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Selective androgen receptor modulators

Salpie Nowinski, Aida Santaolalla, Ben O'Leary, Massimo Loda, Ayesha Mirchandani, Mark Emberton, Mieke Van Hemelrijck, Anita Grigoriadis
Novel approaches for classification, including molecular features, are needed to direct therapy for men with low-grade prostate cancer (PCa), especially men on active surveillance. Risk alleles identified from genome-wide association studies (GWAS) could improve prognostication. Those risk alleles that coincided with genes and somatic copy number aberrations associated with progression of PCa were selected as the most relevant for prognostication. In a systematic literature review, a total of 698 studies were collated...
February 27, 2018: Oncotarget
Haroon Latif Khan, Shahzad Bhatti, Sana Abbas, Yousaf Latif Khan, Rosa Maria Marquez Gonzalez, Muhammad Aslamkhan, Gerardo Rodriguez Gonzalez, Hikmet Hakan Aydin
Background: Despite its worldwide high occurrence, the obscurity regarding the description, epidemiology and management of premature ejaculation remains provocative. It is well established that male premature ejaculatory dysfunction is an increasing problem due to spontaneous ejaculation across a variety of general and clinical subjects. The main goal of this study was to determine the relationships between trinucleotide repeats of the androgen receptor (AR), sex steroids, and pituitary hormones with sexual function in men with type 2 diabetes mellitus (DM) and reported with acquired premature ejaculation (PE)...
2018: Basic and Clinical Andrology
V Krishnan, N J Patel, J G Mackrell, S A Sweetana, H Bullock, Y L Ma, T H Waterhouse, B C Yaden, J Henck, Q Q Zeng, K Gavardinas, P Jadhav, A Saeed, P Garcia-Losada, D A Robins, C T Benson
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...
March 12, 2018: Andrology
Kateřina Pěnčíková, Lucie Svržková, Simona Strapáčová, Jiří Neča, Iveta Bartoňková, Zdeněk Dvořák, Martina Hýžďalová, Jakub Pivnička, Lenka Pálková, Hans-Joachim Lehmler, Xueshu Li, Jan Vondráček, Miroslav Machala
The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics...
March 5, 2018: Environmental Pollution
Sok Kuan Wong, Nur-Vaizura Mohamad, Putri Ayu Jayusman, Ahmad Nazrun Shuid, Soelaiman Ima-Nirwana, Kok-Yong Chin
Selective estrogen receptor modulators (SERMs) represent a class of drugs that act as agonist or antagonist for estrogen receptor in a tissue-specific manner. The SERMs drugs are initially used for the prevention and treatment of osteoporosis in postmenopausal women. Bone health in prostate cancer patients has become a significant concern, whereby patients undergo androgen deprivation therapy is often associated with deleterious effects on bone. Previous preclinical and epidemiological findings showed that estrogens play a dominant role in improving bone health as compared to testosterone in men...
March 6, 2018: Aging Male: the Official Journal of the International Society for the Study of the Aging Male
Nisha M Badders, Ane Korff, Helen C Miranda, Pradeep K Vuppala, Rebecca B Smith, Brett J Winborn, Emmanuelle R Quemin, Bryce L Sopher, Jennifer Dearman, James Messing, Nam Chul Kim, Jennifer Moore, Brian D Freibaum, Anderson P Kanagaraj, Baochang Fan, Heather Tillman, Ping-Chung Chen, Yingzhe Wang, Burgess B Freeman, Yimei Li, Hong Joo Kim, Albert R La Spada, J Paul Taylor
Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies...
March 5, 2018: Nature Medicine
Tomofumi Yatsu, Taichi Kusakabe, Keisuke Kato, Yoshio Inouye, Kiyomitsu Nemoto, Yuichiro Kanno
Androgens are key regulators that play a critical role in the male reproductive system and have anabolic effects on bone mineral density and skeletal muscle mass. We have previously reported that YK11 is a novel selective androgen receptor modulator (SARM) and induces myogenic differentiation and selective gene regulation. In this study, we show that treatment of YK11 and dihydrotestosterone (DHT) accelerated cell proliferation and mineralization in MC3T3-E1 mouse osteoblast cells. Further, YK11-treated cells increased osteoblast specific differentiation markers, such as osteoprotegerin and osteocalcin, compared to untreated cells...
2018: Biological & Pharmaceutical Bulletin
Takako Kawanami, Tomoko Tanaka, Yuriko Hamaguchi, Takashi Nomiyama, Hajime Nawata, Tosihiko Yanase
We previously identified a novel selective androgen receptor modulator (SARM), S42, which does not stimulate prostate growth but has a beneficial effect on lipid metabolism. In the prostate cancer (PC) cell line LNCaP, S42 did not induce androgen receptor (AR) transactivation but antagonized 5α-dihydrotestosterone (DHT)-induced AR activation. Next, we investigated whether S42 suppresses the growth of PC cell lines. Basal growth of LNCaP cells was significantly suppressed by treatment with S42 compared with vehicle, as determined by cell counting and BrdU assays...
February 12, 2018: Endocrinology
B Gray, M Viljanto, E Menzies, L Vanhaecke
The detection of drugs in human hair samples has been performed by laboratories around the world for many years and the matrix is popular in disciplines such as workplace drug testing. To date, however, hair has not become a routinely utilised matrix in sports drug detection. The analysis of hair samples offers a number of potential advantages to doping control laboratories, not least of which are the greatly extended detection window and the ease of sample collection and storage. This paper describes the development, validation and utilisation of a sensitive ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC-MS/MS) method for the detection of 50 compounds...
