Perampanel

Discussion in 'Treatments' started by Danny Boy, Jul 12, 2015.

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    1. Danny Boy
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      Revolutionary new drug set to be available on NHS cuts risk of fatal epileptic seizures
      • Once-a-day pill, costing £5, helps prevent the most dangerous seizures
      • Trial found 23% of those taking it stopped having such seizures completely
      • Epilepsy affects about 600,000 people in the UK and fits can cause serious injury or sudden death



      Epilepsy sufferers have been thrown a lifeline by a revolutionary new drug that can significantly reduce their number of potentially fatal seizures.

      The once-a-day pill, to be available on the NHS, helps prevent the most dangerous seizures, which leave patients unconscious and can lead to serious injury or sudden death.

      The worst affected can have dozens of fits a month, usually without warning, so many are afraid to go out and can’t socialise normally. Some even lose their jobs.

      29265CD100000578-0-image-a-2_1436622193053.jpg

      A revolutionary new drug that can significantly reduce their number of potentially fatal epileptic seizures is to made available on the NHS

      But an international trial of the drug Perampanel found 23 per cent of those taking it stopped having such seizures completely. A further 64 per cent saw seizures cut by more than half.

      The drug will cost the NHS £5 a day per patient – about £1,800 a year.

      Glasgow University’s Professor Martin Brodie, director of the Epilepsy Unit at the city’s Western Infirmary, said: ‘This lets people get on with their lives and relax, without worrying whether the next seizure means breaking bones or ending up in hospital.


      ‘Their quality of life hugely improves. The results from the trial are encouraging, but I would expect the drug to perform even better in the real world, because a wider range of people will have access to it.’

      Epilepsy affects about 600,000 people in the UK.

      The drug is licensed for those with genetic epilepsy (around a third of sufferers) who also experience the most serious seizures, known as primary generalised tonic-clonic, or PGTC.

      These increase the risk of sudden unexplained death in epilepsy, which is linked to some 1,000 deaths in the UK every year. It is estimated that about 91,000 people fall into this category.

      Perampanel, manufactured by Eisai, targets a new mechanism in the brain to prevent cells from becoming overexcited.

      0457084C0000044D-0-image-a-1_1436622165067.jpg

      Epilepsy sufferers can have dozens of fits a month, usually without warning, so many are afraid to go out and can’t socialise normally. Some even lose their jobs

      It has been available for those with partial-onset seizures since 2012, which means that NHS organisations are already able to prescribe it.

      Scott Barclay, 34, from Glasgow, lost his job as a financial adviser after suffering seizures in front of clients.

      He had up to 15 fits a day and ended up in a wheelchair after one left him with a broken back. But since taking Perampanel he averages a seizure a month.

      Mr Barclay said: ‘My life has changed completely. I can go out by myself and be at home by myself, travel and socialise. For the first time, I can be an adult.’
       
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    2. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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      By the way, the cost works out as 150 pound a month, which is cheaper than trobalt (Trobalt costs £159.60 a month for 400mg x84 pills). Gosh, we need to try this...
       
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    3. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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      Perampanel is an anticonvulsant used to treat seizures in adults and children who are at least 12 years old.

      Side-effects:

      • changes in mood, behaviour, or personality;
      • anger, aggression, anxiety, trouble sleeping, feeling hostile or irritable;
      • talking more than usual;
      • unusual thoughts, paranoid behaviour, panic attacks;
      • thoughts about suicide, or thoughts about hurting someone else;
      • trouble walking, loss of balance or coordination;
      • an accidental fall; or
      • severe dizziness, spinning sensation, feeling like you might pass out.

      Common side effects may include:

      • mild dizziness;
      • drowsiness, tiredness;
      • nausea;
      • weight gain; or
      • headache, joint pain, back pain.



