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    Comparing IC 50 values? 
    #1
    Two drugs in question:

    Atomoxetine = 0.36 nM


    Reboxetine = 8.2 nM


    Perhaps there are more accurate IC50 values out there though.


    Atomoxetine is dosed up to 100 mg

    Reboxetine to 10 mg max.


    Reboxetine supposedly failed clinical trials as an AD, but was approved anyways.


    Atomoxetine supposedly failed clinical trails as an AD, but was approved for ADHD.

    For myself - I've only ever responded to NE enhancing drugs so, I'm just looking for the most powerful one in that capacity.



    According to them IC50 values - that would be atomoxetine, right?
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    #2
    iC specifies potency of attaching to the target site, not telling efficacy.
    Ie. it may bind and be a partial agonist not exerting full effect, or jus bind and doesnt give effect at all (antagonist), or bind then give reversd effect(inverse agonist)

    I think what you are looking for is EC50 value, that determines the efficacy
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    #3
    EC50 values for them two meds are no where to be found.

    I had difficulty enough finding their IC50 values.

    Can anyone point me in a favourable direction??



    PS - is "racing thoughts" a symptom kind of, synonymous with depression?
    I was actually just reading that on drugs.com reviews for atomoxetine.
    Racing thoughts, to an extreme degree - apparently cause some people, chronic lethargy.
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    #4
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    These are reuptake inhibitors so there will be no EC50 to be found.

    RE: "racing thoughts", you may also think about the terms mania/hypomania and rumination, and the former is common in bipolar while the latter is very common in all depressions. Its possible that rumination plays a big role in the causality of depression, and many antidepressant treatments seem to address the hyperactivation of the "default mode network", a neural network linked to rumination and depression.

    ADHD medicines typically stimulate the executive control network - a network somewhat in opposition to the default mode network.
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    #5
    Quote Originally Posted by Cotcha Yankinov View Post
    These are reuptake inhibitors so there will be no EC50 to be found.

    RE: "racing thoughts", you may also think about the terms mania/hypomania and rumination, and the former is common in bipolar while the latter is very common in all depressions. Its possible that rumination plays a big role in the causality of depression, and many antidepressant treatments seem to address the hyperactivation of the "default mode network", a neural network linked to rumination and depression.

    ADHD medicines typically stimulate the executive control network - a network somewhat in opposition to the default mode network.
    Default mode network being relative to all monoamines?
    Predominantly serotonin perhaps?

    Executive function - similar to control I'm guessing: I read a clinical trial claiming the use of noradrenergic agents are specific to executive control.
    I haven't come across the term "default mode network" - any paper links on that?


    So - without EC50 values - in terms of kind of labelling which of the two would have greater potency at the NE transporter.

    In non specific terms, the fact that reboxetine was approved for neither depression nor ADHD by the FDA, but atomoxetine was approved for depression - perhaps alluding to more effectiveness in some capacity?
    That being said - atomoxetine seemed to have been rejected by it's own company, Pfizer itself - in terms of potential use as an anti-depressant.
    Yet there are many case studies where it is used effectively as an adjunct to ameliorate lethargy etc.
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    #6
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    Default mode network relating to all neurotransmitters, but there is a high level of expression of serotonin terminals in some parts of the cingulate for example.

    Here are some DMN papers
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4797836/
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891968/

    EC50 is kind of a measure of how much of the substance you need to produce a half maximal increase in excitability, so in the case of transporters, there would only be an EC50 value for a reuptake enhancer. But reuptake inhibitors do have IC50 (inhibitory concentration 50) values. EC50 values are more useful for helping determine the potency of agonists, which may activate a receptor more or less. I'm sure that not all reuptake inhibitors block transporters the same way (see cocaine as a DAT inverse agonist), but I doubt its that appreciable.

    There are pharmacokinetic factors that make determining transporter occupation difficult. You may be able to find PET studies that examine transporter occupancy at different dosages.

    The non-approval of reboxetine may have to due with PK factors or side effects, not necessarily related to its actions at NET. But I still get the feeling that a selective NRI will not be a very complete antidepressant. It may be a helpful adjunct (especially in people who would already benefit from stimulants with regards to ADHD), or may help relieve a specific symptom like lethargy, but I don't know if its really the whole package that some people need.
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    I remember vaguely that atomoxetine/Straterra was intended to compete with or replace fluoxetine/Prozac. Checking structures, you can see that Prozac is just a flourinated Straterra.

