Potiga/Retigabine review notes - August 31st 2013
OK, I want to start with a 'warning and disclaimer/explanation' here.
LPA!!! = LONG POST ALERT!!! (But a helluva lot shorter than it could be!)
This post is just a somewhat cavalier
summary of some of my conclusions, observations, wonderings, outright confusion, amazement, cautions and general recognition of my ignorance, in relation to Retigabine = Potiga (in USA and Canada) = Trobalt in the civilized world.
I have been perusing a lot of documentation to get a better handle on this drug and understand the risks as well as how it works. I have
never, in all my years, scrutinized a drug as thoroughly as this. Yet I must admit, that there are indeed some definite outstanding (as in "we have no idea yet!") issues with it. Perhaps you will see that as you go along for the ride…if you go along!
So if I haven't scared you off yet, here's my conclusory killer app. for the really impatient…
I am going to take this drug asap if Autifony does not pull wick and announce their Phase II guidelines this week.
Alright…there you go. Now I can concentrate on the die-hards who are into the meat and potatoes of this thread and med. The rest is for you.
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As I said, this is a SUMMARY! It is by no means complete. It is by no means objective…in fact it's massively subjective, as I only go into aspects or sections that interested or concerned me. I am hoping some of you will pull it to pieces and kick it around the block. Add to it. Agree with it. Whatever…Ultimately I hope it will be helpful.
I have "uploaded" (if it works as Markku says)…my two Word documents wherein I took my notes, cuts and pastes, and so forth from the pertinent original source material. That is where you will find
my extracted details of what I present in brief below. These are just my notes OK, though they cover a number of the areas we have been thrashing around on this thread since day one, plus some cool details on what our great Oracle (
@benryu), and others, have been teaching us. Where you see an * and italics, that's me = my wise-arse comment or whatever. [Ahaaa...I think they up-booted to the bottom of this post. Super!]
Below, I will try and make sure that I put extracts and quotes from sources in a different
font colour so that they stand out a bit from the font I am using here. I don't want to italicize as it may get confusing.
The Australian Public Assessment Report of October 2013 (which kicked into the thread a few times early on, but a bear to read) is
the definitive article/source/document on Retigabine IMHO. This AUS report is where I got most of my detail, though splashed around elsewhere as you will see if you read the docs.
Speaking of which, it is somewhat intriguing that the Aussies have still not put the stuff on the market according to our 'down under' friends. They write Tablet of Moses on the stuff yet hold the release??? Veeeery interesting, as Shultz used to say. (You have to have been around in the 50's). Also what is interesting is that of the three main, up front uber warnings on the FDA sheet that jazz posted a long time ago, only the second one – urinary retention, is given any significant play in the AUS Report. This is weird to me, as the whole vision thing and pigmentation thing is basically ignored, yet the AUS Report is dated October, 2013!!! This is all they give us more or less:
Following completion of the clinical evaluation report, the sponsor advised of additional safety issues of discolouration of the nails, skin and mucosal surfaces and an isolated case of retinal pigmentation.
What happened??? Why so little??? I mean dig this below from May 10th 2013…
http://www.medscape.com/viewarticle/803825
A Startling New Side Effect
The US Food and Drug Administration (FDA) issued a drug safety communication[1]on April 26, 2013, alerting the medical community that ezogabine (Potiga™; GlaxoSmithKline, Research Triangle Park, North Carolina), one of the newest antiepileptic drugs, may cause blue-gray skin discoloration and retinal pigment changes.
Incidentally, if you get kicked out of this link or unable to open it because it asks for a login, clear your cache and cookies and you should be able to access it. This may work with other "no access" sites too. You get one look then 'fired'.
And then stuff like this (check the dates!)…
https://www.epilepsy.org.uk/news/news/trobalt-warning-effects-skin-and-eyes [05/09/2013]
Extract… Trobalt is manufactured by GlaxoSmithKline, which is now working with the FDA on gathering information on these side-effects. Speaking to the press, a spokesperson from GSK said: "Patient safety is GSK's top priority, which is why we continue to monitor patients who participated in our clinical trials after the medicine has been approved by regulators.
"In the case of retigabine, we became aware that after prolonged treatment (generally more than two years) some of these patients have developed a blue-grey discolouration of the nails, lips, skin and in some cases, eye tissues.
"We have informed the regulatory authorities about this and are working with them to update the medicine's labeling and develop an associated communication to healthcare providers."
Anyway, I suggest everyone go back and look at page 1 of this Retigabine thread and re-familiarize yourselves with the basic warnings that came out back then. It's easy to lose sight of them in the "Kudzu" growth speed of all this.
This (c/o jazz) is I believe release dated in April, 2013 (though the FDA sheet it says Nov. 6th 2013)
http://www.fda.gov/downloads/Drugs/DrugSafety/UCM259619.pdf
SO YEAH, DO THE EYE EXAM THING AND BE AWARE OF ANY CHANGES IN VISION AFTER A LIKLEY BLURRING INITIALLY THAT SHOULD GO AWAY QUICKLY.
Pill splitting! Check this out...
Immediate release, film coated tablets in a wide range of strengths are proposed: 50, 100, 200, 300 and 400 mg. These are all made from a common granulate using conventional excipients (which are unlikely to react with the nucleophilic drug). The five strengths are distinguished by tablet markings, colour and/or shape. The proposed tablets are not scored.