      Compared with Trobalt:


      Very common: More than 1 in 10 people who take Trobalt

      • eye colour changes – this may lead to problems with vision. This may happen if Trobalt is taken for a long period of time
      • feeling dizzy
      • skin colour changes including nails or lips – this may happen if Trobalt is taken at a high dose for long period of time
      • sleepiness
      • tiredness
      Common: More than 1 in 100 people who take Trobalt

      • abnormal gait
      • abnormal laboratory test results
      • appetite gain
      • balance problems
      • blood in the urine
      • blurred vision
      • concentration problems
      • confusion
      • constipation
      • coordination problems
      • difficult or painful urination
      • double vision
      • dry mouth
      • feeling anxious
      • feelings of disorientation
      • general feeling of being unwell
      • hallucinations
      • indigestion
      • memory problems
      • muscle twitching
      • nausea
      • oedema of the extremities
      • paraesthesiae
      • psychosis or psychotic-like behaviour
      • speech problems
      • tremors
      • urinary hesitation
      • urine colour changes
      • vertigo
      • weakness
      • weight gain
      Uncommon: More than 1 in 1000 people who take Trobalt

      • increased sweating
      • kidney stones
      • skin rash or rashes
      • slowing or reduction of physical movements
      • swallowing difficulties
      • urinary retention
      The frequency of these side-effects is unknown

      • heart problems
      • may affect the results for certain tests
      • thoughts of committing suicide - seek medical advice if you have thoughts of committing suicide
       
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    4. Rube
      Fine

      Rube Member Benefactor

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      And how do you figure this helps t? Also do you ever sleep mate?
       
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    5. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

      Location:
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      Tinnitus Since:
      7/2014
      Cause of Tinnitus:
      Ear infection
      Perampanel, manufactured by Eisai, targets a new mechanism in the brain to prevent cells from becoming overexcited.

      And tinnitus is what? Hyperactive neurons.
       
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    6. Rube
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      Rube Member Benefactor

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      I didn't realize it was that simple. Well, done mate
       
    7. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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      Well...Why do you think most epileptic drugs work for tinnitus?
       
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    8. Rube
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      Rube Member Benefactor

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      I'm not aware of any that have been properly double blind tested for tinnitus with positive results.
       
    9. Sharpfire
      No Mood

      Sharpfire Member

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      Interesting. Do you know if it's on the market or still in trials?
       
    10. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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      There won't be for this drug, it's new lol
       
    11. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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      Perampanel was granted EU approval in July 2012 and is now available in a number of European countries, including the UK.
       
    12. Rube
      Fine

      Rube Member Benefactor

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      Are you going to try it out? Maybe it's also available in Spain!
       
    13. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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      Lol, I don't know the list of counties...I would love to try it, but no doctor would give it to me...
       
    14. Richard zurowski

      Richard zurowski Member Benefactor

      Location:
      England
      Tinnitus Since:
      27/12/2012
      Cause of Tinnitus:
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      So it's got less side effects then trobalt?
       
    15. Rube
      Fine

      Rube Member Benefactor

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      Nobody knows, nobody even knows if it does anything for t.
       
    16. Xorthian
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      Xorthian Member Benefactor

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      Initial 2012. Massive spike 4/2015
      Cause of Tinnitus:
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    17. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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      Perampanel (INN/USAN, trade name Fycompa) is an antiepilepticdrug developed by Eisai Co. that acts as a selective non-competitive antagonistof AMPA receptors, the major subtype of ionotropic glutamate receptors.[2][3]

      Ion channel function[edit]
      Each AMPAR has four sites to which an agonist (such as glutamate) can bind, one for each subunit.[5] The binding site is believed to be formed by the N-terminal tail and the extracellular loop between transmembrane domains three and four.[16] When an agonist binds, these two loops move towards each other, opening the pore. The channel opens when two sites are occupied,[17]and increases its current as more binding sites are occupied.[18] Once open, the channel may undergo rapid desensitization, stopping the current. The mechanism of desensitization is believed to be due to a small change in angle of one of the parts of the binding site, closing the pore.[19] AMPARs open and close quickly [how quickly ?], and are thus responsible for most of the fast excitatory synaptic transmission in the central nervous system.[17] The AMPAR's permeability to calcium and other cations, such as sodium and potassium, is governed by the GluR2 subunit. If an AMPAR lacks a GluR2 subunit, then it will be permeable to sodium, potassium, and calcium. The presence of a GluR2 subunit will almost always render the channel impermeable to calcium. This is determined by post-transcriptional modification — RNA editing — of the Q-to-R editing site of the GluR2 mRNA. Here, A→I editing alters the uncharged amino acid glutamine (Q) to the positively charged arginine (R) in the receptor's ion channel. The positively charged amino acid at the critical point makes it energetically unfavourable for calcium to enter the cell through the pore. Almost all of the GluR2 subunits in CNS are edited to the GluR2(R) form. This means that the principal ions gated by AMPARs are sodium and potassium, distinguishing AMPARs fromNMDA receptors (the other main ionotropic glutamate receptors in the brain), which also permit calcium influx. Both AMPA and NMDA receptors, however, have an equilibrium potential near 0 mV. The prevention of calcium entry into the cell on activation of GluR2-containing AMPARs is proposed to guard against excitotoxicity.[20]

