SARM S-4 doses being used are TOO HIGH!!

[cvictorg]

I think that the yellow vision and impaired night vision that people are reporting are side effects of acute overdose of S-4.

The only clinical trials on S-4 are the ones that GTx is doing for Ostarine (their brand name for S-4). But their clinical trials used up to 3mg TOTAL per day, not per kg of bodyweight per day. That's a difference of a couple orders of magnitude. The dosing for this chemical has been WAY too high, because one of the primary people selling it does not understand the research.

GTx Presents Phase II Ostarine (MK-2866) Cancer Cachexia Clinical Trial Results at Endocrine Society Annual Meeting

This preliminary study on S-4 in rats found that anabolism in muscle was maxed out at around 0.75 mg or 2.82 mg/kg per day

Pharmacodynamics of Selective Androgen Receptor Modulators
PubMed Central, Fig. 5: J Pharmacol Exp Ther. 2003 March; 304(3): 1334–1340. doi: 10.1124/jpet.102.040840.

When corrected for body surface area and converted to dosing for humans, the dose that maxes out the anabolic response would be around 0.46 mg/kg. In a 200 lb male, that works out to about 40 mg/day. That may sound low, but it's still 13 times higher than the highest dose they used in the clinical trials. You sure as hell don't need hundreds of mgs per day.

Here's a paper on converting animal doses to humans

Dose translation from animal to human studies revisited -- Reagan-Shaw et al. 22 (3): 659 -- The FASEB Journal

As the abstract states, "The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight..." The FDA has stated that the extrapolation of animal dose to human dose is correctly performed only through normalization to body surface area. To convert mg/kg in rats to mg/kg in humans, you multiply by 0.162 (6/37). For mice to humans, multiply by 0.081 (3/37). There are several other values for other animals.

So I really don't think one needs to take 100 or more mgs of S-4 per day

Comments appreciated

 

[cvictorg]

Pharmacokinetics of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide in rats, a non-steroidal selective androgen receptor modulator

Analysis of variance showed no significant difference in the CL of S-4 at doses of 0.5, 1 and 10 mg kg−1 ( p>0.05). Previous in vivo studies in the present authors' laboratory showed that the dose required to restore the levator ani muscle weight in castrated animals, an indicator of anabolic activity, compared with that of intact animals was less than 4 mg kg−1 day−1 (Yin et al. 2003). Thus, S-4 demonstrates linear pharmacokinetics within the dose range needed to exert maximal pharmacological effects.

The lack of parent drug in the urine suggests that S-4 is extensively metabolized. Assuming a hepatic blood flow of 13.8 ml min −1 in the rat (Davies and Morris 1993), the hepatic extraction ratio of S-4 would be less than 0.05. Based on this hepatic extraction ratio, a greater than 95% bioavailability (i.e. less than 5% of the drug would be removed by first-pass metabolism) is predicted. The present results confirmed this prediction, as S-4 was completely bioavailable following pharmacologically relevant doses (i.e. doses ≤ 10 mg kg−1).

The CL of S-4 at a dose of 0.5 mg kg−1 (1.92 ml min−1 kg−1) was significantly ( p<0.001) greater than that observed for the 30 mg kg−1 dose (1.00 ml min−1 kg−1). These data suggest that saturation of the drug-metabolizing enzymes might be occurring at this higher dose. Therefore, one would expect to see further suppression of CL following doses greater than 30 mg kg−1. However, due to the potency of S-4, the authors do not anticipate the need for such high doses during clinical use. Forthcoming data from the present authors' laboratory will provide needed information about the hepatic metabolism and pharmacokinetics of S-4 in this and other species.

The pharmacological activity and pharmacokinetics of S-4 in rats suggest that this compound has the properties of an ideal SARM as defined by Negro-Vilar (1999). It is rapidly absorbed following p.o. doses (tmax, 48−84 min), and it exerts tissue-specific anabolic effects in vivo, with anabolic effects in muscle and bone but lesser effects in the prostate and seminal vesicles (Kearbey et al. 2003, Yin et al. 2003). These properties coupled with forthcoming reports from the present authors' laboratory about the pharmacological effects of S-4 in other pertinent animal models and its pharmacokinetics and metabolism in dogs and humans, favour the continued development of S-4 as an orally bioavailable non-steroidal SARM.

So at a dose of 4mg/kg/day (using the dose conversion of .162 for rats) you're looking at a dose of appx 65mgs/day - still much less than the 100+mgs/day some here are using

BUT - at a dose of .5mgs/kg/day - you're only looking at a dose of appx 8mgs for a 100kg human!

 

[bushin]

Good info! looks like youve been doing your research

 

[truckdaddy]

agreed, I find no sides at 50mg ed....perfect.

