Well our teams of researchers were also curious and following their extensive studies they have been able to report to us the following benefits and research studies linked to the use of RAD 140.

The first phase of the study on RAD-140 in humans who suffer from deadly weight loss due to cancer cachexia (which literally means the wasting away of muscle caused by cancer) was initiated after researchers discovered its impressive ability to stimulate muscle weight without anabolic reactions. The study also reports that RAD-140 promotes the stimulation of the seminal vesicles stimulated by testosterone, resulting in more sperm, and added benefit!

Research has shown that RAD140 acts on selective androgen receptors exclusively in muscle and bone tissues therefore it mimics hormone receptors. Research has shown rapid increase in building muscular tissues and also research has shown RAD-140 shows strong increases in stamina and endurance during high intensity exercise to go along with great increases in muscle recovery.

Research studies have shown that RAD-140 has greater anabolic effects than testosterone because it produces more reinforced results without side effects and it’s great for those that need supplemental hormonal therapy. Research has shown RAD-140 preserves neurons in the brain and have neuroprotective properties as with testosterone and is a great benefit to those with neurodegenerative diseases. Summing everything up research has shown RAD-140 is a great SARM for rapid increases in muscle growth, improvements in endurance, and increases overall athletic performance.

So if you’re looking to increase your muscles this is the product for you. Why you may ask, well it’s actually quite simple…up until now you have been lifting heavy and spending a lot of time at the gym but at a given point you reach a point where you have maxed out your personal threshold. This is where RAD 140 comes in.

This product helps you develop muscles beyond your personal limitations; it helps you pass that speed bump which we refer to you as your plateau. Taking RAD 140 finds its way in your system to help you push past the limits to continue to build and increase your muscles.

 

 

 

RAD 140 is potent and orally bioavailable, nonsteroidal selective androgen receptor modulator, which means it has very much the same effects as anabolic steroids but it does not have the negative side effects that come with taking anabolic steroids. You may be asking yourself how is that possible…. let us explain.

This specific Sarmsamerica product gives your body the mild boost of testosterone which in turn interacts with your hormonal receptors in your tissues without the estrogenic side effects which anabolic steroids brings on.

Samrsamerica RAD 140 product helps in increasing your muscle and its effects are done so quickly. This product is often used an alternative to hormone replacement therapy in men with low testosterone levels without the same risks for developing prostate cancer or accelerating the progression of existing prostate cancer. With the use of Sarmsamerica product RAD 140 you don’t need to worry about getting ``man boobs`` or the water retention that goes with the use of high estrogen intakes, as RAD 140 does not convert to estrogen in the body.

Based on studies in the research of RAD 140 the following groups of people can benefit from this product.

Athletes and bodybuilders in need of more performance but who desire to avoid potential negative side effects of traditional performance enhancing drugs.

People using steroid cycles who are looking to bridge the time between their cycles to maintain results without damaging their organs.

Men with decreased testosterone levels due to abuse of anabolic steroids or general health issues that cause hypogonadism

Men sensitive to gynecomastia side effects when using testosterone.

Additional Benefits include

It is important to note that because this specific SARM is new, no serious side effects have yet been observed or noted as are usually seen in anabolic steroid users.

With RAD-140 you will build muscle and burns fat. With multiple published human trials under its belt, RAD-140 (also called Testolone) is one of the best-studied SARMs. Those studies found powerful results, too. Testolone shows no meaningful side effects and is very effective at building muscle.

Users have said they lost body fat on Testolone (RAD140) and this is due to an increase in metabolism. When you increase lean muscle mass, you also will have an easier time losing body fat.

Testolone treatment has been clinically shown to suppress cancer cell growth by blocking the effects of estrogen on tissues. Specifically, RAD140 prevents the production of a protein called ESR1, which is implicated in the development of cancer.

RAD-140 has greater anabolic effect than testosterone. Elderly men and women who took modest doses of Testolone for 12 weeks grew 3 pounds of muscle and lost a pound of fat, with no changes to diet or exercise. Cancer patients saw nearly identical results along with a similar timeframe. There were no side effects in either study. A pound of muscle a month is about what you would expect with a solid workout routine – but the people taking Testolone in these studies weren’t exercising. Combining the two would be even more powerful, in theory. Pretty impressive!

