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  1. I have previously stated that I believe transdermal prohormones to be the most effective supplements ever to hit the market. That statement must now be amended. Transdermal prohormones are indeed the most effective MUSCLE BUILDING supplements ever to hit the market. But, topical fat loss products have the potential to be an even bigger overall breakthrough in the never ending quest to improve body composition.

    There are four areas that need to be addressed in regards to topical fat loss products and so called "spot reducers" in general. First, one needs to distinguish between the products that are merely diuretics and those that the manufacturer (assuming they have a brain) actually thinks might significantly reduce body fat. Second, we have to have an understanding of the andrenergic system, which is primarily what these products attempt to manipulate in order to aid lipolysis Thirdly, we must have an understanding of transdermal/percutaneous delivery, in order to understand why a topical formulation could present advantages vs. orals, as well as to understand why every product of this kind currently on the market, other than LipoDerm-Y, fails. Within this category there are 2 issues -- getting adequate amounts past the skin barrier and localizing its distribution to adipose tissue. And, finally, there is the issue of Yohimbine HCl vs. yohimbe. After reading this, you should have an understanding of why true "spot reduction" is physiologically quite possible, as well as enough information to make an informed decision as to which products can and cannot accomplish it.
    Fatloss Agents vs. Diuretics
    Assuming we are not preparing for a photoshoot or competition, a product that merely acts as a diuretic rather than significantly aiding actual lipolysis is basically worthless. "Cutting Gel" belongs in this category -- its active ingredient is aminophylline:

    Aminophylline is a xanthine derivative, similar to caffeine, which is not a particularly potent fat burner. In rat studies, it has shown good thermogenic properties due to blockade of adenosine receptors (which provide one of the negative feedback mechanisms for catecholamine induced thermogenesis) and inhibition of phosphodiesterase (which degrade cyclic AMP) -- but this is at extremely high doses, which would kill a human, so it is not applicable (1,2). At therapuetic doses, only adenosine blockade occurs, which will act to increase norepinephrine levels (3)-- but as you will see norepinephrine stimulates alpha 2 receptors (bad) in addition to beta 2 receptors (good) -- and in stubborn fat, alpha 2's outnumber beta 2's (4). 

    Like caffeine, it is a good diuretic (5), which would account for the girth loss in the study they reference, which did not measure actual fat loss (6,7). One study did look at fat depth after use of an aminophylline cream, and no difference was found vs. control (8). As a local diuretic, it might be effective, but as a true fat loss agent, it quite likely is not.

    Precontest, such a product could be extremely beneficial if it would truly localize the water loss, as it would allow one to get rid of extracellular water with out the total body dehydration produced by drugs such as Lasix -- thus, one could have fuller muscles, less cramping, etc. I am not particularly familiar with the physiology of diuresis, as I have not researched it to any great extent, so I don't know if it could actually be localized.

    Products such as LipoDerm-Y, Impact's DermaLean, and S.A.N.'s LipoBurn (basically any of the products with yohimbine and a handful of other ingredients) fall into the latter category. They are intended to manipulate the adrenergic system, thus, theoretically, such products could cause true localized fat loss if formulated properly:

    The Adrenergic System: Introduction
    One of the major contributors to body weight homeostasis in the human body is the adrenergic system. There are two types of adrenergic receptors, alpha and beta, as well as subtypes of each -- and depending on which are activated, lipolysis (breakdown of fat) can be either stimulated or inhibited.

    The most well-known adrenoreceptors to bodybuilders are the beta receptors. These can be divided into subtypes 1, 2, and 3 -- and it is through these receptors that drugs such as the ephedrine/caffeine stack and Clenbuterol exert their effects. While Clenbuterol acts directly on beta 2 receptors, ephedrine exerts its effects indirectly by stimulating the release of norepinephrine (NE), the body's primary endogenous thermogenic hormone. Unlike Clenbuterol, NE is not selective in its binding. In addition to binding to the beta 2 receptor, it also binds to both alpha receptors, as well as the beta 1 and 3 receptors. It is in regards to its binding to the alpha 2 receptor that yohimbine comes into play.