 

[tomtom76]

agreed, I find no sides at 50mg ed....perfect.

is it any good ???

 

[Newman]

First, I want to say thank you for posting this. Very good info.



Now for the reason I'm responding:

So at a dose of 4mg/kg/day (using the dose conversion of .162 for rats) you're looking at a dose of appx 65mgs/day - still much less than the 100+mgs/day some here are using

BUT - at a dose of .5mgs/kg/day - you're only looking at a dose of appx 8mgs for a 100kg human!

I may embarrass myself here, but I think you may have made a math error.

Specifically, at 0.5 mgs per Kg, wouldn't a 100Kg BBer use 50mgs rather than only 8mgs?

Thanks.

 

[cvictorg]

First, I want to say thank you for posting this. Very good info.



Now for the reason I'm responding:



I may embarrass myself here, but I think you may have made a math error.

Specifically, at 0.5 mgs per Kg, wouldn't a 100Kg BBer use 50mgs rather than only 8mgs?

Thanks.

Remember you have to convert animal doses to human doses

So - .5mgs/kg x 100kgs x .162 = 8mgs

 

[Newman]

Remember you have to convert animal doses to human doses

So - .5mgs/kg x 100kgs x .162 = 8mgs

Yes, but I thought that you had already done that when you reduced the dosage from 4mgs per Kg ED to 0.5mg per Kg ED.

You even mentioned the conversion from rats to humans in the section I quoted in my last post. It was taken from the last 2 sentances of your post #2 of this thread.

Maybe I misunderstood...

 

[Newman]

So at a dose of 4mg/kg/day (using the dose conversion of .162 for rats) you're looking at a dose of appx 65mgs/day - still much less than the 100+mgs/day some here are using

BUT - at a dose of .5mgs/kg/day - you're only looking at a dose of appx 8mgs for a 100kg human!

This is where I got the idea that the rat-to-human conversion had already taken place. You mentioned converting from rat dosage, then reduced the dose from 4mg to 0.5mg, so I figured the conversion had already occurred. I admit I never crunched the numbers, but based on what was written (the WAY it was written) it seemed that the conversion was already accounted for. If it hadn't been done, then I'm not sure why you reduced from 4mg to 0.5mg?



Anyway, I'm not trying to nit-pick over minor details, I only wanted to make sure I was understanding you correctly. Essentially, I get the overall point that somve vendors (it doesn't matter who) may have made over estimated the dosage & inadvertantly caused excessive sides. If true, then I'm VERY glad you cought this oversight because I think SARMS-4 is probably going to become one of the best medical & sport tools available.



On a side note, I'm unaware as to whether significant downregulation occurs at moderate to heavy doses over extended periods. (I haven't studied the compound much) Do you know whether downregulation is an issue with SARMS-4? If so, then I figure it's probably best used in PCT, rather than as a synergistic on-cycle ancilliary.

 

[EasyEJL]

Essentially, I get the overall point that somve vendors (it doesn't matter who) may have made over estimated the dosage & inadvertantly caused excessive sides. If true, then I'm VERY glad you cought this oversight because I think SARMS-4 is probably going to become one of the best medical & sport tools available.

honestly, whether at the excessive doses or lower, I still haven't seen very exciting results that lead me to think its worth using given the possibility of longer term optical effects. The fact that it is a side that occurs at higher doses leads me to wonder what will happen over time, or 3-4 years out.

 

[Newman]

honestly, whether at the excessive doses or lower, I still haven't seen very exciting results that lead me to think its worth using given the possibility of longer term optical effects. The fact that it is a side that occurs at higher doses leads me to wonder what will happen over time, or 3-4 years out.

Interesting POV.

Were you using it on cycle as an ancilliary, or after cycle as PCT?

 

[EasyEJL]

Oh I haven't used it at all because of those reasons, but I do know others who have used it.

 

[Newman]

Oh I haven't used it at all because of those reasons, but I do know others who have used it.

Fair enough.

To be honest, I'm surprised that you'd dismiss anything as promising as this without trying it at least once.

Personally, I've never tried it either, but it seems to make sense that if it functions as advertised, then the most benefit would be gained in use as part of a PCT to help keep the gains given by gear & gh etc.

 

[EasyEJL]

well, its promising, but i've seen such inconsistent/disappointing results from most guys who take it at 50mg/day that it doesn't seem like the risk reward ratio is worthwhile vs other things out there. And keep in mind I'm on TRT so I don't ever do PCT. Maybe if I wasn't on TRT it would seem worthwhile for that.

 

[Conciliator]

I think that the yellow vision and impaired night vision that people are reporting are side effects of acute overdose of S-4.