How to use RAD 140

When you take Rad 140 you need to swallow it first and then you can follow it with a full glass of water. Researchers have indicated that using RAD 140 daily for a 12 week cycle is optimal to reinforce is productivity level. Following your 12 week cycle you can take a break for approximately 4-12 weeks and then restart your program cycle. The recommended dosage levels is between 20 and 30 mg.

 

Summary

Taking MK-677 or RAD-140 individually will give you results, but for even better body composition, muscle gain, anti-aging and fat loss results, you can cycle MK-677 with RAD-140 together by taking 25 mg per day of MK-677 and 20 mg per day of RAD 140 for 12 weeks. Then, after taking a break for 4-12 weeks, you can start it up again.

 

References

  1. Lu N. Z.; Wardell S. E.; Burnstein K. L.; Defranco D.; Fuller P. J.; Giguere V.; Hochberg R. B.; McKay L.; Renoir J. M.; Weigel N. L.; Wilson E. M.; McDonnell D. P.; Cidlowski J. A. International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol. Rev. 2007, 584782–97. [PubMed]
  2. Testosterone Action Deficiency Substitution, 3rd ed.; Nieschlag E., Behre H., Eds.; Cambridge University Press: 2004.
  3. Kilbourne E. J.; Moore W. J.; Freedman L. P.; Nagpal S. Selective androgen receptor modulators for frailty and osteoporosis. Curr. Opin. Invest. Drugs 2007, 810821–829. [PubMed]
  4. Bhasin S.; Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr. Opin. Clin. Nutrition Metab. Care 2009, 123232–240. [PMC free article] [PubMed]
  5. Mohler M. L.; Bohl C. E.; Narayanan R.; He Y.; Hwang D. J.; Dalton J. T.; Miller D. D. Nonsteroidal tissue-selective androgen receptor modulators. Methods Principles Med. Chem. 2008, 39, 249–304 (Nuclear Receptors as Drug Targets).
  6. Kim J.; Wu D.; Hwang D. J.; Miller D. D.; Dalton J. T. The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators. J. Pharmacol. Experimental Therapeutics 2005, 3151230–239. [PubMed]
  7. Ostrowski J.; Kuhns J. E.; L J. A.; M M. C.; Beehler B. C.; Krystek S. R. Jr.; B Y.; Sun C.; Seethala R.; Golla R.; Sleph P. G.; Fura A.; An Y.; Kish K. F.; Sack J. S.; Mookhtiar K. A.; Grover G. J.; Hamann L. G. Pharmacological and X-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats. Endocrinology 2007, 14814–12. [PubMed]
  8. Gao W.; Bohl C. E.; Dalton J. T. Chemistry and structural biology of the androgen receptor. Chem. Rev. 2005, 10593352–3370. [PubMed]
  9. Gao W.; Dalton J. T. Ockham’s razor and selective androgen receptors (SARMs): Are we overlooking the role of 5α-reductase?. Mol. Interventions 2007, 7110–13. [PMC free article] [PubMed]
  10. pK data in rats for compound 3 is provided in the Supporting Information.
  11. Oral data for compounds 3 and 4 in the Herschberger assay is shown in the Supporting Information.
  12. Human and rat microsome data are shown in the Supporting Information.
  13. The left-hand side of the molecule as written is presumed to overlay with the A-ring of testosterone. This particular left-hand side equivalent has been utilized to good effect previously in nonsteroidal SARMs:
    a. Li J. J.; Sutton J. C.; Nirschl A.; Zou Y.; Wang H.; Sun C.; Pi Z.; Johnson R.; Krystek S. R. Jr.; Seethala R.; Golla R.; Sleph P. G.; Beehler B. C.; Grover G. J.; Fura A.; Vyas V. P.; Li C. Y.; Gougoutas J. Z.; Galella M. A.; Michael A.; Zahler R.; Ostrowski J.; Hamann L. G. Discovery of Potent and Muscle Selective Androgen Receptor Modulators through Scaffold Modifications. J. Med. Chem. 2007, 50133015–3025. The precursor fragment 6 has been described for the preparation of SARMs in: . [PubMed]
    b. Schlienger N.; Lund B. W.; Pawlas J.; Badalassi F.; Bertozzi F.; Lewinsky R.; Fejzic A.; Thygesen M. B.; Tabatabaei A.; Bradley S. R.; Gardell L. R.; Piu F.; Olsson R. Synthesis, structure−activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators. J. Med. Chem. 2009, 52, 7186–7191. [PubMed]
  14. US2010/0041721.
  15. Wipf P.; Miller C. P. A new synthesis of highly functionalized oxazoles. J. Org. Chem. 1993, 58143604–3606.
  16. Johns B. A.; Weatherhead J. G.; Allen S. H.; Thompson J. B.; Garvey E. P.; Foster S. A.; Jeffrey J. L.; Miller W. H. 1,3,4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position. Biorg. Med. Chem. Lett. 2009, 1961807–1810. [PubMed]
  17. The scheme shown was used to successfully produce approximately 2 kg of compound 5 in >99% purity under GMP manufacturing conditions.
  18. The AR binding assay was performed as specified from the manufacturer. The assay is a fluorometric assay using a tracer made from fluorescent tagged AR-ligand methyltrienolone (R1881). Ki values were derived by the Cheng−Prushoff equation (Ki = (IC50/(1 + [S]/Km)), where Km was set equal to Kd, Kd = 25 nM (fluorometric R1881), and [S] = 1.