    I think the verdict is that atomoxetine just isn't good enough an AD to compete with fluoxetine, and just iffy enough with ADHD that they marketed it that way instead. Something similar may have happened with reboxetine. My point being is it sounds not particularly good at anything (compared to the rest of the market), but I haven't exactly gone through clinical results. I always think of this one as a reminder that drug development is hazy and no one really knows what they're doing to your brain. Every pharm is an experiment.


    And that default mode network vs. executive control mode is great info,thanks. I can't help but think, though, about implications for "mind" and how there's a 2500 year-old practice for diminishing the former in favor of the latter by just sitting.

    I remember now! Sorry, I'm on a multiday awake binge that I didn't even plan. The SPECIAL thing about atomoxetine,in re: depressio/anxiety, is that it's an NMDA antagonist, ala ketamine (obviously a less potent one). My understanding is that preliminary trials showed success with some special class of PTSD and chronic fatigue. It came up elsewhere, what with ketamine IV appearing to be an interventionist ER cure for depression for a week or two.[
    Last edited by Scrofula; 17-10-2017 at 11:04.
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    #8
    Quote Originally Posted by Scrofula View Post
    I remember vaguely that atomoxetine/Straterra was intended to compete with or replace fluoxetine/Prozac. Checking structures, you can see that Prozac is just a flourinated Straterra.

    I think the verdict is that atomoxetine just isn't good enough an AD to compete with fluoxetine, and just iffy enough with ADHD that they marketed it that way instead. Something similar may have happened with reboxetine. My point being is it sounds not particularly good at anything (compared to the rest of the market), but I haven't exactly gone through clinical results. I always think of this one as a reminder that drug development is hazy and no one really knows what they're doing to your brain. Every pharm is an experiment.


    And that default mode network vs. executive control mode is great info,thanks. I can't help but think, though, about implications for "mind" and how there's a 2500 year-old practice for diminishing the former in favor of the latter by just sitting.

    I remember now! Sorry, I'm on a multiday awake binge that I didn't even plan. The SPECIAL thing about atomoxetine,in re: depressio/anxiety, is that it's an NMDA antagonist, ala ketamine (obviously a less potent one). My understanding is that preliminary trials showed success with some special class of PTSD and chronic fatigue. It came up elsewhere, what with ketamine IV appearing to be an interventionist ER cure for depression for a week or two.[
    Atomoxetine was beneficial as an NMDA blocker in cases of chronic fatigue?

    The property shared with ketamine - which is, a dissociative anaesthetic?

    Atomoxetine is reputed to, not irregularly induce lethargy - I'm now thinking that that property is perhaps the cause in that sense.

    And - being a pure NRI, no 5HT action - wouldn't that make it an entirely different class from prozac?

    I tried prozac - it did less than squat for me.
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    #9
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    Atomoxetine's a weird one for me. Brings on a type of tingly euphoria that nothing else (aside, perhaps, from sibutramine) does. Which just goes to show that personal mileage can vary dramatically, theorised expectations aside.
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    #10
    Quote Originally Posted by CFC View Post
    Atomoxetine's a weird one for me. Brings on a type of tingly euphoria that nothing else (aside, perhaps, from sibutramine) does. Which just goes to show that personal mileage can vary dramatically, theorised expectations aside.
    What else you tried?
    Other NRI's?

    Do you get the fatigue on it?
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    #11
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    I think you asked me this last year, but a lot of things. Of the 'pure' NRIs that's the only one. I've also used bupropion and desipiramine before that are largely NRI.

    As for fatigue, it depends on the type you mean. Not a chronic fatigue type no, but the normal tiredness/somnolence I get from dosing a stimulant at therapeutic ranges yes.
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    #12
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    Quote Originally Posted by JohnBoy2000 View Post
    Atomoxetine was beneficial as an NMDA blocker in cases of chronic fatigue?

    The property shared with ketamine - which is, a dissociative anaesthetic?