The only clinical trials on S-4 are the ones that GTx is doing for Ostarine (their brand name for S-4). But their clinical trials used up to 3mg TOTAL per day, not per kg of bodyweight per day. That's a difference of a couple orders of magnitude. The dosing for this chemical has been WAY too high, because one of the primary people selling it does not understand the research.

GTx Presents Phase II Ostarine (MK-2866) Cancer Cachexia Clinical Trial Results at Endocrine Society Annual Meeting

This preliminary study on S-4 in rats found that anabolism in muscle was maxed out at around 0.75 mg or 2.82 mg/kg per day

Pharmacodynamics of Selective Androgen Receptor Modulators
PubMed Central, Fig. 5: J Pharmacol Exp Ther. 2003 March; 304(3): 1334–1340. doi: 10.1124/jpet.102.040840.

When corrected for body surface area and converted to dosing for humans, the dose that maxes out the anabolic response would be around 0.46 mg/kg. In a 200 lb male, that works out to about 40 mg/day. That may sound low, but it's still 13 times higher than the highest dose they used in the clinical trials. You sure as hell don't need hundreds of mgs per day.

Here's a paper on converting animal doses to humans

Dose translation from animal to human studies revisited -- Reagan-Shaw et al. 22 (3): 659 -- The FASEB Journal

As the abstract states, "The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight..." The FDA has stated that the extrapolation of animal dose to human dose is correctly performed only through normalization to body surface area. To convert mg/kg in rats to mg/kg in humans, you multiply by 0.162 (6/37). For mice to humans, multiply by 0.081 (3/37). There are several other values for other animals.

So I really don't think one needs to take 100 or more mgs of S-4 per day

Comments appreciated

Come on now. Don't plagiarize me. Give credit where credit is due... http://www.professionalmuscle.com/forums/689444-post4.html

 

[Conciliator]

This is where I got the idea that the rat-to-human conversion had already taken place. You mentioned converting from rat dosage, then reduced the dose from 4mg to 0.5mg, so I figured the conversion had already occurred. I admit I never crunched the numbers, but based on what was written (the WAY it was written) it seemed that the conversion was already accounted for. If it hadn't been done, then I'm not sure why you reduced from 4mg to 0.5mg?

Same here. I don't understand where he gets the figure of .5mgs/kg/day from.

On a side note, I'm unaware as to whether significant downregulation occurs at moderate to heavy doses over extended periods.

Down-regulation of what?

 

[Conciliator]

The only clinical trials on S-4 are the ones that GTx is doing for Ostarine (their brand name for S-4). But their clinical trials used up to 3mg TOTAL per day, not per kg of bodyweight per day. That's a difference of a couple orders of magnitude. The dosing for this chemical has been WAY too high, because one of the primary people selling it does not understand the research.

Also, we now know that Ostarine is NOT S-4. GTx has not released the chemical structure of Ostarine. S-4 is actually andarine. See this recent paper, which was authored by GTx. They explain, "Ostarine was selected for advanced clinical development based on corporate strategy. Readers are cautioned to note that the name Ostarine is often mistakenly linked to the chemical structure of [S-4], which is also known as andarine. The chemical structure of Ostarine has not been publicly disclosed. The authors are unable to provide additional information."

 

[Newman]

Hi Conciliator. Good to have you here. (always a pleasure)

Down-regulation of what?

SARMS-4 reception & subsequent enhancement of anabolism (if any).

I admit that you are more erudite on ergogenic aids than I, but I've gotta assume that there's some form of naturally existing receptor that acts on. There may be no SARMS-4 in nature, but if it works, then it being absorbed somewhere.

I assume it doesn't simply weep through the cell wall, like AAS in Duchaine's Non AR Mediated theory. Even if it did, once in the nucleus, it must affect something in there. Or not...

 

[Conciliator]

...but I've gotta assume that there's some form of naturally existing receptor that acts on.

I'm not sure if you're being serious or joking. Do you know what SARM stands for?

 

[Newman]

I'm not sure if you're being serious or joking. Do you know what SARM stands for?

Yes, I know it refers to ARs, but if AAS use can eventually lead to AR downregulation (both AAS & SARMS-4 act on ARs), then I'm wondering whether SARMS-4 can/will eventually have dimishing effects also.

If so, then this may be why EasyEJL has seen such lacklustre results in his friends use of SARMS-4.

Having not yet read the medical research studies on SARM-4, I'm unaware if there may be any factor in SARMS-4 in-vivo biochemical mechanism of action that eventually causes dimishing effects.

I guess I could have been more specific in my earlier posts. Sorry.



If the med research studies used much lower doses than we're seeing guys use for BBing purposes & they still showed reasonably decent results over extended periods, then I have no clue what could be the cause of some people not getting good results.

Perhaps larger doses desensitise the ARs to the AR sensitization effects noted in the med studies???

Thanks.