  19. The C2C12 osteoblast differentiation assay procedure is explained in the Supporting Information.
  20. Hershberger L. G.; Shipley E. G.; Meyer R. K. Myotropic activity of 19-nortestosterone and other steroids determined by a modified levator ani muscle method. Proc. Soc. Exp. Biol. Med. 1953, 83, 175–80. [PubMed]
  21. This dose of TP provides an approximate EC70 on prostate and EC90 on muscle in our Herschberger assays.
  22. RAD140 demonstrated fairly linear increases in exposure in male rats up through the 10 mg/kg po dose range, thereby ruling out an exposure limited efficacy as opposed to compound-limited efficacy. Antagonism of TP is further evidence of a mechanism-specific, limited efficacy as opposed to a pharmacokinetic limitation of the compound.
  23. Testosterone levels in castrated rats are <0.5 ng/mL; i.e. see: D’Souza S. S.; Selmin F.; Murty S. B.; Qiu W.; Thanoo B. C.; DeLuca P. P.Assessment of fertility in male rats after extended chemical castration with a GNRH antagonist AAPS. Pharm. Sci. 2004, 6 (1), Article 10. [PubMed]
  24. For the intact animal dosing, we had originally planned not to run testosterone as a comparator, since the intact animals were relied on to provide their own controls and we were primarily concerned with how RAD140 behaved within and against the animal’s endogeneous background. Nevertheless, we ultimately did include testosterone in one dose group but used a slightly lower dose because the animals already have endogeneous testosterone present. Nevertheless, we did not run a separate testosterone curve in order to determine what the EC30, EC50, or EC70 for testosterone was in this model.
  25. The monkeys were placed into groups of three at day-21, and the weight of each monkey recorded at each time point and the mean weight of each group are reflected on the graph. Coincidentally, by day −1, the mean weight of each group had each converged to a very similar value of 4.26 kg, 4.29 kg, and 4.28 kg for the 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg groups, respectively.
  26. pK analysis at various time points throughout this monkey study indicated that significant increases in exposure were seen with dose.
  27. Since these were young, intact male cynomolgous monkeys (3 to 4 years of age), they had fairly high endogeneous total plasma testosterone at day −1 (approximately 600−800 ng/dL), which is similar to the approximately 600 ng/mL that human males have between the ages of 25 and 54 (the levels then gradually decline with age). After 28 days of dosing with RAD140, the testosterone levels in all three groups was suppressed to approximately 200−300 ng/dL, with similar suppression in all three groups, although testosterone levels were significantly different for only the 0.01 mg/kg group (p < 0.05). Although this measurement did not account for possible diurnal variations in the animals and LH levels were not definitive, since they were below the level of detection in most pre- and postdose groups (LH < 0.8 ng/mL), one might still consider the possibility that even the 0.01 mg/kg dose was a fully effective, testosterone replacement dose, since body weight and lean mass were at least maintained (if not increased) in the low dose group despite significant testosterone suppression. Beyond this finding, we do not know whether testosterone suppression is a proxy for other CNS-related androgen effects beyond LH interference, such as mood, libido, and cognition, but we do believe a SARM with potent androgen agonist, CNS-type activity would be an interesting tool for that sort of exploration.
  28. For a thorough examination of the effect of high dose, injected dihydrotestosterone (DHT) on lipids in female, ovariectomized cynomolgus monkeys, see: Nantermet P.; Harada S.; Liu Y.; Spring C.; Johnson C.; Yu Y.; Kimme D.; Holder D.; Phillips R.; Ray W. Gene expression analysis in cynomolgus monkeys provides mechanistic insight into high-density liproprotein-cholesterol reduction by androgens in primates. Endocrinology 2008, 14941551–1561. [PubMed]
  29. Lee H.; Ha M.-H.; Christian D. C. Body weight, alcohol consumption and liver enzyme activity−a 4-year follow up study. Int. J. Epidemiol. 2001, 304766–770. [PubMed]
  30. Mean triglyceride changes by group were (−26%, −36%, −37%), LDL (+8%, −24%, −53%), and HDL (−13%, −42%, −64%) for 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg, respectively. Mean liver enzyme (ALT) changes by group were (ALT) (−15%, −2%, +43%) and (ALP) (−9%, +3%, +31%) for 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg, respectively.
  31. Nishimo Y.. Effects of androgens and related steroids on liver function and enzymes. Pharmacol. Ther., B 1975, 1 (2), pp 187−207.

