Levetiracetam (Keppra) Worked for My Hyperacusis
- Thread starter Danny Boy
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SV2A, a membrane glycoprotein present in the synaptic vesicles of neurons and the secretory vesicles of endocrine cells [30], is believed to be present in virtually all neurons of vertebrates. SV2A has a structure that is homologous to bacterial and eukaryotic transporters; however, a transport function of SV2A has not been demonstrated. Various hypotheses have been advanced for the function of SV2A, such as trapping soluble neurotransmitter molecules, diminishing intravesicular osmotic pressure, modifying synaptic vesicle exocytosis by binding to synaptotagmin I, and serving as a scaffold protein to regulate vesicle shape or participate in vesicle trafficking [31]. None of these proposed mechanisms have been verified. Recently, Custer et al. [32•] have proposed that SV2A is a positive modulator of low-frequency synaptic transmission that may act by preparing vesicles for fusion. These authors found a reduction in excitatory synaptic potential responses in hippocampal neuron cultures from mice in which SV2A had been deleted by gene targeting. The reduction was restricted to low-frequency trains of stimuli or to the initial synaptic responses to trains, and appeared to be due to a smaller, readily releasable pool of vesicles, leading to a reduction in initial release probability. Synapses were morphologically normal and there was no change in the number of docked vesicles. This led the authors to conclude that SV2A does not influence docking but rather has a role in facilitating "priming" (the events that render docked vesicles competent for calcium-triggered fusion). It is not apparent how functional alterations in the activity of SV2A and the resultant effects on vesicle dynamics might influence epileptic excitability. However, SV2A knockout mice develop severe seizures and die within the first weeks of life [33]. Heterozygous animals do not show spontaneous seizures, but they do exhibit enhanced seizure susceptibility [34]. Thus, there is a link between SV2A and epilepsy, although the physiologic basis remains to be elucidated. Although its functional role is not well understood, SV2A exhibits two well-accepted interactions with xenobiotics. First, botulinum neurotoxin A binds to SV2A (and its B and C isoforms), which allows the toxin to enter neurons [35]. Second, the AED levetiracetam and its analogs bind to SV2A, and this interaction seems to mediate the anticonvulsant activity of the drugs. In 1995, [3H]levetiracetam was found to exhibit saturable binding to an abundant site in the brain with Kd of 780 nM [36]. Further studies using a higher-affinity analog, UCB 30889, showed that the binding site was SV2A [37]. There was a high correlation between the binding affinities of a series of levetiracetam analogs and their potencies for protection against audiogenic seizures in mice, suggesting that SV2A is the molecular target for anticonvulsant activity. Using this binding assay to screen a library of 12,000 compounds, brivaracetam, the n-propyl analog of levetiracetam, was identified as having 10-fold greater affinity than levetiracetam for sites in brain labeled with [3H]levetiracetam [38]. Brivaracetam was more potent than levetiracetam in several animal seizure models and may have an expanded spectrum of activity. Like levetiracetam, it demonstrates a large separation between the doses conferring seizure protection and acute neurologic impairment. A recent phase 2 clinical trial in 208 patients demonstrated that brivaracetam produced a dose-dependent reduction in the frequency of seizures in adults with refractory partial seizures [39]. Remarkably, brivaracetam had an adverse event profile indistinguishable from placebo. The results of the clinical trial provide ultimate validation of SV2A as an AED target because binding to this site was the initial screen used to select brivaracetam for further development.
Hmm, I'm unable to find the part which tells that levetiracetam and brivaracetam are kv3.1 modulators. Can you be more specific?
Experimental and simulation studies on the mechanisms of levetiracetam-mediated inhibition of delayed-rectifier potassium current (KV3.1): contribution to the firing of action potentials.
Huang CW1, Tsai JJ, Huang CC, Wu SN.
