Elevated eosinophils from Ketamine?

[suspect: riverkat]

Background:
Cytology reports on 9 ketamine users who had presented non-infective cystitis showed eosiniphilic penetration. (see ref) I haven't had a chance to ask someone from the team, but they didn't report whether the CBCs for them showed raised eosinophils.

Patient X has suffered abdominal discomfort and pain (doesn't appear gastroenterological) since youth, and it has worsened since prolonged and exposure to IV ketamine (upwards of 1.75 grams per day for almost 2 years with 3x1-4 monh breaks). After suffering symptoms on urinary tract inflammation, cystoscopy revealed increased vascularity. CBC for this patient has presented continual and slow raising eosinophils, the rest is normal (AST/ALT fine, bilirubin, alk phosphate, etc). They're the only thing that seem to be related to the patients symptoms. Ultrasonography, CT, esophagogastroduodenoscopy and so forth are normal.
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Clinical, Biochemical, and Physiological Questions

-Patient X has IgE reactivity problems already (extensively sensitized to large scores of plant protein.. some of which cause anaphylaxis)... Could IgE-mediated degranulation of eosinophils explain the increased vascularity and inflammation (cystitis), or upper abdominal pain (treated by opioid therapy currently).
-Could eosinophilic infiltration and possibly be what knocks down our k-tards like bowling pins (ie - k-pains and cystitis)? Could IgE reactivity play some role in susceptibility?
-Is there any slightly less lame/inelegant methods of lowering these ill-tempered/interleukin-5 mediated granulocytes than glucocorticoids?

-Know your eosinophil-calcium stuff well? Could modulation of Ca++ signalling pathways via prolonged NMDA antagonism be related to eosinophil proliferation?
-Does the cytotoxicity in rats from NMDA antagonists (Olney's lesions) look light it couuld be via the RNAse aptly named eosinophil-derived neurotoxin?
-Does anyone enjoy using drug-addled compadres for furthuring biomedical knowledge too?
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Related Drug-related trivia: Eosinophil proliferation thought be to associated with crappy L-tryptophan was the mechanism by which all those people got cut from life, causing the FDA to ban L-tryptophan sales (though they've relaxed the rules since then).

ref: Shahani R, Streutker C, Dickson B, Stewart RJ. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology. 2007 May;69(5):810-2.

 

[Jamshyd]

Interesting questions, and unfortunately I am not in a position to answer most of them... not only because I am no scientist, but also because I have never experienced either the "k-pains" or UTI.

I will tell you this though, in the past 3 years in which I've been using K (daily whenever I have it in sub-psychotropic doses), I have only gotten sick (cold, flu..etc) twice.

esophagogastroduodenoscopy

... Somehow I think you and I aren't the only two peopl on K

 

[raybeez]

- Could eosinophilic infiltration and possibly be what knocks down our k-tards like bowling pins (ie - k-pains and cystitis)?

Some thoughts:

- Ketamine itself does not induce the chemotaxis of eosinophils in vitro (Br J Anaesth. 1999 Aug;83(2):333-5)

- Eosinophilic cystitis (urinary tract specific) is usually a symptom of some other underlying urinary tract disorder that also produces inflammation (J Urol. 2001 Mar;165(3):805-7.)

- Lower urinary tract irritation/inflammation activates neurons in the dorsal horn /dorsal commissure, and this activation is blocked by MK-801, showing a role for NMDA-mediated responses to urinary irritations. (Am J Physiol (1996) 270)

Perhaps the ketamine is interfering with neural response to urinary tract irritation. The lack of this neural response could equate to a failure to activate certain physiological pathways that would help to clear the irritation. Irritation persists and gets worse, leading to inflammation/eosinophil recruitment/the symptoms presented in these cases.

 

[fastandbulbous]

The pain that feels like nothing you could imagine is, as far as I'm aware, due to a colic spasm of the gall bladder, which is short term and only normally associated with severe chronic ketamine use. Don't know the mechanism of this, but if I had to guess, I'd say the culprit is most probably norketamine & not ketamine itself as only severe chronic use produces appreciable levels of plasma norketamine

 

[Adrenochrome]

Would a pure S-Ketamine be less painful than the racemate?

 

[suspect: riverkat]

- Ketamine itself does not induce the chemotaxis of eosinophils in vitro (Br J Anaesth. 1999 Aug;83(2):333-5)

Chemotaxis and proliferation don't work the same way... though this does imply that Ketamine isn't drawing them there. Thanks for ref. However, what you go on to say...

- Eosinophilic cystitis (urinary tract specific) is usually a symptom of some other underlying urinary tract disorder that also produces inflammation (J Urol. 2001 Mar;165(3):805-7.)

- Lower urinary tract irritation/inflammation activates neurons in the dorsal horn /dorsal commissure, and this activation is blocked by MK-801, showing a role for NMDA-mediated responses to urinary irritations. (Am J Physiol (1996) 270)

Perhaps the ketamine is interfering with neural response to urinary tract irritation. The lack of this neural response could equate to a failure to activate certain physiological pathways that would help to clear the irritation. Irritation persists and gets worse, leading to inflammation/eosinophil recruitment/the symptoms presented in these cases.

So this theory would hypothesize that if these supposed irritants were removed from diet (assuming it was allergen-mediated... if they are a purely auto-immune... that sucks balls), then the symptoms would reverse?

And you would suggest that Ketamine doesn't cause proliferation (ref?), and the elevation of blood eosinophils in this case is symptomatic of the presence of an allergenic irritant which the body cannot adapt to because of a sensory block?

As this would be visceral sensory, where do these neurons relay to (sorry if I'm asking too much... I dont know if you're into functional neuroanatomy)?

This is a very elegant explanation... esp if you can provide some peice of data concerning ketamine not inducing eosinophilic proliferation in vivo; especially since this 'toxicological' effect is not reliable in heavy ketamine users.

 

[MobiusDick]

Is this normocytic hypereosinophilia without extravascular granulomas? Why do you expect norketamine to produce this and not ketamine? Do you have any references?

Eosinophils have been shown to express and activate both ionotropic and metabotropic glutamate receptors (including NMDA and AMPA)*. What do you think the clinical significance of hypereosiniphilia is in heavy ketamine users?

MobiusDick

* Human Peripheral Blood Eosinophils Express Functional Glutamate Receptors.
Journal of Allergy and Clinical Immunology, Volume 117, Issue 2, Pages S188-S189
S. Odemuyiwa, V. Lam, M. Benn, A. Ghahary, M. Duszyk, R. Moqbel