ArticleLiterature Review

Nonsteroidal Selective Androgen Receptor Modulator Ostarine ™ in Cancer Cachexia

Taylor & Francis
Future Oncology
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Abstract

Cancer cachexia is a complex syndrome, affecting up to 60% of the approximately 1.4 million patients diagnosed with cancer each year in the USA. This condition is characterized by progressive deterioration of a patient's nutritional status, weight loss, anorexia, diminished quality of life and increased mortality and morbidity. Current therapy with progestational, anti-inflammatory and anabolic agents is often ineffective and has a large number of undesirable effects. The newly developed nonsteroidal selective androgen receptor modulator Ostarine has demonstrated promising results in Phase I and II clinical trials, increasing total lean body mass, enhancing functional performance and decreasing total tissue percent fat. This selective androgen receptor modulator may have the ability to perform as a potent anabolic agent with minimal side effects on other organs (prostate and hair follicles), thus presenting a new strategy in managing cancer cachexia. However, more extensive data is required before its efficacy is confirmed.

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... Dobs et al, 2013;Miller et al., 2011;Ponnusamy, Sullivan, Thiyagarajan, Tillmann, Getzenberg, & Narayanan, 2017), efekt byl v několika případech srovnatelný s účinkem dihydrotestosteronu (Dubois et al., 2015;Simitsidellis et al., 2019). Dalšími souvisejícími efekty jsou zvýšení svalové síly nebo zlepšení ve funkčních testech (Zilbermint & Dobs, 2009). Pozitivní efekt na zvýšení síly potvrzují Liva et al. (2020). ...
... Obecně nejsou konstatovány androgenní efekty jako u anabolických steroidů (Solomon et al., 2018 (Dalton et al., 2011;Zilbermint & Dobs;2009) se prokázal účinek zlepšení inzulinové rezistence. V některých případech byly popsány vedlejší účinky jako suprese testosteronu (Basaria et al., 2013), nauzea, únava, průjem (Zilbermint & Dobs, 2009) U vybraných SARM lze shledat podobné efekty, které lze srovnávat s účinky testosteronu. ...
... Obecně nejsou konstatovány androgenní efekty jako u anabolických steroidů (Solomon et al., 2018 (Dalton et al., 2011;Zilbermint & Dobs;2009) se prokázal účinek zlepšení inzulinové rezistence. V některých případech byly popsány vedlejší účinky jako suprese testosteronu (Basaria et al., 2013), nauzea, únava, průjem (Zilbermint & Dobs, 2009) U vybraných SARM lze shledat podobné efekty, které lze srovnávat s účinky testosteronu. ...
... In addition to their potential use for the treatment of hypogonadism (7,8), SARMs are being explored as a potential therapy for osteopenia/osteoporosis (9)(10)(11)(12)(13)(14), A l z h e i m e r 's d i s e a s e ( 1 5 ) , p r o s t a t e c a n c e r ( P C a ) (16,17), benign prostatic hyperplasia (BPH) (18), male contraception (19), breast cancer (20), stress-induced urinary incontinence (21), sarcopenia (22), muscular dystrophy (23,24), and even cancer and chronic diseaserelated cachexia (25)(26)(27)(28)(29)(30). While SARMs present an opportunity for therapy in several debilitating conditions, recently doubts concerning their ability to meet expectations have surfaced, especially concerning their utility in the treatment of cachexia. ...
... However, because they are not metabolized to dihydrotestosterone (DHT) by 5 -reductase, the risk of androgenic effects is reduced (27,38). In addition, SARMs are not metabolized to estrogen by aromatase, limiting estrogenic effects (30). While the benefits of firstgeneration SARMs appear modest compared to those of androgens (39), the ability of SARMs to preferentially stimulate bone and muscle growth, shrink the prostate, and inhibit breast cancer growth without significant systemic (40)(41)(42)(43)(44)(45)(46). ...
... One can envision the potential utility of SARMs as a treatment for BPH by acting as an AR antagonist. Zilbermint et al. observed that because SARMs are not metabolized to DHT by 5 -reductase, the risk of prostatic hyperplasia is reduced (30). While previous studies have observed that SARMs can decrease prostatic weight in rat models (18,43), a single phase II clinical trial (NCT03297398) was recently initiated to study the efficacy and safety of OPK-88004 in men with BPH. ...
Article
Full-text available
Selective androgen receptor modulators (SARMs) are small molecule drugs that function as either androgen receptor (AR) agonists or antagonists. Variability in AR regulatory proteins in target tissues permits SARMs to selectively elicit anabolic benefits while eschewing the pitfalls of traditional androgen therapy. SARMs have few side effects and excellent oral and transdermal bioavailability and may, therefore, represent viable alternatives to current androgen therapies. SARMs have been studied as possible therapies for many conditions, including osteoporosis, Alzheimer's disease, breast cancer, stress urinary incontinence (SUI), prostate cancer (PCa), benign prostatic hyperplasia (BPH), male contraception, hypogonadism, Duchenne muscular dystrophy (DMD), and sarcopenia/muscle wasting/cancer cachexia. While there are no indications for SARMs currently approved by the Food and Drug Administration (FDA), many potential applications are still being explored, and results are promising. In this review, we examine the literature assessing the use of SARMS for a number of indications.
... [12][13][14] SARMs have begun to be studied in the pre-clinical and clinical phases as treatment options for cancer related cachexia, breast cancer, benign prostatic hyperplasia, and hypogonadism. [2,15,16] There are several ongoing Phase 1 or Phase 2 clinical trials investigating the use of SARMs. ...
... [17,18] Several labs began working on identifying lead candidates and specific pharmacophores, with early work being centered around a class of aryl-propionamides identified from hydroxyflutamide analogs in 1998. [15] Over the past 20 years the number of bioactive SARMs under investigation has continued to grow, as has our knowledge of their mechanisms of action. ...
... -ENOBOSARM TRIALS Several clinical trials are assessing the application of SARMs as novel treatment agents for cancer related cachexia, breast cancer, stress urinary incontinence, and prostate cancer. [15,16] A summary of current clinical trials listed on www.clinicaltrails.gov using SARMS can be found in Table 1. ...
Article
Introduction: Selective androgen receptor modulators (SARMs) differentially bind to androgen receptors depending on each SARM's chemical structure. As a result, SARMs result in anabolic cellular activity while avoiding many of the side effects of currently available anabolic steroids. SARMs have been studied in the treatment of breast cancer and cachexia and have also been used as performance-enhancing agents. Here, we evaluate and summarize the current literature on SARMs. Aim: To present the background, mechanisms, current and potential clinical applications, as well as risks and benefits of SARMs. Methods: A literature review was performed in MEDLINE using the terms selective androgen receptor modulator, hypogonadism, cachexia, breast cancer, benign prostatic hyperplasia, libido, and lean muscle mass. Both basic research and clinical studies were included. Main outcome measure: To complete a review of peer-reviewed literature. Results: Although there are currently no U.S. Food and Drug Agency-approved indications for SARMs, investigators are exploring the potential uses for these compounds. Basic research has focused on the pharmacokinetics and pharmacodynamics of these agents, demonstrating good availability with a paucity of drug interactions. Early clinical studies have demonstrated potential uses for SARMs in the treatment of cancer-related cachexia, benign prostatic hyperplasia (BPH), hypogonadism, and breast cancer, with positive results. Conclusion: SARMs have numerous possible clinical applications, with promise for the safe use in the treatment of cachexia, BPH, hypogonadism, breast cancer, and prostate cancer. Solomon ZJ, Mirabal JR, Mazur DJ, et al. Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications. Sex Med Rev 2019;7:84-94.