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Abstract
Levetiracetam (LEV) is an S-enantiomer pyrrolidone derivative with established antiepileptic efficacy in generalized epilepsy and partial epilepsy. However, its effects on ion currents and membrane potential remain largely unclear. We investigated the effect of LEV on differentiated NG108-15 neurons. In these cells treated with dibutyryl cyclic AMP, the expression level of the K(V)3.1 mRNA was elevated. With the aid of patch clamp technology, we found that LEV could suppress the amplitude of delayed rectifier K(+) current (I(K(DR))) in a concentration-dependent manner with an IC(50) value of 37 microM. LEV (30 microM) shifted the steady-state activation of I(K(DR)) to a more positive potential by 10 mV, without shifting the steady-state inactivation of I(K(DR)). Neither Na(+), nor erg (ether-a-go-go-related)-mediated K(+) and ATP-sensitive K(+) currents were affected by LEV (100 microM). LEV increased the duration of action potentials in current clamp configuration. Simulation studies in a modified Hodgkin-Huxley neuron and network unraveled that the reduction of slowly inactivating I(K(DR)) resulted in membrane depolarization accompanied by termination of the firing of action potentials in a stochastic manner. Therefore, the inhibitory effects on slowly inactivating I(K(DR)) (K(V)3.1-encoded current) may constitute one of the underlying mechanisms through which LEV affect neuronal activity in vivo.
Dude, I'm not a scientist. What part makes it kv3.1 modulator?
I can google myself but interpreting the text is another thing.
Exactly my point. Recommending max Epilepsy dosage to someone who is trying Keppra for H is irresponsible. As far as i know, no one is a specialist here.
Dude, I'm not a scientist. What part makes it kv3.1 modulator?
I can google myself but interpreting the text is another thing.
It says it, in the title lol
Ok, so you are saying, based on experimental/simulation study, that levetiracetam mediated inhibition in delayed rectifier channel makes it kv3.1 potassium channel modulator?
I hope that science community acknowledges this and defines levetiracetam as kv3.1 modulator
Well, don't think they care.
Look at amitriptyline that drug is crazy...
Amitriptyline acts primarily as a serotonin-norepinephrine reuptake inhibitor, with strong actions on the serotonin transporterand moderate effects on the norepinephrine transporter.[31][32] It has negligible influence on the dopamine transporter and therefore does not affect dopamine reuptake, being nearly 1,000 times weaker on it than on serotonin.[32] It is metabolised tonortriptyline—a more potent and selective norepinephrine reuptake inhibitor—which may complement its effects on norepinephrine reuptake.[3]
Amitriptyline additionally functions as a 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, H1, H2,[33] H4,[34][35] and mACh receptor antagonist, and σ1 receptor agonist.[36][37][38][39] It has also been shown to be a relatively weak NMDA receptornegative allosteric modulator at the same binding site as phencyclidine.[40] Amitriptyline inhibits sodium channels, L-type calcium channels, and Kv1.1, Kv7.2, and Kv7.3 voltage-gated potassium channels, and therefore acts as a sodium, calcium, and potassium channel blocker as well.[41][42]
Recently, amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors.[43] It promotes theheterodimerization of these proteins in the absence of NGF and has potent neurotrophic activity both in-vivo and in-vitro in mouse models.[43][44] These are the same receptors BDNF activates, an endogenous neurotrophin with powerful antidepressant effects, and as such this property may contribute significantly to its therapeutic efficacy against depression. Amitriptyline also acts as a functional inhibitor of acid sphingomyelinase.
- Dec 24, 2013
- 933
- Tinnitus Since
- (1956) > 1980 > 2006 > 2012 > (2015)
- Cause of Tinnitus
- Ac. Trauma & Ac.Trauma + Meds.
Hey folks... Short story is, that the Huang study (2009) is the only reference I could find to any form of ion-gated Potassium channel action, (Danny's post # 516 above: http://www.ncbi.nlm.nih.gov/pubmed/20065495) ...and I think it is basically semi 'bosh'... Or at minimum unsubstantiated by any further and more updated research that is much more exhaustive. Re-read the last sentence of that synopsis too!
Basically, it is just more of the "we don't know WTF is really going on" conclusions that most of these studies are saying between the lines re most of these 'new' AEDs (anti-epileptic drugs).
