A new look at MXE / ACh / NMDA antagonist bladder issues

[dopamimetic]

A new look at MXE / ACH / NMDA antagonist bladder issues

http://www.ncbi.nlm.nih.gov/pubmed/24580056

So when flooding mice with injected MXE in dosages that no addict probably ever reaches (but then again there are differences in metabolism, afaik when taking values from rats one uses a security measure of 1:12, dunno about mice - and of course, these little differences often enough turn animal tests worthless) they get kidney and bladder inflammation and necrosis. The study did not test if these changes would be reversible upon cessation.

My questions now - does that say anything about human usage (besides the speculation that it -could be- harmful, that has been existed before)? What about human equivalent dosages and differences concerning oral / intranasal or sublingual x vs. intraperitoneal application?

• Is it yet known if these nasty bladder issues from K and probably related substances are either - absolute dosage dependent (e.g. independent of the potency of the substance, meaning a higher potency one like MXE would be favorable) or relative dosage dependent, or even more or less independent?
  
• The same about if they origin from the molecular structure of the compound or a metabolite (in the ketamine case, it's norketamine afaik - whilst in MXE we are supposed to have an n-ethyl instead of n-methyl metabolite, for example) or by a direct action - either inseparable like if there are NMDA receptor like proteins in the bladder whose (chronic) antagonism is deleterious - or independent of the main NMDA antagonism, like - say for example, relative to an nACh antagonism, or something like that?
  
• And following that, what can we suspect about not directly related compounds like the -phenidines or, what especially interests me, dextrorphan - or of course any of the other known dissociatives?

Memantine, which (next to xenon and nitrous oxide) seems to me like next to the "compactest" nmda antagonist possible - also has cystitis in it's list of side effects. But it's also a partial anticholinergic and is designed for long term intake. Indeed I am taking it since maybe 2-3 years in dosages slightly higher than the 20mg/d recommended, not to mention the numerous grams of MXE consumed over that time, without having acute problems.

But, well, I fear of the long term safety. Especially thinking that, alzheimers' patients' mortality in mind, no one might have thought about taking this compound in the youth and for many years.

 

[endotropic]

My questions now - does that say anything about human usage (besides the speculation that it -could be- harmful, that has been existed before)? What about human equivalent dosages and differences concerning oral / intranasal or sublingual x vs. intraperitoneal application?

Well it doesn't say anything definitive that's for sure. Until you see a clinical trial on the issue (and don't hold your breath) I think your best bet would be to compare the toxicity demonstrated in this study to a similarly designed study using ketamine.

The dosage conversion factor I remember seeing was 1:12 for mice, 1:6 for rats, but honestly it's been a while so I might be off on that. Those factors are just meant as a rule of thumb anyways, different responses to different drugs can vary wildly from those ratios. As far as RoA differences I can tell you that I.P. injections reach the brain very rapidly - so think closer to intranasal than oral or sublingual (but not quite intravenous rates).

Is it yet known if these nasty bladder issues from K and probably related substances are either - absolute dosage dependent (e.g. independent of the potency of the substance, meaning a higher potency one like MXE would be favorable) or relative dosage dependent, or even more or less independent?

Really you're asking whether the bladder/renal toxicity issues are NMDA receptor mediated or not. If they are then dissociative potency and bladder tox potency will go hand in hand.

I don't know the answer to that question, but if you can find some information on that it would go a long way towards deciding whether we should favor higher potency NMDA antagonists from a bladder/renal toxicity perspective.

 

[s0rsha]

It seems like someone did a MSc on the mechanisms of human ketamine-induced urinary tract damage a few years ago. While I haven't had the chance to acquaint myself with it too extensively yet it seems like the findings, if they hold up to further scrutiny, might be useful in determining whether these renal toxicity concerns are mediated through NMDA antagonism or not.

 

[dopamimetic]

Very interesting read, thanks.

Confusing fact is that MK-801 does not exhibit toxicity on its own but enhances that of Ketamine when administered together. So I guess there is some connection with the NMDA antagonist action but bladder-safe dissociatives are a possibility.

 

[Zilpe]

I was under the impression that a specific metabolite of ketamine was the culprite. I was also under the impression that there was a study showing mxe did not produce this specific metabolite. That of course doesn't give sufficient evidence to claim mxe is bladder safe but it seems to me that NMDA antagonism in itself isn't the cause. Are there even NMDA receptors outside of the CNS?

 

[dopamimetic]

In that paper linked above they tested ketamine as well as its main metabolite norketamine against cloned human bladder cells. There was not much difference between both chemicals in that they caused irritation of the cells.

I thought it was mainly that methoxetamine is n-ethyl while ketamine is n-methyl what was thought to make the difference, besides from mxe being more potent. As that study on mice with mxe is the only one currently afaik, and does not really answer anything, well there's much room for speculation I'd say.

 

[dopamimetic]

Are there any news about this subject?

 

[anubis23]

"Urinary nitric oxide synthase activity and cyclic GMP levels are decreased with interstitial cystitis and increased with urinary tract infections."
and
http://www.ncbi.nlm.nih.gov/pubmed/15891334


That is what is very confusing indeed, the MK801/Ketamine discrepancy. One part of me believes Nitric oxide synthase plays a role in mechanical damage. Perhaps after prolonged, repeated administration these pathways mentioned in the paper below are disrupted in their expression, compounding the factors in the development of cystitis.
http://www.fasebj.org/content/28/1_Supplement/1131.5
From anecdotal experience I definitely felt the same sort of inability to piss on ketamine or mxe that I did on even therapeutic doses of anticholinergics, something that only ludicrously high doses of dxm were required to produce. I think ketamine was shown to be a muscarinic antagonist, but cannot recall if MK-801 shared that mechanism. That may also help to explain the discrepancy.

 

[dopamimetic]

Oh wow, many thanks for this link... one more very very interesting piece regarding NO synthase..