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Topic starter
28/06/2019 6:41 pm
Expert Opin Investig Drugs. 2006 Apr;15(4):377-87.
Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery.
Segal S, Narayanan R, Dalton JT.
Selective androgen receptor modulators (SARMS) bind to the androgen receptor and demonstrate anabolic activity in a variety of tissues; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents are able to induce bone and muscle growth, as well as shrinking the prostate. The potential of SARMS is to maximise the positive attributes of steroidal androgens as well as minimising negative effects, thus providing therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, end-stage renal disease, osteoporosis, frailty and hypogonadism. This review summarises androgen physiology, the current status of the R&D; of SARMS and potential therapeutic indications for this emerging class of drugs.
The Men's Health Biotech Company, today announced completion of recruitment of its proof of concept Phase II clinical trial of its first- in-class drug candidate, ostarine, a selective androgen receptor modulator (SARM). GTx expects to report data from the trial in the fourth quarter 2006.
(07/20/2006)
Ostarine is a selective androgen receptor modulator, SARM, that appears to be highly selective in building muscle with favorable pharmacokinetic properties including a long half life in animal models.
-----------------------------------
Drug Metab Dispos. 2006 Mar;34(3):483-94.
Pharmacokinetics and metabolism of a selective androgen receptor modulator in rats: implication of molecular properties and intensive metabolic profile to investigate ideal pharmacokinetic characteristics of a propanamide in preclinical study.
Wu D, Wu Z, Yang J, Nair VA, Miller DD, Dalton JT.
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12 Ave., Columbus, OH 43210, USA.
S-1 [3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide] is one member of a series of potent selective androgen receptor modulators (SARMs) that are being explored and developed for androgen-dependent diseases. Recent studies showed that S-1 holds great promise as a novel therapeutic agent for benign hyperplasia [W. Gao, J. D. Kearbey, V. A. Nair, K. Chung, A. F. Parlow, D. D. Miller, and J. T. Dalton (2004) Endocrinology 145:5420-5428]. We examined the pharmacokinetics and metabolism of S-1 in rats as a component of our preclinical development of this compound and continued interest in structure-activation relationships for SARM action. Forty male Sprague-Dawley rats were randomly assigned to treatment groups and received either an i.v. or a p.o. dose of S-1 at a dose level of 0.1, 1, 10, or 30 mg/kg. S-1 demonstrated a low clearance (range, 3.6-5.2 ml/min/kg), a moderate volume of distribution (range, 1460-1560 ml/kg), and a terminal half-life ranging from 3.6 to 5.2 h after i.v. doses. The oral bioavailability of S-1 ranged from 55% to 60%. Forty phase I and phase II metabolites of S-1 were identified in the urine and feces of male Sprague-Dawley rats dosed at 50 mg/kg via the i.v. route. The two major urinary metabolites of S-1 were a carboxylic acid and a sulfate-conjugate of 4-nitro-3-trifluoromethylphenylamine. Phase I metabolites arising from A-ring nitro reduction to an aromatic amine and B-ring hydroxylation were also identified in the urinary and fecal samples of rats. Furthermore, a variety of phase II metabolites through sulfation, glucuronidation, and methylation were also found. These studies demonstrate that S-1 is rapidly absorbed, slowly cleared, moderately distributed, and extensively metabolized in rats.
-------------------------------
Drug Metab Dispos. 2006 Jul 12.
in vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs.
Perera MA, Yin D, Wu D, Chan KK, Miller DD, Dalton JT.
The Ohio State University.
Compound S-4 (S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide) is a novel nonsteroidal androgen agonist that mimics many of the beneficial pharmacologic effects of testosterone with lesser effects on the prostate. S-4 demonstrated high androgen receptor (AR) binding affinity as well as anabolic specificity during in vivo pharmacologic studies in rats, identifying it as the first member of a new class of selective androgen receptor modulators (SARMs). The purpose of these studies was to determine the pharmacokinetics and metabolism of S-4 in dogs. S-4 showed linear pharmacokinetics after both intravenous (IV) and oral (PO) administrations at pharmacologically relevant doses, with a mean clearance of 4.6 ml/min/kg and a mean half-life of about 200 minutes. Interestingly, dose-dependent oral bioavailability was seen. However, at pharmacologically relevant doses, the oral bioavailability of S-4 was 91%. Species differences were observed in S-4 metabolism, the major metabolic pathway for S-4 in dogs was deacetylation of the B ring acetamide group and reduction of the A ring nitro group, while the major metabolic pathway for S-4 in rats was hydrolysis on the amide bond and reduction of the A ring nitro group. In addition, oxidative metabolites and phase II metabolites were identified in both rats and dogs. These studies demonstrate that S-4 maintains its promising pharmacokinetic properties in dogs (i.e., high oral bioavailability and linear kinetics) and is largely eliminated via hepatic metabolism by both phase I and phase II enzymes.
