Monday, 3 November 2014

Rolipram not good for MS

Bielekova B, Richert N, Howard T, Packer AN, Blevins G, Ohayon J, McFarland HF, St├╝rzebecher CS, Martin R. Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood--brain barrier disruption in multiple sclerosis.Mult Scler. 2009;15:1206-14.

Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear.



A phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system . Nausea, emesis, and related general gastrointestinal side-effects are the most commonly implicated side-effects of PDE4 inhibitors. Other possible side effects include respiratory and urinary tract infections.

It is indeed the case that many studies reported that rolipram can inhibit the development of EAE. However MS is not just an immune response and we showed (in 2003), that rolipram could make symptoms worse once EAE became established. 

Why would Rolipram inhibit EAE and make MS worse. One can only guess but there is one common feature and this is the ability of rolipram to inhibit tumor necrosis factor. Anti-TNF in animals can inhibit the development of EAE, but anti-TNF can make MS worse, so should disease worsening with Rolipram have been an  expected result?

Ibubilast is another PDE4 inhibitor that inhibits EAE but made no impact on releapse rate or lesions in an MS trial and thankfully did not make MS worse when studied in a large number of MSers. Indeed it seemed to slow progression, so now there are two trials in progression, one in US and one in the UK.

6 comments:

  1. Can you clarify what you mean by anti-TNF can make MS worse though? I thought that copaxone and avonex suppress TNF?

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    1. Copaxone does every thing :-) however it is not a TNF inhibitor as compared to a proper anti-TNF. In MS trials this made MS worse and there were cases of people with arthritis getting demyelination.

      TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. [No authors listed] Neurology. 1999 Aug 11;53(3):457-65.

      Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2.
      van Oosten BW, Barkhof F, Truyen L, Boringa JB, Bertelsmann FW, von Blomberg BM, Woody JN, Hartung HP, Polman CH.
      Neurology. 1996 Dec;47(6):1531-4.

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    2. Forgot to mention there was another PDE4 tried in MS (Pentoxifylline) without event

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    3. Very interesting. I also remember reading a while back that DMF also inhibits TNF in psoriasis (and unless that super-expensive enteric coating makes all the difference, I'd imagine in MS too). What makes it 'safer'?

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    4. Every immunosuppressive drug will block TNF to some extent, however what they are really doing is blocking the cells activity and sothey do not produce TNF and this I think is different from blocking the TNF that is produced. Cytokines are produced in balances and if you remove one then others compensate in a way we may not want. I doubt the immunosuppressives such as DMF have a wipe out of TNF. DMF may hit the lymphocytes but what about astrocytes, and other cells that can produce TNF that would not be touched whereas ant-TNF could target that activity.

      I suspect that TNF is involved in nerve conduction. It was interesting that with Alemtuzumab when the white cells are being destroyed you get a cytokine storm including TNF release and this appears to reactivate old lesions, maybe via conduction block. This is reason you get steroids with Alemtuzumab infusions to limit this happening.

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    5. Thanks for getting back. Reading Professor Giovanonni's update just now on DMF, I can't say I'm reassured!

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