Sunday, December 2, 2012
A study just recently popped-up which examined the photostability of trenbolone, its metabolites trendione and 17a-hydroxy-trenbolone, and the synthetic progestin melengestrol. The abstract:
Phototransformation Rates and Mechanisms for Synthetic Hormone Growth Promoters Used in Animal Agriculture.
Long story short: When in solution & exposed to sunlight, all of the steroidal compounds degraded within roughly 20-30 minutes. What they turned into is uncertain. It looks like the photometabolites of those trienes are mono-, di-, and trihydroxylated, but the positions where these changes take place are unknown. Mono-hydroxylation would probably reduce activity sharply, but there are certain positions where this might not be the case. It is quite certain that the more polar dihydroxyl and trihydroxyl derivatives have little or no anabolic activity.
A very similar 1994 study examined the photostability of 'bovine growth promoting agents' nandrolone, trenbolone, and zeranol in bovine urine. The results were identical: Zeranol and its metabolites are photostable; the steroidal molecules are not & degrade very quickly. The researchers concluded their article with the recommendation that bovine urine samples be stored in a freezer immediately after collection. The abstract of this study can be reviewed here: http://www.ncbi.nlm.nih.
This photostability problem is not unique to 19-norsteroids in liquid solutions. As per this detailed article, crystalline testosterone undergoes phototransformation to androstenedione and 5a-androstanedione, and methyltestosterone undergoes phototransformation to the useless seco-steroid #162:
Crystalline testosterone propionate, when exposed to UV light, apparently dimerizes like this:
The practical implications of this dimerization are unknown to me at the moment. (But it doesn't look good!)
There isn't more data out there that I am aware of. That said, I believe that steroidal androgens and progestins are generally not photostable, and that they should be stored away from all photon-sources (hv) -- especially sunlight and other ultraviolet light sources, as UV photons are by a wide margin the strongest & the most likely to initiate photochemical transformations.
For what it's worth, amber glass containers offer roughly 80% UVR protection. Green and cobalt glass containers offer around 20% and 40-50%, respectively. Clear glass and most plastics offer essentially no UVR protection.
Friday, August 10, 2012
The Superdrol ban is quickly approaching -- and so this is the end of the line for Ultradrol. We're liquidating it here, and most of our retail partners and distributors are following suit. By Aug 22nd, less than two weeks from today, Ultradrol will be completely unavailable. For legal reasons, we will be unable to answer questions about it and unable to offer product support.
We are attempting to purify the leftover methylstenbolone raws we have. If we are successful, we may license these raw materials to other companies in the industry. We have no intentions to release another methylstenbolone product. Other interesting things are in the works, though, I can promise you that.
Monday, July 9, 2012
Lab results for Demiurge are as follows...
(Method: ESI/MS and ESI/MS/MS "MS2")
The main peak is simply [M+H]+; 240.7 is the usual sodium adduct ion [M+Na]+; the smaller peaks represent fragmentation. The molecule fragments along these lines:
It might be possible to get more fragmentation in MS2 mode, at m/z 117 & 104, but only if we really crank the voltage. ESI may be too 'gentle' a method. Maybe next time we'll use EI as an ion source.
Anyway, this stuff is basically as pure as it gets. It was very difficult to make, so unless there's very great demand, it's not coming back... When this batch is gone, it's probably gone for good.
Thank you very much for taking the time to read this & for your support. More test results, as always, are available upon request.
(...Speaking of which... If there is sufficient interest, we would easily be able to put together a free/public-use library of NMR & MS data for commonly-encountered anabolics, nootropics, stimulants, and other sorts of supplement ingredients... Please email email@example.com if interested.)
Monday, June 11, 2012
A new batch of Ultradrol is finally ready, is already bottled, & will be available for purchase in a couple of days. Without further ado, here are the test results:
Test method: ESI/MS & ESI/MS/MS (MS2)
[M+H]+ = 316.9
[M+Na]+ = 338.9
317.9 represents methylsten with one 13C atom. 339.9 is the same thing +Na.
354.8 is methylsten +K... A potassium adduct.
