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Comparing IC 50 values?

Scrofula said:
I'm pretty sure Ki values are determined in vitro with a cloned receptor. It's an equilibrium constant that can be interpreted as affinity. I don't remember if its specifically for displacement of the ligand or just bound/not bound.

But PET scans are on living patients and are not at all sensitive enough for that
They would both use radiolabels, but Ki would be a scintillation deal--fancy Geiger counter.

It's why you can't rely on Ki for physiological results.
The PET scan would show which brain regions are affected based on metabolism of the ligand. I guess they can get a very rough idea about saturation.

That doesn't mean it's more potent--maybe bupropion does too if you eat the whole bottle. Potency is just dose/result. High potency main benefits are fewer side effect issues.

I also don't know that saturation is that desirable.
Click to expand...

That atomoxetine study referred to saturation, but at clinically used doses.
The purpose I believe to imply that, at pharmacologically administered quantities, it can saturate the transporter.

Not desirable?

I assume you mean in relation the post synaptic receptor?

This saturation would be relative to the pre-synaptic transporter protein.
That wouldn't be desirable because?
 
Post synaptic receptor saturation - the desirable degree seems to be 90%

I don't see how that can be achieve with an NRI in stand alone therapy, not in more disabling cases.
 
Goddamn jitterbug phone five attempts now.

Your post more sense today. But why do YOU think saturation is more important?

E.g. sertraline shows therapy way below max dose, depending on disorder, suggesting saturation isn't necessary, or depends on brain region

Other mechanisms than simply raising synaptic transmitter levels seem to always be invoked for RIs

IDK but could be unnecessary or detrimental in some cases if side effects are severe for no gain.
 
That's what has me scratching my head.

With SNRI's - low occupancy yields effects.
Also, sertraline - which has DRI properties, albeit it very low potency, yields effects consistent with dopamine amplification.

With NRI's , 85 to 90% saturation is required for any kind of effect.

I think what CY way saying in the other thread, regarding possible cross over down stream implications of the separate receptor activations.
It doesn't seem to be well known.

That such seems to be the situation.
 
I've heard of sertraline's DRI action, but my poor understanding was it's clinically irrelevant. What signs of DA amplification have you heard of? It doesn't seem to interact with meth, so I'm curious what possible low level stuff might be occurring and frying my brain.
 
Um - you might be right there.

All I've heard of is what was in Stahls book.

If I recall - something something, potentiated via low DRI effects of bupropion in combination therapy.

Perhaps it is clinically irrelevant in monotherapy.

Supposedly bupropion and sertraline is an efficacious combination for some.
 
You need to know the cLogP & pKa as well as transport(s) and ADME. In vivo is only part of the story. Start with Lipinski's 'rule of 5' and use free on-line software to estimate physical data. There are a few sub-nM releasers with good physical & ADME characteristics but don't forget how good a medicine has to be to pass the FDA/NICE or whoever gives out licenses in your locale. Better than a placebo. That is all. Run enough trials and only publish the flattering ones. Dr Ben Goldacre's book 'Bad Pharma' give all of the inside knowledge. Reboxatine is no better than a placebo, if you see ALL of the trials. Often the benchmark is another poor agent or a decent agent in inappropriate dosages, but I am more or less resigned to the fact that anything licensed since about 1980 is instantly suspect to me.

Everyone is free to wear sunscreen.
 
I was surprised to learn bupropion, after first-pass metabolism, has pretty much zero DAT inhibition, and sertraline has crazy high affinity for it. Maybe your reboxatine will turn out to work on everything but NET.
 
As long as you keep in mind he's overstating as much as he can (to sell stuff, same as big Pharma). I only worked next to Clinical, in in vitro diagnostic development, writing FDA submissions. The actual data that they evaluate for approval. But I had my taste. They seemed to bitch and gossip more than most departments, generally unhappy, but friendly.

