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Combining two NRI's - atomoxetine, reboxetine?

JohnBoy2000

JohnBoy2000

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May 11, 2016
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Will the outcome basically be the combination of the IC50 value to both?

I read something to the effect of atomoxetine having the potential to displace other protein bound molecules, thus potentially interfering with their affect.

I aim to do this in the short term, as at the hands of hapless intern shrink, he's given me reduction phase of one medication, a washout, and then introduce the next at low dose, an titrate up.

He disregarded my contention that this would leave me a bed ridden mess for the timeframe without, and at low dose, of either medication - so fuck him, I'm doing it my way.

The combination would be low dose strattera (40 mg), and normal dose rebox (8 mg).

His primary concern was NA excess - which for me, is not a concern, but the possible resulting hypertension etc.
I'm not worried about that, cause if I can get too much daytime NA, I'm laughing - means all problems have been solved.

But anyways - you guys might have some insights as to this combination??
 
Yeah, I personally doubt I‘d have the patience to to do a dose-reduction, then washout, then slow dose increase.

IMO you should be on the safe side if you were to take a lower dose of your old med for one or two days, then start adding a low dose of the new med, and after a few more days dropping the old one and taking a normal dose of of the new; ideally, you would check your BP on a daily basis.
 
I added in 40 mg atomoxetine to 10 mg rebox this morning.

Significant improvement, in everything - almost immediately.

Guess I'll keep this and when I get approved for a higher dose of atomoxetine, reduce the reboxetine.

Finding a doctor to approve atomoxetine in my case, was/is, a nightmare.

The dude that did approve it, went and freaking retired - so now I'm back to the public system, whom I'm convinced, want to keep me sick, like Nurse Ratched or some shit.
I got some stumble bum intern to do me out a preliminary script for the 40 mg, and in 2 weeks will see their consultant and basically son him into following through with prescribing the full dose, I'm hoping.
 
I was concerned also with possible competitive agonism between the two agents - thus a counter productive effect.
I'm not fully sure of the dynamics of competitive agonism.
In any case, so far so good.
 
In the medical field, what you are doing is strictly off-limits.

Off the record, you may be on to something - but I warn you that any benefits you reap will likely be marginal, difficult to distinguish from placebo, and could probably be accomplished by a very focused dose of either drug.
 
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N0 W4RN1NG said:
In the medical field, what you are doing is strictly off-limits.

Off the record, you may be on to something - but I warn you that any benefits you reap will likely be marginal, difficult to distinguish from placebo, and could probably be accomplished by a very focused dose of either drug.
Click to expand...

Curious as to why that would be your opinion?

Absolutely - the preference would be to have a higher dose of atomoxetine in stand alone, but these fools made sure to script me only the minimal dose before my next appointment, so I don't have access to that.

In regards to the medical field and off-limits - they also mentioned they would never have seen a combo of atomoxetine and mianserin - which I'm on.

They're right.

But there do seem to be several cases of atomoxetine in combo with mirtazapine - which is basically the same thing, but with a serotonin component.

Anyways, as a result, they refuse to go to the full dose of atomoxetine, 100 mg, in future.
Even though several sources have the full dose being listed as 120 mg.
They've capped it at 80 mg.

So, now I need to find another doctor who will take that risk.

The whole psychiatric set up is farcical to me.
 
I got this gnarly graph of a paper examining the receptor occupancy of rebox and atomox:

rdN2SI5.png
 
According to that, rebox would have an occupancy - negligible?

10 mg/kg at 100 kg body weight - maximum dose.
Occupancy comes in at, 5%?

Say, at 2 mg per kg - would be 200 mg of rebox, for a 50 % occupancy.


Atomoxetine - at 40 mg for 100 kg body weight, occupancy would be around 20 %

4 times the potency of rebox.

Now - the paper outlines, them occupancies were determined via a means which underestimates them and, the clinical reality is that, atomoxetine at 1.2 mg/kg - can saturate the target - 100%

So, adjust the initial percentages accordingly.

Atomox - theoretically, still comes in about 4 times more potent.


Sound right?

I almost had a panic attack this morning when I dosed them together, and then anxiety shot up just now when I dosed mianserin.

Gonna give it a few days on atomoxetine without the rebox.

Feels kind of - icky, the two together.
 
