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Ro15-4513 - dose to reverse alcohol intoxication?

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hamhurricane

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i'm going to have the opportunity to work with a small quantity of the GABA-A inverse agonist Ro15-4513. I understand this chemical has no recreational value and even carries risk of seizure, but its still something i wish to investigate as a potential nootropic(1) and for its ability to reverse the effects of alcohol.

what would be a wise oral dose to begin titration, and what would you all estimate the active alcohol reversing dose to be? secondly, i would like to know if there are any signs of an impending seizure i should watch out for, i have heard shaking hands in the past, anything else?

Ro15-4513's close relative Flumazenil is used clinically for benzodiazepine overdose starting at 200µg IV, but i see a variety of doses being described and i intend to use the Ro15-4513 orally. this study(1) indicates Ro15-4513 is twice as potent as Flumazenil, but i'm still having trouble figuring out an oral ED for Ro15-4513...

(1)An Inverse Agonist Selective for 5 Subunit-Containing GABAA Receptors Enhances Cognition
(2)The effects of flumazenil, Ro 15-4513 and β-CCM on the behaviour of control and stressed mice in the staircase test
 
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I would tread extremely lightly with this one. The compound a5IA--the weak partial inverse "agonist" described in your reference #1 (Dawson et al, 2006)--is quite selective for the a5b3y2 isoform of the GABA-A receptor. Ro154513 is not particularly selective and will attenuate the effect of GABA across the board, at a1, a2, a3, a4 and a5-containing GABA receptors. In addition to the all too real potential for inducing seizures, this compound is probably quite a decent panicogen. The azido moiety of this compound would also give me tremendous pause, as azido-substituted compounds are usually used as irreversibly (covalent) binding receptor ligands. I'm assuming this one isn't, as it is listed as having a short duration of effect, but from a chemical SAR point of view, I'm still a little sketched out.

As for the warning signs of impending seizure: during what I consider to be the worst/most stressful part of my life a few years back, I was having all sorts of panic attacks and was prescribed benzos. Well, I hated the cognitive stupefaction they cause, so I decided to quit alprazolam cold turkey. I was also on the highest clinical dose of bupropion and an SNRI at the time. As you can probably guess, this turned out to be a bad idea--I went into status epilepticus and woke up in the hospital, later learning that they had to give me 10mg lorazepam, 10mg diazepam and propofol to quell the seizure. The effects before I blacked out were strange and haunting: the first thing I noticed was a creepy sense of unreality (like an unexpected "sub-hole" dose of an NMDA-receptor antagonist), anxiety, progressive loss of proprioception and visual changes (blurring, increased dynamic range, odd colored blips and bloops; probably akin to the "aura" that some migraine sufferers get). This gave way to full aphasia--I still had the 'inner space' monologue, but my mouth couldn't spit any words out--in fact, I remember coming to in an ambulance for a brief interval, being told I just had a seizure, and then trying to tell the EMTs to give me midazolam and ketamine, but being unable to speak the words. All in all, $10k worth of hospital bills later, I learned to never fuck with my GABA-A receptors again.

The greatest hazard of this compound is that if it triggers seizure, you will not be able to easily employ benzos to terminate the seizure. If you do try it, have a 200nm-filtered solution of ketamine (prepped for SC/IM administration) standing by and have a sitter on-hand who knows how to administer it properly (because you will not be able to).
 
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Original Article

Clinical Pharmacology and Therapeutics (1989) 46, 317–323; doi:10.1038/clpt.1989.145

Flumazenil disposition and elimination in cirrhosis

Supported by the Robert Bosch Foundation Stuttgart and by F. Hoffmann-La Roche & Co. Ltd., Basel, Switzerland.

Ulfert Janssen MD, Siegfried Walker MD, Karlernst Maier MD, Ulrich von Gaisberg MD and Ulrich Klotz PhD Stuttgart, West Germany

Divisions of Clinical Pharmacology and Gastroenterology, Robert Bosch Hospital and Hospital Bad Cannstatt

Correspondence: Ulrich Klotz, PhD, Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Auerbachstr. 112, D-7000 Stuttgart 50, West Germany.

