Uncut- more ingredients

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    Uncut- more ingredients


    So far we have amentoflavone and caffeine; here are some additional ingredients in Uncut- I am saving some of the best for last:

    -Huperzine A (from Huperzia serrata)
    Bioavailability- high; logP 2.02
    Onset- 5-10 minutes
    Tᵐᵃᵡ-60 minutes
    A potent, reversible, and selective inhibitor of Acetylcholine esterase (AChE), an enzyme that converts acetylcholine into acetate and choline. Huperzine A possesses very high bioavailability, and can cross the Blood-Brain Barrier (BBB) readily. First discovered in the early 80’s, structure activity relationship (SAR studies) have shown that Huperzine A possesses a longer duration of activity and a higher therapeutic index than many pharmaceutical AChE inhibitors. Computer-generated superposition of Huperzine A and ACh show that Hup A contains the same basic structural characteristics of ACh (7); there is a reasonable structural similarity between the nitrogen, carbonyl, and oxygen that is present in ACh, and the amino nitrogen, nitrogen, and oxygen in Hup A (4). Most of the SAR research has been on potential alterations of this 5-aminomethyl-2(1H)-pyridone part of Huperzine A- so it can most likely be considered a pharmacophoric moiety for the inhibition of AChE (a pharmacophore is a spatial arrangement of functional groups necessary for biological activity)(13). Ashani et al. (1992) demonstrated a very slow dissociation rate in solution of the Huperzine A/AChE complex, without any detectable chemical modification in the inhibitor; this demonstrates a strong resistance to metabolism as an AChE-binding agent (1). By inhibiting AChE, Huperzine A increases acetylcholine in the central and peripheral nervous systems (CNS and PNS), and acetylcholine levels in the PNS are a major rate-limiting step in contractile activity in skeletal muscle (along with calcium release from the sarcoplasmic reticulum)(16). This may explain some of the positive effects of Uncut™ on increased muscular contractility, as acetylcholine acts as an excitatory neurotransmitter at the neuromuscular junction (NMJ), and the production and availability of acetylcholine tend to be limiting factors in muscular contraction at the NMJ.

    Naringin (Citrus paradisi macfaydven)-
    Bioavailability- moderate; logP -0.16
    Onset- 15-20 minutes
    Tᵐᵃᵡ- 180 minutes
    A citrus bioflavanoid, naringin has been reported to change the pharmacokinetics of a wide variety of drugs due to the inhibition of the metabolizing cytochrome P450 (CYP) 3A enzymes, a barrier protein for drug absorption. Naringin has been shown to significantly alter the pharmacokinetics of caffeine and PDE5 inhibitors such as slidenafil, increasing the bioavailability of these compounds; naringin has also been shown to have some p-glycoprotein inhibitory characteristics. P-glycoprotein (p-gp) is an efflux protein found in the intestines that is responsible for the removal of compounds from target cells; p-glycoprotein is strongly associated with MDR (multi-drug resistance), a condition in which decreased levels of drugs (or supplements) accumulate within target cells. By inhibiting p-glycoprotein, an alteration in the AUC of many different co-ingested drugs (and supplements) has been observed; Ali et al. (2009) found that naringin had a modulatory effect on the expression of p-gp and a trapping effect when naringin was ingested concurrently with anti-mestatic drugs; Dahan et al. (2009) found that naringin can significantly increase the oral bioavailability of colchicine (similar in structure to higenamine) through decreasing p-gp expression and MDR. This effect could potentially carry over to higenamine due to similarities in structure (but not function) between the two ingredients; a similar study by Shirasaka et al. (2009) found that the co-ingestion of naringin and a β-AR₁-antagonist (talinolol) significantly altered the bioavailability of talinolol through a change in p-gp expression.

    -Chlorogenic Acid (from Green Coffee Bean)-
    Bioavailability- moderate; logP -0.27
    Onset- 5-10 minutes
    Tᵐᵃᵡ-35 minutes
    Catechol-containing phenol from coffee; strong inhibitor of Catechol-O-Methyltransferase (COMT, an enzyme that metabolizes catecholamines and other catechol structures), as evidenced in study by Zhu et al. (2008), who found “chlorogenic acid, caffeic acid, and caffeic acid phenethyl ester (three catechol-containing polyphenols richly present in coffee)….. are highly effective inhibitors for the human liver and placental COMT-mediated O-methylation of catechol estrogens in vitro….. computational values showed that the binding energy of chlorogenic acid was much lower than caffeic acid, which suggests that the binding affinity of the former was much higher than the latter and the competitive component of COMT inhibition would be stronger by chlorogenic acid than caffeic acid…..it is expected that collectively these coffee polyphenols may provide a biologically-meaningful inhibition of the O-methylation of various endogenous catechols in vivo. It will be of interest to determine in human subjects the extent of inhibition of the metabolic methylation of endogenously-formed catechol estrogens and possibly other endogenous catechol substrates (such as catecholamines).(41)” COMT is the major enzyme that metabolizes higenamine via the hydroxyl structures on the tetrahydroisoquinolone moeity; hydroxylation at C6 is necessary for adrenergic binding of higenamine. A study by Kimura (1989) found that higenamine had positive inotropic effects (a sign of adrenergic binding), while R-Coclaurine and S-Reticuline (similar structures, but are methylated @ C6) had opposite effects, indicating an inhibitory effect on adrenergic binding via the methylation that normally occurs during higenamine metabolism (42,50). Uncut™ seeks to prolong the action of higenamine by inhibiting COMT via chlorogenic acid, thus keeping C6 intact for a longer period of time(42).
    Dirk Tanis, BA, MSci
    Chief Operating Officer, Applied Nutriceuticals