      The subunit composition of the AMPAR is also important for the way this receptor is modulated. If an AMPAR lacks GluR2 subunits, then it is susceptible to being blocked in a voltage-dependent manner by a class of molecules called polyamines. Thus, when the neuron is at a depolarized membrane potential, polyamines will block the AMPAR channel more strongly, preventing the flux of potassium ions through the channel pore. GluR2-lacking AMPARs are, thus, said to have an inwardly rectifying I/V curve, which means that they pass less outward current than inward current.

      Alongside RNA editing, alternative splicing allows a range of functional AMPA receptor subunits beyond what is encoded in the genome. In other words, although one gene (GRIA1GRIA4) is encoded for each subunit (GluR1–GluR4), splicing after transcription from DNA allows some exons to be translated interchangeably, leading to several functionally different subunits from each gene.

      The flip/flop sequence is one such interchangeable exon. A 38-amino acid sequence found prior to (i.e., before the N-terminus of) the fourth membranous domain in all four AMPAR subunits, it determines the speed of desensitisation[21] of the receptor and also the speed at which the receptor is resensitised[22] and the rate of channel closing.[23] The flip form is present in prenatal AMPA receptors and gives a sustained current in response to glutamate activation.[24]


      In the DCN, ultrastructure studies have observed a redistribution of AMPARs in fusiform cells not only at AN synapses, where there is decreased peripheral input, but also at parallel fiber (PF) synapses, which does not receive direct auditory input (183). Functionally, acoustic damage is not only associated with increased rate-level functions in the DCN but also a conversion of PF-mediated suppression of fusiform cells to excitation (67). These studies suggest that the loss of auditory input may indeed result in neuron-wide changes in synaptic function that is indicative of homeostatic synaptic scaling. Moreover, these results are interesting in context of somatic modulation of tinnitus (259, 260), as PF input to the DCN is the first site of somatosensory and auditory stimulus convergence.

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208401/



      Post-synaptic neuronal plasticity can be induced by changes in the expression and trafficking of glutamate receptors AMPAR. AMPAR are multimers composed of various subunits, quantity, and ratio of which influences the synaptic strength. The mechanism that mediates HPA-induced changes in AMPA receptors trafficking is attributed to the genomic and non-genomic effects of glucocorticoids (Figure (Figure4).4). In the prefrontal cortex, stress has been demonstrated to activate in a non-genomic way the glucocorticoid-inducible kinase SGK (Popoli et al., 2011). SGK1 is also expressed in stria vascularis, spiral ligament, spiral limbus, organ of Corti, Reissner's membrane and in the spiral ganglion of rats (Zhong and Liu, 2009) but role of SGK1 in the inner ear has not yet been experimentally addressed. The rapid, non-genomic effects of stress are attributed to the presence of mineralcorticoid receptor (Karst et al., 2005; Groeneweg et al., 2012), which is also expressed in the cochlea (Furuta et al., 1994; Yao and Rarey, 1996).

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371598/
       
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    18. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

      Location:
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      Cause of Tinnitus:
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      I posted the side-effects and compared them with trobalt it's in a post above.
       
    19. Christian78
      Alone

      Christian78 Member

      Location:
      Gothenburg
      Tinnitus Since:
      (Sep 2013)
      Cause of Tinnitus:
      progressive tinnitus, time of expiring in next 3-6 months
      we, you meant YOU :p

      yes you did, still you did not post that this drug has nothing to do with calcium channel modulators
       
    20. Xorthian
      Balanced

      Xorthian Member Benefactor

      Location:
      Poland
      Tinnitus Since:
      Initial 2012. Massive spike 4/2015
      Cause of Tinnitus:
      Noisey Lifestyle. Increase from infection.
      Well its not available in poland so i'm not going to test it.

      Damn :/
       
    21. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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      Perampanel is a new and unique seizure medication that blocks the action of glutamate at AMPA receptors in the brain. Glutamate affects how electrical activity is spread in the brain. It is believed that perampanel helps to reduce seizures by blocking this electrical spread, although the full details are not clear.
       