... As the lack of data is common in novel compounds, the EMCDDA investigated the applicability of in silico methods in assessing novel psychoactive compounds using Ostarine as an example as it was thought that it is unlikely to be psychoactive. Ostarine is a selective androgen receptor modulator (SARMs) that increases muscle mass and that is currently being developed for the treatment of cancer cachexia (Zilbermint and Dobs, 2009). Unlike anabolic steroids, SARMs specifically targets the build-up of muscles without the side effects of anabolic steroids such as hypertension, hypercholesterolemia, liver damage, testicular atrophy and gynecomastia (Mohler et al., 2009). ...
... From Table 1, it can be seen that none of the top 10 targets predicted for Ostarine is likely to elicit a psychoactive effect. The androgen receptor, which is the primary and intended target of this compound (Zilbermint and Dobs, 2009), is ranked highest, underlining that this chemical structure lies within the applicability domain of our model. However, with respect to the particular question asked here, none of the remaining nine targets predicted is known to be involved in eliciting psychoactive effects. ...
... However, it should be noted that although the likelihood of Ostarine being misused as a psychoactive compound is small, it may be misused as a performance enhancing drug (Thevis et al., 2011). This is due to androgen receptors being predicted here and also studies showing that Ostarine does bind to androgen receptors (Zilbermint and Dobs, 2009), in addition to being more prone to show anabolic effects than androgenic effects (Thevis et al., 2009). ...
Article
This study exemplifies computer-aided (in silico) approaches in assessing the risks of new psychoactive substances emerging in the European Union. In this work, we (i) consider the potential of Ostarine exhibiting psychoactivity and (ii) anticipate potential activities and toxicities of 4-methylamphetamine. The approach, termed in silico target prediction, suggests potential protein targets modulated by compounds given their chemical structure. This is achieved by first establishing the associations between chemical structure and protein targets using data from the bioactivity database, ChEMBL, via the use of two different computational algorithms. On the basis of the associations, protein targets and consequently the mode of action of novel compounds were predicted. For Ostarine, none of the targets anticipated are currently known to elicit psychoactivity. Furthermore, Ostarine is unlikely to cross the blood-brain barrier to reach relevant target sites on the basis of its physicochemical properties. For 4-methylamphetamine, toxicities were anticipated, that is, serotonin syndrome (based on the prediction of SERT) and other effects similar to related substances, that is, methamphetamine. From the two case studies, we showed that in silico target prediction appears to have potential in assessing new psychoactive compounds where experimental data are scarce. The applicability domain of target predictions when applied to psychoactive compounds needs to be established in future work. Copyright © 2013 John Wiley & Sons, Ltd.
... After the success of selective estrogen receptor modulators (eg, tamoxifen and clomifene) in the late 1990s, many public and private laboratories have taken steps to study molecules acting on the androgen receptor in view of possible medical applications minimizing the side effects in nontarget tissues. 3,4 Specifically, SARMs were studied for possible therapies in many pathologies, such as benign prostatic hyperplasia, prostate cancer, hypogonadism, stress urinary incontinence, osteoporosis, cancer-related cachexia, Duchenne muscular dystrophy, breast cancer, and Alzheimer's disease. [5][6][7] SARMs were also investigated to enhance sexual function and in male contraception. ...
... Regarding label reliability, the results of the qualitative analysis by mass spectrometry (Table 2) evidenced the presence of the stated SARM in about 70% of samples (samples 1,3,4,6,[8][9][10][11][12]. In 23% of samples, the declared SARM was replaced by a different SARM (samples 2, 5, and 13). ...
Article
Background Selective androgen receptor modulators (SARMs) are small synthetic drug molecules that are still not approved as medicine in Europe or the United States but are sold on illegal websites to improve sport performance, particularly bodybuilding. Aim To address the quality issues of illegal SARM products and their increasing diffusion in Italy with their potential health risks for consumers. Methods Web-based tools were used to investigate retail websites, trending searches, and information exchange via social media. Thirteen SARM products, purchased on retail websites accessible from Italy, were subject to visual inspection and chemical analysis by mass spectrometry and quantitative nuclear magnetic resonance. Outcomes The primary outcome was demonstration of additional health risks due to the illicit presence of other active ingredients, contamination, and misdosage in SARM products sold on the internet. The secondary outcome was to show the increasing trend of interest in Italy for these products. Results Most websites reported misleading information; specifically, the statement “for research only” was reported notwithstanding indications on dosage and training phases. The trending search showed that interest toward SARMs increased in Italy in the last years. The use of these products is clearly encouraged by the emerging phenomenon of “broscience” as revealed in socials. Visual inspection evidenced nonconform labeling. Qualitative analysis confirmed the presence of the stated SARM in about 70% of samples. In 23% of samples, the expected SARM was not detected but a different one instead, and in 1 sample, no SARMs were detected. Other undeclared pharmaceutical substances (tamoxifen, clomifene, testosterone, epimethandienone, tadalafil) were measured in 30% of samples. The copresence of >1 active substance was observed in >60% of samples. Quantitative nuclear magnetic resonance data showed nonuniform content ranging from 30% to 90% of the label claim. Clinical Implications The use of SARMs, in the presence of unexpected life-threatening reactions in persons using the products to increase sport performance, should be assessed. Strengths and Limitations This investigation involved an integrated approach to study SARM products and related sociologic aspects. The main shortcomings are the limited number of samples and retail websites in the clear web investigated. Conclusion SARMs sold online as food supplement–like products represent a health hazard due to the presence of unapproved and undeclared active substances. The presence of contaminants clearly indicates the absence of good manufacturing practices in the production, which increases the health risks.
... It has an anabolic effect similar to that of steroids. Due to its nonsteroidal structure, ostarine does not undergo enzymatic transformation with aromatase or 5-α reductase, and thus characterized by a better safety profile (12). Several clinical trials have been conducted in healthy elderly men and cachexia patients. ...
... Research on SARMs, including ostarine, has been going on for many years; however, data on its possible use are scarce. Ostarine has shown promising results in Phase I and II clinical trials, including an increase in total lean body mass, improvement in functional performance, and a decrease in total tissue percent fat in cancer cachexia (12,25). However, to date, ostarine has not been authorized legally on the pharmaceutical market (26). ...
Article
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 fat-burning. 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.