 

Well our teams of researchers were also curious and following their extensive studies they have been able to report to us the following benefits and research studies linked to the use of RAD 140.

The first phase of the study on RAD-140 in humans who suffer from deadly weight loss due to cancer cachexia (which literally means the wasting away of muscle caused by cancer) was initiated after researchers discovered its impressive ability to stimulate muscle weight without anabolic reactions. The study also reports that RAD-140 promotes the stimulation of the seminal vesicles stimulated by testosterone, resulting in more sperm, and added benefit!

Research has shown that RAD140 acts on selective androgen receptors exclusively in muscle and bone tissues therefore it mimics hormone receptors. Research has shown rapid increase in building muscular tissues and also research has shown RAD-140 shows strong increases in stamina and endurance during high intensity exercise to go along with great increases in muscle recovery.

Research studies have shown that RAD-140 has greater anabolic effects than testosterone because it produces more reinforced results without side effects and it’s great for those that need supplemental hormonal therapy. Research has shown RAD-140 preserves neurons in the brain and have neuroprotective properties as with testosterone and is a great benefit to those with neurodegenerative diseases. Summing everything up research has shown RAD-140 is a great SARM for rapid increases in muscle growth, improvements in endurance, and increases overall athletic performance.

So if you’re looking to increase your muscles this is the product for you. Why you may ask, well it’s actually quite simple…up until now you have been lifting heavy and spending a lot of time at the gym but at a given point you reach a point where you have maxed out your personal threshold. This is where RAD 140 comes in.

This product helps you develop muscles beyond your personal limitations; it helps you pass that speed bump which we refer to you as your plateau. Taking RAD 140 finds its way in your system to help you push past the limits to continue to build and increase your muscles.

 

 

 

RAD 140 is potent and orally bioavailable, nonsteroidal selective androgen receptor modulator, which means it has very much the same effects as anabolic steroids but it does not have the negative side effects that come with taking anabolic steroids. You may be asking yourself how is that possible…. let us explain.

This specific Sarmsamerica product gives your body the mild boost of testosterone which in turn interacts with your hormonal receptors in your tissues without the estrogenic side effects which anabolic steroids brings on.

