tag:blogger.com,1999:blog-5081537833114332620.post6845774330680519812..comments2023-10-01T08:39:28.907-07:00Comments on High Tower Pharmacology: Pharmacology of HederageninS.P. O'Brienhttp://www.blogger.com/profile/05914114201709643845noreply@blogger.comBlogger10125tag:blogger.com,1999:blog-5081537833114332620.post-30453578527502470392019-03-18T06:55:49.015-07:002019-03-18T06:55:49.015-07:00Ganodermanondiol is a triterpenoid compound found ...Ganodermanondiol is a triterpenoid compound found in the fruit body of Ganoderma lucidum. Study shows that Ganodermanondiol exhibits the inhibitory effect on the proliferation of HL60 and K562 human tumor cells. <a href="https://www.bocsci.com/ganodermanondiol-cas-107900-76-5-item-160236.html" rel="nofollow">Ganodermanondiol</a><br /><br />Anonymoushttps://www.blogger.com/profile/12128271861530734257noreply@blogger.comtag:blogger.com,1999:blog-5081537833114332620.post-56011278344875719142013-06-06T14:58:14.504-07:002013-06-06T14:58:14.504-07:00Never heard of it, off hand. Does it have a common...Never heard of it, off hand. Does it have a common name? Any research?S.P. O'Brienhttps://www.blogger.com/profile/05914114201709643845noreply@blogger.comtag:blogger.com,1999:blog-5081537833114332620.post-71479515725566514962013-06-04T16:17:46.008-07:002013-06-04T16:17:46.008-07:00any info on 3-(4-aminophenyl)-3-cyclohexyl-2, 6-pi...any info on 3-(4-aminophenyl)-3-cyclohexyl-2, 6-piperidinedioneLendohttps://www.blogger.com/profile/12270232843124968831noreply@blogger.comtag:blogger.com,1999:blog-5081537833114332620.post-51991946770201196362013-05-08T11:25:14.582-07:002013-05-08T11:25:14.582-07:00You are perseverating about the idea of a "po...You are perseverating about the idea of a "porous" BBB. It is a well known axiom that the human BBB is more selective and with much more effective efflux mechanisms. If you want to argue with this idea, then perhaps this blog is not for you.<br /><br />Please tell me the Vd of glycyhrritinic acid. Tyler et al. 1988 is not a suitable citation. The article you referenced was a review article which simply noted a "large" Vd, which is quite subjective depending on the context.<br /><br />Ultimately, if you want to argue that hederagenin would have the potential for BBB penetration, you need to demonstrate an adequate volume of distribution (or an active influx mechanism, which doesn't exit). <br /><br />The second thing you need to explain is how hederagenin would remain unionized in the blood (since hydrophobicity) would establish BBB penetration). A lot of people think the "Log P" of a compound is an adequate reflection of its lipophilicity, however they aren't taking into consideration the solvent for which it will be coadministered. <br /><br />In order to calculate its ionization in the blood, start with the base formula:<br /><br />pH = pKa + log([A-]/[HA])<br /><br />Which can be qualitatively tweaked for a weak acid:<br /><br />log (nonizonized/anionic) = pKa - pH<br /><br />and further:<br /><br />pKa - pH = (4.9 - 7.4) = -2.5<br /><br />The difference of >2 = 99 to 99.9% ionzied (when inverted for the negative)<br /><br />There are ways to decrease ionization (glucuronidation), but they only diminish the BBB permeability coefficient even further (from negligable to zero). <br /><br />I just don't see hederagenin reaching the CNS without covalent modifications.S.P. O'Brienhttps://www.blogger.com/profile/05914114201709643845noreply@blogger.comtag:blogger.com,1999:blog-5081537833114332620.post-41141351822618549512013-05-07T21:52:44.525-07:002013-05-07T21:52:44.525-07:00I'll ask again. From where do you get the ass...I'll ask again. From where do you get the assumption that the rat blood brain barrier is somehow more porous than the human blood brain barrier? The scant evidence out there seems to suggest the opposite, if anything. <br />Cherry-picking is one thing, but I haven't been able to find a shred of evidence which supports your position. I've 'cherry-picked' the only decent studies on the subject, as far as I'm aware. I'd honestly be happy if you were to provide evidence to the contrary.<br /><br /><br />As for boswellic acid: I don't believe that the pharmacokinetic differences would be nearly so great as you suggest, but let's leave it aside for now. Where there is data to look at, most triterpenes seem to have large volumes of distribution. β-glycyhrritinic acid, decidedly not any more amphipathic than hederagenin, is said to have a large volume of distribution: http://webda.mums.ac.ir/pdf/Glycyrrhiza%2520sp.pdf<br />...And, like the boswellic acids and presumably like hederagenin, it also crosses the BBB quite easily. (PMID: 22488528)<br /><br />Celastrol -- an extremely interesting compound, by the way -- crosses the BBB and is strongly neuroprotective in animal models. (PMID: 16092942, 20211007 )<br /><br />Ursolic acid is also presumed to cross the BBB. (PMID: 21835916) It's part of an FDA compound screening library, "selected for their [high] likelihood to cross the blood-brain barrier."