February 12, 2018: Drug Testing and Analysis
Ashlyn Swift-Gallant, Paula Duarte-Guterman, Dwayne K Hamson, Muna Ibrahim, D Ashley Monks, Liisa A M Galea
Adult hippocampal neurogenesis occurs in many mammalian species. In rats, the survival of new neurons within the hippocampus is modulated by androgen action via the androgen receptor (AR), however it is not known whether this holds true in mice. Furthermore, evidence is mixed as to whether androgens act in neural tissue or via peripheral non-neural targets to promote hippocampal neuron survival. We evaluated whether androgen action via AR underlies the survival of new neurons in mice, and asked whether increasing AR selectively in neural tissue would increase new neuron survival in the hippocampus...
February 7, 2018: Journal of Neuroendocrinology
Tetsuya Fujimura, Kenichi Takayama, Satoru Takahashi, Satoshi Inoue
Androgen deprivation therapy (ADT) has been widely prescribed for patients with advanced prostate cancer (PC) to control key signaling pathways via androgen receptor (AR) and AR-collaborative transcriptional factors; however, PC gradually acquires a lethal phenotype and results in castration-resistant PC (CRPC) during ADT. Therefore, new therapeutic strategies are required in clinical practice. In addition, ARs; estrogen receptors (ERs; ERα and ERβ); and estrogen-related receptors (ERRs; ERRα, ERRβ, and ERRγ) have been reported to be involved in the development or regulation of PC...
January 23, 2018: Cancers
Megumi Morimoto, Katsuji Aikawa, Takahito Hara, Masuo Yamaoka
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...
December 2017: Oncology Letters
Annelie Hansson, Heather Knych, Scott Stanley, Emma Berndtson, Liora Jackson, Ulf Bondesson, Mario Thevis, Mikael Hedeland
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...
December 7, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Neeraj Garg, Annelie Hansson, Heather K Knych, Scott D Stanley, Mario Thevis, Ulf Bondesson, Mikael Hedeland, Daniel Globisch
Selective androgen receptor modulators (SARMs) are a class of androgen receptor drugs, which have a high potential to be performance enhancers in human and animal sports. Arylpropionamides are one of the major SARM classes and get rapidly metabolized significantly complicating simple detection of misconduct in blood or urine sample analysis. Specific drug-derived metabolites are required as references due to a short half-life of the parent compound but are generally lacking. The difficulty in metabolism studies is the determination of the correct regio and stereoselectivity during metabolic conversion processes...
January 10, 2018: Organic & Biomolecular Chemistry
Masakazu Saitoh, Nicole Ebner, Stephan von Haehling, Stefan D Anker, Jochen Springer
Sarcopenia is a common feature, and affects 20-47% of patients with heart failure (HF). Sarcopenia is also an independent predictor of impaired functional capacity, even after adjusting for clinical relevant variables, which is associated with adverse outcome in patients with HF. Areas covered: Several different pathophysiological pathways are involved in sarcopenic processes including altered nutrient intake and absorption, hormonal factor, inflammatory processes, oxidative stress, cellular proteolysis, and unhealthy lifestyle...
January 7, 2018: Expert Review of Cardiovascular Therapy
Mario Thevis, Dietrich A Volmer
Selective androgen receptor modulators (SARMs) have been identified as a promising class of drug candidates potentially applicable to diverse pathological conditions commonly associated with significantly reduced muscle mass. Due to a suspected and meanwhile repeatedly proven misuse of SARMs in elite and amateur sport, sustaining constantly updated doping control analytical methods is critical for sports drug testing laboratories. These test methods predominantly utilize mass spectrometry-based instrumentations and, consequently, studies on the mass spectrometric behavior of new compounds and, where available, their metabolic products are vital for comprehensive doping controls...
February 2018: European Journal of Mass Spectrometry
Megumi Morimoto, Yuichiro Amano, Masahiro Oka, Ayako Harada, Hisashi Fujita, Yukiko Hikichi, Ryuichi Tozawa, Masuo Yamaoka, Takahito Hara
Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models...
2017: PloS One
Ryan M Van Wagoner, Amy Eichner, Shalender Bhasin, Patricia A Deuster, Daniel Eichner
Importance: Recent reports have described the increasing use of nonsteroidal selective androgen receptor modulators, which have not been approved by the US Food and Drug Administration (FDA), to enhance appearance and performance. The composition and purity of such products is not known. Objective: To determine the chemical identity and the amounts of ingredients in dietary supplements and products marketed and sold through the internet as selective androgen receptor modulators and compare the analyzed contents with product labels...
November 28, 2017: JAMA: the Journal of the American Medical Association
Jochen Springer, Joshua-I Springer, Stefan D Anker
Sarcopenia (loss of muscle mass and muscle function) is a strong predictor of frailty, disability and mortality in older persons and may also occur in obese subjects. The prevalence of sarcopenia is increased in patients suffering from chronic heart failure. However, there are currently few therapy options. The main intervention is resistance exercise, either alone or in combination with nutritional support, which seems to enhance the beneficial effects of training. Also, testosterone has been shown to increased muscle power and function; however, a possible limitation is the side effects of testosterone...
November 2017: ESC Heart Failure
Agnieszka Wnuk, Małgorzata Kajta
Apoptosis and autophagy are involved in neural development and in the response of the nervous system to a variety of insults. Apoptosis is responsible for cell elimination, whereas autophagy can eliminate the cells or keep them alive, even in conditions lacking trophic factors. Therefore, both processes may function synergistically or antagonistically. Steroid and xenobiotic receptors are regulators of apoptosis and autophagy; however, their actions in various pathologies are complex. In general, the estrogen (ER), progesterone (PR), and mineralocorticoid (MR) receptors mediate anti-apoptotic signalling, whereas the androgen (AR) and glucocorticoid (GR) receptors participate in pro-apoptotic pathways...
November 11, 2017: International Journal of Molecular Sciences
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