Samrsamerica RAD 140 product helps in increasing your muscle and its effects are done so quickly. This product is often used an alternative to hormone replacement therapy in men with low testosterone levels without the same risks for developing prostate cancer or accelerating the progression of existing prostate cancer. With the use of Sarmsamerica product RAD 140 you don’t need to worry about getting ``man boobs`` or the water retention that goes with the use of high estrogen intakes, as RAD 140 does not convert to estrogen in the body.

Based on studies in the research of RAD 140 the following groups of people can benefit from this product.

Athletes and bodybuilders in need of more performance but who desire to avoid potential negative side effects of traditional performance enhancing drugs.

People using steroid cycles who are looking to bridge the time between their cycles to maintain results without damaging their organs.

Men with decreased testosterone levels due to abuse of anabolic steroids or general health issues that cause hypogonadism

Men sensitive to gynecomastia side effects when using testosterone.

Additional Benefits include

It is important to note that because this specific SARM is new, no serious side effects have yet been observed or noted as are usually seen in anabolic steroid users.

With RAD-140 you will build muscle and burns fat. With multiple published human trials under its belt, RAD-140 (also called Testolone) is one of the best-studied SARMs. Those studies found powerful results, too. Testolone shows no meaningful side effects and is very effective at building muscle.

Users have said they lost body fat on Testolone (RAD140) and this is due to an increase in metabolism. When you increase lean muscle mass, you also will have an easier time losing body fat.

Testolone treatment has been clinically shown to suppress cancer cell growth by blocking the effects of estrogen on tissues. Specifically, RAD140 prevents the production of a protein called ESR1, which is implicated in the development of cancer.

RAD-140 has greater anabolic effect than testosterone. Elderly men and women who took modest doses of Testolone for 12 weeks grew 3 pounds of muscle and lost a pound of fat, with no changes to diet or exercise. Cancer patients saw nearly identical results along with a similar timeframe. There were no side effects in either study. A pound of muscle a month is about what you would expect with a solid workout routine – but the people taking Testolone in these studies weren’t exercising. Combining the two would be even more powerful, in theory. Pretty impressive!

How to use RAD 140

When you take Rad 140 you need to swallow it first and then you can follow it with a full glass of water. Researchers have indicated that using RAD 140 daily for a 12 week cycle is optimal to reinforce is productivity level. Following your 12 week cycle you can take a break for approximately 4-12 weeks and then restart your program cycle. The recommended dosage levels is between 20 and 30 mg.

 

Summary

Taking MK-677 or RAD-140 individually will give you results, but for even better body composition, muscle gain, anti-aging and fat loss results, you can cycle MK-677 with RAD-140 together by taking 25 mg per day of MK-677 and 20 mg per day of RAD 140 for 12 weeks. Then, after taking a break for 4-12 weeks, you can start it up again.

 