... Enobosarm (ostarine, MK-2866, or GTx-024) is a non-steroidal SARM that binds to the androgen receptor (AR) with tissue 1 3 selectivity and cannot be converted to dihydrotestosterone and estrogen [10]. Therefore, it is thought to cause fewer side effects than testosterone [9,11]. Treatment with enobosarm is not approved for human use in any country so far; however, it is sold on the internet [10]. ...
... In accordance with our data, other preclinical studies on arylpropionamide SARMs, including andarine and ostarine (enobosarm), reported increased weight of the levator ani in Orx rats to the level of shamoperated animals and only partially increased the weight of the prostate. Furthermore, enobosarm was more potent than testosterone propionate at the levator ani in rats [9,11,38,39], which is in agreement with our data. The lack of androgenic activity of T treatments in the prostate can be explained by the limited bioavailability of oral testosterone propionate. ...
Article
Full-text available
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.
... The therapeutic use, though, of Insulin, GH, or IGF-1 is currently not recommended due to massive side effects [83]. GH/IGF-1 provides an anti-apopototic environment that could eventually accelerate the development of cancer [84,85]. ...
... SARMs correspond with androgen-receptors in the muscle tissue only, minimizing the systemic side effects of androgen treatment. Ostarine has been tested with promising results in Phase I and II clinical trials and it has been shown that they may have acted as a potent anabolic agent with minimal side effects [85]. Similarly, Enobosarm, a SARM under investigation, has already been used to treat other muscle-wasting diseases. ...
Article
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Cachexia is a major characteristic of multiple non-malignant diseases, advanced and metastatic cancers and it is highly prevalent in pancreatic cancer, affecting almost 70-80% of the patients. Cancer cachexia is a multifactorial condition accompanied by compromised appetite and changes in body composition, i.e., loss of fat. It is associated with lower effectiveness of treatment, compromised quality of life, and higher mortality. Understanding the complex pathways underlying the pathophysiology of cancer cachexia, new therapeutic targets will be unraveled. The interplay between tumor and host factors, such as cytokines, holds a central role in cachexia pathophysiology. Cytokines are possibly responsible for anorexia, hypermetabolism, muscle proteolysis, and apoptosis. In particular, cachexia in pancreatic cancer might be the result of the surgical removal of pancreas parts. In recent years, many studies have been carried out to identify an effective treatment algorithm for cachexia. Choosing the most appropriate treatment, the clinical effect and the risk of adverse effects should be taken under consideration. The purpose of this review is to highlight the pathophysiological mechanisms as well as the current ways of cachexia treatment in the pharmaceutical and the nutrition field.
... Cancer cachexia remains a significant challenge in the management of cancer patients as no clear standard of care exists. Cancer Cachexia impacts approximately 60% of the 1.4 million patients diagnosed with cancer in the United States each year [1,2]. Among late stage patients, cachexia affects 50-80% patients and is responsible for 20% of cancer related deaths [3]. ...
... Clinically, cachexia is defined through a consensus definition of weight loss of ≥5% of body weight in the past 6 months or ≥ 2% loss in patients with body mass index (BMI) of < 20 kg/m 2 [5]. In addition to weight loss, patients with cancer cachexia suffer from multisystem syndrome characterized by anorexia, loss of muscle mass, systemic inflammation, insulin resistance, and functional decline [2,6,7]. Furthermore cachexia patients have also shown to have anemia, hypoalbuminemia, and asthenia [8]. ...
Article
Full-text available
Background Cachexia is a multisystem syndrome characterized by weight loss, anorexia, loss of muscle mass, systemic inflammation, insulin resistance, and functional decline. Management of cachexia involves addressing multiple underlying biological mechanisms. Previous review on pharmacological management of cancer cachexia identified progestins and corticosteroids as effective agents for treatment of cachexia. However, to date no consensus exists on a single effective or standard treatment for management of cachexia. The aim of this systematic review is to determine the effectiveness of pharmacological treatments used to manage cachexia among adult cancer patients. Methods We performed literature searches of PubMed (NLM), Embase (Ovid), and Medline(Ovid) to identify clinical trials focused on pharmacological management of cancer cachexia among adult cancer patients from 2004 to 2018. Three reviewers screened a random selection of abstracts to measure for interrater reliability. After this step, each screener screened two-thirds of all abstracts and 177 studies were identified for full text review. The primary outcome was impact of pharmacological management on change in either weight or lean body mass in cancer patients. Results We identified 19 articles (representing 20 RCTs) that focused on pharmacological management of cancer cachexia. Agents showing promising results included Anamorelin and Enobosarm. Anamorelin at 50 or 100 mg per day for 12 weeks showed a consistent benefit across all studies and resulted in significant improvement in weight as compared to baseline among cancer patients. Enobosarm at 1 and 3 mg per day was also effective in improving lean body mass and QOL symptoms among advancer stage cancer patients. Finally, use of combination agents provide evidence for targeting multiple pathways underlying cachexia mechanism to achieve maximum benefit. No agents showed functional improvement in cancer patients. Conclusion Anamorelin as a single agent shows promising results in improving cachexia related weight loss among cancer patients. Further research on combination therapies may be helpful to address critical gaps in cachexia management. Electronic supplementary material The online version of this article (10.1186/s12885-018-5080-4) contains supplementary material, which is available to authorized users.
... Cancer cachexia remains a significant challenge in the management of cancer patients as no clear standard of care exists. Cancer Cachexia impacts approximately 60% of the 1.4 million patients diagnosed with cancer in the United States each year [1,2]. Among late stage patients, cachexia affects 50-80% patients and is responsible for 20% of cancer related deaths [3]. ...
... Clinically, cachexia is defined through a consensus definition of weight loss of ≥5% of body weight in the past 6 months or ≥ 2% loss in patients with body mass index (BMI) of < 20 kg/m 2 [5]. In addition to weight loss, patients with cancer cachexia suffer from multisystem syndrome characterized by anorexia, loss of muscle mass, systemic inflammation, insulin resistance, and functional decline [2,6,7]. Furthermore cachexia patients have also shown to have anemia, hypoalbuminemia, and asthenia [8]. ...
... Reduced energy expenditure and weight increase are seen as an undesirable side-effect of beta blockers in general. In CHF patients, similar post-hoc observations in large beta-blocker trials have Dietary supplementation BCCAs Leu, Ile, Val, Hmb [204, 205] PUFAs EPA, DHA [206, 207] Appetite stimulants Anti-histaminic drugs, progestational agents, ghrelin [208] ACE inhibitors Enalapril [211] Compounds with anabolic activity Steroidal androgens Testosterone [213] SARMs Ostarine and enobosarm214215216 Growth factors IGF-1, insulin [218] Beta2-agonist Formoterol [220] Anti-inflammatory drugs TNFα antibodies Etancercept, infliximab [221, 222] Cyclooxygenase-2 inhibitors Celecoxib [223] Modulating the energetic crisis of skeletal muscle Adipocyte-derived cytokine Adiponectin (diabetes and obesity) [228] Insulin sensitizer Thiazolidinediones [233] PPARα confirmed that antagonizing high catecholamine levels increases body weight. ...