----------------------------------
J Pharmacol Exp Ther. 2003 Mar;304(3):1334-40.
Pharmacodynamics of selective androgen receptor modulators.
Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, Marhefka CA, Veverka KA, Miller DD, Dalton JT.
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E(max)) and dose for half-maximal effect (ED(50)) were determined for each compound and compared with that observed for Testosterone Propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.
-------------------------------------
J Pharmacol Exp Ther. 2003 Mar;304(3):1323-33.
Pharmacology, pharmacokinetics, and metabolism of acetothiolutamide, a novel nonsteroidal agonist for the androgen receptor.
Yin D, Xu H, He Y, Kirkovsky LI, Miller DD, Dalton JT.
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
The present study characterized the in vitro androgen receptor (AR) binding affinity, in vitro and in vivo pharmacological activity, and in vivo pharmacokinetics and metabolism of acetothiolutamide, a nonsteroidal AR ligand. AR binding was determined by a competitive binding assay. In vitro AR agonist activity was examined by a cotransfection assay. Acetothiolutamide displayed high AR binding affinity (K(i) = 4.9 +/- 0.2 nM) and full agonist activity in the in vitro studies. Next, the androgenic, anabolic, and antiandrogenic activity of acetothiolutamide was evaluated in a castrated immature rat model. In this animal model, acetothiolutamide exhibited an overall negligible androgenic effect, but a statistically significant anabolic effect at high subcutaneous doses. Also, acetothiolutamide demonstrated a noticeable antiandrogenic effect in castrated rats supplemented with testosterone propionate. To understand the causes for the observed disparity between in vitro and in vivo activities, pharmacokinetics and metabolism of acetothiolutamide were studied in male Sprague-Dawley rats. Acetothiolutamide was rapidly cleared from rat plasma (clearance of about 45 ml/min/kg) in a concentration-independent manner after i.v. dosing. Acetothiolutamide was completely absorbed after subcutaneous administration, but not bioavailable after oral dose. In the metabolism study, the unchanged molecule and its metabolites in urine and fecal samples were detected by high-performance liquid chromatography-mass spectrometry. The structures of major metabolites were elucidated with liquid chromatography-tandem mass spectrometry. After i.v. administration, acetothiolutamide was excreted in urine and feces as unchanged drug and a variety of metabolites. Oxidation, hydrolysis, and sulfate conjugation of phase I metabolites were the major metabolic pathways of acetothiolutamide in rats. Overall, the high plasma clearance of acetothiolutamide, due to its extensive hepatic metabolism, likely contributed to its lack of androgenic activity in vivo.
----------------------------------
Role of the Steroid Receptor Coactivator SRC-3 in Cell Growth
Ge Zhou,Yoshihiro Hashimoto,Inseok Kwak,Sophia Y. Tsai,and Ming-Jer Tsai
----------------------------
Mol Endocrinol. 2006 May;20(5):1048-60.
The corepressors silencing mediator of retinoid and thyroid hormone receptor and nuclear receptor corepressor are involved in agonist- and antagonist-regulated transcription by androgen receptor.
Yoon HG, Wong J.
Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, College of Medicine, Yonsei University, Seoul, South Korea.