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    I'm going out on a limb here but I'm assuming higenamine will be in the formula based on the reasoning behind including GCB. Interesting formula so fa r I like how AN isn't another me too company and brings new and interesting formulas to the market.
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    Quote Originally Posted by xhrr View Post
    I'm going out on a limb here but I'm assuming higenamine will be in the formula based on the reasoning behind including GCB. Interesting formula so fa r I like how AN isn't another me too company and brings new and interesting formulas to the market.
    Good inference- I see you caught that last part....here is a little info on higenamine- on the ingredient descriptions, I discussed SAR quite a bit and the half-lives of the ingredients- I didn't include the structures for comparison, but they are in the final write-up....all of our product development will look like this from here on out- the formula has to make sense, based on a number of factors......

    There are several different options for reducing COMT in the short term- chlorogenic acid is one, plus several other polyphenols contained in coffee. They all have fairly rapid time to onset, and a relatively expedient plasma accumulation, making them a good choice because of the short half-life of higenamine....

    Higenamine-
    Bioavailability- high; logP 2.23
    Onset- within 5 minutes
    Tᵐᵃᵡ- 8-20 minutes (may be extended with a COMT-inhibitor or something to inhibit glucorinidation)
    A compound found in Nandina domestica, Aconite root, and Nelumbo nucifera; benzyl tetrahydroisoquinolone structure dictates poor availability in the CNS due to polar hydrogen atoms on ring structure, but structural orientation on the tetrahydroisoquinolone moiety (meta/para-hydroxylation @ C6 and C7) will allow for beta (βAR-2) and alpha adrenergic receptor docking (αAR)(27,42,51). One side of the molecule (benzyl ring and amine) is a pharmacophore of PEA (left, below), with a chiral center; the distal side of the molecule contains a tetraisoquinolone structure, giving the molecule multiple binding characteristics in different tissues (4). For better insight, note the comparison to methylphenidate (Ritalin) below and the similarities between the left side of the structure of higenamine (PEA pharmacophore) and methylphenidate, with two main differences. One difference is the inclusion of an acetate ester on the beta position of methylphenidate (included for solubility purposes); difference two concerns hydroxylation of the phenyl ring(s). Notice the lack of hydroxylation on the phenyl ring on methylphenidate- this allows the compound to penetrate the BBB with little issue, much like amphetamine or 1,3 DMAA; the hydroxylation on both phenyl rings of higenamine will decrease BBB penetration significantly(20). However, the molecule does contain alpha methylation within the PEA moiety (note R3 in SAR below), making it resistant to metabolism via MAO-B (metabolism of the molecule via COMT is a different story, see chlorogenic acid), which may extend the relative half-life (42). The characteristics of higenamine as a βAR-2 agonist are of greatest interest in Uncut™, as βAR-2 stimulation has been associated with greater acetylcholine release in skeletal muscle, as well as increased eNOS (endothelial nitric oxide synthase, βAR are expressed in vascular tissue) and cellular L-arginine transport via NO-mediated membrane hyperpolarization. Acetylcholine acts as an excitatory neurotransmitter at the neuromuscular junction (NMJ), and the production and availability of acetylcholine tend to be limiting factors in muscular contraction at the NMJ; increasing eNOS allows for the formation greater amounts of nitric oxide (a potent vasodilator) and cyclic GMP.
    Dirk Tanis, BA, MSci
    Chief Operating Officer, Applied Nutriceuticals
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    Awesome stuff I always enjoy reading AN's product write ups. Any logging or sample opportunities on bb.com I'm a little bit more well known there than on this board? Looking forward to the rest of the ingredients, and release of this product.
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    Quote Originally Posted by xhrr View Post
    Awesome stuff I always enjoy reading AN's product write ups. Any logging or sample opportunities on bb.com I'm a little bit more well known there than on this board? Looking forward to the rest of the ingredients, and release of this product.
    I will post structures in the final write-up- this will make a lot more sense with some visual aids. The structures won't transfer over to my post from an MS Word doc; and to answer your question, yes, we will be sampling this product heavily, and there will be a lot of logging opportunities- we want everyone to compare it to what they are currently using for their pre-workout supplementation.....
    Dirk Tanis, BA, MSci
    Chief Operating Officer, Applied Nutriceuticals
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    Sounds very interested.
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    It seems like something I would love to try! I've been using pwo for along time and this reads like it would be up there with the best
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    The pre-workout market is super saturated with the same formulas of X Y and Z in different amounts with a little bit of A B and/or C. Too much of the exact same thing. Yesterday I was in a store looking to try something new but ended up not getting anything because it was all the same stuff over and over. Nothing new and unique... until now.