    Norepinephrine and Yohimbine
    Activation of the alpha 2 receptor inhibits the release of NE. Thus, by binding to this receptor, NE functions as its own negative feedback signal. In other words, it shuts off its own release. Obviously, this is not a good thing for fat loss. This is particularly true at rest (which, unless you are a marathon runner is 95% of your day) -- this is because alpha 2 receptors are activated at lower catecholamine levels than are the beta receptors (9). Thus, thermogenesis is basically always turned off. It is the differences in regional distribution of alpha 2 and the beta receptors that is responsible for the gender differences in bodyfat storage (4). Basically, females have a large number of alpha 2 receptors and few beta receptors in the gluteofemoral area (hips, thighs, and butt), while men have the same problem in the midsection. With exercise or the use of compounds such as the ephedrine/caffeine stack, catecholamine levels can be increased to a point where the alpha 2 induced inhibition of lipolysis is partially overcome (9). However, even then, the alpha 2 receptors ARE still acting to reduce lipolysis.

    Yohimbine is a selective alpha 2 antagonist (10) and can thus short circuit this feedback loop, maximizing NE levels, thus maximizing fat loss, particularly in these problem areas -- and even more so if we can achieve high levels of yohimbine and NE in the adipose tissue. Unfortunately, to do so with orals, or any other method that results in high blood levels means that we will also have high levels in the heart and CNS -- thus, we will also have unpleasant and dangerous side effects. Considering the subject of this article, I obviously believe the solution lies in transdermal administration, but more on that in a bit.

    Blood Flow
    A second, more indirect, mechanism by which Yohimbine can aid lipolysis via the adrenergic system is by increasing peripheral blood flow (11, 12). Adipose tissue is known to have rather poor vascularity. When triglycerides are broken down into free fatty acids and glycerol during lipolysis, they must also be transported away from the fat cell or they risk being reincorporated into adipose tissue. Beta receptor activation causes vasodilation, thus increasing blood flow, however, it does not increase enough to remove all of the free fatty acids released during lipolysis (13). Alpha 1 and 2 receptor activation, on the other hand, causes a decrease in blood flow (4, 14). Thus, antagonism of the alpha 2 receptor with yohimbine would be expected to increase blood flow, and thus increase the mobilization and disposal of these FFA's, further aiding fat loss. And, again, the more we can get in the adipose tissue without it reaching the heart and CNS, the better.

    Percutaneous Delivery
    Though the terms are often used interchangeably in the literature, there are two distinct forms of drug delivery through the skin. The first, and most common, is "Transdermal Delivery" -- this involves a drug bypassing the skin barrier in order to be taken up into the bloodstream and distributed systemically (15). This basically does the same thing as oral delivery, but it is inherently time released and avoids first pass metabolism in the liver which can limit bioavailability and cause hepatotoxicity, so it is is advantageous for delivering many drugs. 

    The second is "Percutaneous Delivery" (15)-- with this method, one bypasses the skin barrier, but with the purpose of delivering the drug to specific target tissues in the body, while AVOIDING uptake into the blood and subsequent systemic delivery. In the pharmaceutical realm, this has been pursued primarily for antibiotics and NSAIDS -- the former, to avoid destruction of systemic microflora (so-called "good bacteria"), and the latter to avoid hepatic recirculation, which is responsible for gastrointestinal problems. 

    Unfortunately, the people who have developed most of the topical fat loss products thus far either do not know about or understand this difference or they do not understand its paramount importance in regards to adrenergic modulators such as yohimbine. With prohormones, systemic uptake and distribution is our goal -- they have poor oral bioavailability, so we are just trying to avoid the liver in order to get significant amounts in the bloodstream. 

    However, with yohimbine and other adrenergic agents, oral bioavailabilty is not the issue -- at about 22%, it is more than adequate (16). We can readily achieve adequate blood levels with oral usage. The issue with these is that as we increase dosages (and thus blood levels) in order to increase distribution to adipose tissue to aid fat burning, we also increase distribution to the heart and CNS where we create numerous unwanted side effects such as rapid heart rate, high blood pressure, and overstimulation, which is particularly noticeable with exercises. Yohimbine is also used clinically to produce anxiety (17). Ideally, we want our drug to reach fat cells in high doses, without the dangerous side effects of high levels in the heart and central nervous system.

    So, how do we do this?? Unfortunately, it is easier said the done. Typically, drugs that penetrate the skin barrier and traverse the epidermis and dermis are rapidly taken up by the dermal microvasculature, where they are delivered systemically (just like with orals) -- this is well characterized in the literature (15,18,19) -- with direct tissue penetration being limited to 1-4 mm, which obviously is not exactly deep into the adipose tissue. And, considering that these substances have good oral bioavailability, if the dermal microvasculature is not taken into account, we end up with a product that not only does not localize delivery, it does not even deliver it systemically as efficiently as an oral would do. Considering these products cost far more than there oral counterparts, and could also be thought of as inconvenient in that you have to rub them on your body, any supplement developer who doesn't take dermal uptake into account has obviously missed the boat quite badly. And, guess what... Not one single product other than LipoDerm-Y does. And guess what else -- they probably are not going to because we have filed a use patent on the one carrier that has been shown in the literature to effectively accomplish this.