<br /><br />I believe that the consensus opinion is that betulinic acid also crosses the BBB. It was, at least, shown to cross the BBB in mice to some extent. <br /><br />We'll both agree that the bioavailability of hederagenin is very poor. That said, I think that it's misguided to assume that hederagenin has absolutely null bioavailability and zero ability to cross the blood brain barrier, when there seems to be plenty of evidence to the contrary.<br />As an aside, I quite enjoy reading your blog. Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-5081537833114332620.post-44299787824986139662013-05-07T14:20:43.942-07:002013-05-07T14:20:43.942-07:0011-keto-beta-boswellic acid is an amphipathic comp...11-keto-beta-boswellic acid is an amphipathic compound which allows for greater distributive properties in addition to BBB penetration (thus explaining the Vd and the BBB permeability you report). Hederagenin is not. They are not physicochemically similar except for possessing the steroidal backbone.<br /><br />They first study you posted above is in reference to a specific active transport mechanism (P-glycoprotein), and hederagenin is not even a substrate.<br /><br />The second study is contextually irrelevant. Please do not cherry pick the literature.S.P. O'Brienhttps://www.blogger.com/profile/05914114201709643845noreply@blogger.comtag:blogger.com,1999:blog-5081537833114332620.post-41193973643101150122013-05-07T13:08:37.607-07:002013-05-07T13:08:37.607-07:00There is indeed little data out there where Hedera...There is indeed little data out there where Hederagenin is concerned. So let's look at very similar molecules instead of pure conjecture: 11-keto-beta-boswellic acid has a Vd of approximately 141 L in human volunteers, following oral administration. (PMID: 15070181) It is extremely close to Hederagenin in terms of chemical structure and molecular properties. What's more, there's evidence that it, too, crosses the BBB. <br /><br />(When assessing a compound's a ability to cross the blood brain barrier, Vd is certainly not the only thing I would look at, but that's another matter entirely...)<br /><br />From where do you draw the assumption that the rat BBB is so much less permeable than ours? I don't think that the data is on your side here. There are several studies to look at, but this is perhaps the most direct: http://dmd.aspetjournals.org/content/37/3/635.long<br />"Distribution to the brain of the three studied radioligands [11C]verapamil, [11C]GR205171, and [18F]altanserin were clearly higher in humans, monkeys, and minipigs than in rats and guinea pigs, as described with brain concentrations; SUV; and the brain-to-plasma concentration ratios, Kp."<br /><br />In this study, morphine seemed to have a significantly harder time crossing the rat BBB as opposed to the human or porcine BBB: http://europepmc.org/abstract/ETH/8586<br /><br />The pharmacokinetic studies of Hederagenin in rats are compelling, and to discount them utterly without a clear reason for doing so is nonsensical.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-5081537833114332620.post-44517597631014663222013-05-06T17:42:32.043-07:002013-05-06T17:42:32.043-07:00If it had significant access to the CNS (Vd > 1...If it had significant access to the CNS (Vd > 100 L), then it could act as a stimulant. Unfortunately, we know very little about its pharmacodynamic profile. For example, some reuptake inhibitors (i.e. vanoxerine) also block other catecholamine receptors, and so the end effect could be anything but stimulation. Based on the numbers above (0.22±0.04 nm), hederagenin appears to be *significantly* more potent at inhibiting norepinephrine reuptake, which may actually make it sedating (i.e. atomoxetine). Ultimately, I do not see this compound being able to penetrate the blood brain barrier (at all) and so its probably just an exercise in mental gymnastics.S.P. O'Brienhttps://www.blogger.com/profile/05914114201709643845noreply@blogger.comtag:blogger.com,1999:blog-5081537833114332620.post-14669043162312803972013-05-06T17:28:12.291-07:002013-05-06T17:28:12.291-07:00Anteus Labs Axon?Anteus Labs Axon?Lendohttps://www.blogger.com/profile/12270232843124968831noreply@blogger.comtag:blogger.com,1999:blog-5081537833114332620.post-77643362691498117692013-05-06T16:22:15.608-07:002013-05-06T16:22:15.608-07:00someone in the bodybuilding forum said it is a sti...someone in the bodybuilding forum said it is a stimulant, do you agree with that? Curious about it.Anonymoushttps://www.blogger.com/profile/18243721939630967036noreply@blogger.com