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Ostarine (enobasarm) is a selective androgen receptor modulator with great therapeutic potential. However, it is also used by athletes to promote muscle growth and enhance performances without the typical adverse effects of anabolic steroids. Ostarine popularity increased in recent years, and it is currently the most abused "other anabolic agent" (subclass S1.2. of the "anabolic agents" class S1) from the World Anti-Doping Agency's (WADA) prohibited list. Several cases of liver toxicity were recently reported in regular users. Detecting ostarine or markers of intake in biological matrices is essential to document ostarine use in doping. Therefore, we sought to investigate ostarine metabolism to identify optimal markers of consumption. The substance was incubated with human hepatocytes, and urine samples from six ostarine-positive cases were screened. Analyses were performed via liquid chromatography–high-resolution tandem mass spectrometry (LC-HRMS/MS) and software-assisted data mining, with in silico metabolite predictions. Ten metabolites were identified with hydroxylation, ether cleavage, dealkylation, O-glucuronidation, and/or sulfation. The production of cyanophenol-sulfate might participate in the mechanism of ostarine liver toxicity. We suggest ostarine-glucuronide (C25H22O9N3F3, diagnostic fragments at m/z 118, 185, and 269) and hydroxybenzonitrile-ostarine-glucuronide (C25H22O10N3F3, diagnostic fragments at m/z 134, 185, and 269) in non-hydrolyzed urine and ostarine and hydroxybenzonitrile-ostarine (C19H14O4N3F3, diagnostic fragments at m/z 134, 185, and 269) in hydrolyzed urine as markers to document ostarine intake in doping. [ABSTRACT FROM AUTHOR]

Ostarine (enobasarm) is a selective androgen receptor modulator with great therapeutic potential. However, it is also used by athletes to promote muscle growth and enhance performances without the typical adverse effects of anabolic steroids. Ostarine popularity increased in recent years, and it is currently the most abused “other anabolic agent” (subclass S1.2. of the “anabolic agents” class S1) from the World Anti-Doping Agency’s (WADA) prohibited list. Several cases of liver toxicity were recently reported in regular users. Detecting ostarine or markers of intake in biological matrices is essential to document ostarine use in doping. Therefore, we sought to investigate ostarine metabolism to identify optimal markers of consumption. The substance was incubated with human hepatocytes, and urine samples from six ostarine-positive cases were screened. Analyses were performed via liquid chromatography–high-resolution tandem mass spectrometry (LC-HRMS/MS) and software-assisted data mining, with in silico metabolite predictions. Ten metabolites were identified with hydroxylation, ether cleavage, dealkylation, O-glucuronidation, and/or sulfation. The production of cyanophenol-sulfate might participate in the mechanism of ostarine liver toxicity. We suggest ostarine-glucuronide (C25H22O9N3F3, diagnostic fragments at m/z 118, 185, and 269) and hydroxybenzonitrile-ostarine-glucuronide (C25H22O10N3F3, diagnostic fragments at m/z 134, 185, and 269) in non-hydrolyzed urine and ostarine and hydroxybenzonitrile-ostarine (C19H14O4N3F3, diagnostic fragments at m/z 134, 185, and 269) in hydrolyzed urine as markers to document ostarine intake in doping.

Introduction: The selective androgen receptor modulator ligandrol (LGD-4033 or VK5211) has been shown to improve muscle tissue. In the present study, the effect of ligandrol on bone tissue was investigated in ovariectomized rat model. Materials and methods: Three-month-old Sprague Dawley rats were either ovariectomized (OVX, n = 60) or left intact (NON-OVX, n = 15). After 9 weeks, OVX rats were divided into four groups: untreated OVX (n = 15) group and three OVX groups (each of 15 rats) treated with ligandrol orally at doses of 0.03, 0.3, or 3 mg/kg body weight. After five weeks, lumbar vertebral bodies (L), tibiae, and femora were examined using micro-computed tomographical, biomechanical, ashing, and gene expression analyses. Results: In the 3-mg ligandrol group, bone structural properties were improved (trabecular number: 38 ± 8 vs. 35 ± 7 (femur), 26 ± 7 vs. 22 ± 6 (L), 12 ± 5 vs. 6 ± 3 (tibia) and serum phosphorus levels (1.81 ± 0.17 vs.1.41 ± 0.17 mmol/l), uterus (0.43 ± 0.04 vs. 0.11 ± 0.02 g), and heart (1.13 ± 0.11 vs. 1.01 ± 0.08 g) weights were increased compared to the OVX group. Biomechanical parameters were not changed. Low and medium doses did not affect bone tissue and had fewer side effects. Body weight and food intake were not affected by ligandrol; OVX led to an increase in these parameters and worsened all bone parameters. Conclusion: Ligandrol at high dose showed a subtle anabolic effect on structural properties without any improvement in biomechanical properties of osteoporotic bones. Considering side effects of ligandrol at this dose, its further investigation for the therapy of postmenopausal osteoporosis should be reevaluated. [ABSTRACT FROM AUTHOR]

Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular amongst recreational athletes. Recent case reports of drug-induced liver injury (DILI) and tendon rupture raise serious concerns for the safety of recreational SARM users. On 10 November 2022 PubMed, Scopus, Web of Science, and ClinicalTrials.gov were searched for studies that reported safety data of SARMs. A multi-tiered screening approach was utilized, and any study or case report of generally healthy individuals exposed to any SARM was included. Thirty-three studies were included in the review with 15 case reports or case series and 18 clinical trials (total patients N = 2136 patients, exposed to SARM N = 1447). There were case reports of drug-induced liver injury (DILI) (N = 15), Achilles tendon rupture (N = 1), rhabdomyolysis (N = 1), and mild reversible liver enzyme elevation (N = 1). Elevated alanine aminotransferase (ALT) was commonly reported in clinical trials in patients exposed to SARM (mean 7.1% across trials). Two individuals exposed to GSK2881078 in a clinical trial were reported to have rhabdomyolysis. Recreational SARM use should be strongly discouraged, and the risks of DILI, rhabdomyolysis, and tendon rupture should be emphasized. However, despite warnings, if a patient refuses to discontinue SARM use, ALT monitoring or dose reduction may improve early detection and prevention of DILI.

Pancreatic cancer (PC) continues to be devastating due to its highly malignant nature and poor prognosis. The limited benefits of the chemotherapeutic drugs and increasing resistance pose a critical challenge to overcome and warrant investigations for new therapeutic agents. Several preclinical and clinical studies have suggested a possible role of the androgen receptor (AR) signaling pathway in PC development and progression. Nevertheless, the studies are limited and inconclusive in explaining the molecular link between AR signaling and PC. Selective androgen receptor modulators (SARMs) are small molecule drugs with high affinity for the androgen receptor. SARMs elicit selective anabolic activities while abrogating undesired androgenic side effects. There is no study focusing on the utility of SARMs as inhibitors of PC. Here, we report the first study evaluating the possible anti-carcinogenic influences of andarine, a member of the SARMs, on PC. The data we presented here has illustrated that andarine repressed PC cell growth and proliferation via cell cycle arrest at G 0 /G 1 phase. Gene expression analysis revealed that it downregulates CDKN1A expression level accordingly. Furthermore, we established that the anti-carcinogenic activity of andarine is not mediated by the PI3K/AKT/mTOR signaling pathway, a crucial regulator of cell survival. Our findings suggest that andarine might be considered as a prospective drug for PC. [Display omitted] • Andarine is a potent and highly bio-available selective androgen receptor modulator. • Andarine's anti-cancer properties have not been investigated in pancreatic cancer. • Andarine restricted cell proliferation and caused cell-cycle arrest at G 0 /G 1. • The observed activity was independent of PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Overweight and obesity are associated with severe metabolic disorders and an increased risk of cardiovascular diseases. It is a known fact that physical activity has a positive effect on metabolic parameters, and also reduces the risk of diseases such as diabetes. Some products can enhance the rate of lipolysis and help in improving fat loss. One of these are selective androgen receptor modulators (SARMs) which act as anabolic agents and are also believed to aid in fatburning. In this study, we investigated whether 30 days of ostarine administration could potentially improve metabolic parameters using the rat model of obesity combined with exercise. We assessed the levels of biochemical and hormonal parameters in serum samples as well as insulin sensitivity indices of tissues. There were significant changes in the metabolic parameters with exercise. However, we did not find any additive effects of ostarine and exercise on most of the parameters tested. Similar results were obtained from the analysis of gene expression and the concentration of leptin and adiponectin. Our results indicated that ostarine had a lowering effect on cholesterol concentration in the serum (P<0.05). Moreover, when combining ostarine and exercise, additive changes were only observed in the levels of total and HDL cholesterol. No significant change was observed in the metabolic parameters of obese rats with the use of ostarine at the dose of 0.4 mg/kg body weight. Since ostarine is known to enhance performance, further research on its effects is needed. [ABSTRACT FROM AUTHOR]

Selective Androgen Receptor Modulators (SARMs) have anabolic properties but less adverse effects than anabolic androgenic steroids. They are prohibited in both equine and human sports and there have been several cases of SARMs findings reported over the last few years. The aim of this study was to investigate the metabolite profile of the SARM ACP-105 (2-chloro-4-[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]-3-methylbenzonitrile) in order to find analytical targets for doping control. Oral administration of ACP-105 was performed in horses, where blood and urine samples were collected over a time period of 96 h. The in vivo samples were compared with five in vitro incubation models encompassing Cunninghamella elegans, microsomes and S9 fractions of both human and equine origin. The analyses were performed using ultra-high performance liquid chromatography coupled to high resolution Q ExactiveTM OrbitrapTM mass spectrometry (UHPLC-HRMS). A total of 21 metabolites were tentatively identified from the in vivo experiments, of which several novel glucuronides were detected in plasma and urine. In hydrolyzed urine, hydroxylated metabolites dominated. The in vitro models yielded several biotransformation products, including a number of monohydroxylated metabolites matching the in vivo results. The suggested analytical target for equine doping control in plasma is a dihydroxylated metabolite with a net loss of two hydrogens. In urine, the suggested targets are two monohydroxylated metabolites after hydrolysis with β-glucuronidase, selected both due to prolongation of the detection time and the availability of reference material from the in vitro models.

Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular amongst recreational athletes. Recent case reports of drug-induced liver injury (DILI) and tendon rupture raise serious concerns for the safety of recreational SARM users. On 10 November 2022 PubMed, Scopus, Web of Science, and ClinicalTrials.gov were searched for studies that reported safety data of SARMs. A multi-tiered screening approach was utilized, and any study or case report of generally healthy individuals exposed to any SARM was included. Thirty-three studies were included in the review with 15 case reports or case series and 18 clinical trials (total patients N = 2136 patients, exposed to SARM N = 1447). There were case reports of drug-induced liver injury (DILI) (N = 15), Achilles tendon rupture (N = 1), rhabdomyolysis (N = 1), and mild reversible liver enzyme elevation (N = 1). Elevated alanine aminotransferase (ALT) was commonly reported in clinical trials in patients exposed to SARM (mean 7.1% across trials). Two individuals exposed to GSK2881078 in a clinical trial were reported to have rhabdomyolysis. Recreational SARM use should be strongly discouraged, and the risks of DILI, rhabdomyolysis, and tendon rupture should be emphasized. However, despite warnings, if a patient refuses to discontinue SARM use, ALT monitoring or dose reduction may improve early detection and prevention of DILI. [ABSTRACT FROM AUTHOR]

New Findings: What is the main observation in this case?Co‐administration of LGD‐4033 and MK‐677 increased body mass, lean mass and fat mass, while negatively impacting bone, serum lipids, liver enzymes, testosterone (total and free) and, probably, follicle‐stimulating hormone.What insights does it reveal?Our cross‐sectional data imply that these compounds might alter intramuscular androgenic hormone and receptor concentrations along with promoting muscular strength, when compared with previously published data from trained males. LGD‐4033, a selective androgen receptor modulator, and MK‐677, a growth hormone secretagogue, are being used increasingly amongst recreationally active demographics. However, limited data exist describing their effects on health‐ and androgen‐related biomarkers. The purpose of this case study was to determine changes in body composition and biomarkers during and after continued co‐administration of LGD‐4033 and MK‐677. We also aimed to examine muscular strength and intramuscular androgen‐associated biomarkers relative to non‐users. A 25‐year‐old male ingested LGD‐4033 (10 mg) and MK‐677 (15 mg) daily for 5 weeks. Blood and body composition metrics were obtained pre‐, on‐ and post‐cycle. One‐repetition maximum leg and bench press, in addition to intramuscular androgens and androgen receptor content, were analysed on‐cycle. We observed pre‐ to on‐cycle changes in body composition (body mass, +6.0%; total lean body mass, +3.1%; trunk lean body mass, +6.6%; appendicular lean body mass, +4.3%; total fat mass, +15.4%; trunk fat mass, +2.8%; and appendicular fat mass, +14.8%), bone (bone mineral content, −3.60%; area, −1.1%; and bone mineral density, −2.1%), serum lipid‐associated biomarkers (cholesterol, +14.8%; triglycerides, +39.2%; low‐density lipoprotein–cholesterol, +40.0%; and high‐density lipoprotein–cholesterol, −36.4%), liver‐associated biomarkers (aspartate aminotransferase, +95.8%; and alanine aminotransferase, +205.0%) and androgen‐associated biomarkers (free testosterone, −85.7%; total testosterone, −62.3%; and sex hormone‐binding globulin, −79.6%); however, all variables returned to pre‐cycle values post‐cycle, apart from total fat mass, appendicular fat mass, bone area, total cholesterol and low‐density lipoprotein–cholesterol. Follicle‐stimulating hormone was below clinical reference values on‐ (1.2 IU/L) and post‐cycle (1.3 IU/L). Intramuscular androgen receptor (−44.6%), testosterone (+47.8%) and dihydrotestosterone (+34.4%), in addition to one‐repetition maximum leg press and bench press (+39.2 and +32.0%, respectively), were different in the case subject compared with non‐users. These data demonstrate that LGD‐4033 and MK‐677 increase several body composition parameters, whilst negatively impacting bone and several serum biomarkers. Given the sparsity of data in recreationally using demographics, further research is warranted to elucidate the acute and chronic physiological effects of these anabolic agents. [ABSTRACT FROM AUTHOR]