The last "MS2" page shows the fragmentation spectrum of methylsten. This is necessarily identical to previous batches. Superdrol's fragmentation spectrum is actually very different -- I have it on file & can email it to interested individuals. I can also email the rest of the test results. (There are a few more pages, but all are very similar to the ones posted above.)
Anyway... If you compare the results of this batch to those of previous batches, it's apparent that this new one is the best & purest which we have ever made.
Design note: Ultradrol's label has been changed, and the capsules are white. This is due to changes at the manufacturing (bottling/capping) facility that we use.
With respect to other products:
-A new batch of Mechabol has been released. The capsules are orange, and the label is also changing very soon.
-Aegis will be available once again in several days. No changes at all have been made to this product.
-A new nootropic (Codename: Demiurge) will be available very shortly. On or around the end of this month.
If you'd like to see more testing results, or if you have any questions, comments, or concerns, please feel free to email me directly: info[at]antaeuslabs.com.
If you need a crash-course (or a refresher) in spectrometry, this is a good general overview.
Thanks very much for taking the time to read this.
Wednesday, May 2, 2012
Having already written a little bit about the effects of food & how inhibiting drug-metabolizing enzymes can increase bioavailability, what remains is to discuss some more uncommon methods which might increase the bioavailability of orally-administered compounds. Of these, three are especially interesting:
1. Intestinal Permeation Enhancers.
I have written many times about chemical penetration enhancement for transdermal systems... But I may have neglected to mention that the same principles can also be applied to oral drug delivery. The mechanism of action is basically identical: Use chemicals to modulate intestinal cellular membranes and/or loosen/liquefy the tight junctures between intestinal epithelial cells. The former approach is better-suited to lipophilic drugs, whereas the latter appears to be preferable for hydrophilic drugs and small peptides, which are only rarely absorbed into cells.
Sodium caprate, a C10 fatty acid which can be isolated from coconut oil, is perhaps the best-known and most frequently studied intestinal permeation enhancer. It operates via both the transcellular and the paracellular routes, and has been shown to increase the bioavailability of compounds as wildly diverse as berberine (ref), norfloaxin (ref), the small polymer ardeparin (ref), the anti-sense nucleotide ISIS 104838 (ref), and a plant polysacharride weighing ~3500da (ref), among others. A short review can be found here.
Despite its seemingly broad utility, sodium caprate is not very frequently used in commercial preparations. Like most compounds which modulate cell membranes, it compromises cell viability to some degree & may lead to cell death and gastrointestinal damage after extended periods of use.
There are many other intestinal permeation enhancers -- most of the effective ones are either sodium salts of medium-chain fatty acids (like s. caprate) or zwitterionic surfactants. Both 'flavors' are associated with some degree of gastrointestinal toxicity.
Interestingly (to me, anyway,) there are some claims that chemicals routinely used as transdermal permeation enhancers may also be effective as intestinal penetration enhancers. The manufacturer of "NexACT-88", an ages-old transdermal penetration enhancer, recently started making claims that it is also useful for increasing oral drug bioavailability. They don't elucidate much, but it makes sense... Though toxicity may still be a major concern....
In materials science, a 'nanoparticle' is any particle with a size of 1000nm or less. Pharmaceutical nanoparticles are drug particles with sizes in the 100-1000nm range -- but most typically between 200-600nm. Their large-scale production was invented in the mid 90's & is now used to process four currently-available FDA-approved drugs. (Rapamine, Emend, TriCor, and Megace ES.)
Nanoparticle formulation improves oral bioavailability by a very simple mechanism: Increased solubility & faster dissolution rate. The Ostwald–Freundlich/Kelvin equation essentially states that smaller particles are exposed to greater dissolution pressures in liquid media due to increased surface curvature; the Noyes–Whitney equation states that dissolution velocity rises with surface area. (One hundred 200nm particles has 10x more total surface area than ten 2microM particles, which itself has 10x more surface area than a single 20microM particle.) Improving solubility and dissolution time should greatly increase bioavailability --- and this certainly seems to be the case with nanoparticle drug formulations, which exhibit much better total bioavailability than their micronized counterparts. (Typically around +150-200%.) Tmax also plummets due to increased dissolution velocities & faster absorption.
Megace (Megestrol Acetate) is an especially interesting case. Check out this study.
