Repeat use...but look at the skin in the mirror after application. It will be noticeable red

J Pharmacol Exp Ther. 2007 Nov 26 [Epub ahead of print]Click here to read Links
Pharmacological Characterization of MK-0974, a Potent and Orally Active CGRP Receptor Antagonist for the Treatment of Migraine.
Salvatore C, Hershey J, Corcoran H, Fay J, Johnston V, Moore E, Mosser S, Burgey C, Paone D, Shaw A, Graham S, Vacca J, Williams T, Koblan K, Kane S.

Merck Research Laboratories.

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiology of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical proof-of-concept in the acute treatment of migraine was demonstrated with an intravenous formulation of the CGRP receptor antagonist BIBN4096BS. Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-0974. In vitro, MK-0974 is a potent antagonist of the human (Ki = 0.77 nM) and rhesus (Ki = 1.2 nM) CGRP receptors, but displays > 1500-fold lower affinity for the canine and rat receptors as determined via [(125)I]-hCGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilatation, generated by capsaicin-induced release of endogenous CGRP, with plasma concentrations of 127 nM and 994 nM required to block 50% and 90% of the blood flow increase, respectively. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist which may be valuable in the acute treatment of migraine.

PMID: 18039958 [PubMed - as supplied by publisher]

Good sign of vasodilation methinks.

Does anyone have any studies that show that [i]directly[/u] raspberry ketones are vanilloid agonists and/or that they cause CGRP release?

Raspberry Ketones
Raspberries are appropriately touted as a wonderfully nutritious fruit and snack. Interestingly, several of its chemical constituents -- when extracted and isolated -- are found to have medicinal benefits. Such is the case with the raspberry ketone (4-(4-hydroxyphenyl) butan-2-one; abv. RK). Researchers were curious to contrast its affects to structurally similar drugs: synephrine and capsaicin.

As one might expect the physical characteristics of RK elicit a unique response at the cellular level. Whereas synephrine has been shown to directly bind and activate beta receptors, a quality that RK's lack, their key functional role lies in the potentiation of the rate limiting step in the fat burning process: the hydrolysis of triacylglycerol (TAG). This process is mediated by the catalytic protein HSL, or hormone-sensitive lipase, which is recruited to lipid droplets in the cytoplasm in a cAMP-dependent manner (21). RK's have been shown to sufficiently enhance the localization of HSL within the cell to dramatically increase the rate of this crucial reaction (22).

Unfortunately, the literature has yet to characterize RK's to the degree in which its structural analogs, notably capsaicin, have been scrutinized and investigated. With caution, we can extend their physical similarity unto the potential for paralleled signaling pathways, and thus observe commonalities in downstream cellular events. In this vein, the warming sensation observed in our beta testing suggests that RK's do have similar metabolic consequences when administered in a topical matrix. Offering support are the observations made by Kawada et al (1986) whose group documented comparable increases in oxygen consumption following ingestion of either capcaisin, or RK's (23). Additionally, unpublished data recorded the ability for RK's to enhance a critical marker of mitochondrial activity, cytochrome C oxidase, demonstrating RK's ability to increase cellular metabolism, albeit in a mouse model.

Further consideration should be given to the capsaicin-like properties of RK's given their potency as a vasodialator, and its ability to induce transient insulin insensitivity. The latter, through stimulation of vanilliod receptors prompting the release of Calcitonin Gene Related Peptide (CGRP), another highly potent vasodialator. CGRP is highly instrumental in reducing the capacity of the adipocyte to absorb glucose through the insensitivity alluded to above. While this property is unfavorable in other tissues, starving adipocytes of the necessary energy supply is a novel mechanism to induce apoptosis and consequently lose fat! This brilliant hypothesis brought us SpookyDerm, a vicious blend of Lipoderm Ultra, pain-inducing capsaicin, and nicotine. While we have Spook to thank for the original concept, we have RK's to thank for the widespread popularity of this pain-free approach to unsurpassed topical fat loss.