We have investigated the role of corepressors SMRT (silencing mediator of retinoid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) in transcriptional regulation by androgen receptor (AR) in the LNCaP prostate cancer cell line. Using specific small interference RNAs to knock down SMRT and/or N-CoR in LNCaP cells, we found that SMRT and N-CoR not only mediate antagonist-dependent inhibition of AR activation but also have a widespread role in suppressing agonist-dependent activation of several AR target genes we have tested, including PSA (prostate-specific antigen), TSC22 (TSC22 domain family member 1), NKX3-1 (NK3 transcription factor locus 1), and B2M(beta-2-microglobulin). By sequencing analysis followed by analysis of physical association by chromatin immunoprecipitation assay, we mapped the putative androgen response elements in the NKX3-1 and B2M. Consistent with a role in both antagonist- and agonist-regulated transcription by AR, chromatin immunoprecipitation analysis revealed that both SMRT and N-CoR were recruited by AR to these genes in the presence of either flutamide or R1881. Knocking down SMRT and N-CoR enhanced the recruitment of the coactivators steroid receptor coactivator 1 and p300 by agonist-bound AR and led to increased hyperacetylation of histone H3 and H4, suggesting that the corepressors actively compete with coactivators for binding to agonist-bound AR. Taken together, our data indicate that SMRT and N-CoR corepressors are involved in transcriptional regulation by both agonist- and antagonist-bound AR and regulate the magnitude of hormone response, at least in part, by competing with coactivators.
Mol Cell Biol. 2006 Sep;26(17):6633-55.
Nuclear compartmentalization of N-CoR and its interactions with steroid receptors.
Wu Y, Kawate H, Ohnaka K, Nawata H, Takayanagi R.
Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
The repression mechanisms by the nuclear receptor corepressor (N-CoR) of steroid hormone receptor (SHR)-mediated transactivation were examined. Yellow fluorescent protein (YFP)-N-CoR was distributed as intranuclear discrete dots, while coexpression of androgen receptor (AR), glucocorticoid receptor alpha, and estrogen receptor alpha ligand-dependently triggered redistribution of YFP-N-CoR. In fluorescence recovery after photobleaching analysis, mobility of the N-CoR was reduced by 5alpha-dihydrotestosterone (DHT)-bound AR. The middle region of N-CoR mostly contributed to the interaction with agonist-bound SHRs and the suppression of their transactivation function. N-CoR impaired the DHT-induced N-C interaction of AR, and the impaired interaction was dose-dependently recovered by coexpression of SRC-1 and CBP. N-CoR also impaired the intranuclear complete (distinct) focus formation of SHRs. Coexpression of SRC-1 or CBP released YFP-N-CoR or endogenous N-CoR from incomplete foci and simultaneously recovered complete foci of AR-green fluorescent protein. These results indicate that the relative ratio of coactivators and corepressors determines the conformational equilibrium between transcriptionally active and inactive SHRs in the presence of agonists. The intranuclear foci formed by agonist-bound SHRs were completely destroyed by actinomycin D and alpha-amanitin, indicating that the focus formation does not precede the transcriptional activation. The focus formation may reflect the accumulation of SHR/coactivator complexes released from the transcriptionally active sites and thus be a mirror of transcriptionally active complex formation.
-----------------------------------------------
.
dr frankenstein
28/06/2019 6:57 pm
Just wondering what do you have in mind with the aforementioned articles.
"The medals don't mean anything and the glory doesn't last. It's all about your happiness. The rewards are going to come, but my happiness is just loving the sport and having fun performing" ~ Jackie Joyner Kersee.
28/06/2019 7:20 pm
Maybe he is documenting the latest releases on SARMS ?
Here is an excerpt from Smith and O�Malley � Coregulators and SRM Specificity Endocrine Reviews, February 2004, 25(1):45�71 47
It details the current progress in the area quite well I feel. If selective receptor modulation of any kind is your field of interest, I highly recommend this study as one of the first to read.
D. Selective AR modulators (SARMs)
AR expression is widespread throughout the body, and
androgens play a desirable role in promoting and maintaining
bone strength, increasing muscle mass, decreasing fat
tissue, and enhancing libido (34). Although androgen therapies
are currently available, they are primarily based on
delivery of testosterone or its derivatives by injections or skin
patches (35). Neither approach is optimal because injections
result in undesirable fluctuations in serum testosterone levels,
and skin patches are associated with irritation and rashes.