... The positive effects of anabolic steroids, as well as testosterone administration, on protein synthesis, have to be weighed against possible hazards, such as hepatic toxicity, virilising effects, fluid retention, and in the case of testosterone, the development of prostate complications and malignancy. Further development and testing of nonsteroidal androgen receptor modulators (SARMs) might lead to useful alternatives [214], as indeed observed in the case of ostarine [215] and enobosarm [216]. Several cachexia-prone diseases represent a state of GH resistance: high levels of GH and inappropriately low circulating and locally expressed IGF-1, which is considered the main GH mediator [217]. ...
Article
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Skeletal muscle atrophy is defined as a decrease in muscle mass and it occurs when protein degradation exceeds protein synthesis. Potential triggers of muscle wasting are long-term immobilization, malnutrition, severe burns, aging as well as various serious and often chronic diseases, such as chronic heart failure, obstructive lung disease, renal failure, AIDS, sepsis, immune disorders, cancer, and dystrophies. Interestingly, a cooperation between several pathophysiological factors, including inappropriately adapted anabolic (e.g., growth hormone, insulin-like growth factor 1) and catabolic proteins (e.g., tumor necrosis factor alpha, myostatin), may tip the balance towards muscle-specific protein degradation through activation of the proteasomal and autophagic systems or the apoptotic pathway. Based on the current literature, we present an overview of the molecular and cellular mechanisms that contribute to muscle wasting. We also focus on the multifacetted therapeutic approach that is currently employed to prevent the development of muscle wasting and to counteract its progression. This approach includes adequate nutritional support, implementation of exercise training, and possible pharmacological compounds.
... Ostarine (OST, enobosarm, S-22, MK-2866, or GTx-024) and ligandrol (LIG, LGD-4033, or VK5211) are nonsteroidal SARMs that bind to the androgen receptor (AR) with some tissue selectivity and cannot be converted to dihydrotestosterone and estrogen. They are thought to have fewer side effects than testosterone [7][8][9][10]. OST and LIG are still being investigated in clinical trials and are not currently approved for human use in any country [9,[11][12][13][14]. ...
Article
Full-text available
The effects of combination treatments using the selective androgen receptor modulators (SARMs) ostarine (OST) or ligandrol (LIG) with treadmill exercise (TE) were studied in healthy adult rats. Fifteen-week-old male Wistar rats were divided into groups (n = 10/group). Experiment 1 consisted of (1) Control group: sedentary rats receiving vehicle; (2) OST: sedentary rats receiving OST; (3) TE: training rats receiving vehicle; (4) OST + TE: training rats receiving OST. Experiment 2 consisted of (1) LIG: sedentary group receiving LIG; (2) LIG + TE: training group receiving LIG. The TE regime was as follows: 25 m/min, 5° elevation, 40 min, five times/week, and the sedentary regime was 5 min, three times/week. OST and LIG were administered subcutaneously (0.4 mg/kg body weight/day, five times/week). After eight weeks, bone samples underwent microcomputed tomographical, biomechanical, histological, and ashing analyses. All the treatments had weak effects on the bone structure without affecting bone biomechanics. The OST + TE improved bone structure, while the LIG + TE had unfavorable effects. In serum, OST, OST + TE, and LIG + TE altered cholesterol and lipoprotein levels; TE did not change the serum parameters. The SARM treatments had no clear bone benefit, and the serum effects can be considered as side effects. TE represents a safe treatment. Because SARMs are increasingly applied in gyms along with physical activities, attention should be paid to possible side effects.
... Patients with cachexia may not tolerate chemotherapy treatment and may also affect the patient's quality of life, life expectancy, and response to treatment [3,4]. About 60% of the 1.4 million patients with cancer in the United States suffer from cachexia each year [5,6]. Contrary to patients intending to lose diet, patients with cachexia have decreased appetite, reduced food intake, and insulin sensitivity [7]. ...
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Introduction Insulin resistance has been suggested as one of the known metabolic disorders during cachexia. This study hypothesized that cachexia in cancer patients might be due to insulin resistance as early as cachexia development. Method This study was performed on 46 patients with metastatic gastrointestinal cancer. Anthropometric characteristics and biochemical markers were assessed at baseline, second month, and third month. Insulin resistance was assessed using the HOMA IR method. SFQ-36 questions were used to assess the patients' quality of life at baseline, second and third months. Results Patients' anthropometric characteristic was significantly associated between pre-cachectic and non-pre-cachectic patients in the third month. Cholesterol (P-value: 0.93), albumin (P-value: 0.82), and serum creatinine (P-value: 0.88) in pre-cachectic patients decreased over three months. There was an increasing trend of insulin resistance between pre-cachectic and non-pre-cachectic patients in the third month. Cholesterol had an upward trend with a significant relation in cachectic patients [(P-value: 0.00), (P-value: 0.03), (P-value: 0.01)]. We detected a decreasing trend of insulin resistance between cachectic and non-cachectic patients from the second to the third month (Pvalue= 0.04). SFQ evaluation had no significant relation with cachectic status. Conclusion Significant relation between anthropometric variables with pre-cachexia and cachectic conditions was concluded. Patients' outcome and its relation with insulin resistance (age of 30≤, and above 30≥) demonstrated a significant relation between the cachectic and non-cachectic patients in the third month. We also detected the increased serum cholesterol level in cachectic patients, moreover, higher cholesterol levels in expired cachectic patients than in the living.
... 36-item Short Form questionnaire (SFQ-36) was used to assess the patients' quality of Life at Baseline, second and third months (29). The growing use of measures of health which provide data on the subjective experience of respondents has brought with it a need for guidelines for interpretation. of the 1.4 million patients with cancer in the United States suffer from cachexia each year (5,6). Contrary to patients intending to lose diet, patients with cachexia have decreased appetite, reduced food intake, and insulin sensitivity (7). ...
Article
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Background: Insulin resistance has been suggested as one of the known metabolic disorders during cachexia. This study hypothesized that cachexia in cancer patients might be related to insulin resistance as early as cachexia development. Methods: This study was performed on 46 patients with metastatic gastrointestinal cancer. Anthropometric characteristics and biochemical markers were assessed at baseline, second and third month. Insulin resistance was assessed using the homeostasis model assessment-estimated insulin resistance (HOMA IR) method. SFQ-36 questions were used to assess the patients' quality of life at baseline, second and third months. Results: Anthropometric characteristic was significantly associated between pre-cachectic and non-pre-cachectic patients in third month. Cholesterol (P-value = 0.93), albumin (P-value: 0.82), and serum creatinine (P-value = 0.88) in pre-cachectic patients decreased over three months. There was an increasing trend of insulin resistance between pre-cachectic and non-pre-cachectic patients in third month. Cholesterol had an upward trend with a significant relation in cachectic patients [(P-value = 0.00), (P-value = 0.03), (P-value = 0.01)]. We detected a decreasing trend of insulin resistance between cachectic and non-cachectic patients from second to third month (P-value = 0.04). SFQ evaluation had no significant relation with cachectic status. Conclusion: Previous studies showed that the use of NSAIDs, progesterone’s, corticosteroids, COX-2 inhibitors, anabolic agents and drugs targeting inflammatory cytokines may be beneficial for improving of symptoms of cachexia. Significant relation between anthropometric variables with pre-cachexia and cachectic conditions was concluded. Patients' outcome and its relation with insulin resistance demonstrated a significant relation between the cachectic and non-cachectic patients in the third month. We also detected the increased serum cholesterol level in cachectic patients, moreover, higher cholesterol levels in expired cachectic patients than in the living.