Retigabine is taken orally in three divided doses each day, with or without food. "The tablets should be swallowed whole, and not chewed, crushed or divided." Doses are titrated.
Ahhhh, so tell me. If this is a "common granulate" why the hell should it not be divided??? If we are talking $$$ and titration, it is a helluva lot cheaper to use 100 mg tablets and cut them than 50 mg tablets. Sure is what I intend to do.
Now the other issue here is that these are obviously not "time release" either, so the TID ~ three times a day aspect is implying an effort to keep plasma levels of the drug fairly constant.
http://www.ncbi.nlm.nih.gov/pubmed/23342983 The median half life is supposedly 6-8 hours, so with my plan to titrate up super slow I am going to have issues with plasma levels if I don't do a three times a day regime. Ummmmmmm…well, I will have to think about that.
The urinary retention issue comes up and seems to be one of the few "Uh-oh" aspects in our current guinea pig heroes. Well this explains why:
KCNQ1 subunits are predominantly expressed in the heart and vasculature, cochlea, intestine and kidney. KCNQ subunits 2-5 are predominantly expressed in the nervous system, although they have also been localised to vascular smooth muscle, and a study by the sponsor demonstrated expression of KCNQ1, KCNQ3, and KCNQ5 subunits in rat urinary bladder smooth muscle cells. In addition, a functional study indicates that (as yet unidentified) KCNQ subunits are expressed in gall bladder smooth muscle. KCNQ5 also shows widespread expression in the CNS, often co localised with KCNQ2 and 3.
Our old friend GABA and the Benzo's question! They consider it a "non issue"…
Non KCNQ effects of retigabine
The anticonvulsant activity of retigabine may also involve potentiation of GABAergic inhibitory neurotransmission, although results have been somewhat contradictory. Retigabine (1-10 μM) enhanced GABA mediated currents in primary cortical neurones from fetal rats in vitro, and (at 10-50 μM) dose dependently enhanced monosynaptically evoked inhibitory currents mediated by GABAA activation. However, sponsor studies indicated that retigabine does not appear to interact directly with the GABAA, GABAB, or benzodiazepine receptor binding sites, and did not show agonist, antagonist, or modulatory activity on GABAA α3β3γ2 subunits expressed in HEK293 cells. Retigabine may instead interact with the steroid binding site, since, in the former study, the potentiating effects of GABAergic currents by retigabine and 5-alpha-dihydroprogesterone were not additive. In addition, an allosteric interaction between retigabine and GABA at the picrotoxin site has been demonstrated.
Other reported actions of retigabine in vitro include reductions in depolarisation induced increases in neuronal intracellular calcium concentration, prevention of stimulation by the pro convulsant 4AP of de novo synthesis of glutamate, aspartate and GABA (while increasing their de novo synthesis in the absence of 4AP) and lowering of brain concentrations of glutamate and glutamine, while GABA transaminase activity was reduced. These effects are likely to be mediated by the actions of retigabine on KCNQ2 and KCNQ3 channel subunits. Inhibition of voltage gated sodium and calcium channels was also reported, but these effects are not anticipated to be relevant clinically, since they were only relatively modest even at supra therapeutic retigabine concentrations of 10-100 μM.
The whole auditory and Tinnitus connection. As we know, it was totally glossed over in the Retigabine release info. Yeah they may indeed have already been funneling energy into Autifony (see in main thread for more). In the AUS Report, this is about it. Big deal huh???!!!
CNS
…..Based on these results, there may be some potential for mildly impaired CNS activity with retigabine at higher clinical doses.
…..Based on the results of in vitro studies demonstrating KCNQ4 channel localisation in the inner ear, and the activity of retigabine on this subtype of KCNQ channel, perturbations of inner ear function might be anticipated with high doses of retigabine, but these have not been assessed in the nonclinical studies.
Now something that I noticed coming up far more (plus other sources) was the cardiac and arterial/circulatory implications. If you look into that in my supplemental notes my bottom line recommendation is: DO REGULAR BLOOD PRESSURE CHECKS ON YOURSELF and be aware if you get any goofy heart or pulse shit happening! I don't think we have emphasized this enough so far.
Incidentally I bought a really good Omron (no,
not Moron) blood pressure monitor not long ago on Amazon for $30 and it is super. (I was getting crazy high readings in doc's office like 145/95, but at home I get more like 115/75 and so on. There's a name for this "doctor's office visit phenomenon" or something, yet I have zero doc anxiety I'm aware of. After all it was
his floor I threw up on after IV-NAC so they should be the anxious ones, not me! But I digress…).
A final mulling…Based on how Retigabine is detoxified it may not be a bad idea to do IM (intra-muscular) injections of Glutathione – yeah no fun jabbing yourself in the leg every few days! Or maybe the oral liposomal version. Glutathione is fundamental to detox pathways and if you have any shortages there bad things can happen. However, I have no idea how effective supplementation is or event the IM stuff. I did a ton of them over many months when I was severely ill for years with ????????????????????????? and did not notice any effects. But then, maybe it was not a detox issue.
Life is full of mysteries.
GOOD LUCK! Zimichael
Member
please keep us informed.
Telis, we are all in the same "boat" lol.
Founder