    Targeted Delivery
    Let's now take a look at the literature that supports the idea of tissue specific delivery of therapeutic substances. As mentioned previously, when it comes to targeted delivery, the pharmaceutical realm, and thus the literature, has primarily concerned itself with antibiotics/anti-fungals and NSAIDS. We will look at the three most important ones.

    Editors note: I am not going to give the name of the substance that has been shown to be effective as a vehicle for local delivery at this time. I may do so when the product comes out, as it has to listed on the label. Though we have filed a patent on it, there are many companies whom that will not stop from attempting to steal our intellectual property. They lack the intelligence and creativity to discover this sort of thing on there own (as well as the integrity to think such things matter) so they choose to make their money in this manner.

    The first study (19b) involved the NSAID indomethacin as the drug to be delivered. The drug was given orally (O) , topically without the "special delivery solvent" (WO), and with the "special delivery solvent" (W). The topicals were applied to the shoulder. For the first two hours after administration, concentrations of the drug in the deltoid (which is obviously even deeper than adipose tissue) were 5 times higher in W than in either O or WO. After 4 hours, it was 3 times as high, and by 8 hours it was still twice as high. Obviously, the formulation containing the "special delivery solvent" was vastly superior at delivering the drug to the target tissue. But what about delivery to unwanted tissues? If it was just a case of the "special delivery solvent" allowing more drug to cross the skin, this would not be a big deal -- we could just use more. What we also need is for a minimal amount of the drug to be delivered systemically, and once again, the "special delivery solvent" was shown to be superior. Maximal blood levels of all three compounds occurred at the 2 hour mark. W displayed levels about 1/3 that of O and 1/2 that of WO. 

    If the significance of this is not clear, it basically means that localized delivery (what we want) per unit systemic delivery (what we don't want) for W was 15 times that of O and 10 times that of WO -- and this was to the muscle. Considering the adipose tissue is closer to the skin (which had levels 10 times as high as the muscle) and that the joint capsule (which is below the muscle) had levels 1/3 that of the muscle while with WO there were equal levels at the muscle and joint, the ratio of delivery to adipose tissue vs. systemic delivery for W is likely significantly higher.

    The second study (19c) utilized the antibiotic erythromycin as the delivery drug. Formulations for W and WO were identical to the above study. Oral administration was not tested. Exact counts of the concentration in muscle tissue was not reported, but the authors stated that after 4 hours, there was a major increase in the muscle mass below the site of application (I have contacted the authors to try to get exact data). Kidney and liver levels (indicative of systemic distribution) were significantly lower for W than WO -- about 1/2 for the former and 1/4 for the latter over 24 hours.

    The third study (19d) we will look at utilized the antifungal griseofulvin as the delivery drug and compared W with oral intake. The formulation for W was the same as the previous two studies. The accumulation of the active compound in the area of application for W was several hundredfold greater than that which accumulated in the organs, and brain levels were non-detectable, which is extremely important considering we are trying to avoid excessive CNS stimulation -- and all of this was a full four days after application. Compare this to oral delivery which showed concentrations that were approximately identical in all areas, which would be expected if systemic uptake occurred.

    Penetration Enhancement
    I think it should be clear from the previous studies that it is quite possible to achieve targeted delivery. However, if we cannot get adequate amounts of our substance past the skin barrier, it is a mute point. And, considering one of the skin primary purposes is as a water barrier (20), hydrophilic substances such as yohimbine do not readily pass through (21, 22,23). Thus, we need to turn to the topic of penetration enhancement (for a more thorough presentation, see my previous article Transdermal Delivery. 

    Yohimbine HCl, with a LogP of about .75 (24), is fairly polar/hydrophilic, thus penetration enhancers should be chosen accordingly -- namely we want those which affect the polar route. This rules out many commonly employed penetration enhancers -- a fact many companies do not seem to be aware of. Since there is very little direct data on penetration enhancement with Yohimbine HCl, we will look at data when substances with similar physical properties were used.