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    Agreed!!!!
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    Completely agreed!!!


    The pwo needs a jump start!!!
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    Quote Originally Posted by rms80 View Post

    I will post structures in the final write-up- this will make a lot more sense with some visual aids. The structures won't transfer over to my post from an MS Word doc; and to answer your question, yes, we will be sampling this product heavily, and there will be a lot of logging opportunities- we want everyone to compare it to what they are currently using for their pre-workout supplementation.....
    Aussies able to?

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    Quote Originally Posted by runner_79 View Post

    Aussies able to?

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    Good question.
    By believing passionately in something that still does not exist, we create it. The nonexistent is whatever we have not sufficiently desired.
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    Quote Originally Posted by OrganicShadow View Post

    Good question.
    I would love to log it or sample it.

    Especially for endurance and power training

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    Quote Originally Posted by runner_79 View Post
    I would love to log it or sample it.

    Especially for endurance and power training

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    Probably not, unfortunately, BUT I am formulating multiple encapsulated products right now for Australia- they should be hitting the shelves down there over the next few months
    Dirk Tanis, BA, MSci
    Chief Operating Officer, Applied Nutriceuticals
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    Quote Originally Posted by rms80 View Post

    Probably not, unfortunately, BUT I am formulating multiple encapsulated products right now for Australia- they should be hitting the shelves down there over the next few months
    Thanks Dirk.

    Will get some from Nutra. Any hint for us Aussies what's coming down here?

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    Quote Originally Posted by runner_79 View Post
    Thanks Dirk.

    Will get some from Nutra. Any hint for us Aussies what's coming down here?

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    We have a new version of the Black Cats drink we are about to manufacture in a couple weeks- it will be blue raspberry flavor, and quite a bit stronger than the first version in terms of stims......we also have several encapsulated products in the works in multiple different categories- testosterone enhancement, energy, and several others- stay tuned
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    Quote Originally Posted by rms80 View Post

    We have a new version of the Black Cats drink we are about to manufacture in a couple weeks- it will be blue raspberry flavor, and quite a bit stronger than the first version in terms of stims......we also have several encapsulated products in the works in multiple different categories- testosterone enhancement, energy, and several others- stay tuned
    I am becoming a fan of stim drinks. Able to adjust dosage according to scoop. Very good man

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    I have yet to try an App Nut product. I do not know how that came to be, but when this is released, it may be my first.

    Especially interested in amentoflavone. Pretty good article here (if anyone hasn't read it yet: http://hightowerpharmacology.blogspo...toflavone.html
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    Quote Originally Posted by domore View Post
    I have yet to try an App Nut product. I do not know how that came to be, but when this is released, it may be my first.

    Especially interested in amentoflavone. Pretty good article here (if anyone hasn't read it yet: http://hightowerpharmacology.blogspo...toflavone.html
    thanks for the link!
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    Quote Originally Posted by JudoJosh View Post
    thanks for the link!
    No, problem, Judo!
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    Quote Originally Posted by domore View Post
    I have yet to try an App Nut product. I do not know how that came to be, but when this is released, it may be my first.

    Especially interested in amentoflavone. Pretty good article here (if anyone hasn't read it yet: http://hightowerpharmacology.blogspo...toflavone.html
    This is Neuron's blog from BB.com if I am not mistaken- I give him special credit in the finished write-up- he is extremely sharp...
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    Re: Uncut- more ingredients


    Quote Originally Posted by rms80 View Post
    This is Neuron's blog from BB.com if I am not mistaken- I give him special credit in the finished write-up- he is extremely sharp...
    Yes it is. He goes by madchemist on this board

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    Quote Originally Posted by JudoJosh View Post
    Yes it is. He goes by madchemist on this board

