a mix
with safety issues at the beginning of the presentation.
Response :We apologize for the confusion. We adjusted the text so that the order is now 1st outcome,
2nd outcomes and safety issues.
The evolution of the pain levels using the VAS and the WOMAC scores (please, provide WOMAC
Total and Pain score !) should be both provided as absolute levels and % of variation with time.
Response : We apologize for the confusion. The table showed absolute levels and % of variation
with time. Using absolute levels of WOMAC total and pain only, the recalculation did not yield a
significant difference.
The same should apply with the C2C levels in blood, but the provide Figures are difficult to read and
therefore, the results cannot be well appreciated...please find a better way to represent the results.
Response : The table showed absolute levels and % of variation with time in addition to the figure
showing WOMAC result.
To the Reviewer 2, Prof. David Neustadt, MD
To begin, the manuscript is too long and needs to be cut.
Response : We have shortened our manuscript.
It is somewhat confusing that the authors states that their classification of osteoarthritis on
radiograph was changed from “Koshino” class to Kellgren. It would be simpler and less confusing to
just give the Kellgren-Lawrence classification, which is used in both the United States and England.
Response : We changed the “Koshino” classification to the Kellgren-Lawrence classification.
The authors state that the trial was “held” in a “single center”. What does this mean? There were
seven authors and, according to the title pages, five were from Nagasaki and two Fukuoka prefecture.
This is somewhat confusing and needs clearing up, especially with only a total of twenty patients.
Response : We performed this study only at the Nagasaki University Hospital. Nagasaki and
Fukuoka prefecture are located close to one another. YK had once worked at Nagasaki University.
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These two scientists provided pharmaceutical special knowledge and technique for this study.
Top of page in “Summary” section it is stated “in spite of a different injection fashion”… this needs
clarification as well as a reference to “the previous studies in Australia”.
Response : This information was deleted.
The use of “improvement of cartilage metabolism” is vague and needs to be explained.
Response : We changed “improvement of cartilage metabolism” to
C2C collagen type2
metabolism.
In the second “introduction”, which I assume should be a “comment or discussion section” certainly
needs to be shortened.
Response : We moved the second “introduction” to the discussion section and shortened it.
If this compound (NAPPS) was used in Europe for about “fifty years” the additional significant data
and references should be given.
Response : We queried bene Arzneimittel GmbH, Munich, Germany about this. The answer was that
NaPPS has been on the market in Germany since June 1949 (“Medizinische Klinik”, 1949 (44),
professional journal, company archive of bene Arzneimittel GmbH)
According to the Summary of Product Characteristics of Pentosan polysulfate SP 54 and the official
periodic safety update report (PSUR) for pentosan polysulfate sodium, they mentioned the
following:
In the content of Overall Safety Evaluation, during the reporting period, no ADRs have been
reported, which would have had an influence on the overall evaluation of the drug pentosan
polysulfate. The nature of the ADRs listed in this PSUR does not require a change in the medical
evaluation of this well-known substance.
During the reporting period, no ADRs have been reported, which would have had an influence on the
overall evaluation of the drug pentosan polysulfate. The nature of the ADRs listed in this PSUR does
not require a change in the medical valuation of this well-known substance.
The exclusions and methodology all needs to be presented in a simpler and
shortened fashion.
Response : We have shortened and simplified this section.
The information on the anticoagulant properties of the drug needs elucidation and consolidation.
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Response : We mentioned in the discussion that pentosan interferes with the binding of factor Xa to
thrombin by an AT-III-independent mechanism. Pentosan has anti-inflammatory properties and
strong fibrinolytic activity.
The section on Statistics needs consolidation and sharpening. A statement as to the statistical validity
of this twenty patient open label study should be included.
Response : In this study, statistical differences were calculated. However, the reliability of a clinical
trial with only 20 examples is not predictable. This is preliminary and explorative research in Japan.
The validity of the results should be verified in the future by performing a trial with a larger number
of subjects.
The demographics should be given early in the protocol, not under “results”.
Response : We moved the demographics data to the early section of the protocol.
Discussing Koshino’s classification after stating it has been changed to Kellgren is more confusing.
Response : As mentioned above, we changed the “Koshino” classification into Kellgren-Lawrence
classification.
In the final “discussion”, there is much repetition and irrelevant information, which should be
eliminated.
Response : We eliminated repetitive and irrelevant information.
All of the discussion and comments on other available and research type medications does not
belong in an article reporting a therapeutic trial with a “new” compound.
Response : We corrected and adjusted the discussion based on the comment of referee 1.
Under “Conclusions”, I don’t understand “many clinical benefits, including cartilage metabolism”.
Response : The conclusions has been rewritten, based on the comment of referee 1.
The list of abbreviations is not necessary and could be eliminated.
Response : We eliminated the list of abbreviations.
The part on “competing interests” could be simplified and shortened.
Response : We changed the sentence to read "We do not have any competing interests".
If you have any questions about our manuscript, please contact Kenji Kumagai, M.D., Ph.D., the
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corresponding author at the address shown below.
We are looking forward to your reply, hopefully saying this article is accepted in your journal.
We hope your best regards.
Sincerely yours,
Kenji
Kenji Kumagai, M.D., Ph.D. : Corresponding author
Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences,
Nagasaki University
1-7-1, Sakamoto, Nagasaki, 852-8501, Japan
Tel: +81-95-819-7321,
Fax: +81-95-849-7325
E-mail: kenjikum@nagasaki-u. ac.jp
Enc.
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