Sv2A, Ca+, Na+, K+, GABA, NMDA, AMPA...etc. They are all interweaving in this possible T Tango. Pick your favorite dancer and go for a whirl.
Last up... @Danny Boy, just in case anyone thinks I am getting on your wick here because I am "questioning" a number of these drugs you have invested a lot of time in bringing to our attention...that is not my purpose or intent!
I am in fact grateful and impressed that you are least uncovering some new "pharma rocks" to look under in relation to T and 'neurological excitation', etc., etc. as I for one think that it is our best future hope for a least invasive "fix". (Like compared to the Genvec stuff etc. and cutting your cochlea open, etc.). For me, with such shall we say "entrenched" T and H, the vast majority of other aspects for T 'help and habituation' etc. are 'irrelevant'. Been there, done that...for decades.
Think I am about done with this subject for now... A bit 'disappointing' to say the least. However, I think anyone who has intransigent/un-dissipating H should at least give Keppra a go, as it is one of the least potentially harmful candidates in the cosmic crap shoot of "choices" that may help - and has helped some folks!
Good luck... Zimichael
Basically, it is just more of the "we don't know WTF is really going on" conclusions that most of these studies are saying between the lines re most of these 'new' AEDs (anti-epileptic drugs).
Sv2A, Ca+, Na+, K+, GABA, NMDA, AMPA...etc. They are all interweaving in this possible T Tango. Pick your favorite dancer and go for a whirl.
Last up... @Danny Boy, just in case anyone thinks I am getting on your wick here because I am "questioning" a number of these drugs you have invested a lot of time in bringing to our attention...that is not my purpose or intent!
I am in fact grateful and impressed that you are least uncovering some new "pharma rocks" to look under in relation to T and 'neurological excitation', etc., etc. as I for one think that it is our best future hope for a least invasive "fix". (Like compared to the Genvec stuff etc. and cutting your cochlea open, etc.). For me, with such shall we say "entrenched" T and H, the vast majority of other aspects for T 'help and habituation' etc. are 'irrelevant'. Been there, done that...for decades.
Think I am about done with this subject for now... A bit 'disappointing' to say the least. However, I think anyone who has intransigent/un-dissipating H should at least give Keppra a go, as it is one of the least potentially harmful candidates in the cosmic crap shoot of "choices" that may help - and has helped some folks!
Good luck... Zimichael
That's okay. I am just bringing more and more drugs to our attention and it's our job to try them and see if it works. I mean, epileptic drugs seem to work for tinnitus and to be honest, our understanding on what these drugs can do for tinnitus isn't as known as we'd like. I am just trying to bring things forward to prevent people from giving up.
Well, because of false information I almost gave up with AUT00063. This was because "somebody" told that Levetiracetam is Kv3.1 modulator (like Aut00063) and many people who has tested it, reported, that it didn't affect their T.
Well now when we got the facts right, thanks to Zimichael and we can say that levetiracetam (or brivaracetam) are not kv3.1 modulators which is good because we cant draw any correlation between LEV, BRIV and AUT00063.
Btw, this is from the UCB website who developed Brivaracetam:
Brivaracetam (UCB34714) is a novel high-affinity synaptic vesicle protein 2A (SV2A) ligand.
They also don't say keppra is a KV3.1 modulator. Anyway, nobody has said keppra works for tinnitus? I'm saying it works for hyperacusis. Keppra has an unknown mechanism and nobody knows what it is. We won't know if Brivatacetam will work for hyperacusis or tinnitus until somebody tries it. Autifony works directly on KV3.1 so don't know why you would give up on it?
As we say in Finland: "Ill' try to twist this from iron wire for you"
- You keep saying that Keppra is Kv3.1 modulator, which it apparently isn't
- Any smart person can draw some conclusions that if some drug, which is said to be kv3.1 modulator, doesn't work on T - there is a great chance that none of them works on T (this is why I almost gave up on AUT00063).
Again, I'm saying that check your facts Mr. "I just want to help" that you don't mislead people. And we all do mistakes but you are the one who lives in denial after making one. To be honest, this forum seems to be some kind of social playground for you to gain some kind of social status in a way or on another.
