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Showing posts with label mechanism of action. Show all posts
Showing posts with label mechanism of action. Show all posts

Sunday, September 6, 2015

{REVIEW} Top Extracts Kava Extract 70% Kavalactones Extract (Piper Methysticum)


Since I was very pleased with my experience of Top Extracts Syrian Rue product; I decided to give their Kava extract a go as well!

Now Kava is one of my favorite relaxing herbs for a number of reasons.

1.) It doesn't cause cognitive / memory related issues and is not classically a 'sedative'.

2.) It has some euphoric properties.

3.) It doesn't give you that 'dulled out' feeling so many other herbal anxiolytic's do.

Next -  I am going to quickly go over the mechanism of action of this remarkable plant. It's a pharmacologically active psychotropic herbal substance.
It's effects are primarily mediated through compounds in the plant known as 'kavalactones'. As a herbal supplement - it's difficult to tell how much EXACTLY we are getting - but based my extensive experience with herbs; including Kava - I can tell you this is the most potent brand and a bang for your buck!


KAVA < Mechanism of Action >
HOW DOES IT WORK

1.) It's main mechanism of action as far as anxiety is concerned - seems to be as a positive allosteric modulator of the GABA-A system(1).  Ironically, it is also able to inhibit excessive GABA-A function as well(2).

2.) However, it's euphoric properties and reported efficacy against social anxiety may come from it's dopaminergic properties - this is the "true" "feel-good" property of the Kava(3). Specifically, it acts as a MAO-B inhibitior which prevents the breakdown of dopamine thus raising it's levels in the periphery, brainsteam, hypothalamus etc (4) (5)

3.) Kava has some similarities to Cannabis; in fact, it acts on the same receptors cannabis acts on to modulate brain-neural activity. Kava's constitutes stimulate the CB1 receptor; but less potently than THC and other 'true' cannbinoids(6).

4.) Kava has sodium channel blocking (Na+) and calcium/calmodulin channel blocking properties (Ca2+) - it also increases potassium channel (K+) outflow which is similar to the mechanism of action of mood stabilizer drugs - this accounts for some of Kava's central anti-anxiety effects as well(7).


Sodium channels interact with neuronal systems; generally increasing the firing of histaminergic and noradrenergic systems - in turn, sodium channel ions are also provoked on the inverse pathway ; such as when histamine or noradrenaline are increased .

Thus it is a supportive - interexchangeable pathway which leads to a cycle of anxiety and epilepsy is thought to in part, be  a result of excessive sodium channel activity.

Calcium channels also can have stimulating effects - but their effects are dependent on whether the activated current is 'L-TYPE' or 'N-TYPE' - generally though, blocking calcium channels reduces sympathetic nervous system activity leading to less anxiety and heart rate as well!

Potassium channels generally are calming, however - they can also lead to increased noradrenalin release - increased noradrenaline can technically have the opposite effect but it depends on where it is located and how much...noradrenaline in low-moderate amounts can actually help with anxiety and attention - but high amounts lead to a plethora of anxiety disorders..kava seems to over-step or bypass the traditional adrenergic pathways - so the net effect is still a calming-one with a reduction in anxiety and mania.



Let me get into the taste..and by the way I confirm this is DEFINITELY genuine KAVA KAVA and the shop owner is a very nice guy and definitely reasonable. As stated in my last review!


                                                 TASTE 


  • Kava almost has a light nutmeg type taste - I don't really know how else to describe it, it's a little 'sweeter' than Syrian Rue but not really 'sweet' per se..if that makes sense.
  • It isn't a harsh taste as long as you don't gobble down several teaspoons at once and you dilute it properly..it's just another 'non-native' 'exotic' TEA-TASTE!
  • It's a yellow-ish powder, darker than dandelion but lighter than gold.


