Wednesday, 14 June 2017

#ResearchSpeak & #OffLabel: are you up for taking seroquel?

Can seroquel be the drug people with MS need to remyelinate their damage axons? #ResearchSpeak #OffLabel


Yesterday some joker mentioned Seroquel (quetiapine) on the blog; he suggested MD had missed a few doses. Paul Simon even popularises the drug in his recent hit 'In a Parade' on his album 'Stranger to Stranger'.

Some nights the ER is quiet as an EKG
But tonight it feels like every broken bone

Tonight it feels like every wounded soul
Is filling out a form or on the 'phone

I can't talk now, I'm in a parade
I can't talk now, I'm in a parade
Can't talk to you now, I'm in a parade
I can't talk now, I'm in a parade

Diagnosis: schizophrenic
Prognosis: guarded
Medication: Seroquel
Occupation: Street Angel

I drank some orange soda
Then I drank some grape
I wear a hoodie now to cover my mistake
My head's a lollipop
My head is a lollipop
My head's a lollipop and everyone wants to lick it
I wear a hoodie now so I won't get a ticket
I write my verse for the universe
That's who I am

I can't talk now, I'm in a parade
I can't talk now, I'm in a parade
I can't talk now, I'm in a parade
Can't talk to you now, I'm in a parade

Diagnosis: schizophrenic
Prognosis: guarded
Medication: Seroquel
Occupation: Street Angel

Jokes, and songs, aside quetiapine is an interesting drug. Quetiapine is often prescribed to pwMS to treat psychiatric and non-psychiatric symptoms of MS including depression, anxiety, insomnia, agitation, hypomania, psychosis and rarely as a last resort for some pain syndromes. It has been hypothesised to have off target effects and work as a potentially remyelinating agent. In the non-hypothesis driven drug screen that delivered clemastine as a potential remyelinating agent, quetiapine was one of the hits that came-up very high on the list of potential drugs to promote remyelination. 


We now have a path for testing for remyelination therapies in MS, but what we don't have is a path for repurposing generic drugs (quetiapine is now off-patent). How are we as a community going to solve this thorny problem of repurposing off-patent drugs? We have posted on this issue before and could do with some inspiration. Off-label prescribing is not the solution as it rarely attracts the necessary investment to generate the class 1 data for getting a drug licensed or used in clinical practice. 

Zhornitsky et al. Quetiapine fumarate for the treatment of multiple sclerosis: focus on myelin repair. CNS Neurosci Ther. 2013 Oct;19(10):737-44.

Multiple sclerosis (MS) is a central nervous system disorder that is associated with progressive oligodendrocyte and neuronal loss, axonal degeneration, and demyelination. Several medications that mitigate immune abnormalities reduce both the frequency of relapses and inflammation on magnetic resonance imaging, leading to improved outcomes for people with the relapsing-remitting form of MS. However, there are no treatments for the progressive forms of MS where neurons and axons continue to degenerate; here, neuroprotective therapies, or medications that rebuild myelin to confer axonal well-being, may be useful. Quetiapine fumarate is an atypical antipsychotic with reported remyelinating and neuroprotective properties in inflammatory and noninflammatory models of demyelination, including experimental autoimmune encephalomyelitis, and both cuprizone- and global cerebral ischemia-induced demyelination. Preclinical studies suggest that quetiapine may exert these effects by stimulating proliferation and maturation of oligodendrocytes, releasing neurotrophic factors, increasing antioxidant defences, scavenging for free radicals, and inhibiting activated microglia, astrocytes, and T lymphocytes. Additionally, quetiapine may be beneficial for psychiatric and nonpsychiatric symptoms of MS including depression, anxiety, insomnia, and possibly even pain. These data indicate that clinical trials are justified to determine the safety, tolerability, and efficacy of quetiapine fumarate in MS.

Mei et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med. 2014 Aug;20(8):954-60.



Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.

27 comments:

  1. Interesting post. Can't you simply go ahead an do a proof of concept trial and hope a Pharma company then takes over with a related, but new, compound?

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    1. Maybe we should have an adaptive trial to test these head to head and throw out the ones that fail. In the last year we have had a large number of candidates mentioned.

      Can we measure remyelination? The anti-LINGO trials suggest a way forward.

      Have we actually shown that these agents can repair long-established demyelination in a gliotic environment....No

      We could do the same for neuroprotection, I could give a list of candidates in a few minutes but would it be smart to do these before MS-SMART reads out

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    2. We do have trial designs that at least tell us if the drugs are having a biological effect on myelination. We can do acute optic neuritis (anti-LINGO), chronic optic neuropathy (clemastine), single lesion MTR (GSK239512) and whole brain MTR (alemtuzumab).

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  2. Thank you for something completely different. I was going to suggest changing the name of this blog to B-cell.

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    1. The B-cell is where all the action and is the home of EBV the cause of MS. How can you get bored? We are so close to bringing it all together. Watch this space at least it makes a nice story.

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    2. Bored of B, Bored of Knowledge? Todays post is about data analysis, and how it can send you down the garden path

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    3. Bored of B-cells? Then how bored could a person be of T-cells? I have visions of a very old man with a long beard, bushy eyebrows, covered in cobwebs and dust, hunched over musty books on a desk, listening to a stuck record on an ancient gramaphone - a recording of a voice droning "T-cells! T-cells! T-cells!"