... However, this was not due to a decreased food intake, as seen for RAL treatment alone, but due to the reduced visceral fat weight. Treatments with EN in Phase-I and Phase-II clinical trials demonstrated increased total lean body mass, enhancing functional performance, and decreased total tissue percent fat [54]. In our study, only the combined EN + RAL treatment effectively reduced fat weight. ...
Article
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Purpose Enobosarm (EN), a selective androgen receptor modulator and raloxifene (RAL), a selective estrogen receptor modulator, have been shown to improve bone tissue in osteoporotic males. The present study evaluated the effects of a combination therapy of EN and RAL on bone properties in orchiectomized rats compared to the respective single treatments. Methods Eight-month-old male Sprague–Dawley rats were either left intact (Non-Orx) or orchiectomized (Orx). The Orx rats were divided into four groups (n = 15 each): 1) Orx, 2) EN treatment (Orx + EN), 3) RAL treatment (Orx + RAL), 4) combined treatment (Orx + EN + RAL). EN and RAL (0.4 mg and 7 mg/kg body weight/day) were applied immediately after Orx with a soy-free pelleted diet for up to 18 weeks. The lumbar spine and femora were examined by micro-CT, biomechanical, histomorphological, ashing, and gene expression analyses. Results EN exhibited an anabolic effect on bone, improving some of its parameters in Orx rats, but did not affect biomechanical properties. RAL exhibited antiresorptive activity, maintaining the biomechanical and trabecular parameters of Orx rats at the levels of Non-Orx rats. EN + RAL exerted a stronger effect than the single treatments, improving most of the bone parameters. Liver weight increased after all treatments; the kidney, prostate, and levator ani muscle weights increased after EN and EN + RAL treatments. BW was reduced due to a decreased food intake in the Orx + RAL group and due a reduced visceral fat weight in the Orx + EN + RAL group. Conclusion The EN + RAL treatment appeared to be promising in preventing male osteoporosis, but given the observed side effects on liver, kidney, and prostate weights, it requires further investigation.
... . The magnitude of AR activation is highly dependent on whether the binding ligand promotes or inhibits the interactions between the two functional (N-terminal and C-terminal) domains of the AR30 .The conformation of the resulting N/C interaction (or lack thereof) affects which coregulators and transcription factors are recruited, thereby affecting how/if the entire complex interacts with DNA33,35 .When AAS bind to the AR, the hydrophobic residues of the LBP accommodate the steroid core, while the hydrophilic amino acids of the LBP form hydrogen bonds with the polar atoms of AAS31 . These interactions affect the stability, specificity, and selectivity of ligand binding and thus, may explain some of the distinct phenotypical characteristics among various AAS.However, AAS are limited by their rigid steroid plane, which hinders the structural flexibility of the ligand-receptor complex and narrows the range of customizability in terms of selective coregulators/transcription factors and/or DNA binding conformation66 .On the other hand, the more pliable nonsteroidal SARMs can be designed to induce specific conformational changes to the LBD, promote/inhibit N/C terminal interaction, modulate surface topology and thermodynamic partitioning, alter protein-protein interactions between the AR and coregulators/transcription factors, and ultimately yield tissue-specific gene regulation68,69 . In the prostate-specific antigen (PSA) enhancer site of LNCaP cells, DHT recruited steroid receptor coactivator 1 (SRC-1) but not nuclear receptor corepressor (N-CoR), acting as an overall strong agonist while an aryl propionamide-derived SARM recruited both SRC-1 and N-CoR in these cells, acting as an overall weak agonist in this androgenic tissue model32,33,67 . ...
Article
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In the clinical setting, anabolic agents serve to ameliorate muscle- and bone-wasting diseases. However, many of these anabolic agents are also used by bodybuilders to surpass natural limits of body composition as performance-enhancing drugs (PEDs). The first generation of PEDs comprises testosterone-derived anabolic-androgenic steroids (AAS) which have demonstrated significant myotropic effects. However, AAS lack optimal tissue-selectively and thus, are prone to numerous adverse health consequences. Hence, a newer generation of PEDs, selective androgen receptor modulators (SARMs), was developed with the goal of achieving superior tissue-selectivity (i.e., exerting anabolic effects only in muscle and bone tissue, while minimally affecting other body systems). In general, AAS and SARMs enhance muscle growth primarily through androgen receptor (AR) agonism in target tissues. Despite multiple attempts, no single AAS nor SARM to date is completely risk free. As such, a significant portion of research efforts has been dedicated to manipulating anabolic pathways beyond the AR. Another class of PEDs, myostatin inhibitors, have shown to cause drastic muscle anabolism across multiple species by inhibiting myostatin, the primary deterrent to continuous muscle growth. The myostatin inhibitor, YK-11, blocks myostatin by upregulating its antagonist, follistatin. This effect appears to be mediated through the AR, suggesting a novel and promising gene-selective approach to engineering AR ligands that isolate benefits from risks. At any rate, the exact mechanisms by which these PEDs function is not well understood. Further pioneering regarding these topics is encouraged as it appears that the innovation of a truly tissue-selective anabolic agent is within reach.
... Ostarine (S-22), which is the field leader of SARMs, was able to reduce muscle loss and to decrease the total fat percentage, with minimal side effects on the prostate (Zilbermint and Dobs 2009). In a double-blind study in postmenopausal women and older men, Ostarine increased lean body mass and also had a favourable effect on insulin resistance. ...
Article
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The current issue is the third of the eighth volume of the Athens Journal of Sports, published by the Sport, Exercise, & Kinesiology Unit of the ATINER under the aegis of the Panhellenic Association of Sports Economists and Managers (PASEM).
... [1] Cancer-related anorexia/cachexia syndrome (CACS) is a multisystem syndrome, characterized by anorexia, weight loss, loss of skeletal muscle and body fats, systemic inflammation, and functional decline of cancer patients. [2][3][4] Cancer cachexia affects 50%-80% patients in the advanced stage and is responsible for 20% of cancer-related deaths. [5] The etiology of cancer cachexia remains unknown. ...
Article
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Background In clinical practice, the management of cancer-related anorexia/cachexia syndrome (CACS) is a great challenge. We conducted an observational study to find the effectiveness and safety of megestrol acetate (MA) for the treatment of CACS. Patients and Methods One hundred patients of advanced cancer were randomly assigned in the study. Patients received MA 160 mg/oral twice daily. The duration of treatment was 8 weeks. Results The analysis of the study group demonstrated a statistically significant increase from baseline in body weight ( P ≤ 0.01), quality of life ( P = 0.02), appetite ( P = 0.01), and the Eastern Cooperative Oncology Group performance status ( P = 0.03). Conclusion We concluded that MA is effective and safe in the treatment of CACS.