Oral preparations of currently available androgens are not
recommended because of their relatively low efficacy and
potential hepatic toxicity. There is, therefore, a desire to develop
a form of androgen therapy that is easily administered
orally and that will avoid the considerable fluctuations of
serum androgens observed for injectables. More importantly,
the goal exists to obtain androgenic therapies that do
not exert undesirable side effects such as alterations in lipid
profiles (e.g., high- and low-density lipoproteins), fluid retention,
liver toxicity, prostatic hypertrophy, and gynecomastia.
The more severe side effects associated with supraphysiological
doses of androgens taken by body builders and
athletes, such as increased aggression, decreased testicular
size, and azoospermia, are unacceptable under all conditions.
Simply stated, the goal of preservation of positive
androgen effects in some tissues, while minimizing negative
side effects in other tissues, has stimulated a search for
SARMs.
Although the use of estrogens and SERMs is widespread,
there has not been an equivalent trend observed for androgen
therapies. This is not due to a lack of indication for
androgen treatment, as this type of therapy would be of
benefit for treatment of men with primary or secondary
hypogonadism, osteopenia and osteoporosis, HIV wasting
and cancer-related cachexia, anemias, various muscle dystrophies,
and, potentially, male contraception. Although
there is a paucity of well-designed studies supporting an
indication for androgen therapy in women, androgen therapy
has been advocated for improvement of bone strength,
libido and other sexual parameters, as well as a sense of
well-being in postmenopausal women (36).
Indeed, the current lack of SARM-based therapies results
from a lack of a suitable agent. However, the greater understanding
of the molecular events through which SERM actions
are achieved established a rational basis for identifying
and characterizing SARMs. Ideally, such an agent would be
orally active, and, as a treatment for hypogonadism, should
be capable of stimulating muscle mass and strength, bone
strength, libido, and virilization but with minimal hypertrophic
effects on the prostate. For osteopenia or osteoporosis
indications, a SARM with anabolic activity in bone and possibly
muscle, but with relatively little activity on sex-accessory
tissues, would be desirable. SARMs for females might
target libido and other sexuality parameters while avoiding
virilization. Progress has been made in this area, and several
compounds that possess a mixture of agonist- and antagonist-
like activities in transient transfect assays measuring AR
trans-activation of a target gene in cells have been identified
(37, 38). Assessments of the in vivo SARM activity of these
compounds is underway in animals as well as in humans,
and they show a promising tissue-selective activity profile.
Animal experiments with one such SARM, LGD2226, revealed
that it prevented loss of bone mineral density associated
with orchidectomy in rats and exerted anabolic activity
in the levator ani muscle; in contrast, LGD2226 did not
stimulate prostate weights above those observed for intact
rats (39).
Good things come to those who weight.
The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.
Topic starter
28/06/2019 7:47 pm
Just wondering what do you have in mind with the aforementioned articles.
muscle without side effects,maybe bigger muscles too.
now, i have suffered of androgen induced hypothyroidism.
understanding nature, this way I avoid diseases and I obtain more results.
example:
Yang X, Downes M, Yu R, Bookout AL, He W, Straume M, Mangelsdorf DJ and Evans RM (2006). Nuclear receptor expression links the circadian clock to metabolism. Cell 126, 801-810.
then:
in this study,show higher levels of mRNA levels at 10 am,
for ar,skeletal muscle, this way i take Stanozolol and methandrostenolone at 6-7 am, train at 9 am,and get the best from mRNA available.
dr frankenstein
28/06/2019 8:09 pm
muscle without side effects,maybe bigger muscle too.
now, i have androgen induced hypothyroidism.
Never heard of it. Have you been using gear for a long time? So do you use t3 or T4 for your condition?
"The medals don't mean anything and the glory doesn't last. It's all about your happiness. The rewards are going to come, but my happiness is just loving the sport and having fun performing" ~ Jackie Joyner Kersee.
Topic starter
28/06/2019 8:40 pm
Never heard of it. Have you been using gear for a long time? So do you use T3 or T4 for your condition?
t4 no yet,first i have to discard secondary adrenal insufficiency.
this week i will do the cortisol test.
but now i have not hypothyroidism,it left me transitorily,now i am using fast roids,I think that I have it again, but very mild .
dr frankenstein
28/06/2019 8:56 pm
Maybe he is documenting the latest releases on SARMS ?Here is an excerpt from Smith and O�Malley � Coregulators and SRM Specificity Endocrine Reviews, February 2004, 25(1):45�71 47
It details the current progress in the area quite well I feel. If selective receptor modulation of any kind is your field of interest, I highly recommend this study as one of the first to read.