...When taken with food, both the nanoparticle and the micronized suspensions are fairly comparable. (The nanoparticle formulation was a little bit more effective, roughly around 50%.) But when taken on an empty stomach, the micronized suspension was effectively useless, whereas the nanoparticle suspension was still extremely effective. We can draw some conclusions from this re: increased aqueous solubility.
Another interesting thing: The nanoparticle suspension was used at 125mg/ml, whereas the micronized suspension was only at 40mg/ml... and yet the nanoparticle suspension was much less viscous, at 10 centipoise vs. 163 centipoise. The properties of nanoparticles in liquids are really incredible.
There are two methods of making nanoparticles, and this applies to metals and semiconductors as well as carbon-based drugs: "Top-down" & "bottom up." The top-down approach involves taking large particles and breaking them down with a mill or a piston; the bottom-up approach involves building nanoparticles from their constituent atoms --- where drugs are concerned, this tends to involve re-crystallizing them from a solution in very particular and painstaking ways. There are standardized, and patented, pharmaceutical approaches for both methods: NanoMorph®, IDD-P™, Dissocubes®, Nanopure®
, NANOEDGE®, and others.
Though extremely useful, I think that nanoparticle formulations would be difficult for any supplement company to manufacture. Most of the effective and easy methods are patented; the milling machines required generate lots of heat, & they are also typically very large, expensive, and difficult to maintain/clean properly; lastly, all nano-milling processes are extremely time-consuming, as nanoparticles tend to agglomerate into larger particles as you mill them.
...Still interesting, though.
3. Cyclodextrin complexing.
This is a very popular method. Cyclodextins have been used in more drugs and household products than I care to mention. (Though usually under trade-names such as "Clenzaire".) A very capable expert by the name of Thorsteinn Loftsson has already summarized their properties and pharmaceutical uses here and here. Worth a read.
Where steroids, triterpenes, and other very lipophilic small molecules are concerned, there are essentially no drawbacks associated with cyclodextrin complexing. It's an excellent and highly useful method for their oral delivery, sublingual delivery, intranasal delivery, and for their transdermal delivery in aqueous systems... And while it can be expensive, it's still a lot cheaper than buying a nano-mill & safer than using intestinal permeation enhancers.
In a study which compared three different forms of the synthetic androgen Danazol -- nanocrystalline, danazol-
hydroxypropyl-β-cyclodextrin complex, and a regular micronized suspension -- the cyclodextrin complex was the most efficacious, with an absolute bioavailability of 106.7 ± 12.3%. The nanoparticles were a little bit less effective, at 82.3 ± 10.1%. The micronized suspension was no good at all, with only 5.1 ± 1.9% total bioavailability. Read the abstract here... Then keep in mind that the dogs were fasted, so these values would certainly be very different in 'fed' dogs. The micronized suspension would do much better, the nanoparticles would also be a bit more effective, and the cyclodextrin complex's bioavailability would probably remain unchanged.
Other studies abound.
--"Self-microemulsifying drug delivery systems" (SMEDDS) are 'wet' solvent/surfactant/oil-based systems for liquid orals or gelcaps. They are designed to emulsify completely upon contact with aqueous media, especially under conditions of heat and pressure. The fact that they tend to contain high concentrations of surfactants can be a problem -- for example, the Cremophor in Taxol® is known to cause allergic reactions. Systemic toxicity is a drawback also associated with the oral use of cosolvents such as propylene glycol... Then, furthermore, one must consider that chemical stability tends to be pretty low with these systems, that batch variation can be high, that shelf-life may be very short, and that they are also expensive to produce...
...Bioavailability doesn't seem to improve by enough to make it worth the trouble. All in all, microemulsions are a pretty ham-handed approach to improving drug bioavailability.
--Drugs can be loaded into mesoporous silicon particles -- nano-scale silicon honeycombs which are very stable and which can be filled with drug or nutrient molecules. This cyclodextrin-like method can presumably be applied to increase the oral bioavailability of large molecules such as peptides. A review of this method -- which is still in early/experimental stages -- can be found here.
That's all that I know enough to write about. If anybody knows of any additional ways to increase the oral bioavailability of drugs and nutrients, I'd love to hear of 'em...!