Case: A 36-year-old male competitive powerlifter sustained asynchronous bilateral Achilles tendon ruptures after using 2 types of selective androgen receptor modulators (SARMs). Both tendon ruptures occurred near the myotendinous junction and were treated with open surgical repair and an initial period of immobilization followed by progressive weightbearing and rehabilitation; no postoperative complications were observed. Conclusion: Previous studies have reported that anabolic androgenic steroids have a deleterious impact on tendon structure and function. This case suggests that SARM compounds may also predispose users to Achilles tendon rupture. [ABSTRACT FROM AUTHOR]

Performance-enhancing drugs (PEDs) can be categorized into various classes based on the physiological mechanism of the compound, with the most popular being anabolic steroids, selective androgen receptor modulators, and growth hormones. Ancillary compounds, such as selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders, are commonly utilized alongside a PED to counterbalance any potential undesired side effects. With little clinically relevant data to support the use of these ancillary compounds, medical education and evidence-based approaches aimed at monitoring the potential adverse effects of PED use are sparse.This study aims to identify emerging trends in the interest of PEDs and related ancillary compounds, hypothesize the physiological effects of the continued respective behavior, and propose a proxy for use by clinicians to approximate off-label drug use and subsequently modify their practices accordingly. Several significant trends were identified for non-FDA-regulated compounds (i.e., selective androgen receptor modulators such as RAD-140) and off-label indications for FDA-regulated drugs (i.e., SERMs such as tamoxifen). A significant increase in interest regarding selective androgen receptor modulators, mirrored by anecdotal reports in clinical settings and online forums, is coupled with stagnant or decreasing interest in both post-cycle therapies and anabolic steroids. Ultimately, we propose a call to action for utilizing social data and/or prescription data as a proxy for clinicians to better understand trends in these compounds and thus refine their treatment protocols in a concordant manner., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Holubeck et al.)

Enobosarm (ostarine, MK-2866, or GTx-024) is a non-steroidal selective androgen receptor modulator. This study evaluated the effect of various regimens of enobosarm (EN) on bone healing in an orchiectomized rat model for aged male osteoporosis and compared it to testosterone (T) treatment. Ninety eight-month-old male Sprague Dawley rats were either orchiectomized (Orx) or left intact (Non-Orx) and divided into groups (n = 15/group): (1) Non-Orx; (2) Orx; (3) Orx+T-th; (4) Orx+EN-th; (5) Orx+T-pr; and (6) Orx+EN-pr. Prophylaxis (Pr) treatments were applied immediately after Orx for up to 18 weeks. Therapy (Th) treatments were applied 12 weeks after Orx for up to 6 weeks. Bilateral tibia osteotomy with plate osteosynthesis was performed 12 weeks after Orx in all groups. EN and T were mixed with the diet; the daily dosage was 0.35 ± 0.06 and 41 ± 8 mg/kg BW, respectively. Both T treatments improved bone healing by increasing callus volume and area, bone volume and density, and cortical width; they had no effect on prostate or levator ani weight. EN-pr increased the callus area and callus density and decreased cortical density, but increased prostate weight. The effect of T-pr and T-th on bone was stronger than EN-pr. EN-th affected bone healing negatively by reducing callus density and area and delaying osteotomy bridging. Levator ani weight was increased in both EN groups. EN treatment after fracture is not advisable in aged males. EN-pr treatment as a therapy for bone healing in men could be further investigated; endocrinological side effects must be closely monitored. [ABSTRACT FROM AUTHOR]

Abstract SARM‐2f a selective androgen receptor (AR) modulator, increases skeletal muscle mass and locomotor activity in rats. This study aimed to clarify its pharmacological effects in monkeys. In reporter assays, the EC50 values of SARM‐2f for rat, monkey, and human AR were 2.5, 3, and 3.6 nmol/L, respectively; those of testosterone were 12, 3.2, and 11 nmol/L, respectively. A single oral administration (10 mg/kg SARM‐2f) produced a maximal plasma concentration of 3011 ng/mL, with an area under the 24 hours concentration‐time curve of 8152 ng·h/mL in monkeys. Body weight (BW), lean body mass (LBM), and plasma levels of total cholesterol, triglyceride, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, lipoprotein (a), alanine aminotransferase, and asparagine aminotransferase were measured after 4 weeks of treatment with SARM‐2f (1, 3, and 10 mg/kg/day, QD, p.o.) or testosterone enanthate (TE; 2 mg/kg/2 weeks, s.c.) in monkeys. BW and LBM were significantly increased by 12% each by SARM‐2f at 10 mg/kg, and by 5% and 8%, respectively, by TE, but these effects were not statistically significant. Plasma levels of all lipids were either decreased or showed a tendency to be decreased by SARM‐2f. TE decreased the triglyceride level and increased the low‐density lipoprotein cholesterol level. Liver marker levels were not changed by either SARM‐2f or TE. Our data demonstrated that SARM‐2f exerted anabolic effects and produced a lipid profile that differed from that produced by testosterone in monkeys, suggesting that SARM‐2f might be useful for diseases such as sarcopenia.