D. Selective AR modulators (SARMs)
AR expression is widespread throughout the body, and
androgens play a desirable role in promoting and maintaining
bone strength, increasing muscle mass, decreasing fat
tissue, and enhancing libido (34). Although androgen therapies
are currently available, they are primarily based on
delivery of testosterone or its derivatives by injections or skin
patches (35). Neither approach is optimal because injections
result in undesirable fluctuations in serum testosterone levels,
and skin patches are associated with irritation and rashes.
Oral preparations of currently available androgens are not
recommended because of their relatively low efficacy and
potential hepatic toxicity. There is, therefore, a desire to develop
a form of androgen therapy that is easily administered
orally and that will avoid the considerable fluctuations of
serum androgens observed for injectables. More importantly,
the goal exists to obtain androgenic therapies that do
not exert undesirable side effects such as alterations in lipid
profiles (e.g., high- and low-density lipoproteins), fluid retention,
liver toxicity, prostatic hypertrophy, and gynecomastia.
The more severe side effects associated with supraphysiological
doses of androgens taken by body builders and
athletes, such as increased aggression, decreased testicular
size, and azoospermia, are unacceptable under all conditions.
Simply stated, the goal of preservation of positive
androgen effects in some tissues, while minimizing negative
side effects in other tissues, has stimulated a search for
SARMs.
Although the use of estrogens and SERMs is widespread,
there has not been an equivalent trend observed for androgen
therapies. This is not due to a lack of indication for
androgen treatment, as this type of therapy would be of
benefit for treatment of men with primary or secondary
hypogonadism, osteopenia and osteoporosis, HIV wasting
and cancer-related cachexia, anemias, various muscle dystrophies,
and, potentially, male contraception. Although
there is a paucity of well-designed studies supporting an
indication for androgen therapy in women, androgen therapy
has been advocated for improvement of bone strength,
libido and other sexual parameters, as well as a sense of
well-being in postmenopausal women (36).
Indeed, the current lack of SARM-based therapies results
from a lack of a suitable agent. However, the greater understanding
of the molecular events through which SERM actions
are achieved established a rational basis for identifying
and characterizing SARMs. Ideally, such an agent would be
orally active, and, as a treatment for hypogonadism, should
be capable of stimulating muscle mass and strength, bone
strength, libido, and virilization but with minimal hypertrophic
effects on the prostate. For osteopenia or osteoporosis
indications, a SARM with anabolic activity in bone and possibly
muscle, but with relatively little activity on sex-accessory
tissues, would be desirable. SARMs for females might
target libido and other sexuality parameters while avoiding
virilization. Progress has been made in this area, and several
compounds that possess a mixture of agonist- and antagonist-
like activities in transient transfect assays measuring AR
trans-activation of a target gene in cells have been identified
(37, 38). Assessments of the in vivo SARM activity of these
compounds is underway in animals as well as in humans,
and they show a promising tissue-selective activity profile.
Animal experiments with one such SARM, LGD2226, revealed
that it prevented loss of bone mineral density associated
with orchidectomy in rats and exerted anabolic activity
in the levator ani muscle; in contrast, LGD2226 did not
stimulate prostate weights above those observed for intact
rats (39).
Reserchers from Shrering (Germany) say that Nebido therapy will stop the undesirable fluctuations in serum testosterone levels from conventional TRT, since testosterone undecaonate keeps test levels constant.
"The medals don't mean anything and the glory doesn't last. It's all about your happiness. The rewards are going to come, but my happiness is just loving the sport and having fun performing" ~ Jackie Joyner Kersee.
Topic starter
28/06/2019 9:15 pm
Reserchers from Shrering (Germany) say that Nebido therapy will stop the undesirable fluctuations in serum testosterone levels from conventional TRT, since testosterone undecaonate keeps test levels constant.
it does not seem to me, already it exists like oral.
anyway bring side effects, have no selectivity like sarms.