Received 31 January 1989; Accepted 17 April 1989.

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Abstract
Flumazenil, a new and specific benzodiazepine antagonist that appears to be free of intrinsic pharmacologic action, is extensively metabolized by oxidative processes and represents a high-clearance drug. Consequently, it could be anticipated that hepatic disease affects the elimination and oral bioavailability of flumazenil. Therefore, the pharmacokinetics of flumazenil was evaluated in eight patients who had moderate cirrhosis and in eight age-matched healthy volunteers after a single oral dose (30 mg) and after an intravenous dose (2 mg). The mean half-life (t½) was 0.8 versus 1.4 hours (p = 0.003) and total plasma clearance was 1201 versus 705 ml per minute (p = 0.009) for control subjects versus patients with cirrhosis. Bioavailability increased from the normal 28% to 65% (p = 0.001) in patients with hepatic dysfunction. Routine liver tests did not correlate with the elimination of flumazenil in individual patients. It can be concluded that elimination of flumazenil is impaired in patients who have stable alcoholic cirrhosis. Despite the relative wide margin of safety of flumazenil, somewhat lower doses could be effective in such patients if long-term oral use is anticipated.
 
It is interesting to speculate what drop in DWI incidents and deaths would occur were there the access to such a pill that would upon administration negate the debilitating effects of alcohol
 
It is funny (well, not 'ha ha' funny) that the majority of people out there still consider caffeine and amphetamine to be "ethanol antidotes," not realizing that giving a stimulant to a drunk may result in a wide-awake drunk, but doesn't improve coordination or driving skill.
 
Just give em antabuse... they wouldn't be drunk in the first place...
 
eight age-matched healthy volunteers after a single oral dose (30 mg) and after an intravenous dose (2 mg)
Click to expand...

the oral dose of Flumazenil is much higher than i would have expected, there will only be 10mg of Ro15-4513 available for experimentation, i do not wish to use it IV and insufflation is too difficult to dose with accuracy (and this will be in soln.(which just made me realize that their maybe be solubility issues in EtOH?)) so 10mg may only be a single oral dose...

EDIT: personally i think the logic that this drug should not be released because it would encourage people to drive home after drinking is totally idiotic, its in the same line as people who think that an HPV vaccine will encourage people to have unprotected sex, for both the answer is - yes, probably. but what is immoral about unprotected sex or safe drives home? that said there are obviously other risks involved and the real solution is for people to stop drinking alcohol.
 
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Man.... you are going to take a GABA-A inverse agonist? Don't you think this is a bad idea?
 
I read that there was a GABA antagonist widely clinically used for inducing seizures - Metrazol. You might want to check it out in order to see its effects. It doesn't sound like something you would want to OD on.
 
no one can say for sure and i posted that study as indeed that seemed the best evidence to give a dose estimation and indeed it would appear 10mg would be quite sound to reverse the effects of moderate ethanol 'overdose'
 
Short half-life. Misdose can cause seizures. Effects come back as soon as it wears off.

Not worth it.
 
Riemann Zeta said:
It is funny (well, not 'ha ha' funny) that the majority of people out there still consider caffeine and amphetamine to be "ethanol antidotes," not realizing that giving a stimulant to a drunk may result in a wide-awake drunk, but doesn't improve coordination or driving skill.
Click to expand...

It may work the other way around. This is purely anecdotal but i've noted a sharp increase in alcohol tolerance while using moderate amounts of d-amp. I imagine this has more to do with the amphetamine not allowing the GABA-b receptor modulating effects of alcohol to fully kick in.
 
I was just reading about this and Flumenazil the other day - it sounds like it would be torture to take this drug. Like instant withdrawal symptoms... NOT recreational.

Please post your results if you experiment, but I would not recommend it - similar experiments with related compounds have caused symptoms like "psychological terror" and "fear of imminent death."
 
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