Isosorbide and NSAID mentioned as stronger than steroids...?

Hi
Just read the latest Treat-NMD newsletter and they mentioned that

2.Isosorbide and NSAID
3.Flavocoxid -

might have greater effects than steroids...? anyone knows more?
thanks Dori

http://www.ncbi.nlm.nih.gov/pubmed/19786019
http://www.treat-nmd.eu/about/news/news/782/

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Actually, I just looked into this. Giulio Cossu's group is working on it. They obtained very good results in mice (outperformed Prednisone and they are expected to have a lot less side effects). They are running a small pilot study in DMD patients at the moment. If the results in boys replicate, they will run a trial comparing this combination of existing drugs (ibuprofen+ISDN (isosorbide dinitrate)) with Prednisone.

Please take a look at this patent presenting the results obtained in mice: http://www.freepatentsonline.com/y2009/0304815.html

This is the answer I obtained from Emilio Clementi who is working on this:

Dear Ofelia, I have seen the correspondence between you and Giulio.

The patente refers to a treatment to slow muscle wasting in DMD using a combination of a non steroidal antiinflammatory drug (ibuprofen) and the NO donor isosorbide dinitrate. they are both on the market as generics . A pilot open trial using these drugs off-label is now undergoing and we expect to obtain the results in a month or so. Whereas in mice prednisolone was clearly shown to have less efficacy and more relevant side effect we have not yet carried out a comparison of the treatments in humans. This should be part of a clinical trial that will be undertaken should the results of the pilot study be of success.

Best,

Emilio
Interesting. Thanks for passing it on.

Are Cossu & Clementi in Italy? Is that where the small study is taking place?
Yes, Italy.

Keith Van Houten said:
Interesting. Thanks for passing it on.

Are Cossu & Clementi in Italy? Is that where the small study is taking place?
This meeting took place. Summaries will be posted April 2.

http://www.treat-nmd.eu/about/news/news/806/

A multidisciplinary group of seventeen members of the international TREAT-NMD Advisory Committee for Therapeutics met in Rome on the 6th-7th February 2010 to conduct the first drug review meeting. Two additional TACT members who were unable to attend in person provided written assessments that contributed to the reviews (Didier Caizergues, Jeff Towbin). Due to severe snow storms in the US Jerry Mendell, Kevin Flanigan and Avital Cnaan were unable to attend the meeting in person; however, they heroically participated via teleconference at selected times over the one and a half days of the meeting.

During the meeting TACT reviewed three proposals for clinical trials submitted by academic clinical research applicants from Italy and the US:

Losartan - Christopher Spurney, Children’s National Medical Centre.
Isosorbide plus Ibuprofen - Emilio Clementi and Grazia D’Angelo, H Sacco University Hospital, University of Milano.
Flavocoxid -Sonia Messina and Giuseppe Vita, University of Messina.
Each applicant attended the meeting (via teleconference or in person) for approximately one hour to discuss their proposal with the committee, which provided helpful additional context for applicants and reviewers as well as clarifying specific areas where the applicants are seeking advice. By March 19th (within 6 weeks of the meeting) the committee will provide to the applicants an assessment report providing recommendations, including specifics to strengthen the proposal and to answer questions raised by the applicants. TACT hopes that this advice will be useful in effectively planning the next steps for the projects.

TACT will also generate a review summary, with input from the applicants, which will be made available via the TREAT-NMD website by 2nd April 2010, as well as some general recommendations for applicants and reviewers based on the experience with the first applications.

The deadline for applications to be reviewed at the next TACT meeting (5th-6th June 2010 in Barcelona) is the 15th March 2010 and all potential applicants should contact the TACT secretariat (TACT_Core@treat-nmd.eu) to discuss their proposal before completing the full application form. The experience of the first meeting suggests that the TACT review process can be very useful for applicants and add real value to their plans. We look forward to their feedback as they move forward with their programs.

TACT Meeting Participants:


TACT Core Group: Cristina Csimma
TACT Chair
Petra Kauffman Clinical
Rudolf Korinthenberg Clinical - Lead for Isosorbide plus Ibuprofen
John McCall Drug discovery/ medicinal chemistry
Elizabeth McNeil Regulatory
Kanneboyina Nagaraju Preclinical - Isosorbide plus Ibuprofen, Flavocoxid
Dominic Wells Preclinical - Lead for Flavocoxid
One note. I do not see the point of another Losartan trial since there is the Lisinopril vs Losartan going on here in the US.

In fact, Mendell & Flanigan attended the meeting:

TACT Core / Members participating via teleconference / written review:

TACT Core Group: Jerry Mendell Clinical - Lead for Losartan

Didier Caizergues Regulatory (written reviews)

Additional TACT experts: Kevin Flanigan Clinical - Losartan, Flavocoxid

Jeff Towbin Clinical - Losartan, Isosorbide plus Ibuprofen, Flavocoxid (written reviews)

Avital Cnaan Statistics - Isosorbide plus Ibuprofen, Flavocoxid (written reviews)
http://www.treat-nmd.eu/about/TACT/previous-reviews/

There goes the "replacement to steriods" hope for now. Just hope next week will bring some good news for a change.

In summary, based on the preclinical data with the combination of these drugs in mdx mice, TACT recommended further dose ranging and PK studies in mice and in pilot human studies to define if an effective level of drug is likely without unacceptable side effects. As proposed by the applicants, TACT believed that a trial of these agents in the non-ambulant DMD population could be feasible provided certain aspects of the trial design, as outlined in the report to the applicant, were addressed. From a regulatory perspective involvement of EMA and FDA at an early stage including orphan drug designation was recommended, as was the approach of treating these compounds as "two products simultaneously".

has anyone tried this combination and got good result?

This is the newly published paper about the clinical trial with this combination.

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