Abstract No approved therapy exists for cancer‐associated cachexia. The colon‐26 mouse model of cancer cachexia mimics recent late‐stage clinical failures of anabolic anti‐cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx‐024. The histone deacetylase inhibitor (HDACi) AR‐42 exhibited anti‐cachectic activity in this model. We explored combined SARM/AR‐42 therapy as an improved anti‐cachectic treatment paradigm. A reduced dose of AR‐42 provided limited anti‐cachectic benefits, but, in combination with GTx‐024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR‐42 suppressed the IL‐6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx‐024‐mediated β‐catenin target gene regulation was apparent in cachectic mice only when combined with AR‐42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx‐024 therapy and a blockade of GTx‐024‐mediated anabolic signaling. AR‐42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx‐024. Combining GTx‐024, a clinically established anabolic therapy, with AR‐42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.

Non-steroidal selective androgen receptor modulators, including ostarine, have been developed as an alternative to steroidal hormones. Ostarine has shown a beneficial effect on bone in experimental studies, but no data regarding the effect of ostarine on bone healing have yet been reported. We investigated effects of ostarine on bone healing in ovariectomized rats. Sprague-Dawley rats (3 months old) were ovariectomized (Ovx, n = 46) or left intact (Non-Ovx, n = 10). After 8 weeks, an osteotomy of the tibia metaphysis was created in all rats, and the Ovx rats were divided into four groups: untreated Ovx (n = 10) and three Ovx groups (each of 12 rats) treated with ostarine at doses of 0.04, 0.4, or 4 mg/kg BW (OS-0.04, OS-0.4, and OS-4 groups). Five weeks later, bone healing was analyzed. The OS-4 dose enhanced callus formation, increased callus density, accelerated bridging time of the osteotomy, and elevated alkaline phosphatase gene expression in callus and its protein expression in serum. In the Ovx group, most of the callus parameters were diminished. All OS treatments increased the weight of the gastrocnemius muscle, but only partly enhanced uterus weight in OS-0.4 and OS-4. Serum cholesterol level was reduced, and serum phosphorus was elevated in OS-0.04 and OS-4. Ostarine appeared to have a positive effect on early bone healing in ovariectomized rats. Considering its favorable effect on non-osteotomized bone and muscle, this treatment could be further explored as a therapy for osteoporosis. However, possible metabolic side effects should first be evaluated. [ABSTRACT FROM AUTHOR]

SARM‐2f a selective androgen receptor (AR) modulator, increases skeletal muscle mass and locomotor activity in rats. This study aimed to clarify its pharmacological effects in monkeys. In reporter assays, the EC50 values of SARM‐2f for rat, monkey, and human AR were 2.5, 3, and 3.6 nmol/L, respectively; those of testosterone were 12, 3.2, and 11 nmol/L, respectively. A single oral administration (10 mg/kg SARM‐2f) produced a maximal plasma concentration of 3011 ng/mL, with an area under the 24 hours concentration‐time curve of 8152 ng·h/mL in monkeys. Body weight (BW), lean body mass (LBM), and plasma levels of total cholesterol, triglyceride, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, lipoprotein (a), alanine aminotransferase, and asparagine aminotransferase were measured after 4 weeks of treatment with SARM‐2f (1, 3, and 10 mg/kg/day, QD, p.o.) or testosterone enanthate (TE; 2 mg/kg/2 weeks, s.c.) in monkeys. BW and LBM were significantly increased by 12% each by SARM‐2f at 10 mg/kg, and by 5% and 8%, respectively, by TE, but these effects were not statistically significant. Plasma levels of all lipids were either decreased or showed a tendency to be decreased by SARM‐2f. TE decreased the triglyceride level and increased the low‐density lipoprotein cholesterol level. Liver marker levels were not changed by either SARM‐2f or TE. Our data demonstrated that SARM‐2f exerted anabolic effects and produced a lipid profile that differed from that produced by testosterone in monkeys, suggesting that SARM‐2f might be useful for diseases such as sarcopenia. [ABSTRACT FROM AUTHOR]

• Sarcopenia is an independent risk factor for increased mortality and morbidity in patients with cancer. • Computed tomographic studies obtained during follow up of patients with cancer, can also be used to monitor changes in lean body mass. • Radiologists may be expected to include information on changes in lean body mass, in their standard report. [ABSTRACT FROM AUTHOR]