"Therefore, tissue selectivity of nonsteroidal androgen action may depend upon ligand-induced AR conformation and recruitment of a tissue-specific repertoire of coregulatory factors that function as coactivators and corepressors."
dr frankenstein
28/06/2019 9:33 pm
it does not seem to me, already it exists like oral.
anyway bring side effects, have no selectivity like sarms."Therefore, tissue selectivity of nonsteroidal androgen action may depend upon ligand-induced AR conformation and recruitment of a tissue-specific repertoire of coregulatory factors that function as coactivators and corepressors."
You might want to read this one:
================================
Harle L, Basaria S, Dobs AS. Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism. Expert Opin Pharmacother. 2005;6(10):1751-9.
ABSTRACT
Over the last six decades, tremendous strides have been made in the development of safe, efficacious and 'patient-friendly' modalities of testosterone replaGROWXXLent therapy in men. The most recent forms of androgen replaGROWXXLent that are in widespread use include testosterone patch and gel. These preparations are convenient in their use and deliver a physiological amount of testosterone. Although these transdermal preparations are gaining popularity, many hypogonadal men still receive treatment with intramuscular esters. Testosterone Enanthate remains the most commonly prescribed ester. Although testosterone esters are efficacious in terms of improving bone and muscle mass, they possess unfavourable pharmacokinetics that result in fluctuations in the mood, energy and sexual function of patients. Furthermore, these esters need to be injected every 2-4 weeks. Hence, there has been a need to develop long-acting esters that can be administered infrequently and deliver a physiological amount of testosterone without major fluctuations. Recently, injectable testosterone undecanoate (Nebido) has become available in Europe and will soon be marketed in south America, Asia and Australia. In this paper, the structure, pharmacokinetics, efficacy and side-effect profile of testosterone undecanoate will be reviewed and also compared with other existing testosterone esters.
"The medals don't mean anything and the glory doesn't last. It's all about your happiness. The rewards are going to come, but my happiness is just loving the sport and having fun performing" ~ Jackie Joyner Kersee.
28/06/2019 10:02 pm
I think this one is better:
================================
Schubert M, Minnemann T, Hubler D, Rouskova D, Christoph A, Oettel M, Ernst M, Mellinger U, Krone W, Jockenhovel F. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J Clin Endocrinol Metab. 2004;89(11):5429-34.
ABSTRACT
In an open-label, randomized, prospective trial, we investigated pharmacokinetics and several efficacy and safety parameters of a novel, long-acting testosterone (T) undecanoate (TU) formulation in 40 hypogonadal men (serum testosterone concentrations < 5 nmol/liter). For the first 30 wk (comparative study), the patients were randomly assigned to receive either 10 x 250 mg T enanthate (TE) im every 3 wk (n = 20) or 3 x 1000 mg TU im every 6 wk (loading dose) followed by 1 x 1000 mg after an additional 9 wk (n = 20). In a follow-up study, observation continued in those patients who completed the comparative part and opted for TU treatment (8 x 1000 mg TU every 12 wk in former TU patients and 2 x 1000 mg TU every 8 wk plus 6 x 1000 mg every 12 wk in former TE patients) for an additional 20-21 months. Here we report only the pharmacokinetic aspects of the new TU formulation for the first approximately 2.5 yr of treatment. At baseline, serum T concentrations did not significantly differ between the two study groups. In the TE group, mean trough levels of serum T were always less than 10 nmol/liter before the next injection, whereas in the TU group, mean trough levels of serum T were 14.1 +/- 4.5 nmol/liter after the first two doses (6-wk intervals) and 16.3 +/- 5.7 nmol/liter after the 9-wk interval at wk 30. The mean serum levels of dihydrotestosterone and estradiol also increased in parallel to the serum T pattern and remained within the normal range. In the follow-up study, the former TU patients (n = 20) received eight TU injections at 12-wk intervals, and the TE patients (n = 16) switched to TU and initially received two TU injections at 8-wk intervals (loading) and continued with six TU injections at 12-wk intervals (maintenance). This regimen resulted in stable mean serum trough levels of T (ranging from 14.9 +/- 5.2 to 16.5 +/- 8.0 nmol/liter) and estradiol (ranging from 98.5 +/- 45.2 to 80.4 +/- 14.4 pmol/liter). The present study has shown that 1000 mg TU injected into male patients with hypogonadism at 12-wk intervals is well tolerated and leads to T levels within normal ranges, using four instead of 17 or more TE injections per year. An initial loading dose of either 3 x 1000 mg TU every 6 wk at the beginning of hormone substitution or 2 x 1000 mg TU every 8 wk after switching from the short-acting TE to TU were found to be a adequate dosing regimens for starting of treatment with the long-acting TU preparation.