... In this matter, research on exploring the molecular mechanisms underlying muscle atrophy during cancer cachexia has expanded in the last years to discover several poten-tial therapeutic targets. (29) In detail, agents increasing the levels of PGC-1α, transcription factor jun-B (JUNB) or SIRT1 to slow muscle wasting in various catabolic status, (30) myostatin to antagonize "myostatin -activin A -GDF-11" signaling as an autocrine factor limiting muscle size, (31) IGF-1 analogues, ghrelin mimetic, (32,33) β 2 -adrenoreceptor agonists, (34) and androgen/selective androgen receptor modulators (35) are under active development. With substantial progress, some such as myostatin and activin A antagonists are under high expectation, but future use of these agents is still under expectation with warranty of ultimate safety. ...
Article
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Cancer cachexia is syndrome accompanying weight reduction, fat loss, muscle atrophy in patients with advanced cancer. Since tumor necrosis factor-α (TNF-α) played pivotal role in cancer cachexia, we hypothesized preemptive administration of TNF-α antibody might mitigate cancer cachexia. Detailed molecular mechanisms targeting muscle atrophy, cachexic inflammation, and catabolic catastrophe were explored whether TNF-α antibody can antagonize these cachexic mechanisms. Stimulated with preliminary finding human antibody, infliximab or adalimumab, significantly inhibited TNF-α as well as their signals relevant to cachexia in mice, preemptive administration of 1.5 mg/kg adalimumab was done in C-26-induced cancer cachexia. Adalimumab significantly mitigated cancer cachexia manifested with significantly lesser weight loss, leg muscle preservation, and higher survival compared to cachexia control (p<0.05). Significant ameliorating action of muscle atrophy were accompanied significant decreases of muscle-specific UPS like atrogin-1/MuRF-1, Pax-7, PCG-1α, and Mfn-2 after adalimumab (p<0.01) and significantly attenuated lipolysis with inhibition of ATGL HSL, and MMPs. Cachexic factors including IL-6 expression, serum IL-6, gp130, IL-6R, JAK2, and STAT3 were significantly inhibited with adalimumab (p<0.01). Genes implicated in cachexic inflammation like NF-κB, c-Jun/c-Fos, and MAPKs were significantly repressed, while mTOR/AKT was significantly increased adalimumab (p<0.05). Conclusively, pre­emptive administration of adalimumab can be tried in high risk to cancer cachexia.
... Ostarine (S-22), which is the field leader of SARMs, was able to reduce muscle loss and to decrease the total fat percentage, with minimal side effects on the prostate (Zilbermint and Dobs 2009). In a double-blind study in postmenopausal women and older men, Ostarine increased lean body mass and also had a favourable effect on insulin resistance. ...
Article
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Selective androgen receptor modulators (SARMs) are an exciting group of molecules with pronounced anabolic effects and very weak to missing androgenic ones. This is due to the tissue selectivity they possess and is their big advantage over anabolic androgenic steroids (AAS). As a result of this SARMs tend to be a big promise for improving the treatment process in different socially significant diseases such as osteoporosis, muscle wasting, benign prostatic hyperplasia, hypogonadism, sexual dysfunction, neurodegenerative diseases etc. SARMs are included in the prohibited list of World Anti-Doping agency (WADA) as they are a temptation for a lot of athletes regarding the exerted strong anabolic effect. However, as SARMs are freely available on the internet there are some reports for positive doping tests in professional sports connected with them. Still further research is needed to examine all the side effects of SARMs. Some of them may be harmful so both professional and amateur sportsmen, their coaches and doctors should be informed about this interesting topic. Keywords: SARM(s), anabolic effect, sports, doping, side effects
... The efficiency of the SARM representative in this model is comparable to that of testosterone propionate, and the effect is achieved by affecting the signal pathways which regulate the homeostasis of the muscles (45). Ostarine (S-22), another nonsteroidal selective androgen receptor modulator, has also been shown to reduce SELECTIVE ANDROGEN RECEPTOR MODULATORS VOL. 5 (1) muscle loss and decrease total fat percentage, with minimal side effects on the prostate (46). In a double-blind study in postmenopausal women and older men, Ostarine increased lean body mass and also had a favourable effect on insulin resistance. ...
... Several nonsteroidal SARMs, such as ostarine [13,14], GSK2881078 [15], and LGD4033 [16], were developed for clinical trials (Figure 1). Among them, ostarine was shown to improve muscle functions in patients with cancer cachexia [17]. ...
Article
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The pentafluorosulfane (SF5) group, as a more electronegative bioisostere than the trifluoromethyl (CF3) group, has been gaining greater attention and increasingly reported usage in medicinal chemistry. Ostarine is the selective androgen receptor modulators (SARMs) containing a CF3 group in clinical trial III. In this study, 21 ostarine derivatives for replacing the CF3 group with SF5 substituents were synthesized. Some SF5-derivatives showed androgen receptor (AR) agonistic activities in vitro. The results pointed to the potential of using this scaffold to develop new AR agonists.
... De hecho, estos ensayos han demostrado mejoras significativas en la masa muscular, pero el aumento de la fuerza o la capacidad funcional ha sido menos convincente (46). Se suma además que el enobosarm es un medicamento seguro y bien tolerado, sus efectos adversos comunes incluyen fatiga, anemia, náuseas y diarrea, elevación de alanina aminotransferasa que ha sido notado en unos pocos pacientes y no ha ocurrido dosis limitante por toxicidad (47). Analizando el desarrollo de este medicamento en los estudios de fase I y fase II encontrados, se evidencia la mejoría de parámetros antropométricos como peso y masa magra, pero además en varios de los nuevos ensayos, demostraron mejoría en la funcionalidad física comparado con el placebo lo cual adicionaría seguridad al uso de los medicamentos tipo SARM, a la planteada previamente. ...
Thesis
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Introduction: A systematic review and evaluation of the current literature was carried out in search of pros and cons of the different nutritional and pharmacological interventions existing in the cancer and cachectic patient, and their impact on palliative care. Review question: Are current nutritional and pharmacological interventions effective in palliative cancer patients? Inclusion criteria: Randomized and quasi-randomized clinical trials in oncological patients with cachexia and / or pre-cachexia, use of some pharmacological intervention, nutritional supplementation or use of physical exercise. Methodology: The search strategy was carried out since October 2018, with DeCS and MeSH thesauri in Pubmed, Scielo, Medline, CINAHL and the Cochrane collaboration, and the Google Academic search engine. The quality of the articles was measured with the CASPe tool. Results: Of 6,303 records identified, 233 full text articles were examined, and 89 experimental and non-experimental clinical studies were included, measuring the impact of the interventions through weight gain, nutritional status and functionality. The current evidence has not yet been modified in broad strokes. Conclusions: The pathophysiology of malnutrition and cachexia is complex, which justifies a specific treatment strategy. There is scientific evidence that shows that a comprehensive multimodal approach is the indicative. Clinical trials should be continued, blinded and with representative samples, that allow evaluating the efficacy, tolerability and safety of different types of nutritional, pharmacological or physical exercise interventions. Key Words: Cachexia, Cancer, Nutrition, Palliative Care.