Selective Androgen Receptor Modulators (SARMs) have anabolic properties but less adverse effects than anabolic androgenic steroids. They are prohibited in both equine and human sports and there have been several cases of SARMs findings reported over the last few years. The aim of this study was to investigate the metabolite profile of the SARM ACP-105 (2-chloro-4-[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]-3-methylbenzonitrile) in order to find analytical targets for doping control. Oral administration of ACP-105 was performed in horses, where blood and urine samples were collected over a time period of 96 h. The in vivo samples were compared with five in vitro incubation models encompassing Cunninghamella elegans, microsomes and S9 fractions of both human and equine origin. The analyses were performed using ultra-high performance liquid chromatography coupled to high resolution Q ExactiveTM OrbitrapTM mass spectrometry (UHPLC-HRMS). A total of 21 metabolites were tentatively identified from the in vivo experiments, of which several novel glucuronides were detected in plasma and urine. In hydrolyzed urine, hydroxylated metabolites dominated. The in vitro models yielded several biotransformation products, including a number of monohydroxylated metabolites matching the in vivo results. The suggested analytical target for equine doping control in plasma is a dihydroxylated metabolite with a net loss of two hydrogens. In urine, the suggested targets are two monohydroxylated metabolites after hydrolysis with β-glucuronidase, selected both due to prolongation of the detection time and the availability of reference material from the in vitro models.

In drug discovery, it is important to identify phase I metabolic modifications as early as possible to screen for inactivation of drugs and/or activation of prodrugs. As the major class of reactions in phase I metabolism is oxidation reactions, oxidation of drugs with TiO2 photocatalysis can be used as a simple non-biological method to initially eliminate (pro)drug candidates with an undesired phase I oxidation metabolism. Analysis of reaction products is commonly achieved with mass spectrometry coupled to chromatography. However, sample throughput can be substantially increased by eliminating pretreatment steps and exploiting the potential of ambient ionization mass spectrometry (MS). Furthermore, online monitoring of reactions in a time-resolved way would identify sequential modification steps. Here, we introduce a novel (time-resolved) TiO2-photocatalysis laser ablation electrospray ionization (LAESI) MS method for the analysis of drug candidates. This method was proven to be compatible with both TiO2-coated glass slides as well as solutions containing suspended TiO2 nanoparticles, and the results were in excellent agreement with studies on biological oxidation of verapamil, buspirone, testosterone, andarine, and ostarine. Finally, a time-resolved LAESI MS setup was developed and initial results for verapamil showed excellent analytical stability for online photocatalyzed oxidation reactions within the set-up up to at least 1 h. Graphical Abstract [ABSTRACT FROM AUTHOR]

Selective androgen receptor modulators (SARMs) are an emerging class of therapeutics targeted to cachexia, sarcopenia, and hypogonadism treatment. LGD‐4033 is a SARM which has been included on the Prohibited List annually released by the World Anti‐Doping Agency (WADA). The aim of the present work was the investigation of the metabolism of LGD‐4033 in a human excretion study after administration of an LGD‐4033 supplement, the determination of the metabolites' excretion profiles with special interest in the determination of its long‐term metabolites, and the comparison of the excretion time of the phase I and phase II metabolites. The results were also compared to those derived from previous LGD‐4033 studies concerning both in vitro and in vivo experiments. Supplement containing LGD‐4033 was administered to one human male volunteer and urine samples were collected up to almost 21 days. Analysis of the hydrolyzed (with β‐glucuronidase) as well as of the non‐hydrolyzed samples was performed using liquid chromatography–high resolution mass spectrometry (LC–HRMS) in negative ionization mode and revealed that, in both cases, the two isomers of the dihydroxylated metabolite (M5) were preferred target metabolites. The gluco‐conjugated parent LGD‐4033 and its gluco‐conjugated metabolites M1 and M2 can be also considered as useful target analytes in non‐hydrolyzed samples. The study also presents two trihydroxylated metabolites (M6) identified for the first time in human urine; one of them was recently reported in an LGD‐4033 metabolism study in horse urine and plasma. ‐ The metabolism of LGD‐4033 in a human excretion study after administration of a supplement containing LGD‐4033 was investigated. ‐ The determination of the metabolites' excretion profiles with special interest in its long‐term metabolites and the comparison of the excretion time of the phase‐I and phase‐II metabolites were performed. ‐ Two isomers of the dihydroxylated metabolite (M5) are preferred target metabolites. Two trihydroxylated metabolites (M6) were identified for the first time in human urine. [ABSTRACT FROM AUTHOR]