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  3. Prof G,

    The researchers keep identifying potential remyelination agents, but they never get to patients. I was so hopeful 5-6 years ago e.g. Anti-Lingo antibody, but the trials never deliver the hype when the agent is first identified. The same goes for neuro-protective agents. I can't see any re-myelination or neuro-protective treatments that will be prescribable for patients. Am I right to feel so pessimistic?

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  4. "How are we as a community going to solve this thorny problem of repurposing off-patent drugs?"

    Do what Biogen did with DMF: patent a new formulation of the drug, e.g. delivered in time-release capsules.

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    1. Ask how much biogen spent doing that....millions and millions, it is a standard drug development pathway once you change it.

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    2. No pain, no gain. And there wasn't even very much pain (other than, perhaps, concern about whether their patent would hold up). They already had tons of safety data from fumaderm patients, and efficacy data from those patients who happened to have MS. And there's been a lot of gain, obviously.

      This is not a simple undertaking, but it seems strictly better from a money-making perspective than developing an entirely new drug.

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  5. I concur with bored of B cells above. Team G produces one decent paper and Mouse is like a kid in a sweetshop. Don't forget that Prof G, Welsh Mouse and heavy metal mouse have over a century of research between them. Is one paper on B cells really a good return? I don't want to rain on your parade, but you guys aren't worthy to wash Prof Coles's underpants! Enjoy your 15 mins of fame and milk your time in the spotlight. However, I will eat some humble pie and admit that you guys have come good (I didn't think you could organise a piss-up in a brewery). Don't live on your laurels and fall back into you old ways (Welsh and heavy metal mice spending too long in the local boozer, Prof G counting all his air miles and dreaming of his pampered life in pre-Mandella South Africa).

    Well done Team G - keep up the good work.


    Headmaster, Angry of Tunbridge Wells etc.

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    1. Thanks for the praise, grudging though it may be, a quick shufty at PubMed and my Hirsch Index reassures me we haven't been wasting our collective time.
      Yet more to come soon that hopefully will meet with your approval.
      I hope the good Dr Coles's underpants won't need the laundry after he's read the alemtuzumab paper ;-)

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    2. Actually please note two good papers this week

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    3. Indeed though for number 2 you should have let me proof-read the title ;-)

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    4. "you guys aren't worthy to wash Prof Coles's underpants!"

      You need to ask yourself why you visit this site and bother to comment. I put it to you that you might find something more fulfilling and constructive to do.

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    5. Would be nice to keep the discussion civil. We are all trying to do the same thing. Improve the lives of pwMS and prevent the disease.

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    6. Re the Number 2

      I didn't do it (proof Read), but DrK is German and I'm sure I would make a few spelling mistakes (it wasn't the original title indeed for the JAMA paper the title and figures and text were changed by the journal), if I wrote papers in German but you (MD2) have been nominated as official TeamG proof reader....in fact this happened a few days ago.

      P.S. MD2 has done this job for me for years, as you know I can't spell for toffee so when you see the state of the spellin in papers just imagine what they were like before...

      "You don't have too" you say "you have read my blog posts;-(

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  6. Paul Simon has a recent hit?

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    1. Maybe not; I am a big Paul Simon fan. His last album was very good, but I would agree may be not in the same league as Graceland.

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  7. Where there is a will there is a way. Is there any way of the MS community doing a Seroquel trial quickly using social media? Similar to what PatientsLikeMe did with lithium and Lou Gehrig's disease?

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  8. I'd rather take simvastatin over seroquel. Re: easy trials.... apparently Michael Gove has got it sorted, maybe hashtag him in in (lol).?

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  9. Interesting posts thank you for sharing your knowledge and research. From a person who has been dealing with MS since 1986 and just went on a dmd 2 years ago. Never on steroids never hospitalized.. Work full time and take a pittance of seroquel 12.5 mg q HS. Can't say it's re-myelinated anything since the amount I take is so low. I have declined but it's 30 years later.

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  10. Oh yes, because the one thing that the MS world needs is a seroquel type disaster................... (there haven't been MS world med disasters, we need to grab some from psychiatry??)

    http://www.abc.net.au/news/2013-11-27/growing-concerns-over-side-effects-of-seroquel/5120554

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  11. The "growing concerns" article referenced above is a bit scary. Here's a quote where Heidi Everett, a musician on three times the recommended dose of the drug (why?) describes its effects "what happens on Seroquel is that it freezes your muscles and shuts your muscle system down. So, it's really hard to walk. And when I did walk I had no control over my ability to stop walking, so I walked into walls." Maybe not such a good drug for remylination for pwMS? I'll stick with Clemastine, common side effects listed as drowsiness, dizziness, headache, constipation, stomach upset, blurred vision, trouble walking/clumsiness, or dry mouth/nose/throat (but they may all decrease as your body gets used to the drug).

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  12. Blimey is there not just a simpler offering lurking somewhere?

    How about cannabis (oil or whatever)? Oh yes of course it is still illegal thanks to GW and their corrupt Tory cronies in government.

    What about a synthetic version then - I thought Barts MS team was working on this, but it is hardly ever mentioned?

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    1. Watch this space, our paper to be published very soon.

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