    One promising chemical in this area is the terpene, l-menthol. Polar molecules undergo significant hydrogen bonding in the stratum corneum, which is the primary reason for their poor passage through the skin barrier (23). Because of the presence of a hydroxyl (OH) group, l-menthol should bond to these hydrogens (25), leaving our drug free to more easily traverse the skin barrier. And, indeed the data has supported this. It increased the permeability coefficient of mannitol 100 fold vs. control (26). In a study using Propranolol HCl which has a partition coefficient almost identical to yohimbine (Log P .74 vs. .75), it increased flux 1000 fold vs. control and also displayed the shortest lag time of all terpenes tested (25). This is in contrast to d-limonene, almost identical, structurally, to l-menthol, with the exception of lacking the afore mentioned hydroxyl group, which has been shown to much less effective for polar compounds (25, 27).

    A second chemical is laurocapram. It too has been shown to be quite successful with polar drugs (23,28,29) likely due to its increasing the water content of the lipid phase of the stratum corneum. In one study, it enhanced the flux of mannitol in a propylene glycol vehicle by over 350 fold (23). Unfortunately, it displays a significant lag time -- meaning it can take as much as 10 hours before it starts to work (30, 31, 32). Consider most of us shower daily, this is not acceptable.

    That brings us to n-methyl-2-pyrrolidinone (NMP). In combination with laurocapram, in a study using morphine hydrochloride, which has physical properties similar to Yohimbine Hydrochloride -- both polar molecules, molecular weight of 322 vs. 390 -- and is thus quite applicable, NMP was shown to significantly reduce the lag time (down to as low as 2 hours) as well as increase the rate of penetration for the drug as indicated by blood levels that were several thousandfold high than controls (32). In addition, it has been shown in several other studies to enhance penetration of polar molecules on its own, including a 256 fold increase with mannitol (23).

    Finally, we have also added glycerol, which provides dual functions. First, it helps to counter any skin irritation that might be caused by the alcohol carriers. This is due to its increasing the water content of the skin, and as alluded to in regards to laurocapram, this increase in water content has the added bonus of increasing penetration for polar molecules such as yohimbine (33, 34).

    Yohimbine vs. yohimbe
    Quite a bit of confusion seems to exist about the difference between Yohimbine and yohimbe. Yohimbine is the principal alkaloid from the herb P. yohimbe. However, there are 31 other yohimbane alkaloids that can be present in herbal yohimbe preparations. Some of these have different and unknown selectivities and potencies (and thus, effects) at the adrenergic receptors (35, 36) -- in addition, these preparations vary greatly from brand to brand and even from batch to batch, as no standardization for extraction exists. In fact, a recent investigation found that most over the counter preparations have little to no actual yohimbine (37). And, even in the more potent preparations, most people find a higher degree of undesirable effects with the herb vs. pure Yohimbine (due to the afore mentioned 31 other yohimbane alkaloids that can be present). With LipoDerm-Y, you are guaranteed 25mg of pure, pharmaceutical grade Yohimbine HCl per milliliter, without the added side effects from other alkaloids - thus, allowing safer, more reliable dosing.

    Because some people are unusually sensitive to yohimbine, I would recommend that one start with a small dose -- 3-4 squirts (50 mg) and then increase the dosage by 25-50mg each day until side effects become unacceptable. Dividing it into two doses would be ideal, but probably not necessary. In our beta testing, we have gone as high as 400mg/day without significant side effects. I have personally done this along with an EC stack, and the only time side effects were particularly noticeable was during workouts.

    Another thing to be considered when using yohimbine is that insulin blunts its lipolytic effects. Because yohimbine is not reaching the pancreas in significant amounts as it would with oral administration, insulin levels will not be as high for a given amount of carbohydrates, but they will still be elevated. Thus, it should ideally be used on a low-carb/ketogenic diet, or at the very least, one should do moderate aerobic activity for an extended period first thing in the morning on an empty stomach.

    I think it should now be exceedingly clear that all topical fat loss products are not created equal -- and you should now be equipped to make an informed decision on which one to use. To sum up:
    • The formulation should contain active ingredients that are significantly lipolytic rather than mere diuretics.
    • The formulation should use yohimbine hydrochloride rather than the yohimbe herb.
    • The formulation must not only include penetration enhancers, but they must be appropriate for polar a molecule.
    • The formulation must avoid uptake by the dermal microvasculature or it will merely be an expensive, inefficient version of a pill.
    The formulation that meets these criteria is LipoDerm-Y.


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    2. Lee TF; Li DJ; Jacobson KA; Wang LC. Improvement of cold tolerance by selective A1 adenosine receptor antagonists in rats. Pharmacol Biochem Behav 1990 Sep;37(1):107-12. 