LGD-3303 is a Selective Androgen Receptor Modulator (SARM) that is prohibited in both equine and human sports due to its anabolic properties. The aim of this study was to investigate the equine in vivo metabolite profile of LGD-3303 and identify drug metabolites that can be suitable as new and improved analytical targets for equine doping control. This was performed by an oral administration of 0.05 mg·kg−1 LGD-3303 to horses, where blood and urine samples were collected up to 96 h after administration. The in vivo samples consisting of plasma, urine and hydrolyzed urine were analyzed utilizing ultra-high performance liquid chromatography hyphenated to a Q Exactive™ Orbitrap™ high resolution mass spectrometer with a heated electrospray ionization source. A total of eight metabolites of LGD-3303 were tentatively identified, including one carboxylated and several hydroxylated metabolites in combination with glucuronic acid conjugates. A monohydroxylated metabolite is suggested as an analytical target for doping control analysis of plasma and urine after hydrolysis with β-glucuronidase, due to the high intensity and prolonged detection time in comparison to parent LGD-3303. • First equine in vivo metabolite study of SARM LGD-3303. • Novel phase I and II metabolites of LGD-3303 identified in horse using LC-HRMS. • Several metabolites gave increased detection time compared to LGD-3303. • New and improved analytical targets suggested for doping control analysis. [ABSTRACT FROM AUTHOR]

Muscle mass and strength decline with age. When severe, the loss is called sarcopenia. Sarcopenia is drawing attention worldwide, especially in highly aged societies, as a disease that should be treated. At present, we have limited tools to combat sarcopenia (e.g. resistance training and nutritional intervention), but accumulating knowledge of the molecular and cellular mechanisms of sarcopenia is accelerating the development of pharmacological therapies for sarcopenia. Because sarcopenia is a complicated pathological condition caused and modified by many aging-related factors, such as inactivity, loss of motor neurons, poor nutrition, decline of anabolic hormones, chronic inflammation, oxidative stress, impaired stem cell function, and comorbidity, the proposed target molecules or pathways for pharmacological intervention are diverse. Here we review recent progress in drug development with emphasis on small-molecule compound-based therapies and review the literature to identify new therapeutic targets to prevent, delay, or reverse sarcopenia.

The treatment of hypogonadism in men is of great interest to both patients and providers. There are a number of testosterone formulations currently available and several additional formulations under development. In addition, there are some lesser-used alternative therapies for the management of male hypogonadism, which may have advantages for certain patient groups. The future of hypogonadism therapy may lie in the development of selective androgen receptor modulators that allow the benefits of androgens whilst minimizing unwanted side effects.

Summary: We have identified a non‐steroidal selective androgen receptor modulator (SARM), termed LY305, that is bioavailable through a transdermal route of administration while highly cleared via hepatic metabolism to limit parent compound exposure in the liver. Selection of this compound and its transdermal formulation was based on the optimization of skin absorption properties using both in vitro and in vivo skin models that supported PBPK modeling for human PK predictions. This molecule is an agonist in perineal muscle while being a weak partial agonist in the androgenic tissues such as prostate. When LY305 was tested in animal models of skeletal atrophy it restored the skeletal muscle mass through accelerated repair. In a bone fracture model, LY305 remained osteoprotective in the regenerating tissue and void of deleterious effects. Finally, in a small cohort of healthy volunteers, we assessed the safety and tolerability of LY305 when administered transdermally. LY305 showed a dose‐dependent increase in serum exposure and was well tolerated with minimal adverse effects. Notably, there were no statistically significant changes to hematocrit or HDL after 4‐week treatment period. Collectively, LY305 represents a first of its kind de novo development of a non‐steroidal transdermal SARM with unique properties which could find clinical utility in hypogonadal men. [ABSTRACT FROM AUTHOR]

LGD-4033 has been found in human doping control samples and has the potential for illicit use in racehorses as well. It belongs to the pharmacological class of selective androgen receptor modulators (SARMs) and can stimulate muscle growth, much like anabolic steroids. However, SARMs have shown superior side effect profiles compared to anabolic steroids, which arguably makes them attractive for use by individuals seeking an unfair advantage over their competitors. The purpose of this study was to investigate the metabolites formed from LGD-4033 in the horse in order to find suitable analytical targets for doping controls. LGD-4033 was administered to three horses after which plasma and urine samples were collected and analyzed for metabolites using ultra high performance liquid chromatography coupled to a high resolution mass spectrometer. In horse urine, eight metabolites, both phase I and phase II, were observed most of which had not been described in other metabolic systems. Six of these were also detected in plasma. The parent compound was detected in plasma, but not in non-hydrolyzed urine. The longest detection times were observed for unchanged LGD-4033 in plasma and in urine hydrolyzed with β-glucuronidase and is thus suggested as the analytical target for doping control in the horse. The metabolite profile determined in the horse samples was also compared to those of human urine and fungal incubate from Cunninghamella elegans . The main human metabolite, dihydroxylated LGD-4033, was detected in the horse samples and was also produced by the fungus. However, it was a not a major metabolite for horse and fungus, which highlights the importance of performing metabolism studies in the species of interest. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a syndrome that impairs the quality of life and overall survival of patients, and thus the effectiveness of anticancer agents. There are no effective therapies for cancer cachexia due to the complexity of the syndrome, and insufficient knowledge of its pathogenesis results in difficulty establishing appropriate animal models. Previously, promising results have been obtained in clinical trials using novel agents including the ghrelin receptor agonist anamorelin, and the selective androgen receptor modulator (SARM) enobosarm to treat cachexia in patients with cancer. The present study examined the pharmacological effects of SARM‑2f, a novel non‑steroidal small molecule SARM, in animal models. SARM‑2f increased body and skeletal muscle weight without significantly increasing the weight of the seminal vesicles or prostates of the castrated male rats. In the mice with tumor necrosis factor α‑induced cachexia, SARM‑2f and TP restored body weight, carcass weight, and food consumption rate. In the C26 and G361 cancer cachexia animal models, body and carcass weight, lean body mass, and the weight of the levator ani muscle were increased by SARM‑2f and TP treatments. Tissue selectivity of SARM‑2f was also observed in these animal models. The results demonstrate the anabolic effects of SARM‑2f in a cytokine‑induced cachexia model and other cancer cachexia models, and suggest that SARM‑2f may be a novel therapeutic option for cachexia in patients with cancer. [ABSTRACT FROM AUTHOR]