References

  1. Lu N. Z.; Wardell S. E.; Burnstein K. L.; Defranco D.; Fuller P. J.; Giguere V.; Hochberg R. B.; McKay L.; Renoir J. M.; Weigel N. L.; Wilson E. M.; McDonnell D. P.; Cidlowski J. A. International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors. Pharmacol. Rev. 2007, 584782–97. [PubMed]
  2. Testosterone Action Deficiency Substitution, 3rd ed.; Nieschlag E., Behre H., Eds.; Cambridge University Press: 2004.
  3. Kilbourne E. J.; Moore W. J.; Freedman L. P.; Nagpal S. Selective androgen receptor modulators for frailty and osteoporosis. Curr. Opin. Invest. Drugs 2007, 810821–829. [PubMed]
  4. Bhasin S.; Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr. Opin. Clin. Nutrition Metab. Care 2009, 123232–240. [PMC free article] [PubMed]
  5. Mohler M. L.; Bohl C. E.; Narayanan R.; He Y.; Hwang D. J.; Dalton J. T.; Miller D. D. Nonsteroidal tissue-selective androgen receptor modulators. Methods Principles Med. Chem. 2008, 39, 249–304 (Nuclear Receptors as Drug Targets).
  6. Kim J.; Wu D.; Hwang D. J.; Miller D. D.; Dalton J. T. The para substituent of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides is a major structural determinant of in vivo disposition and activity of selective androgen receptor modulators. J. Pharmacol. Experimental Therapeutics 2005, 3151230–239. [PubMed]
  7. Ostrowski J.; Kuhns J. E.; L J. A.; M M. C.; Beehler B. C.; Krystek S. R. Jr.; B Y.; Sun C.; Seethala R.; Golla R.; Sleph P. G.; Fura A.; An Y.; Kish K. F.; Sack J. S.; Mookhtiar K. A.; Grover G. J.; Hamann L. G. Pharmacological and X-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats. Endocrinology 2007, 14814–12. [PubMed]
  8. Gao W.; Bohl C. E.; Dalton J. T. Chemistry and structural biology of the androgen receptor. Chem. Rev. 2005, 10593352–3370. [PubMed]
  9. Gao W.; Dalton J. T. Ockham’s razor and selective androgen receptors (SARMs): Are we overlooking the role of 5α-reductase?. Mol. Interventions 2007, 7110–13. [PMC free article] [PubMed]
  10. pK data in rats for compound 3 is provided in the Supporting Information.
  11. Oral data for compounds 3 and 4 in the Herschberger assay is shown in the Supporting Information.
  12. Human and rat microsome data are shown in the Supporting Information.
  13. The left-hand side of the molecule as written is presumed to overlay with the A-ring of testosterone. This particular left-hand side equivalent has been utilized to good effect previously in nonsteroidal SARMs:
    a. Li J. J.; Sutton J. C.; Nirschl A.; Zou Y.; Wang H.; Sun C.; Pi Z.; Johnson R.; Krystek S. R. Jr.; Seethala R.; Golla R.; Sleph P. G.; Beehler B. C.; Grover G. J.; Fura A.; Vyas V. P.; Li C. Y.; Gougoutas J. Z.; Galella M. A.; Michael A.; Zahler R.; Ostrowski J.; Hamann L. G. Discovery of Potent and Muscle Selective Androgen Receptor Modulators through Scaffold Modifications. J. Med. Chem. 2007, 50133015–3025. The precursor fragment 6 has been described for the preparation of SARMs in: . [PubMed]
    b. Schlienger N.; Lund B. W.; Pawlas J.; Badalassi F.; Bertozzi F.; Lewinsky R.; Fejzic A.; Thygesen M. B.; Tabatabaei A.; Bradley S. R.; Gardell L. R.; Piu F.; Olsson R. Synthesis, structure−activity relationships, and characterization of novel nonsteroidal and selective androgen receptor modulators. J. Med. Chem. 2009, 52, 7186–7191. [PubMed]
  14. US2010/0041721.
  15. Wipf P.; Miller C. P. A new synthesis of highly functionalized oxazoles. J. Org. Chem. 1993, 58143604–3606.
  16. Johns B. A.; Weatherhead J. G.; Allen S. H.; Thompson J. B.; Garvey E. P.; Foster S. A.; Jeffrey J. L.; Miller W. H. 1,3,4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position. Biorg. Med. Chem. Lett. 2009, 1961807–1810. [PubMed]
  17. The scheme shown was used to successfully produce approximately 2 kg of compound 5 in >99% purity under GMP manufacturing conditions.
  18. The AR binding assay was performed as specified from the manufacturer. The assay is a fluorometric assay using a tracer made from fluorescent tagged AR-ligand methyltrienolone (R1881). Ki values were derived by the Cheng−Prushoff equation (Ki = (IC50/(1 + [S]/Km)), where Km was set equal to Kd, Kd = 25 nM (fluorometric R1881), and [S] = 1.
  19. The C2C12 osteoblast differentiation assay procedure is explained in the Supporting Information.
  20. Hershberger L. G.; Shipley E. G.; Meyer R. K. Myotropic activity of 19-nortestosterone and other steroids determined by a modified levator ani muscle method. Proc. Soc. Exp. Biol. Med. 1953, 83, 175–80. [PubMed]