    3. Tung CS, Kuan CJ, Tarng JL, Tseng CJ. Effect of adenosine blockade on plasma renin activity and catecholamines. Proc Natl Sci Counc Repub China B 1993 Jan;17(1):21-8

    4. Millet L, Barbe M, Lafontan M, Berlan M, Galitzky J. Catecholamine effects on lipolysis and blood flow in human abdominal and femoral adipose tissue. J Appl Physiol 1998; 85(1):181-188.

    5. Pretzlaff RK, Vardis RJ, Pollack MM Aminophylline in the treatment of fluid overload.Crit Care Med 1999 Dec;27(12):2782-5

    6. Greenway FL, Bray GA, Heber D. Topical fat reduction. Obes Res 1995 Nov;3 Suppl 4:561S-568S 

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    8. Collis N, Elliot LA, Sharpe C, Sharpe DT. Cellulite treatment: a myth or reality: a prospective randomized, controlled trial of two therapies, endermologie and aminophylline cream. Plast Reconstr Surg 1999 Sep;104(4):1110-4; discussion 1115-7

    9. Arner P, Kriegholm E, et al. Adrenergic regulation of lipolysis in situ at rest and during exercise. J Clinical Invest 1990; 85:893-898.

    10. Goldberg MR Robertson D. Yohimbine: a pharmacological probe for study of the a 2-adrenoceptor. Pharmacol Rev 1983;35:143-180.

    11. Berlan M, Galitzky J, Riviere D, et al. Plasma catecholamine levels and lipid mobilization induced by yohimbine in obese and non-obese women. Int J Obesity 1991; 15:305-315.

    12. Galitzky J, Taouis M, Berlan M, Riviere D, et al. a 2-Antagonist compounds and lipid mobilization: evidence for a lipid mobilizing effect oral yohimbine in healthy male volunteers. Eur J Clin Invest 1988; 18:587-594.

    13. Hodgetts V, Coppack S, Frayn KN, Hockaday TDR. Factors controlling fat mobilization from human subcutaneous adipose tissue during exercise. J Appl Phys 1991; 71:445-451.

    14. Ruffolo RR, Bondinell W, Hieble JP. a - and b -Adrenoceptors: From the gene to the clinic. 2. Structure-activity relationships and therapeutic applications. J Med Chem 1995; 38(19):3415-3444.

    15. Roberts MS. Targeted drug delivery to the skin and deeper tissues: role of physiology, solute structure and disease.Clin Exp Pharmacol Physiol 1997 Nov;24(11):874-9 

    16. Le Corre P, Dollo G, Chevanne F, Le Verge R. Biopharmaceutics and metabolism of yohimbine in humans. Eur J Pharm Sci 1999 Oct;9(1):79-84

    17. Joly D D, Sanger DJ Social competition in dominant rats can be attenuated by anxiogenic drugs. D.Behav Pharmacol 1992 Feb;3(1):83-88 

    18. Singh P, Roberts MS. Skin permeability and local tissue concentrations of nonsteroidal anti-inflammatory drugs after topical application. J Pharmacol Exp Ther 1994 Jan;268(1):144-51

    19. Singh P, Roberts MS Dermal and underlying tissue pharmacokinetics of lidocaine after topical application..J Pharm Sci 1994 Jun;83(6):774-82

    19b. Mikulak SA, Vangsness CT, Nimni ME. Transdermal delivery and accumulation of indomethacin in subcutaneous tissues in rats. J Pharm Pharmacol 1998 Feb;50(2):153-8

    19c. Peng L, Nimni ME. Delivery of erythromycin to subcutaneous tissues in rats by means of a trans-phase delivery system. J Pharm Pharmacol 1999 Oct;51(10):1135-41

    19d. Nimni ME, Ertl D, Oakes RA. Distribution of griseofulvin in the rat: comparison of the oral and topical route of administration. J Pharm Pharmacol 1990 Oct;42(10):729-31

    20. Ranade VV. Drug delivery systems. 6. Transdermal drug delivery. J Clin Pharmacol 1991 May;31(5):401-18

    21. Peck KD, Ghanem AH, Higuchi WI. Hindered diffusion of polar molecules through and effective pore radii estimates of intact and ethanol treated human epidermal membrane.Pharm Res 1994 Sep;11(9):1306-14.