                                            EFFECTS 
  • Took 1 gram the first day, and didn't notice a whole heck of a lot.
  • Did 2 grams the second day - twice. My whole agenda was to see whether it would have any effect on anxiety or OCD really. It did seem to help take the edge off but at this dose I still couldn't really call it. 
  • The effects on 2.5 grams on the other hand were much more conceivable - well..noticeable! Interesting how such a small difference in dose could measure up to such 'supplemental' effects.
  • At this point it is on a similar magnitude as magnolia extract - it not only has obliterated my 'intrusive thoughts' but furthermore, on the second dose is when euphoria became more apparent!
  • A beautiful thing indeed!
  • I found it seemed to enthuse and super-charge my personality at 3 grams - though I wouldn't really call it an 'anti-manic' effect, ironically - it actually felt like a minor stimulant but not a jittery type.but at the same time - anxiety was GONE!
  • I also slept like a baby without my normal stack of magnolia and lemon balm! Which is good because I often have terrible insomnia!
  • The effects at higher doses were definitely more on the euphoric end - but the calming never goes away ironically - so no paradoxical negatives there! At higher doses it's like visual-sensory-motory enhancement in terms of everything around you seeming much 'brighter'...it was actually similar to Syrian Rue in some ways which I guess makes sense because they both are MAO inhibitors..
  • Kava had no impairing effects; even at the highest dose I tried (7 grams at once) - it just continued with a euphoric burst - although the odd thing is my appetite was done during this run.
  • You would think being on something more 'relaxing' would equate to higher appetite..but I guess things aren't always that linear..
  • I found lower doses to actually add in some 'odd recall' of old events from my past - and it actually slipped in some 'dream-like' states throughout the day..which brings me to my next point!
  • My dreams were not necessarily disturbing while on KAVA; lucid, but NOT disturbing!
  • Very bizarre and far-fetched, very odd like a bunch of worlds colliding onto one bridge and then that bridge converting into something whilst I was floating near it! That said in a literal sense but also a metaphorical sense - It was like there were dreams overlapping each other in my sleep - more than like a 'movie set' - but rather like a movie composed of optical illusions with some significant 3-D sprites and some very alluring subjects which I tend to emphasize quite a bit (spirits, world events, outer politics etc).
  • Besides these incredibly vivid dreams - I can't say that there is something else really outlandish at all about the herb - but at the same time it certainly is not as 'plain' as like lemon balm or magnolia..the effects are subtle at first but it definitely will hit you more so on day 2 or 3...it does have immediate effects though ; you just have to get the dose right!
  • For those unaware, dose will vary per person - me and a buddy of mine are about the same weight and he needs 3x the amount that I do to feel the same effects!
  • Therefore consume with caution as with any herbal substance or any substance for that matter - always start with lower doses!

ALL IN ALL RATING 
5/5
   Excellent excellent KAVA product, seriously, I love this stuff!!
  Guy offers the most bang for your buck as well! Very Reasonable!



KAVA KAVA extract by TOP EXTRACTS can be bought at the link below. Made it easy for ya!!
---------------------► KAVA EXTRACT TOP EXTRACTS ◄---------------------



Tuesday, July 22, 2014

Full Pharmacodynamics / Mechanism of Action Overview of "ICARIIN"



Another compilation. This time I aim to effectively outline the many mechanisms of action for "Icariin" and this includes the more obscure pathways. Icariin is well-defined as a "natural PDE-5" inhibitor - but it actually affects vascular function by other pathways as well.

Icariin is a compound isolated from the plant "Epimedium" also known more commonly as "Horny Goat Weed" - it has been shown to have neuroprotective effects, anti-depressant effects and erectogenic effects. It may help treat Alzheimer's and other memory disorders and can effectively treat high blood pressure.





MECHANISM #1 

PDE-5 Inhibition / cGMP Synthesis / nNOS Acitvator


    OVERVIEW / SUMMARY 

Icariin decreases the "expression" of PDE-5 enzymes over time, this means that there is a long-term decrease yielding permanent changes in genetic coding to this enzyme. As opposed to just temporarily blocking it, which it also does. 

NOTE :: By this mechanism one could presume (though it has lower affinity than Say, Viagra) that it may give one more leverage over time as well as a permanent enhancing effect. Many people ask then, how long before Icariin supplements kick in or how long do they take to work?

ANSWER :: Based on the studies, it would seem plausible that minor effects would be felt in the first couple days (due to inhibition of PDE-5), but the peak effects would come after any where from 2-4 weeks of use(due to downregulation).
 