Selective androgen receptor modulators (SARMs) are a novel class of androgen receptor ligands. They are intended to exhibit the same kind of effects as androgenic drugs, like anabolic steroids, but be much more selective in their action, targeting particular tissues without any undesirable effects on others. While the main applications of these synthetic substances are for therapeutic purposes, they also have a high potential for misuse in veterinary practice and the sporting world. In order to guarantee for consumers with food from animal origin that it is free from any residues of such compounds, analytical strategies are required to ensure safe food and also to enable fair trade between producers. In this context an animal experiment involving bovines administered with enobosarm was conducted to provide the study with biological matrices. Different animal matrices (urine and faeces) were investigated to select the most appropriate matrix for use for control purposes, in terms of metabolite relevance and detection time window. Based on ultra-high-pressure liquid chromatography (UHPLC) with tandem mass spectrometry (LC-MS/MS) this work highlighted the presence of sulfonated and glucuronated-conjugated forms of the molecule in the urine of treated animals. Enobosarm could be detected in urine up to 9 days after the administration when samples underwent phase II hydrolysis. Faeces was demonstrated to be the main matrix of excretion of enobosarm since values up to 500 times higher compared with urine could be detected for 21 days. There was no difference between the kinetic profiles when a deconjugation step was or was not was applied. [ABSTRACT FROM PUBLISHER]

The androgen-induced alterations in adult rodent skeletal muscle fibre cross-sectional area (fCSA), satellite cell content and myostatin (Mstn) were examined in 10-month-old Fisher 344 rats ( n = 41) assigned to Sham surgery, orchiectomy (ORX), ORX + testosterone (TEST; 7.0 mg week−1) or ORX + trenbolone (TREN; 1.0 mg week−1). After 29 days, animals were euthanised and the levator ani/bulbocavernosus (LABC) muscle complex was harvested for analyses. LABC muscle fCSA was 102% and 94% higher in ORX + TEST and ORX + TREN compared to ORX ( p < .001). ORX + TEST and ORX + TREN increased satellite cell numbers by 181% and 178% compared to ORX, respectively ( p < .01), with no differences between conditions for myonuclear number per muscle fibre ( p = .948). Mstn protein was increased 159% and 169% in the ORX + TEST and ORX + TREN compared to ORX ( p < .01). pan-SMAD2/3 protein was ~30-50% greater in ORX compared to SHAM ( p = .006), ORX + TEST ( p = .037) and ORX + TREN ( p = .043), although there were no between-treatment effects regarding phosphorylated SMAD2/3. Mstn, ActrIIb and Mighty mRNAs were lower in ORX, ORX + TEST and ORX + TREN compared to SHAM ( p < .05). Testosterone and trenbolone administration increased muscle fCSA and satellite cell number without increasing myonuclei number, and increased Mstn protein levels. Several genes and signalling proteins related to myostatin signalling were differentially regulated by ORX or androgen therapy. [ABSTRACT FROM AUTHOR]

• Crystal structures of three YK11 polymorphs were reported. • Structural features were evaluated. • Polymorphs were investigated by XRPD, FT-IR and DSC. [(17α,20E)-17,20-[(1- methoxyethylidene) bis (oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester], widely known under the name of YK11 is a synthetic agent with anabolic properties which belongs to the selective androgen receptor modulators group (SARMs). An extended polymorph screening was accomplished and the crystal structures of three YK11 polymorphs were determined by single crystal X-ray diffraction. The crystal features were analyzed by means of crystal lattice and intermolecular interaction energies as well. Furthermore, the polymorphs were investigated by powder X-ray diffraction, Fourier-Transform infrared spectroscopy and DSC thermal analysis. [ABSTRACT FROM AUTHOR]