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    22. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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    23. Martin69
      Artistic

      Martin69 Member Benefactor

      Location:
      Germany
      Tinnitus Since:
      10/2013
      Cause of Tinnitus:
      (Health) Anxiety
      Was taken from German market in 2013.
      Same reason as with Trobalt: No real benefit was seen compared with placebo.
      Therefore, health insurance companies do not pay.
      We are talking about treating epilepsy, not T.

      We have 600,000 epilepsy patients in Germany, so this is a huge market.
      And hopefully by coincidence, a T drug will be found.
       
    24. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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      That's the same amount of severe tinnitus sufferers in the UK.
       
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    25. Danny Boy
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      Danny Boy Member Benefactor Hall of Fame

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      Come on people...A safe drug which may help with tinnitus?
       
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    26. grate_biff
      No Mood

      grate_biff Member

      Location:
      Oslo, Norway
      Tinnitus Since:
      09/2014
      Cause of Tinnitus:
      aucustic trauma, benzo withdrawl or both
      Would be awsome:)
       
    27. Zimichael

      Zimichael Member Benefactor

      Location:
      N. California
      Tinnitus Since:
      (1956) > 1980 > 2006 > 2012 > (2015)
      Cause of Tinnitus:
      Ac. Trauma & Ac.Trauma + Meds.
      Anyone taking this stuff yet???

      Here is the USA main link: https://www.fycompa.com/hcp/about-fycompa

      Geeezuz...Take your darn pick about which of all our old synaptic or post synaptic gates/doors/entries/whatever could be the "one that rules them all" for Tinnitus! Now we have AMPA receptors in the mix...Sort of a long way from the Kv locations at the start of the axonal freeway ramp! God knows...T = Frustrationville to the power of n.


      2015-07-27_1006.png
       
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    28. Twitch

      Twitch Member

      Location:
      Earth
      Tinnitus Since:
      2014
      Cause of Tinnitus:
      Unknown
    29. Zimichael

      Zimichael Member Benefactor

      Location:
      N. California
      Tinnitus Since:
      (1956) > 1980 > 2006 > 2012 > (2015)
      Cause of Tinnitus:
      Ac. Trauma & Ac.Trauma + Meds.
      Danny ref your post above... As usual we are not going to know shit until people actually try his stuff. As per some our TT based prior theorizations (like c/o magnificent, but long vaporized Benryu)...a la "Kv model" we actually want more flux of potassium ions outward (to thus "unstick the gates") to rectify the potential T screw up. Mmmmm...

      Thus, when the neuron is at a depolarized membrane potential, polyamines will block the AMPAR channel more strongly, preventing the flux of potassium ions through the channel pore. GluR2-lacking AMPARs are, thus, said to have an inwardly rectifying I/V curve, which means that they pass less outward current than inward current.

      And with this below...the Glutamate aspect as far as I recall, all hinged around "initial damage excitation" of Glutamate induction, with who-the-hell-knows about later in time effects. (Like is the "evil Glutamate" still screwing us over years later, or did it just cause the onset damage that then kept going c/o other "stuck" modulation functions???).
      However, there could be an implication here for potential "acute" treatment for T that could shunt off the initial Glutamate induced carnage...perhaps?!

      In the DCN, ultrastructure studies have observed a redistribution of AMPARs in fusiform cells not only at AN synapses, where there is decreased peripheral input, but also at parallel fiber (PF) synapses, which does not receive direct auditory input (183). Functionally, acoustic damage is not only associated with increased rate-level functions in the DCN but also a conversion of PF-mediated suppression of fusiform cells to excitation (67). These studies suggest that the loss of auditory input may indeed result in neuron-wide changes in synaptic function that is indicative of homeostatic synaptic scaling. Moreover, these results are interesting in context of somatic modulation of tinnitus (259, 260), as PF input to the DCN is the first site of somatosensory and auditory stimulus convergence.

      And for sure, good liver and gut functions would seem to be a requirement...Ooooops on the "gut" part for me maybe. 105 hours half life...Wow!
      Perampanel has a prolonged terminal half-life in humans of approximately 105 hours. The drug is 95% bound to plasma protein. Its primary route of metabolism is by CYP3A4

      I suspect we will know a lot more on this drug and T in 3 to 5 years.

      best, Zimichael
       
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    30. Nucleo

      Nucleo Member Benefactor

      Tinnitus Since:
      02/2011
      So it would appear modulation of tinnitus by jaw or neck movements could very well be a symptom of damaged hearing, or more specifically ''decreased peripheral input'' as they put it. Damn you homeostasis.
       

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