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.. While I encourage you to consult you doctors with regards to dosing, an overall concept that I'll point out here is diminishing returns - you wrote "the clinical reality is that, atomoxetine at 1.2 mg/kg - can saturate the target - 100%" - I would appreciate the concept of diminishing returns here - you'll see that the dose-occupancy curve levels off significantly for atomexetine for example

Also, what route of administration are the graphs showing? If they are giving them IV to small animals, I wouldn't assume that orally to a human is.. remotely similar in terms of NET occupation
 
Cotcha Yankinov said:
.. While I encourage you to consult you doctors with regards to dosing, an overall concept that I'll point out here is diminishing returns - you wrote "the clinical reality is that, atomoxetine at 1.2 mg/kg - can saturate the target - 100%" - I would appreciate the concept of diminishing returns here - you'll see that the dose-occupancy curve levels off significantly for atomexetine for example

Also, what route of administration are the graphs showing? If they are giving them IV to small animals, I wouldn't assume that orally to a human is.. remotely similar in terms of NET occupation
Click to expand...

I Can testify for this. Cotcha asking the right questions here! Thank you dear friend
 
Okay - what's the right answers then?

Either way, would it be reasonable to infer that, atomoxetine is significantly more potent in terms of enhancing NA. in contrast to rebox?

Well - I dosed atomox, skipped rebox this morning.

Felt waaaaay better.
No horrid brain fog.
I suspect there was some form of an interaction occurring between them.

Energy was better on 40 atomox, than 10 rebox.

I mean - testing via tomography is the closest we're going to get in terms of understanding how close to saturation the drugs get, right?


Also - diminishing returns.
I get what that means in a general context but, here exactly - do you mean, complete saturation may not be a good thing?
 
The relationship between dosage and saturation isn't necessarily linear - as in, if 25mg/kg of a drug produces 25% saturation of a target, we can't assume that 50mg/kg will produce 50% saturation

You can see this manifest in the graphs as the dosage-occupancy curve levels off quickly, apparently quicker for atomexetine than reboxetine I might add

So saturation of a target above e.g. 95% will be very difficult to achieve. At that point the off target effects of these drugs will become even more appreciable as well.

CY
 
I think previously, reboxetine may have been inhibiting the metabolism of mianserin - cause having gone off it, I found mianserin, not putting me to sleep or increasing my appetite - and I was absolutely bombed today, which would indicate a drop in NA levels.

There is some info on an SPC about rebox mildly inhibiting CYP2D6 isoenzyme, which degrades mianserin, and also being a mild p-glycoprotein inhibitor - which I assume clears mianserin.

Anyways - what I would like to know is, what interactions can occur with atomoxetine?

I find it extremely inaccurate sifting through pharmacokinetic papers, which generally say, "we don't really know....".

So perhaps someone knows from experience?


Atomoxetine itself is metabolized by CYP2D6 - so I assume, not an inhibitor - though I know some drugs have that profile.

Anyone familiar with atomoxetine regarding what it inhibits??
 
My resting heartrate, BPM, has noticeably increased also - on just the 40 mg dose of atomoxetine.

I understand this is relative to hERG coded potassium channel inhibition, expressed in cardiac muscle.
Several reports suggest it's a rather common side effect.

Kind of sucks.

Hope it's one of the effects that subsides with time.
 
Tzcatlipoca said:
Especially if your genes have a preference for a1 receptor subtype expression over a2, correct me if I'm wrong
Click to expand...
Correct, although if you're meaning that a1/a2 are produced from a single gene similar to e.g. NR2A vs. NR2B NMDA receptors (different NMDA receptors spliced from a single gene), I believe a1 and a2 are produced from separate genes
 
Cotcha Yankinov said:
Correct, although if you're meaning that a1/a2 are produced from a single gene similar to e.g. NR2A vs. NR2B NMDA receptors (different NMDA receptors spliced from a single gene), I believe a1 and a2 are produced from separate genes
Click to expand...

Seperate genes is what I meant, thank you for checking me Cotcha, I believe the receptor expression is modulated 50/50% by heritage and habituation?

Best,
Tez
 
I'm fairly confident this is more in line with, cardiac ion channels, primarily because, the heart rate increases, even when there is no symptom alleviation via increased NA or other indicators of increased NA.

Are there any agents that can be administered to deal with the cardiac ion channel issue?

Is it something that can be known to dissipate after a few weeks of treatment etc?

Plus, on only 40 mg now.
Whether ion channel inhibition will occur to a great extent at higher doses - as you would intuitively think it would - remains to be seen.
 
If an increase in heart rate/blood pressure is produced via NE then it could likely be at least partially negated with e.g. beta blockers/alpha blockers, some of which are peripherally selective

For some reason I doubt that the increase in heart rate is due to a direct effect of that drug on cardiac ion channels. I believe calcium channel blockers are occasionally used to treat amphetamine related tachycardia as well

CY
 
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