To further investigate the mechanisms of action of icariin (ICA), we assessed the effects of ICA on the in vitro formation of cGMP and cAMP in isolated rabbit corpus cavernosum. Isolated segments of rabbit corpus cavernosum were exposed to increasing concentrations of ICA and the dose-dependent accumulation of cGMP and cAMP was determined in the tissues samples by means of 125I radioimmunoassay. Responses of the isolated tissues preparations to ICA were compared with those obtained with the reference compounds sildenafil (Sild). Furthermore, the effects of ICA on the mRNA expression of specific cGMP-binding phosphodiesterase type V (PDE5) in rat penis were also observed. After incubation with ICA for 6 h or 14 h respectively, the levels of PDE5 mRNA were examined by reverse transcriptase polymerase chain reaction (RT-PCR). The results showed that ICA increased cGMP concentrations directly (P < 0.05), but there was no significant effect on cAMP concentrations (P > 0.05). In the presence of sodium nitroprusside (SNP), a stimulatory agent of cGMP, both ICA and Sild increased cGMP concentrations with increasing dose (P < 0.01). Their EC50 was 4.62 (ICA) and 0.42 (Sild) micromol/L respectively. Under the same condition, ICA and Sild unaltered cAMP level significantly (P > 0.05). There were PDE5A1 and PDE5A2 mRNA expressions in rat corpus cavernosum with PDE5A2 being the dominant isoform. ICA could obviously inhibit these two isoforms mRNA expression in rat penis, and decrease PDE5A1 more pronouncedly (P < 0.01). The present study indicated that the aphrodisiac mechanisms of icariin involved the NO-cGMP signal transduction pathway, with increasing cGMP levels in the corpus cavernosum smooth muscle. The inhibitory effect of icariin on PDE5 mRNA expression, especially on PDE5A1, might account for its molecular mechanisms for its long-term activity.


                                 ____________________________________________
                     
J Nat Prod. 2008 Sep;71(9):1513-7. doi: 10.1021/np800049y. Epub 2008 Sep 9.

Potent inhibition of human phosphodiesterase-5 by icariin derivatives.

Dell'Agli M1, Galli GV, Dal Cero E, Belluti F, Matera R, Zironi E, Pagliuca G, Bosisio E.

 Abstract

Plant extracts traditionally used for male impotence (Tribulus terrestris, Ferula hermonis, Epimedium brevicornum, Cinnamomum cassia), and the individual compounds cinnamaldehyde, ferutinin, and icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Human recombinant PDE5A1 was used as the enzyme source. Only E. brevicornum extract (80% inhibition at 50 microg/mL) and its active principle icariin (1) (IC50 5.9 microM) were active. To improve its inhibitory activity, 1 was subjected to various structural modifications. Thus, 3,7-bis(2-hydroxyethyl)icaritin (5), where both sugars in 1 were replaced with hydroxyethyl residues, potently inhibited PDE5A1 with an IC50 very close to that of sildenafil (IC50 75 vs 74 nM). Thus, 5 was 80 times more potent than 1, and its selectivity versus phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) was much higher in comparison with sildenafil. The improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make compound 5 a promising candidate for further development.

PMID: 18778098 [PubMed - indexed for MEDLINE]


___________________________________________________________________________________
Abstract

OBJECTIVES: To investigate the effect of icariin on the cyclic guanosine monophosphate (cGMP)-hydrolytic activity of phosphodiesterase-5 (PDE5) isoforms and the cGMP levels in cavernous smooth muscle cells treated with sodium nitroprusside (SNP).




METHODS: PDE5 isoforms (PDE5A1, A2, and A3) were isolated from sf9 insect cells infected with baculoviruses carrying PDE5 isoform cDNA. Icariin was isolated from Epimedii herba. Varying amounts (10(-6) to 10(-11) M) of icariin or zaprinast were added to reaction mixtures containing PDE5 isoforms and cGMP. The inhibitory effects of icariin and zaprinast were analyzed by GraphPad Software and are expressed as concentration that inhibits 50% (IC50) values. Cavernous smooth muscle cells were isolated from 3-month-old rats, treated with icariin (100 and 200 microM) or zaprinast (200 microM) for 15 minutes, and then with 10 microM SNP for 30, 60, 120, 240, and 360 minutes. The cells were then analyzed for the cGMP concentration using an enzyme immunoassay system.

RESULTS: Icariin inhibited PDE5A1, A2, and A3 with an IC50 value of 1.0, 0.75, and 1.1 microM, respectively. The corresponding IC50 values for zaprinast were 0.33, 0.23, and 0.32 microM. Icariin consistently outperformed the control (SNP-only treatment) in maintaining greater cGMP levels, particularly at the greater concentration of 200 microM. In contrast, zaprinast at 200 microM did better than the control only at 60 and 360 minutes. CONCLUSIONS: Icariin was inhibitory to all three PDE5 isoforms with similar IC50 values, which were approximately three times greater than those for zaprinast. Icariin was able to enhance cGMP levels in SNP-treated cavernous smooth muscle cells.