    Sent from my SAMSUNG-SGH-I727 using Tapatalk 2
    Here is one of the main MOA's of the product:
    Effect on Excitation-Contraction
    Uncut™ seeks to increase the mechanisms involved in excitation-contraction coupling via increased acetylcholine release (via βAR stimulation from higenamine) and decreased acetylcholine metabolism (AChE Inhibition via Huperzine A, caffeine, and possibly amentoflavone), and also by enhancing calcium release via increasing receptor sensitivity in the SR (caffeine and amentoflavone). Andersson et al. (2012) found that “the enhancement of contractile force (inotropy) occurs in skeletal muscle following neuroendocrine release of catecholamines and activation of muscle β-adrenergic receptors…..the molecular mechanism underlying skeletal muscle inotropy requires enhanced SR Ca(2+) release due to PKA phosphorylation…..”, while Emrick et al. (2010) found “During the fight-or-flight response, epinephrine released by the adrenal medulla and norepinephrine released from sympathetic nerves increase muscle contractility by activation of the β-adrenergic receptor/cAMP-dependent protein kinase pathway and up-regulation of Ca(V)1 channels in skeletal and cardiac muscle.” Therefore, the underlying mechanisms behind the formulation theoretically should produce marked strength gains in users of Uncut™, far past what can be expected with conventional pre-workouts, via the goal of enhancing the process of excitation/contraction. Post-ingestion, Uncut™ for higher acetylcholine levels, and also prevents the metabolism of the increased acetylcholine via AChE. The increased acetylcholine then binds to nicotinic receptors in the motor end plate (see below), stimulating depolarization. Depolarization allows the voltage-gated sodium channels to open and produce action potentials along the sarcolemma. The action potential spreads into the transverse tubules and stimulates the opening of Ca2+ channels, which (directly or indirectly) causes the opening of voltage-gated Ca2+ channels in the sarcoplasmic reticulum. Amentoflavone and caffeine contribute heavily to increasing this process (keep in mind amentoflavone is 20x stronger than caffeine in this mechanism); to better explain the mechanism of skeletal muscle contractions and calcium release, Endo (2009) states “The source of Ca2+ is either the extracellular medium or the membrane-bound intracellular Ca2+ pool, or both…. In striated muscles, the major source of Ca2+ is the intracellular Ca2+ store, not the extracellular medium. The main intracellular Ca2+ store is the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR). This was first demonstrated in skeletal muscle as well: a microsome fraction from skeletal muscle cells was identified as fragments of SR, which were found to strongly accumulate Ca2+ in the presence of ATP. Therefore, studies on the mechanism of Ca2+ mobilization from intracellular stores naturally began in skeletal muscle, and two groups independently and nearly simultaneously discovered that Ca2+ itself causes Ca2+ release. The phenomenon, called calcium-induced calcium release (CICR), was the first possibly physiological mechanism of the Ca2+ mobilization from the intracellular store to be proposed. The discovery of CICR preceded the early detection of the primary Ca2+ release mechanism in skeletal muscle as a change in the voltage sensor of the t-tubule membrane and was much earlier than the discovery of inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release. The primary event of physiological Ca2+ release, the Ca2+ spark, is the simultaneous opening of multiple channels, the coordinating mechanism of which does not appear to be CICR because of the low probability of CICR opening under physiological conditions. The coordination may require Ca2+, but in that case, some other stimulus or stimuli must be provided simultaneously, which is not CICR by definition. Thus CICR does not appear to contribute significantly to physiological Ca2+ release. On the other hand, CICR appears to play a key role in caffeine contracture and malignant hyperthermia. The potentiation of voltage-activated Ca2+ release by caffeine, however, does not seem to occur through secondary CICR, although the site where caffeine potentiates voltage-activated Ca2+ release might be the same site where caffeine potentiates CICR. “ (16,20,23-24)
    Dirk Tanis, BA, MSci
    Chief Operating Officer, Applied Nutriceuticals
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    Quote Originally Posted by JudoJosh View Post
    Yes it is. He goes by madchemist on this board

    Sent from my SAMSUNG-SGH-I727 using Tapatalk 2
    That would explain some things- it completely changed how I look at a lot of things.....
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    Quote Originally Posted by rms80 View Post
    This is Neuron's blog from BB.com if I am not mistaken- I give him special credit in the finished write-up- he is extremely sharp...
    Yes, it is neuron's blog. Very, very informative. I'm always checking on it to learn new things, and it helps direct (or steer me away) from certain products.

    Quote Originally Posted by JudoJosh View Post
    Yes it is. He goes by madchemist on this board

    Sent from my SAMSUNG-SGH-I727 using Tapatalk 2
    I believe he is banned on here as well.
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    Quote Originally Posted by JudoJosh View Post
    Yes it is. He goes by madchemist on this board

    Sent from my SAMSUNG-SGH-I727 using Tapatalk 2
    Hey judo, check your PM's please.
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