... (26,27) Unmet medical need arises to develop drugs targeted either increasing muscle regeneration or inhibiting atrophy in the last few years. (28) For instances, agents increasing the levels of PGC-1a, transcription factor jun-B (JUNB) or SIRT1 to slow muscle wasting in various catabolic status, (29) myostatin to antagonize myostatin-activin A-GDF11 signaling as an autocrine factor limiting muscle size, (30) IGF1 analogues and ghrelin mimetic, (31,32) b 2 -adrenoreceptor agonists (33) and androgen/ selective androgen receptor modulators (34) are under active development. With substantial progress, some such as myostatin and activin A antagonists are under high expectation, but future use of these agents requires more than demonstration of increased muscle mass necessitating covering multiple mechanisms and ultimate safety. ...
Article
Cancer cachexia is a syndrome accompanying weight loss, skeletal muscle atrophy, and loss of adipose tissue in patients with advanced cancer. Since interleukin-6 (IL-6) is one of core mediators causing cancer cachexia and kimchi can modulate IL-6 response, we hypothesized dietary intake of kimchi can ameliorate cancer cachexia. In this study, we studied preemptive administration of kimchi can ameliorate mouse colon carcinoma cells colon (C26) adenocarcinoma-induced cancer cachexia and explored anti-cachexic mechanisms of kimchi focused on the changes of muscle atrophy, cachexic inflammation, and catabolic catastrophe. As results, dietary intake of kimchi significantly attenuated the development of cancer cachexia, presented with lesser weight loss, higher muscle preservation as well as higher survival from cancer cachexia in mice. Starting from significant inhibition of IL-6 and its signaling, kimchi afforded significant inhibition of muscle specific ubiquitin-proteasome system including inhibition of atrogin-1 and muscle ring finger protein-1 (MuRF-1) with other muscle related genes including mitofusin-2 (Mfn-2) and PGC-1α. Significant inhibition of lipolysis gene such as adipose triglyceride lipase (ATGL) and hormone-sensitive ligase (HSL) accompanied with significant induction of fatty acid synthase (FAS) and sterol response element binding protein 1 (SREBP1) was achieved with kimchi. As gene regulation, IL-6 and their receptor as well as Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were significantly attenuated with kimchi. In conclusion, dietary intake of cancer preventive kimchi can be an anticipating option to ameliorate cancer cachexia via suppressive action of IL-6 accompanied with decreased muscle atrophy and lipolysis.
... Among the tested compounds, (S)-20c and (S)-20e exhibited agonistic activity in Cos-7 cells ( Figure S5) compared with the activity of (S)-22, the most advanced and promising nonsteroidal molecule acting as an androgen receptor agonist. 43 In agreement with the findings of Miller and co-workers, 29 these results confirm the essential role of the linker bulk (i.e., -SO 2 -vs. -O-) in controlling the antagonist/agonist behavior of nonsteroidal AR ligands. ...
Article
The androgen receptor (AR) represents the primary target for prostate cancer (PC) treatment even when it progresses towards the androgen-independent (AIPC) or the castration-resistant (CRPC) forms. Small chemical changes in the structure of non-steroidal AR ligands sensibly detrmine the pharmacological responses of AR, we developed a novel stereoselective synthetic strategy that allows obtaining sterically hindered C2-substituted bicalutamide analogs. Biological and theoretical evaluations demonstrate that the C2-substitution with benzyl and phenyl moieties is a new valuable option toward the improvement of the pan-antagonist behavior. Among the synthesized compounds, (R)-16m, when compared to casodex, (R)-bicalutamide and enzalutamide, displayed very promising in vitro activity in five different prostate cancer cell lines, all representative of CPRC and AIPC typical mutations. Despite being less active than (R)-bicalutamide, (R)-16m also displayed a marked in vivo antitumor activity on VCaP xenografts and thus it may serve as starting point for developing novel AR pan-antagonists.
... Apparently, several pharmaceutical companies are currently testing these agents to fight sarcopenia due to aging and cancer cachexia [66] . For example, Ostarine has demonstrated promising results in Phase Ⅰ and Ⅱ clinical trials and may have the ability to perform as a potent anabolic agent with minimal side effects [67] . Similarly, Enobosarm is currently being tested in phase Ⅱ clinical trials [68,69] . ...
Article
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Cachexia is frequently described in patients with pancreatic ductal adenocarcinoma (PDAC) and is associated with reduced survival and quality of life. Unfortunately, the therapeutic options of this multi-factorial and complex syndrome are limited. This is due to the fact that, despite extensive preclinical and clinical research, the underlying pathological mechanisms leading to PDAC-associated cachexia are still not fully understood. Furthermore, there is still a lack of consensus on the definition of cachexia, which complicates the standardization of diagnosis and treatment as well as the analysis of the current literature. In order to provide an efficient therapy for cachexia, an early and reliable diagnosis and consistent monitoring is required, which can be challenging especially in obese patients. Although many substances have been tested in clinical and preclinical settings, so far none of them have been proven to have a long-term effect in ameliorating cancer-associated cachexia. However, recent studies have demonstrated that multidimensional therapeutic modalities are able to alleviate pancreatic cancer-associated cachexia and ultimately improve patients' outcome. In this current review, we propose a stepwise and pragmatic approach to facilitate and standardize the treatment of cachexia in pancreatic cancer patients. This strategy consists of nutritional, dietary, pharmacological, physical and psychological methods.
... Phase III trials are needed to determine its efficacy. 164,165 There is little evidence as to the effects of recombinant growth hormone and IGF-1 in cachectic patients. 206 Ghrelin Ghrelin, a peptide produced by the stomach and pancreas, positively affects appetite control, food intake, and adiposity and could therefore be a treatment avenue in cancer cachexia. ...
Article
The pathophysiology of cancer cachexia remains complex. A comprehensive literature search was performed up to April 2013 using PubMed, the Cochrane Library, CINAHL and the Google search engine. In this review, we focus on the different mediators of impaired anabolism and up-regulated catabolism that alter the skeletal muscle homeostasis resulting in the wasting of cancer cachexia. We present recent evidence of targeted treatment modalities from clinical trials along with their potential mechanisms of action. We also report on the most current evidence from randomized clinical trials using multimodal treatments in patients with cancer cachexia, but also the evidence from HNC-specific trials. A more complete understanding of the pathophysiology of the syndrome may lead to more effective targeted therapies and improved outcomes for patients. Head Neck, 2014.
... Plusieurs pistes, visant à agir directement ou non sur le muscle, sont envisageables : les inhibiteurs du système ubiquitine-protéasome (bortezomib et carfilzomib), les antimyostatines, les agonistes ␤2, les inhibiteurs de l'angiotensine II (losartan) [30], les inhibiteurs sélectifs de la COX-2, les modulateurs sélectifs des récepteurs aux androgènes (ostarine) [31]. . . Cependant il manque le plus souvent d'études cliniques convaincantes déterminant leur impact putatif sur la perte de masse musculaire, la fonction musculaire et la lutte contre la cachexie. ...
