@Zimichael The door analogy is too simple. Your potassium channels are not electric doors with a binary on/off condition. They are analog magnetic doors that open at a certain voltage threshold. Retigabine lowers that threshold so they tend to open more often. They haven't been jammed shut the whole time you've had tinnitus, they've just had a higher threshold, so open less often than they should.
And retigabine doesn't need to affect Kv3 channels to affect tinnitus. Kv7.4, aka KCNQ4, is important in the cochlea and auditory system All these channels work together in the neuron. We don't know exactly why Autifony has targeted Kv3.1. Modulating Kv3.1 may be a faster and more efficient way of stabilizing the resting potential, or it may simply be that Kv7 channels are harder to isolate.
Going with a one-time big dose is a terrible, possible fatal idea. The brain needs time to adjust, not just to the side effects but to the intended effects of the drug. Your brain is already regulating the activity of your KCNQ channels. If you attack those channels with a mega-dose, it could induce seizures or who knows what else. Remember that of the "Gang of Four", KCNQ4 is the only one we want to regulate, but retigabine doesn't let us that precision. It will affect KCNQ2, 3, and 5 just as powerfully. KCNQ2 and 3 regulate general excitability in the brain, and KCNQ5 is expressed both inside the brain and in skeletal muscle - possibly why retigabine induces gait changes.
Remember that retigabine is only viable at all because it doesn't stimulate Kv7.1. If it did, it would affect your heart, and not in a good way.
AUT00063 is (theoretically) safer at high doses because it (theoretically) only affects the single voltage-gated potassium channel, which (theoretically) is only expressed in the auditory system. That's why you can kick the doors down with an 800mg dose, evidently on day one. Retigabine is a maverick. It kicks too many doors, and some of them are booby trapped. I see why Beryu cautioned us against comparing them.
You have a good plan, I think. Don't let a few setbacks shake you.
And retigabine doesn't need to affect Kv3 channels to affect tinnitus. Kv7.4, aka KCNQ4, is important in the cochlea and auditory system All these channels work together in the neuron. We don't know exactly why Autifony has targeted Kv3.1. Modulating Kv3.1 may be a faster and more efficient way of stabilizing the resting potential, or it may simply be that Kv7 channels are harder to isolate.
Going with a one-time big dose is a terrible, possible fatal idea. The brain needs time to adjust, not just to the side effects but to the intended effects of the drug. Your brain is already regulating the activity of your KCNQ channels. If you attack those channels with a mega-dose, it could induce seizures or who knows what else. Remember that of the "Gang of Four", KCNQ4 is the only one we want to regulate, but retigabine doesn't let us that precision. It will affect KCNQ2, 3, and 5 just as powerfully. KCNQ2 and 3 regulate general excitability in the brain, and KCNQ5 is expressed both inside the brain and in skeletal muscle - possibly why retigabine induces gait changes.
Remember that retigabine is only viable at all because it doesn't stimulate Kv7.1. If it did, it would affect your heart, and not in a good way.
AUT00063 is (theoretically) safer at high doses because it (theoretically) only affects the single voltage-gated potassium channel, which (theoretically) is only expressed in the auditory system. That's why you can kick the doors down with an 800mg dose, evidently on day one. Retigabine is a maverick. It kicks too many doors, and some of them are booby trapped. I see why Beryu cautioned us against comparing them.
You have a good plan, I think. Don't let a few setbacks shake you.
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I haven't even had a chance to review my own notes on it all yet, and for sure know I am playing loose with concepts. However, they help me at least fumble forward. And I hope you are right about Kv doors being 'used less' rather than 'jammed shut', though in the end the proof is always in the pudding...and the Autifony dessert is not looking super edible at the moment. What do they want, "Saint Tinnitus" androids or real live people with T?!
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