Thanks guys. I've already read the writeup and I've seen already studies that show that capsaicin causes CGRP release. What I'm asking is, is there a study that definitively shows that RK's cause CGRP release? Or is this more of a "guess" based on the fact that RK's shares a structural similarity to capsaicin?

Thanks guys. I've already read the writeup and I've seen already studies that show that capsaicin causes CGRP release. What I'm asking is, is there a study that definitively shows that RK's cause CGRP release? Or is this more of a "guess" based on the fact that RK's shares a structural similarity to capsaicin?

A very minute amount of the yohimbine is systematically absorbed (if any) and I believe that the warning about high blood pressure is on every OTC drug and supplement in order to avoid legal issues arising from using several drugs/supps simultaneously.In this case,problems could arise but I really don;t think Napalm would present a problem for you.

Note that this is my personal opinion and I'm not a doctor,nor is this the official party line of Avant Research either.

I'd think someone else should be able to answer this,send Par Deus,Stay Puft or Sir Savage a PM.

Speaking from many years of Lipoderm experience, I have a harsh sensitivity to Yohimbine systemically - most notably my prostate. I have used Lipoderm/Lipoderm-Ultra/Napalm, sometimes at very high dosage, with little to no systemic side effects.

Damn, sounds good until I read the warning about high blood pressure. Mine is elevated now, so I guess I cant fuck with this...

Ditto.

I enjoyed Napalm for the week or so that I used it, but I began to get some skin irritation and stopped. This was at max dosing, so I should probably give it a go again and scale back on the dose a bit.

K, now I'm feeling some warmth, and the skin does indeed turn red. Good sign. Nowhere near the burn of capsaicin, mind you... I may try using Capzacin-HP with it and see what happens.

Are you feeling retarded? Like masochist retarded?

Yeah, I know. It's silly, but the burn feels like it's burning the fat off... purely psychological of course, although it is of course also effective. Maybe I could just throw in some addtional RK's or something.

I also have a problem with leaving well enough alone.

I recall reports of people saying they felt a warming sensation after applying Napalm. Does this happen immediately, or with continued use? I tried it for the first time this morning, and my skin feels cooler more than anything.

I should have this today....Is Colin or someone using plastic bags to put it on? Is this needed, or if you dont use them does it effect your hands, etc?

I should have this today....Is Colin or someone using plastic bags to put it on? Is this needed, or if you dont use them does it effect your hands, etc?

ok thanks guys...another thing, it has to be applied twice a day right? I can do the mornings, but trying to put it on at night with wifey may be a challenge

do it miday then. just spread it out by like 6 hours or so. I wouldn't apply and then go to bed, I would apply and then do some activity. This way if your wifey wants to play tennis with you or whatever you were inferring go for it

do it miday then. just spread it out by like 6 hours or so. I wouldn't apply and then go to bed, I would apply and then do some activity. This way if your wifey wants to play tennis with you or whatever you were inferring go for it

What is the reasoning for this? I'm finishing up some Targex and definitely going to get Napalm once that finishes off. I've always been a right as I wake up, right before I go to bed (if I'm not going to get lucky) type of guy.

Just curious...

What is the reasoning for this? I'm finishing up some Targex and definitely going to get Napalm once that finishes off. I've always been a right as I wake up, right before I go to bed (if I'm not going to get lucky) type of guy.

Just curious...

This is what he was saying...if you don't plan on any adult fun, then right before bed is best...if you do, apply it 1-2 hours before such activity.

Well, in my situation, I do have 'adult fun', and being married and having a 5 1/2 month old, we really cant plan it. The smell doesnt bother me per say, but it is strong, and I dont think wifey would enjoy it. So in my case, Ive been putting the 2nd application on after my afternoon workout.

This is what he was saying...if you don't plan on any adult fun, then right before bed is best...if you do, apply it 1-2 hours before such activity.

Well, in my situation, I do have 'adult fun', and being married and having a 5 1/2 month old, we really cant plan it. The smell doesnt bother me per say, but it is strong, and I dont think wifey would enjoy it. So in my case, Ive been putting the 2nd application on after my afternoon workout.