  21. This dose of TP provides an approximate EC70 on prostate and EC90 on muscle in our Herschberger assays.
  22. RAD140 demonstrated fairly linear increases in exposure in male rats up through the 10 mg/kg po dose range, thereby ruling out an exposure limited efficacy as opposed to compound-limited efficacy. Antagonism of TP is further evidence of a mechanism-specific, limited efficacy as opposed to a pharmacokinetic limitation of the compound.
  23. Testosterone levels in castrated rats are <0.5 ng/mL; i.e. see: D’Souza S. S.; Selmin F.; Murty S. B.; Qiu W.; Thanoo B. C.; DeLuca P. P.Assessment of fertility in male rats after extended chemical castration with a GNRH antagonist AAPS. Pharm. Sci. 2004, 6 (1), Article 10. [PubMed]
  24. For the intact animal dosing, we had originally planned not to run testosterone as a comparator, since the intact animals were relied on to provide their own controls and we were primarily concerned with how RAD140 behaved within and against the animal’s endogeneous background. Nevertheless, we ultimately did include testosterone in one dose group but used a slightly lower dose because the animals already have endogeneous testosterone present. Nevertheless, we did not run a separate testosterone curve in order to determine what the EC30, EC50, or EC70 for testosterone was in this model.
  25. The monkeys were placed into groups of three at day-21, and the weight of each monkey recorded at each time point and the mean weight of each group are reflected on the graph. Coincidentally, by day −1, the mean weight of each group had each converged to a very similar value of 4.26 kg, 4.29 kg, and 4.28 kg for the 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg groups, respectively.
  26. pK analysis at various time points throughout this monkey study indicated that significant increases in exposure were seen with dose.
  27. Since these were young, intact male cynomolgous monkeys (3 to 4 years of age), they had fairly high endogeneous total plasma testosterone at day −1 (approximately 600−800 ng/dL), which is similar to the approximately 600 ng/mL that human males have between the ages of 25 and 54 (the levels then gradually decline with age). After 28 days of dosing with RAD140, the testosterone levels in all three groups was suppressed to approximately 200−300 ng/dL, with similar suppression in all three groups, although testosterone levels were significantly different for only the 0.01 mg/kg group (p < 0.05). Although this measurement did not account for possible diurnal variations in the animals and LH levels were not definitive, since they were below the level of detection in most pre- and postdose groups (LH < 0.8 ng/mL), one might still consider the possibility that even the 0.01 mg/kg dose was a fully effective, testosterone replacement dose, since body weight and lean mass were at least maintained (if not increased) in the low dose group despite significant testosterone suppression. Beyond this finding, we do not know whether testosterone suppression is a proxy for other CNS-related androgen effects beyond LH interference, such as mood, libido, and cognition, but we do believe a SARM with potent androgen agonist, CNS-type activity would be an interesting tool for that sort of exploration.
  28. For a thorough examination of the effect of high dose, injected dihydrotestosterone (DHT) on lipids in female, ovariectomized cynomolgus monkeys, see: Nantermet P.; Harada S.; Liu Y.; Spring C.; Johnson C.; Yu Y.; Kimme D.; Holder D.; Phillips R.; Ray W. Gene expression analysis in cynomolgus monkeys provides mechanistic insight into high-density liproprotein-cholesterol reduction by androgens in primates. Endocrinology 2008, 14941551–1561. [PubMed]
  29. Lee H.; Ha M.-H.; Christian D. C. Body weight, alcohol consumption and liver enzyme activity−a 4-year follow up study. Int. J. Epidemiol. 2001, 304766–770. [PubMed]
  30. Mean triglyceride changes by group were (−26%, −36%, −37%), LDL (+8%, −24%, −53%), and HDL (−13%, −42%, −64%) for 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg, respectively. Mean liver enzyme (ALT) changes by group were (ALT) (−15%, −2%, +43%) and (ALP) (−9%, +3%, +31%) for 0.01 mg/kg, 0.1 mg/kg, and 1.0 mg/kg, respectively.
  31. Nishimo Y.. Effects of androgens and related steroids on liver function and enzymes. Pharmacol. Ther., B 1975, 1 (2), pp 187−207.

 

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