    22. Hansch C, Dunn WJ 3rd. Linear relationships between lipophilic character and biological activity of drugs.J Pharm Sci 1972 Jan;61(1):1-19

    23.Barry BW, Bennett SL. Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin.J Pharm Pharmacol 1987 Jul;39(7):535-46 

    24. Interactive LogKow Demo website: http://esc.syrres.com/interkow/kowdemo.htm

    25. Kunta JR, Goskonda VR, Brotherton HO, Khan MA, Reddy IK. Effect of menthol and related terpenes on the percutaneous absorption of propranolol across excised hairless mouse skin. J Pharm Sci 1997 Dec;86(12):1369-73

    26. Katayama K, Takahashi O, Matsui R, Morigaki S, Aiba T, Kakemi M, Koizumi T. Effect of l-menthol on the permeation of indomethacin, mannitol and cortisone through excised hairless mouse skin. Chem Pharm Bull (Tokyo) 1992 Nov;40(11):3097-9

    27. Koyama Y, Bando H, Yamashita F, Takakura Y, Sezaki H, Hashida M. Comparative analysis of percutaneous absorption enhancement by d-limonene and oleic acid based on a skin diffusion model. Pharm Res 1994 Mar;11(3):377-83 

    28. Lambert WJ, Higuchi WI, Knutson K, Krill SL.Dose-dependent enhancement effects of azone on skin permeability. Pharm Res 1989 Sep;6(9):798-803

    29. Goodman M, Barry BW. Action of penetration enhancers on human skin as assessed by the permeation of model drugs 5-fluorouracil and estradiol. I. Infinite dose technique. J Invest Dermatol 1988 Oct;91(4):323-7 

    30. Hosoya K, Shudo N, Sugibayashi K, Morimoto Y.Effect of Azone on the percutaneous absorption of 5-fluorouracil from gels in hairless rats. Chem Pharm Bull (Tokyo) 1987 Feb;35(2):726-33

    31. Sugibayashi K, Hosoya K, Morimoto Y, Higuchi WI. Effect of the absorption enhancer, Azone, on the transport of 5-fluorouracil across hairless rat skin. J Pharm Pharmacol 1985 Aug;37(8):578-80 

    32. Sugibayashi K, Sakanoue C, Morimoto Y. Utility of topical formulations of morphine hydrochloride containing azone and N-methyl-2-pyrrolidone. Sel Cancer Ther 1989;5(3):119-28

    33. Bettinger J, Gloor M, Peter C, Kleesz P, Fluhr J, Gehring W Opposing effects of glycerol on the protective function of the horny layer against irritants and on the penetration of hexyl nicotinate. Dermatology 1998;197(1):18-24 

    34. Gloor M, Bettinger J, Gehring W Hautarzt Modification of stratum corneum quality by glycerin-containing external ointments.1998 Jan;49(1):6-9 

    35.. Ruffolo RR, Bondinell W, Hieble JP. a - and b -Adrenoceptors: From the gene to the clinic. 2. Structure-activity relationships and therapeutic applications. J Med Chem 1995; 38(19):3415-3444.

    36. Goldberg MR Robertson D. Yohimbine: a pharmacological probe for study of the a 2-adrenoceptor. Pharmacol Rev 1983;35:143-180.

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  2. Primer™ Ingredients

    As Primer™ is primarily a prebiotic, let’s start with those. Prebiotics have come a long way since oat bran and psyllium husks. Beginning with inulin, a huge array of oligosaccharide and glycan type compounds have been found to be fermented and fed on by intestinal bacteria. These newer prebiotics tend to be basically tasteless and dissolve effortlessly, which is quite handy.

    With the importance of microbial diversity for optimal gut and body health, we want a number of different prebiotics for them to feed on. Likewise, we want to choose the ones that best increase the bacteria we want to increase, rather than just randomly feeding all of them.


    Galacto-oligosaccharides (GOS)

    GOS reduced fat mass, food intake by 14%, and elevated expression of pro-satiety peptides. Combining them with Calcium increased propionate formation (116). In addition to reductions in food intake, appetite, bodyweight, and inflammation are also decreased (117). GOS increase beneficial bacteria, particularly Bifidobacterium, with 5-10 fold increases in some subjects being noted (118-121). They also raise Bacteroides levels (121). They are long-acting, providing prebiotic effect throughout the entire length of the colon, while strongly inhibiting pathogenic bacteria (122). This owes to high resistance to conditions early in gut digestion (123).

    GOS provide direct enhancement of intestinal barrier function through interaction with goblet cells, separate from SCFA or anti-inflammatory mediated mechanisms. They also showed a 2-4 fold mucin elevation, which would create a positive environment for mucin feeders such as Akkermansia and Bacteroides (124). They inhibited inflammatory responses, augmented protein junction assembly by 85%, and prevented loss of barrier function (125). GOS displayed a microbiota independent increase in tight junction assembly and improved barrier function (126). Finally, they mitigate LPS induced inflammation and protect against stress induced LPS activity (127, 128).


