So some people are private messaging me and asking what the heck is the Hesperetin for again? Briefly, my theory is that since it's a more selective PDE4 inhibitor than artichoke, but is weaker, combining the two would result in a stronger CILTEP effect with fewer side effects.
There are two ways that I've gone wrong with this stack. First, triggering what are known as PDE4H or "high-affinity rolipram binding sites". For instance, Genistein does this (
http://www.ncbi.nlm....pubmed/20599919). This causes gastrointestinal disturbances. The other problems arise from strongly inhibiting non-PDE4 subtypes. This is caused by using a herbal PDE4 inhibitor with non-selective inhibition. For instance, PDE3 inhibition has undesirable side effects. See (
http://en.wikipedia..../PDE3_inhibitor). PDE2 may have some use as a memory enhancer (
http://www.ncbi.nlm....pubmed/16968949). PDE1 inhibition is considered a possible drug target for treating neuro-degenertive diseases(
http://www.ncbi.nlm....pubmed/15798894). PDE5 is what Viagra and Cialis inhibit and you all know what those do. So basically PDE3 inhibition is the one to avoid and I haven't really heavily looked into the non PDE4 ones, so I would not bother with specifically targeting them.
So these two issues cause the PDE4 inhibitor effect to be limited by the side effects of inhibition of other PDEs, mainly 3, and from the PDE4H effects (gastrointestinal disturbances).
Artichoke (Luteolin) IC50 values:
http://www.ncbi.nlm....pubmed/19853596PDE1-5 activities, with K(i) values of 15.0, 6.4, 13.9, 11.1, and 9.5
So it's inhibiting PDE2, PDE5 and PDE4, most selectively. However PDE3 is getting inhibited and PDE4H is also getting activated:
The therapeutic (PDE4(H)/PDE4(L)) ratios of luteolin and Ro 20-1724 were calculated to be 0.6, and 0.004 ... In conclusion, because of the low therapeutic (PDE4(H)/PDE4(L)) ratio of luteolin, the gastrointestinal adverse effects such as nausea, vomiting and gastric hypersecretion should be carefully monitored, whenever luteolin is used for treating allergies, asthma or chronic obstructive pulmonary disease.
Well I haven't experienced any nausea or vomiting or stomach problems at the two pills or less of artichoke, so I guess I'm not taking enough to encounter these problems at these dosages. Going past taking two pills is not advised.
The bright side of this is that PDE4 inhibition is still low at the dosages I'm taking and there's plenty of room for improvement. In order to get to higher PDE4 inhibition a way needs to be found around the side effects by choosing a more selective PDE inhibitor that has no action at PDE3 and is more selective for PDE4 and doesn't trigger PDE4H receptors.
Enter Hesperetin
http://www.ncbi.nlm....pubmed/22454667Hesperetin was revealed to have a therapeutic (PDE4(H)/PDE4(L)) ratio of >11
...
The respective EC50 (PDE4H) values of rolipram, Ro 20-1724, and hesperetin for displacing [3H]-rolipram binding were 7.5 ± 3.4 (n = 4) nM, 45.6 ± 9.7 (n = 4) nM, and >300μM.
So since high values mean less effectiveness, Hesperetin was several orders of magnitude less likely to trigger PDE4H than the highly targeted synthetic PDE4 inhibitors.
On to PDE inhibition
http://www.ncbi.nlm....pubmed/22074248HDME did not inhibit PDE2 or PDE5 activities (IC50 value > 100 μM), but it concentration-dependently inhibited PDE1, PDE3, and PDE4 activities with respective IC50 values of 22.1 ± 6.4 (n = 4), 24.6 ± 3.5 (n = 4), and 3.0 ± 0.9 μM (n = 4)
The IC50 value of HDME (Lipid Soluble Hesperetin) for PDE4 inhibition was significantly less than those for PDE1 and PDE3 inhibition.
So the lipid soluble version was roughly 7x more selective on PDE4 than PDE3 or PDE1!
The non lipid soluble version also was more selective
http://www.ncbi.nlm....pubmed/15476679Hesperetin and prunetin exhibited more-selective inhibition of PDE4 with IC(50) values of around 30 and 60 microM,
So the PDE4 inhibition of Hesperetin that is not chemically tweaked to be fat soluble is about 1/10th the tweaked version. If the same holds true for PDE3 and PDE1 then their inhibition is very small.So anyway, makes me wonder if I should just replace Artichoke with Hesperetin.
The problem is that Hesperetin has a weak ic50 value for PDE4 inhibition. Thus, I would theorize that if I stacked artichoke underneath it, it will further push up PDE4 inhibition such that it gets a little higher with minimal side effects from PDE3 inhibition and PDE4H binding. I could take a Hesperetin only stack to minimize any possible issues. Maybe 2 Hesperetin and 1 Artichoke?You're probably wondering how is good ol' Quercetin stacking up?
http://www.sciencedi...006295204004770The same was true for quercetin, but we rather consider that it more-selectively inhibited PDE3 and PDE4 (IC50 of <10 μM).
So since I don't want strong PDE3 inhibition, I'll probably avoid Quercetin.
I'll report back later this week if the Hesperetin stack tweak works. So far so good.
TL;DR Hesperetin has less side effects as a PDE4 inhibitor than Artichoke but is weaker. Adding a Hesperetin to the stack seems to help improve the effect without causing negative effects. Might consider halving my artichoke dose and replacing it with Hesperetin.
Edited by abelard lindsay, 25 June 2012 - 08:24 AM.