Ok then? Well, if you can prove that Keppra has no action inadvertently on the KV3.1 channels and you need to remember potency factors in. Then be my guest. Anyway, I agree it may not modulate the channel, it could block them, it could do a number of things. Hence the experimental part. Remember dearly, potency is key. It may not be potent enough to work for tinnitus. Then again, some people post that it helps with tinnitus. So really nobody has any clue.
Also, I am not in denial at all? Keppra is working for people now and is getting good news. And personal attacks aren't nice at all. I don't attack you and accuse you. Social status, seriously!? Haha.
Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action?
Abstract
Levetiracetam (ucb L059; Keppra™) is a novel antiepileptic drug. Its effects on action potential generation and voltage-operated potassium currents were studied in acutely isolated hippocampal CA1 neurones from rat and guinea pig, using the patch-clamp technique in the whole-cell configuration. (i) Levetiracetam reduced repetitive action potential generation and affected the single action potential. Levetiracetam, 100 μM, decreased the total number of action potentials and reduced the total depolarisation area of repetitive action potentials by 21%. Furthermore, levetiracetam increased the duration of the first action potential slightly, prolonged that of the second action potential by 13% and decreased the slope of rise by 23%. (ii) Levetiracetam decreased the voltage-operated potassium current. Without effect on sodium and A-type potassium currents, levetiracetam, 100 μM, reduced the delayed rectifier current by 26%. The concentration of half-maximal block was 47 μM for guinea pig and 6 μM for rat neurones. Thus, the reduction of repetitive action potential generation by levetiracetam can be attributed, unexpectedly, to a moderate reduction of the delayed rectifier potassium current, as supported by a simulation of action potential generation. This suggests that a reduction of potassium currents may contribute to the antiepileptic effect(s) of levetiracetam.
i have 1000mg pills of keppra but want to start slow.. can i break that baby into 4 pieces or is that just too much, i know u can split it in 2 but idk about 4pieces =around 250mg each????
Ok, been off of Keppra for about a week. Lately my good ear was hit by otitis, waiting for it to heal, I've been taking antibiotics and ear drops. Nice uh?
I decided to quit Keppra because my results was inconclusive. And, lately it gave me some libido problems. So, I would suggest caution. There may be a workaround this, if anyone get similar problems, my doc suggested one, you do some blood tests and there is another med for this. But I decided to quit it anyway, since I really could not tell for sure if Keppra helps. Did not want to take another med along with Keppra, so I decided the clean way out...
I decided to quit Keppra because my results was inconclusive. And, lately it gave me some libido problems. So, I would suggest caution. There may be a workaround this, if anyone get similar problems, my doc suggested one, you do some blood tests and there is another med for this. But I decided to quit it anyway, since I really could not tell for sure if Keppra helps. Did not want to take another med along with Keppra, so I decided the clean way out...
A Keppra update for anyone interested . . .
The side effects became too intolerable for me to continue on the dose I was taking of Keppra. I suspected dose accumulation, so I decreased from 250 mg. BID, to 125 mg. in the AM and 250 mg. in the PM. Still bad side effects . . . So I decreased to 125 mg. PM only. I have now been on 125 mg. once a day for three days, and I notice my hyperacusis is getting bad again. Wadding up paper is, once again, painful . . . Argh!
There is good news and bad news here:
1) Bad news is that Keppra is not the "wonder drug" I had hoped it would be (for me, anyway).
2) Good news is that if one can tolerate Keppra without side effects, it may be a good drug (for some) with hyperacusis.
I agree with @skoupidis that I did not want to keep adding more drugs, and as he suggests, use caution. I also agree with @Zimichael that it is a bit "disappointing."
A question remains . . . I have not noticed any females on this forum using Keppra (or using Trobalt for that matter). Are only males trying these drugs? Or am I missing something here? It is becoming more apparent that females respond differently to (some) drugs than do males, as demonstrated by the low dose aspirin studies for heart attack prevention, for example. Which again leads to the subject of "size matters" . . . As do other physiological factors . . .