Pharma absolutely IS evil, it's just the banal evil of every corporation. Think of drug ads the same way you think about car ads or breakfast cereals, just with your life at risk. Then you'll be fine.

Every one should look at drug claims the same way they look at mileage stickers on new cars. No one expects that performance in the real world, but they're still within the rules (except the rare Volkswagen fiasco now and then).
 
Anyone else old enough to remember the first-into-man trials were members of the development team. KW Bentley & two members of his team were given 50ug, 100ug & 200ug SC doses and the guy who got 200ug puked all weekend. I think my design work is more moral. I will take stuff vastly above a reasonable dose and see if it kills me. I ate 750mg of pyrazolam and lost a week. But it proved that it was the inherently safest benzo. When I looked at bromazepam's unusual profile, I knew that it was perfect for subtype selectivity. We had an a5 selective (100% substitutes for ethanol in alcoholics with 3mg = 10g of ethanol) and an a1 selective that had fast (circa 60 minutes) antidepressant action. The former was for substitution and intended to be mixed with 1-aminocycloporoanol (acetaldehyde dehydrogenese inhibitor) to ensure compliance. The latter was to bridge the gap between presentation and existing agents working - those few weeks in which most suicides occur). We got every combination of diazepam-sensitive subtypes because the pyridine's N lone-pair acts differently to (substituted) benzene ring. The trifluoromethyl, cyano, and every other EWG.
Not able to get a patent, sadly. When you find something to help people but no profit is likely, why would big pharma develop such medicines?
 
This bot has racked up nearly 800 posts here? Does BL wait for it to produce by chance the perfect pharmaceutical synthesis?
 
clubcard said:
You need to know the cLogP & pKa as well as transport(s) and ADME. In vivo is only part of the story. Start with Lipinski's 'rule of 5' and use free on-line software to estimate physical data. There are a few sub-nM releasers with good physical & ADME characteristics but don't forget how good a medicine has to be to pass the FDA/NICE or whoever gives out licenses in your locale. Better than a placebo. That is all. Run enough trials and only publish the flattering ones. Dr Ben Goldacre's book 'Bad Pharma' give all of the inside knowledge. Reboxatine is no better than a placebo, if you see ALL of the trials. Often the benchmark is another poor agent or a decent agent in inappropriate dosages, but I am more or less resigned to the fact that anything licensed since about 1980 is instantly suspect to me.

Everyone is free to wear sunscreen.
Click to expand...

Sunscreen stops me getting a nasty burn.

Reboxetine is the best drug I've tried so far.
It's like the outcast son that turned out to be the prodigy.

I'm hoping atomoxetine will be one better.

Regarding the rebox clinical trials - they're bent.
About 1 in 20 people respond to exclusive noradrenergic effects, and given the autoreceptor effects, it really should be administered with an autoreceptor blocker.
From what I understand, SSRI's won't fall victim to this.
I know 5ht1a, somatodendritic autoreceptors - but does enhanced synaptic 5HT really downregulate 5HT release?

Given the above - how could they possible expect large scale trials to show positivity for a selective NRI?

Yet it showed much better results for prozac non-responders.
Alas - that trial was melded into the fray and - suddenly rebox is a "ineffective, potentially harmful drug".
 
Yeah, it's another reason to be cautious with clinical results for psych meds. There aren't any objective tests for the disorders, whose etiology is usually unknown, and no objective measure for results.

You can argue about the risk/benefit ratio of something like statins (or how much greater than one it is), but your outputs are cholesterol levels and death. Those, at least, can't be argued. It's also easier to reveal if there's two populations in your study. I would think anyway.

What are your thoughts then on clonidine and the expectorant-sounding one, guafenasin, which target the autoreceptor, and have you tried them? (Or do you think it's all about imidazoline receptors?)
 
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Clonidine and guafenasin I've again read about but, their side effect profile implicates sedation.

