Pharmacology Safety and Efficacy of Supratherapeutic Doses of Clobazam

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Series: Journal of Child Neurology 2019-jun 19 vol. 34 iss. 12
Author(s): Gedela, Sravya; Gedela, Satyanarayana; Glynn, Peter; Salvator, Ann; Patel, Anup D.
doi: 10.1177/0883073819856834

I'm sure people can locate this paper.

In children clobazam doses are generally up to 1mg/kg/day or 40mg (whichever is the lower).

The key finding for most people is 'supratherapeutic doses of clobazam were well tolerated, without an increased reporting of side effects compared to patients receiving doses that are in the normal therapeutic range as recommended by the FDA. Therefore, patients who do require higher doses can be counseled that the likelihood of side effects may not increase with elevated dosing. Interestingly, patients in our study receiving higher doses of clobazam did not appear to have greater benefit in seizure reduction when compared to normal dose ranges of clobazam.'

What this says is that my inference that clobazam (and almost certainly ALL 1,5-benzodiazepines) have a dose-response curve that plateaus at around 40mg/day. I believe this is because at that dose the α2 subunit that clobazam is (fairly) selective for has almost 100% occupancy.

In short, it seems almost impossible to overdose on clobazam alone. Mixed with other CNS depressants is obviously still a very risky thing to do.

I believe it's key to ensure that clobazam is not brought under the FDAs increasingly strong legal controls. In fact it is my belief that it does not produce a notable abstinence syndrome and could safely be sold as a non-prescription medicine.

 

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I think the ketone at the 4 position is to keep the diazepam ring 'flat' i.e. to keep it in the shape required to maintain the 3D shape that affords affinity - including the position and rotation of the pendant aromatic.

I did quire a lot of work in Chemoffice including finding the minimum-energy conformation of clobazam and diazepam for example (also overlaid etofoxine) and it would appear that the main difference is the rotation of that pendant aromatic. It's position (1 & 4 carbon's overlaid precicely as did amide and the 7-subszituted benzene (7-substitutiin being halide, pseudohalide, nitro, ethynyl or... and this is crazy, a trimethylsilyl).

It's possible to add a triazolo or imidazo ring (like bromazepam->pyrazolam).

So although they can look different in 2D, they are the same in 3D.

Did you look at my paper on methaqualone? Methawualone is a SUPERagonist at some GABAa receptors... it turns out that it's possible to design and make benzodiazepines that are likewise SUPERagonists and go on to make selective derivatives.

I found a 1,4 & a 1,5-benzidiazepine that are a5 selective and so might possibly improve on pyreyzam. As it is, it takes 20mg of pyeyzolam to get 'drunk' and it had some minor issues so I testeted both 1,4 & 15 ligands.

I haven't looked into 2,3-benzodiazepines as most work is in Russian and so didn't work on tifisopam derivatives (although a 4th ring may be possible given that the parent adds alkyls to increase isosteric vulk.