PMID: 17169663 [PubMed - indexed for MEDLINE]

                                                        MECHANISM #2 
                          
                                  Calcium Channel Regulator


Icariin appears to be able to inhibit inward calcium currents and protect against excitotoxicity (namely Glutamate) by this mechanism. Thus, it can be seen as a type of Ca2+ modulator.

Calcium Channels normally act to excite the nervous system and increase levels of glutamate, acetylcholine and norepinephrine.

                 
               http://www.ncbi.nlm.nih.gov/pubmed/20128049
Abstract

Overload of intracellular calcium caused by amyloid-beta peptide has been implicated in the pathogenesis of neuronal damage in Alzheimer's disease. Voltage-gated calcium channels (VGCCs) provide one of the major sources of Ca(2+) entry into cells. Here, we investigated whether icariin had effect on the changes of calcium currents induced by Abeta(25-35) in hippocampal pyramidal neurons. Using whole-cell patch-clamp, we showed that Abeta(25-35) enhanced the inward Ba(2+) and Ca(2+) currents. The currents were partially inhibited by Ni(2+) and completely suppressed by Cd(2+), indicating that Abeta(25-35) disrupts intracellular calcium homeostasis via the modulation of both L- and T-type channels. Furthermore, Icariin nearly complete suppressed the abnormal inward calcium currents induced by Abeta(25-35) in a dose-dependant manner. Our findings suggest that the potential neuroprotective effect of icariin on Abeta(25-35)-induced neurotoxicity via the balance intracelluar calcium homeostasis.

PMID: 20128049 [PubMed - indexed for MEDLINE]



MECHANISM #3   

"Testosterone Mimetic"



Abstract AIM: To evaluate the testosterone mimetic properties of Icariin.

METHODS: Forty-eight healthy male Sprague-Dawley rats at the age of 15 months were randomly divided into four groups with 12 rats each: the control group (C), the model group (M), the icariin group (ICA) and the testosterone group (T). The reproductive system was damaged by cyclophosphamide (intraperitoneal injection, 20 mg/kg x day) for 5 consecutive days for groups M, ICA and T, at the sixth day, ICA (gastric gavage, 200 mg/kg x day) for the ICA group and sterandryl (subcutaneous injection, 5 mg/rat . day) for the T group for 7 consecutive days, respectively. The levels of serum testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), serum bone Gla-protein (BGP) and tartrate-resistant acid phosphatase activity in serum (StrACP) were determined. The histological changes of the testis and the penis were observed by microscope with hematoxylin-eosin (HE) staining and terminal deoxynucleotidyl transferase biotin-dUTP-X nick end labeling (TUNEL), respectively. RESULTS: (1) Icariin improved the condition of reproductive organs and increased the circulating levels of testosterone. (2) Icariin treatment also improved the steady-state serum BGP and might have promoted bone formation. At the same time, it decreased the serum levels of StrACP and might have reduced the bone resorption. (3) Icarrin suppressed the extent of apoptosis of penile cavernosal smooth muscle cells.

CONCLUSION: Icariin has testosterone mimetic properties and has therapeutic potential in the management of hypoandrogenism.

PMID: 16751992 [PubMed - indexed for MEDLINE]


MECHANISM # 4 

"AChE Inhibitor" (Acetylcholinesterase Inhibitor)


Icariin may increase levels of acetylcholine by blocking the enzyme that breaks it down.

Acetylcholinesterase (AChE) inhibitors are mainly used in the treatment of Alzheimer's disease (AD). The inhibitory effect of icariin on the activity of AChE was investigated by inhibition kinetics. The binding interaction and binding sites between icariin and AChE were also studied by using fluorimetry and molecular docking, respectively. The results showed that icariin could potently inhibit the activity of AChE, the IC50 value was determined to be 3.50 x 10(-8) mol x L(-1), and the determined IC50 value to tacrine was 0.75 x 10(-8) mol x L(-1). Kinetic analyses showed that icariin is a reversible and mixed type AChE inhibitor. The inhibition constants K1 and K(IS) were determined to be 2.67 x 10(-8) and 4.43 x 10(-8) mol x L(-1), respectively. Icariin binds selectively to the AChE peripheral anionic site via hydrogen bonds and Van der Waals forces.

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