That seems a little paradoxical for an adrenergic agonist - I can't recall as to whether that's because they're specific for pre or post synaptic receptors.
Similar for dopamine agonists like pramipexole - implicates high sedations, even though dopamine, a catacholamine, at least the endogenous variety, seems to be associated more so with the opposite; activating, energy, motivation etc.

I haven't come across any material explaining why exactly that is the case.
Perhaps something relative to tonic vs phasic release?

But in any case, due to sedation associated with adrenergic agonists, they're not something I would have tried.

Edit - oh you just said they target the autoreceptor.
Well - that explains it then I guess.
That being the case, I guess they'd be counter productive to my owns ends.
 
Clonidine is known to be--at least initially--sleepy. But it gets a lot of positive anecdotes for depression, anxiety and even focus. Although I've heard different mechanisms for mood and focus; mood through some 5ht feedback and focus by potential involvement with imidazoline receptors.

How imidazoline receptors aren't histamine receptors I don't understand either.

So if not better mood and focus, you were hoping for jittery energy?
 
JohnBoy2000 said:
Sunscreen stops me getting a nasty burn.

Reboxetine is the best drug I've tried so far.
It's like the outcast son that turned out to be the prodigy.

I'm hoping atomoxetine will be one better.

Regarding the rebox clinical trials - they're bent.
About 1 in 20 people respond to exclusive noradrenergic effects, and given the autoreceptor effects, it really should be administered with an autoreceptor blocker.
From what I understand, SSRI's won't fall victim to this.
I know 5ht1a, somatodendritic autoreceptors - but does enhanced synaptic 5HT really downregulate 5HT release?

Given the above - how could they possible expect large scale trials to show positivity for a selective NRI?

Yet it showed much better results for prozac non-responders.
Alas - that trial was melded into the fray and - suddenly rebox is a "ineffective, potentially harmful drug".
Click to expand...

As it did for 32% of the people in the officially published trials. People get better with placebos, we know 2 pill placebos are better than 1 pill placebos. If it works for you, fine. But don't say 'it worked for me so it MUST work' because 1 person is not statistically valid.

Antidepressants are famously hard to predict from animal studies. There have been many hundreds of compounds to reach stage 3 only to be dropped. If you invest billions to reach stage 3, bean counters wans a license to sell, utility is of no consequence to them. That is how dirty big pharma.
 
JohnBoy2000 said:
I know 5ht1a, somatodendritic autoreceptors - but does enhanced synaptic 5HT really downregulate 5HT release?
Click to expand...
Animals given SSRIs can show decreased serotonin cell firing in some areas of cortex for the first little while.

JohnBoy2000 said:
Similar for dopamine agonists like pramipexole - implicates high sedations, even though dopamine, a catacholamine, at least the endogenous variety, seems to be associated more so with the opposite; activating, energy, motivation etc.

I haven't come across any material explaining why exactly that is the case.
Click to expand...
Direct dopamine agonists can have different effects in Parkinson's disease patients because when there is destruction of the dopamine releasing cells (the terminals/fibers/somas) that express autoreceptors, the agonists then tend to act on the post-synaptic heteroreceptors (located on non-dopaminergic cells that haven't degenerated), where as in a normal person a dopamine agonist can act more like a sedative up to some point because the autoreceptors are still intact.

If one pushed the dose high enough then autoreceptors would matter not because there would be enough post-synaptic binding to outpace the decrease in pre-synaptic release due to autoreceptor activation, similar to how a releasing agent acts regardless of vesicle fusion related pre-synaptic release/autoreceptor function.
 
Scrofula said:
Clonidine is known to be--at least initially--sleepy. But it gets a lot of positive anecdotes for depression, anxiety and even focus. Although I've heard different mechanisms for mood and focus; mood through some 5ht feedback and focus by potential involvement with imidazoline receptors.
Click to expand...

There are some post synaptic a2 receptors in the cortex - while clonidine will be acting as an autoreceptor agonist in many cases, it may be helpful for some ADD/ADHD patients due to the effects on a2 heteroreceptors.
 
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