    Arabinoxylan-oligosaccharides (AXOS)
    AXOS are strongly Bifidogenic. They increase satiety inducing peptides, while decreasing weight gain, fat mass, and insulin resistance (129). They raise butyrate levels along with Bifidobacterium suggestive of subsequent cross-feeding to butyrate producing bacteria (130).  They also reduce protein fermentation in the gut (130, 131). This spares amino acids for more useful purposes as well as preventing toxic breakdown products.

    AXOS are long-acting, with bacterial fermentation occurring throughout length of colon.  They significantly promote Bacteroides as well as Lactobacillus (132). They are even better than inulin at providing fermentation products to the distal portions of the colon (133). AXOS elevated Roseburia and butyrate levels, with total SCFA increases as high as 2-3 fold (134, 135).  Finally, they increase tight junction proteins, improve barrier function, and inhibit inflammation in adipose tissue (129).


    Xylo-oligosaccharides (XOS)
    XOS increased Bifidobacterium along with acetate and butyrate. Combining with inulin further augmented butyrate formation, as well as increasing propionate, suggesting cross-feeding to butyrate and propionate producing bacteria like Roseburia and Bacteroides (136, 137). And, XOS have indeed been found to promote both Roseburia and Bacteroides, as well as improving the Firmicutes:Bacteroides ratio (138, 139). Bacteroides possess special xylan degrading enzymes, making them a preferred fermenter of XOS (140). Elevated Bacteroides and butyrate from XOS protected against genotoxicity in a colonic simulator (141). They also decreased LPS and increased epithelial cell proliferation (137, 142).


    Lactulose inhibits adipogenesis and fat accumulation, down-regulates adipogenic genes, and reduces caloric extraction efficiency, while increasing energy expenditure and lipolysis (143). It also improves post-prandial blood glucose and insulin levels (144, 145). Lactulose raises Bifidobacterium counts, particularly of the ideal cross-feeder B. adolescentis, as well as Akkermansia (146-148). Finally, it decreases intestinal permeability and proteolysis of amino acids in the gut (147, 149).


    Inulin improved glucose uptake in insulin resistant cells, and activated AMPK (150). It increases Bifidobacterium and butyrate, while reducing protein fermentation (151, 152). It has a prolonged Bifidogenic effect, with more distal fermentation and SCFA production vs. fructo-oligosaccharides, particularly of butyrate and propionate – again, suggestive of cross-feeding (153, 154). In fact, it was found to increase B. adolescentis more than 4-fold and F. Prausnitzii by 50% (155). It also increased Roseburia, while augmenting mucin production 6-fold, leading to large elevations in Akkermansia and propionate, distally (156).


    Resistant Starch 3 (RS3)
    Resistant Starch 3 is formed when starchy foods such as potatoes and rice are cooked and then cooled. This turns formerly digestible starches into resistant starches via a process called retrogradation.  RS3 is particularly, and somewhat uniquely, highly prebiotic for Ruminococcus bromii, with increases up to 4-fold (157-159). R. bromii has superior ability to degrade this resistant starch, which is the most prevalent fermentable carbohydrate in the average diet, making it a “keystone species” by acting as a cross-feeder for other species (160, 161).

    It was also found to be readily consumed by Bacteroides, elevating faecal propionate, rather than butyrate as is often observed following resistant starch feeding of other types. This propionate formation reflects a gut community dominated by the Bacteroides, and it actually became the primary lineage in this study (162).


    Amylopectin was found to be superior to several other prebiotics for increasing butyrate, as well as butyrate producers F. prausnitzii and Roseburia (163). It also raises Bacteroides, with increases in Roseburia and Bacteroides being found to be proportional to the amylopectin content of barley and oats (164, 165).


    Mucin is the glycoprotein constituent of the mucus which lines the wall of the intestines and protects it. Several species of bacteria, including some of the really good ones, feed off of it. Akkermansia is the most well characterized mucin consumer (166, 167). Verrucomicrobia, of which Akkermansia is the primary genus, was increased from .03% to 5.25% by mucin, and in combination with inulin, Bacteroides was raised as well (168).

    Bacteroides thetaiotamicron is a known mucin degrading specialist (169-171). Bacteroides fragillis consumes mucins as well (172, 173). Roseburia intestinalis also colonizes the mucosal layer and feeds on mucins (174).

    With these bacteria colonizing the mucus and being close to the epithelium, particularly with the butyrate producers, bioavailability for epithelial cell regeneration and barrier function is enhanced.