I plan to do three more days of Keppra at 125 mg. per day and then quit altogether. For those who can tolerate Keppra without side effects, it is definitely worth a try for unrelenting hyperacusis. Thanks to everyone who has tried it and reported the results here. In the meantime, for me, out come the paper plates again . . . Sigh!!!
The side effects became too intolerable for me to continue on the dose I was taking of Keppra. I suspected dose accumulation, so I decreased from 250 mg. BID, to 125 mg. in the AM and 250 mg. in the PM. Still bad side effects . . . So I decreased to 125 mg. PM only. I have now been on 125 mg. once a day for three days, and I notice my hyperacusis is getting bad again. Wadding up paper is, once again, painful . . . Argh!
There is good news and bad news here:
1) Bad news is that Keppra is not the "wonder drug" I had hoped it would be (for me, anyway).
2) Good news is that if one can tolerate Keppra without side effects, it may be a good drug (for some) with hyperacusis.
I agree with @skoupidis that I did not want to keep adding more drugs, and as he suggests, use caution. I also agree with @Zimichael that it is a bit "disappointing."
A question remains . . . I have not noticed any females on this forum using Keppra (or using Trobalt for that matter). Are only males trying these drugs? Or am I missing something here? It is becoming more apparent that females respond differently to (some) drugs than do males, as demonstrated by the low dose aspirin studies for heart attack prevention, for example. Which again leads to the subject of "size matters" . . . As do other physiological factors . . .
I plan to do three more days of Keppra at 125 mg. per day and then quit altogether. For those who can tolerate Keppra without side effects, it is definitely worth a try for unrelenting hyperacusis. Thanks to everyone who has tried it and reported the results here. In the meantime, for me, out come the paper plates again . . . Sigh!!!
- Dec 24, 2013
- 933
- Tinnitus Since
- (1956) > 1980 > 2006 > 2012 > (2015)
- Cause of Tinnitus
- Ac. Trauma & Ac.Trauma + Meds.
@lapidus ...Sorry if I did not make that clear.
Yes I am still on 250 mg BID = Total 500 mg total per day. Take morning and evening about 12 hours apart. May just continue for the hell of it and finish up my pills and do not seem to have any noticeable side effects...well except for "disappointment" I guess. Which can be a really big side effect in it's own right. As @svintegrity knows..."I feel her pain"...especially if it 'worked' for her by dint of increasing return of H after dropping dose, etc., etc.
Incidentally. For those who bothered to read my 'science' stuff in prior posts in this thread...I think "Dose" is mostly/often overrated. Sort of a very 'human thing' maybe of: "If some is good, more is better!" Anyone who has had a serious hangover the day after knows the fallacy of that argument.
Remember too, that nearly all the drugs we experiment with here for T/H are 'trialed' for other health conditions - epilepsy, anxiety, depression, whatever.
Effective dose for off label use = TINNITUS, or Hyperacusis, is what works for you! Period...Unless "drug X" has sound bio-chemical/pharmacodynamic substantiation implying otherwise. Hell, they started AUT00063 smack on "full dose" for a reason.
Ultimately with the little 'we' know about the Kv drugs (Tobalt/Retigabine; seemingly AUT00063; probably SF0034; other AED's = anti-epileptic drugs)...Dose does seem to matter. But Keppra not being a primary Kv modulator (in my opinion) makes the "dose" argument for it more "open to question".
Look at @svintegrity struggling at 250 mg...yet I hardly felt a thing with a fast taper up to 2,000 mg.
Only way to know dose is...TRY IT! (Yes, especially more women).
Good luck... Zimichael
@svintegrity
there ist at least one female here, who has really bad T and is trying Trobalt soon.
Im not gonna give away username tho.
There was also Lynn, who wanted to try out keppra really bad...I dont know if shes still on this board.
there ist at least one female here, who has really bad T and is trying Trobalt soon.
Im not gonna give away username tho.
There was also Lynn, who wanted to try out keppra really bad...I dont know if shes still on this board.
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