"The medals don't mean anything and the glory doesn't last. It's all about your happiness. The rewards are going to come, but my happiness is just loving the sport and having fun performing" ~ Jackie Joyner Kersee.
Topic starter
28/06/2019 10:24 pm
You might want to read this one:================================
Harle L, Basaria S, Dobs AS. Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism. Expert Opin Pharmacother. 2005;6(10):1751-9.
ABSTRACT
Over the last six decades, tremendous strides have been made in the development of safe, efficacious and 'patient-friendly' modalities of testosterone replaGROWXXLent therapy in men. The most recent forms of androgen replaGROWXXLent that are in widespread use include testosterone patch and gel. These preparations are convenient in their use and deliver a physiological amount of testosterone. Although these transdermal preparations are gaining popularity, many hypogonadal men still receive treatment with intramuscular esters. Testosterone enanthate remains the most commonly prescribed ester. Although testosterone esters are efficacious in terms of improving bone and muscle mass, they possess unfavourable pharmacokinetics that result in fluctuations in the mood, energy and sexual function of patients. Furthermore, these esters need to be injected every 2-4 weeks. Hence, there has been a need to develop long-acting esters that can be administered infrequently and deliver a physiological amount of testosterone without major fluctuations. Recently, injectable testosterone undecanoate (Nebido) has become available in Europe and will soon be marketed in south America, Asia and Australia. In this paper, the structure, pharmacokinetics, efficacy and side-effect profile of testosterone undecanoate will be reviewed and also compared with other existing testosterone esters.
well,we will have to give a try.
dr frankenstein
Topic starter
28/06/2019 10:41 pm
How and why:
A likely explanation as to how these synthetic ligands act
as agonists or antagonists is related to their ability to induce
specific conformational changes in AR. The AR ligand
binding domain is composed of 12 alpha-helices. In the
crystal structure, relatively few amino acid residues were
found to interact directly with the steroidal agonists, DHT
and methyltrienolone (R1881). Most of these residues
are hydrophobic in nature and interact with hydrophobic
moieties in the ligand, whereas fewer residues are hydrophilic
and may form hydrogen bonds with polar atoms in the
ligand. In the case of nonsteroidal ligands, AR binding is
likely to be influenced by stereoisomeric conformation and
steric and electronic effects. It remains to be determined
whether the same amino acids in the ligand binding pocket
interact with both steroidal and nonsteroidal ligands. As
evidenced by structure-function studies of nonsteroidal ligands,
minor differences in ligand structure can lead to either
agonist or antagonist activity. The AR can use different
transactivation domains, AF-1 and AF-5 in the amino-terminal
domain and AF-2 in the carboxy-terminal domain
. The AF-2 function is strongly dependent upon interaction
with nuclear receptor coactivators, whereas strong
agonist, but not antagonist, binding induces ligand-dependent
interaction internally between the AF-2 and AF-1 domains
. When steroid agonists bind to AR, helix 12
containing the AF-2 region in the ligand binding domain
closes over the binding pocket revealing an interface for
coactivator interaction. Conversely, binding of antagonists
maintains helix 12 in an open conformation directed away
from the binding pocket. Therefore, tissue selectivity of nonsteroidal androgen action may depend upon ligand-induced AR conformation and recruitment of a tissue-specific repertoire
of coregulatory factors that function as coactivators *
dr frankenstein
28/06/2019 11:05 pm
Are you replying to my post or just adding more data?
"The medals don't mean anything and the glory doesn't last. It's all about your happiness. The rewards are going to come, but my happiness is just loving the sport and having fun performing" ~ Jackie Joyner Kersee.
Topic starter
28/06/2019 11:23 pm
Are you replying to my post or just adding more data?
not replying.
dr frankenstein