daande
06-03-2010, 04:01 PM
Role of SARMs in Androgen Therapy for Men
Currently used androgenic formulations for replacement therapy are largely restricted to injectable or skin delivery formulations of testosterone or testosterone esters. Marketed injectable forms of testosterone esters (such as testosterone enanthate, propionate, or cypionate) produce undesirable fluctuations in testosterone blood levels, with supraphysiological concentrations early, and subnormal levels towards the end of the period before the next injection, providing an unsatisfactory profile and in some cases undesired side effects. Skin patches do provide a better blood level profile of testosterone, but skin irritation and daily application still limit the usefulness and acceptability of this form of therapy (1, 20, 21, 22). Oral preparations such as fluoxymesterone and 17{alpha}-methyltestosterone are not currently used due to concerns about liver toxicity linked to the 17{alpha}-alkyl group and because of somewhat lower efficacy. Thus, these compounds are considered obsolete (1, 20) and do not represent a viable form of therapy.
The discovery and development of SARMs provides the opportunity to design molecules that are not only orally active, but that target AR in different tissues to elicit the desired activity for each of the key indications benefiting from androgen therapy. The desired activity profile of novel SARMs is described in Table 1Go. For simplicity, we have listed the desired activity in tissues or specific parameters for one specific indication (i.e., male hypogonadism) side by side with a category for selected indications. The latter provides a menu of choices for the design of molecules that can address very specific needs in the treatment of different disorders. Thus, we envision that an ideal SARM for the treatment of primary or secondary male hypogonadism (Table 1Go) would have the following profile: orally active, ideally with a pharmacokinetic profile consistent with once a day administration, capable of stimulating prostate, seminal vesicles, and other sex accessory tissues at doses equipotent to those needed to provide increases in muscle mass and strength and fat-free mass, support bone growth, and maintain/restore libido, virilization, and male habitus. Unlike testosterone which, when converted to DHT in the prostate has an enhanced proliferative activity in relation to other peripheral tissues, these SARMs are not substrates for 5{alpha}-reductase activity, nor do they affect the activity of the enzyme. Other activities that are considered undesirable should be diminished or eliminated, such as potential liver toxicity, blood pressure effects and fluid retention, induction of gynecomastia, and overstimulation of erythropoiesis. On the other hand, use of SARMs for selected indications provides the rationale for developing molecules with distinct tissue specificity. For example, if the target is bone growth in elderly men with osteopenia or osteoporosis, but with no overt signs of hypogonadism, a more anabolic SARM with clear effects on bone and muscle, but lesser activity on prostate or other sex accessory tissues would be more desirable.
Source: http://jcem.endojournals.org/cgi/content/full/84/10/3459#T1
Anyone have any more information on this stuff?
Currently used androgenic formulations for replacement therapy are largely restricted to injectable or skin delivery formulations of testosterone or testosterone esters. Marketed injectable forms of testosterone esters (such as testosterone enanthate, propionate, or cypionate) produce undesirable fluctuations in testosterone blood levels, with supraphysiological concentrations early, and subnormal levels towards the end of the period before the next injection, providing an unsatisfactory profile and in some cases undesired side effects. Skin patches do provide a better blood level profile of testosterone, but skin irritation and daily application still limit the usefulness and acceptability of this form of therapy (1, 20, 21, 22). Oral preparations such as fluoxymesterone and 17{alpha}-methyltestosterone are not currently used due to concerns about liver toxicity linked to the 17{alpha}-alkyl group and because of somewhat lower efficacy. Thus, these compounds are considered obsolete (1, 20) and do not represent a viable form of therapy.
The discovery and development of SARMs provides the opportunity to design molecules that are not only orally active, but that target AR in different tissues to elicit the desired activity for each of the key indications benefiting from androgen therapy. The desired activity profile of novel SARMs is described in Table 1Go. For simplicity, we have listed the desired activity in tissues or specific parameters for one specific indication (i.e., male hypogonadism) side by side with a category for selected indications. The latter provides a menu of choices for the design of molecules that can address very specific needs in the treatment of different disorders. Thus, we envision that an ideal SARM for the treatment of primary or secondary male hypogonadism (Table 1Go) would have the following profile: orally active, ideally with a pharmacokinetic profile consistent with once a day administration, capable of stimulating prostate, seminal vesicles, and other sex accessory tissues at doses equipotent to those needed to provide increases in muscle mass and strength and fat-free mass, support bone growth, and maintain/restore libido, virilization, and male habitus. Unlike testosterone which, when converted to DHT in the prostate has an enhanced proliferative activity in relation to other peripheral tissues, these SARMs are not substrates for 5{alpha}-reductase activity, nor do they affect the activity of the enzyme. Other activities that are considered undesirable should be diminished or eliminated, such as potential liver toxicity, blood pressure effects and fluid retention, induction of gynecomastia, and overstimulation of erythropoiesis. On the other hand, use of SARMs for selected indications provides the rationale for developing molecules with distinct tissue specificity. For example, if the target is bone growth in elderly men with osteopenia or osteoporosis, but with no overt signs of hypogonadism, a more anabolic SARM with clear effects on bone and muscle, but lesser activity on prostate or other sex accessory tissues would be more desirable.
Source: http://jcem.endojournals.org/cgi/content/full/84/10/3459#T1
Anyone have any more information on this stuff?