    Rhamnose is a preferred sugar for the propanediol pathway of propionate production by Roseburia inulinivorans (175, 176). It is quite selectively metabolized to propionate (177, 178). It is much more selective for propionate formation than lactulose or glucose, which utilize different, less selective pathways, resulting in 4 times more propionate than with lactulose or glucose (179). Rhamnose was also found to decrease triglyceride synthesis and serum triglyceride levels, likely due to propionates effects on the SCFA receptors FFAR 2/3 (180).


    Glutamine is the primary substrate of rapidly diving cells, a category to which the epithelial cells of the digestive tract belong. It increases tight junction protein production (181). It does so by activating the mammalian target of rapamycin (mTOR) cell signaling in enterocytes.   It enhances intestinal growth, enterocyte proliferation and survival, and regulates intestinal barrier function in injury, infection, stress, inflammation, and other catabolic conditions (182). It is basically both the leucine (protein) and the glucose (carbohydrate), to go along with butyrate as the fat, for the fueling of survival, growth, and reproduction of the enterocyte. This makes it quite possibly the most important nutrient for intestinal barrier health and function.

    Glutamine also reduces utilization of other amino acids (asparagine, aspartate, serine, lysine, leucine, valine, ornithine, and arginine) in the gut, preserving them for more useful things while reducing toxic metabolites (183, 184). It decreases intestinal permeability and enhances intestinal mucosa and barrier function (185). Glutamine improves intestinal barrier impairment and quells the LPS mediated inflammatory cascade (186). It also prevents mucosal injury and promotes recovery from LPS induced inflammatory damage, as well as downregulating TLR-4 expression (187, 188).

    Inflammatory conditions increase the requirements for Glutamine to maintain the intestinal barrier (189). It has specifically been shown to protect the intestinal barrier against processed, Western diet style foods (190). AMPK mediates its enhancement of tight junction integrity and barrier preservation (191).

    Conversion to glutamate and subsequent cellular uptake is a pivotal step in its protective effects (192). Monosodium Glutamate has been found to promote the colonization of F. prausnitzii and Roseburia (193). And, finally, L-glutamate enhances barrier function (194).


    Calcium Phosphate
    Increasing dietary Calcium produced a reduction in weight gain and fat pad mass of 26-39% with a 51% inhibition of adipocyte fatty acid synthase expression and activity, while stimulating lipolysis by 3 to 5-fold (195). In another study, an almost 50% increase in weight loss was found (196). A high-Calcium diet decreased fat gain by 55%, stimulated adipose tissue uncoupling protein (UCP2) and skeletal muscle UCP3 expression, increased thermogenesis and lipolysis,  while lowering fatty acid synthase expression and activity (197, 198). Calcium also elevated peptides GLP-1 and GLP-2, which increase satiety and decrease food intake (199, 200).

    Calcium improves intestinal permeability, strengthens the mucosal barrier, reduces inflammation, and alleviates colitis (201). Prebiotics have actually been found to have negative effects on intestinal permeability and inflammation without Calcium Phosphate rather than the positive effects produced when it is present (202, 203). This protection is dependent on Phosphate, thus Calcium likely pulls it into the colon, improving luminal buffering capability (204). This is because SCFAs produced by prebiotic fermentation could lower pH too much in its absence.

    Finally, Calcium is necessary for the Calcium/Calmodulin-dependent Protein Kinase Kinase 2 (CaMKK2) mediated AMPK signaling and barrier maintenance produced by Glutamine (205).


    Multi-Berry Powder

    Multi-berry powder has the power of berries!! A day’s worth of Primer™ is equal to ¼ cup of mixed berries. It has the polyphenols and fiber and such that berries have, but it is mostly in here because it gives it a nice, subtle berry flavor.



    Primer™ takes the concept of prebiotic far beyond where anyone has previously taken it before. It starts by carefully and selectively feeding the most beneficial bacterial species, including novel probiotic species that you cannot attain, anywhere. It does so in a way that no other product comes even close to doing. It protects against dysfunction of the gut and microbiota to promote better health, better appetite control, better metabolism, and better fat loss. Finally, its supporting ingredients go to work on making your inflamed and leaky gut as good as new, leaving your body functioning in the optimal way it is intended to.

    Primer™ is a gourmet meal for your microbiota and a happy-ending massage for your gut. It is a one of a kind product that fits in perfectly with and enhances any diet and exercise program, any supplement regimine, any lifestyle.


    For references, see "View Full Science Write-Up" here: http://neobium.org/product-line/primer/

  3. Dr. Gonzo's Hour of Power

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