    Atomoxetine is reputed to, not irregularly induce lethargy - I'm now thinking that that property is perhaps the cause in that sense.

    And - being a pure NRI, no 5HT action - wouldn't that make it an entirely different class from prozac?

    I tried prozac - it did less than squat for me.
    They'd be in the same structural class. You can ask the RC folks how a single hydroxyl in a new position can change a drug's effects. And I think it has some serotonergic effects.

    But yes, it's also an NMDA antagonist., Same way the powerful hallucinogen and dissociative diphenhydramine is sold otc as an antihistamine, it's about dosage and potency..

    I think there's speculation that's where the AD action occurs. The chronic fatigue study I was thinking of involved actual ketamine I think.

    But why wouldn't an NRI cause stimulation and even anxiety at first? Or the paradoxical sleepy relaxation I get smoking meth?
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    #13
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    Quote Originally Posted by Scrofula View Post
    But why wouldn't an NRI cause stimulation and even anxiety at first? Or the paradoxical sleepy relaxation I get smoking meth?
    NE seems to have biphasic effects, the three major groups of adrenergic receptors (a1, a2 and b2) seem to play different roles at different concentrations of NE. I suppose with NRI there is also the complicating increase in dopamine in the PFC, which may inhibit some cells in PFC.
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    #14
    Re atomoxetine with or without food:

    AbsorptionAtomoxetine has high permeability and is rapidly and almost completely absorbed after oraldosing reaching Cmax approximately 1 to 2 hours after dosing. STRATTERA can beadministered with or without food. In clinical trials with children and adolescents,administration of STRATTERA with food resulted in a 9% lower Cmax. Administration ofSTRATTERA with a standard high-fat meal in adults did not affect the AUC, but diddecrease the rate of absorption resulting in a 37% lower Cmax. The absolute bioavailability ofatomoxetine following oral administration of STRATTERA ranged from 63% to 94%depending upon inter-individual differences in the modest first pass metabolism.


    Says it doesn't affect absorption, but lowers Cmax by about 40 %.

    What does that mean?

    Does that mean the potency of the drug is 40% less when taken with food?
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    Slows absorption. Cmax = peak serum conc --> that means the curve is smoother. So food mediates absorption, but doesn't significantly alter total bioavailability (auc).
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    #16
    Quote Originally Posted by CFC View Post
    Slows absorption. Cmax = peak serum conc --> that means the curve is smoother. So food mediates absorption, but doesn't significantly alter total bioavailability (auc).
    Very good.

    Did you gain that knowledge via wiki or papers or such?

    I've read entire chapters on pharmacokinetics in pharm books and still have difficulty with pharmacokinetic principles.
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    #17
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    As long as your Lineweaver-Burke plots are straight you got your Km. And Vmax. Atomoxetine isn't an enzyme; I just felt like sharing.
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    #18
    The other question I have, that I didn't necessarily want to make a new thread for was:

    When determining the binding affinities of drugs, the Ki values - am I correct in saying, this is done via administration of a radioligand (not the drug in questions), and the ease with which the drug in question displaces this ligand from the receptor in question, is the resulting Ki value?

    Cause I never fully understood that but, currently looking at PET radioligand studies for reboxetine and atomoxetine.

    One study seems to indicate, complete NET saturation can be achieved with atomoxetine.
    https://link.springer.com/article/10...259-009-1118-9
    Which would mean that, basically, it's as potent an NET implicating drug as it's possible to get?

    But reboxetine - I can't find much that gives me a clear idea of receptor occupancy.

    Perhaps ya'll have something on that, to hand?
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    #19
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    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.
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    #20
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    Quote Originally Posted by JohnBoy2000 View Post
    When determining the binding affinities of drugs, the Ki values - am I correct in saying, this is done via administration of a radioligand (not the drug in questions), and the ease with which the drug in question displaces this ligand from the receptor in question, is the resulting Ki value?
    You could look up more about a radioligand binding assay if you like, but a PET radioligand study to determine in vivo occupancy works in a very similar manner
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    #21
    Quote Originally Posted by Scrofula View Post
    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.
    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?
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    #22
    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.
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    #23
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    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.
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    #24
    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.
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    #25
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    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.
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