Article
There are several treatment options with drugs in sarcopenia or cachexia: anabolic products (androgens, growth hormone and insulin-like growth factor-1), anticatabolic products (insulin, anti-cytokines) and appetite stimulants (corticosteroids, synthetic progestins). But many questions remain unanswered, making delicate the use of these products. For example, appetite stimulant drugs increase food intake, with an effect on body fat but not on muscle mass. In fact, their use is not recommended, except in a palliative care. On the other hand, vitamin D induced on several randomized controlled trials of good quality an improved muscle strength and a reduced risk of falls. The anticatabolic effects of omega-3 are possible, but they seem moderate and with insufficient evidence. Side slopes of amino acids such as leucine or citrulline are currently being investigated in sarcopenia. New therapeutic muscle targets are under investigation. In practice, it is especially important to combine several approaches (nutrition, physical activity).
... Recently, SARMs have received much attention as potential muscle-targeted treatments for cancer cachexia. In humans, Phase I and II clinical trials have shown that SARMs increased LBM and enhanced functional status (Zilbermint and Dobs, 2009). In a recent phase IIb randomised, double blind, placebo controlled study, treatment with enobosarm (GTx-024) was shown to significantly increase lean body mass and muscle function in 120 healthy elderly men and women (Dalton et al., 2011) At present, enobosarm is being assessed in a randomised, placebo-controlled, phase III clinical trial in patients with non-small-cell lung cancer receiving first-line chemotherapy treatment (clinicaltrails.gov/NCT01355497). ...
... The chemical composition of ostarine can be found in patent databases, but GTx has not formally disclosed the structure. Ostarine treatment leads to increased lean body mass and improved muscle function but has no apparent effects on the prostate, skin, or pituitary gland (Zilbermint and Dobs, 2009). ...
Article
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Nuclear receptors are ligand-activated transcription factors and include the receptors for steroid hormones, lipophilic vitamins, sterols, and bile acids. These receptors serve as targets for development of myriad drugs that target a range of disorders. Classically defined ligands that bind to the ligand-binding domain of nuclear receptors, whether they are endogenous or synthetic, either activate receptor activity (agonists) or block activation (antagonists) and due to the ability to alter activity of the receptors are often termed receptor "modulators." The complex pharmacology of nuclear receptors has provided a class of ligands distinct from these simple modulators where ligands display agonist/partial agonist/antagonist function in a tissue or gene selective manner. This class of ligands is defined as selective modulators. Here, we review the development and pharmacology of a range of selective nuclear receptor modulators.
Article
In recent years, an increasing focus has been given to the study of selective androgen receptor modulators (SARMS) due to the fewer side effects they exhibit compared to anabolic androgenic steroids. The crystal structure of ostarine (Os) and andarine (AND) has been determined by X-ray single crystal diffraction. It was found that ostarine crystallizes in the monoclinic system, P21 space group with Z = 2 and one molecule in the asymmetric unit, while andarine crystallizes in the tetragonal system, P42212 space group with Z = 8 and one molecule per asymmetric unit. A polymorph of ostarine (Os–P1) has been identified as being monoclinic, space group P21, Z = 2 with two molecules in the asymmetric unit and has been solved by X-ray powder diffraction using Parallel tempering Monte Carlo technique and refined by Rietveld method. This polymorph has been obtained by phase change as a result of heating. All studied compounds were further characterized by IR spectroscopy, differential thermal analysis (DTA) and thermogravimetric analysis (TGA). The molecular self-assembly architectures are built by hydrogen bonds as O–H⋯N and N–H⋯O in ostarine, respectively O–H⋯O, N–H⋯O in andarine. Crystal packing energies were calculated using atom-atom force field method (London-Coulomb-Pauli, CLP) which involves the evaluation of Coulombic, polarization, dispersion and repulsion terms. Furthermore, Hirshfeld surface and fingerprint plot analysis was carried out in order to understand the presence of different intermolecular interactions and how hydrogen bonding holds the stability of the crystal structure.
Chapter
Muscle is the most abundant tissue in human body, and it can be atrophy when synthesis is inferior to degradation. Muscle atrophy is prevalent as it is a complication of many diseases. Besides its devastating effects on health, it also decreases life quality and increases mortality as well. This review provides an overview of muscle atrophy, including its prevalence, economic and health burden, and clinical therapy. Its clinical therapy includes exercise training, nutritional therapy, electrical stimulation, and drugs such as testosterone and ghrelin/IGF-1 analogues. More large-scale, long-term clinical trials are needed for therapies for muscle atrophy. In addition, more therapeutic targets are highly needed.
Article
Rationale: Selective androgen receptor modulators (SARMs) represent an emerging class of therapeutics targeting inter alia conditions referred to as cachexia and sarcopenia. Due to their anabolic properties, the use of SARMs is prohibited in sports as regulated by the World Anti-Doping Agency (WADA), and doping control laboratories test for these anabolic agents in blood and urine. In order to accomplish and maintain comprehensive test methods, the characterization of new drug candidates is critical for efficient sports drug testing. Hence, in the present study the mass spectrometric properties of the SARM YK-11 were investigated. Methods: YK-11 was synthesized according to literature data and three different stable-isotope-labeled analogs were prepared to support the mass spectrometric studies. Using high-resolution/high-accuracy mass spectrometry following electrospray ionization as well as electron ionization, the dissociation pathways of YK-11 were investigated, and characteristic features of its (product ion) mass spectra were elucidated. These studies were flanked by density functional theory (DFT) computation providing information on proton affinities of selected functional groups of the analyte. Results and conclusions: The steroidal SARM YK-11 was found to readily protonate under ESI conditions followed by substantial in-source dissociation processes eliminating methanol, acetic acid methyl ester, and/or ketene. DFT computation yielded energetically favored structures of the protonated species resulting from the aforementioned elimination processes particularly following protonation of the steroidal D-ring substituent. Underlying dissociation pathways were suggested, supported by stable-isotope labeling of the analyte, and diagnostic product ions for the steroidal nucleus and the D-ring substituent were identified. Further, trimethylsilylated YK-11 and its deuterated analogs were subjected to electron ionization high-resolution/high-accuracy mass spectrometry, complementing the dataset characterizing this new SARM. The obtained fragment ions resulted primarily from A/B- and C/D-ring structures of the steroidal nucleus, thus supporting future studies e.g. concerning metabolic pathways of the substance. Copyright © 2017 John Wiley & Sons, Ltd.
Article
Cachexia is defined as a complex metabolic syndrome associated with underlying illness that is characterized by the loss of body weight consisting of muscle and fat mass wasting. Sarcopenia is defined as the ageing related loss of muscle mass in health and disease that may not have an effect on body weight. As millions of patients are in cachectic or sarcopenic states, both conditions contribute to high numbers to death worldwide. A number of treatments have been proposed for cachexia and sarcopenia, but these are either in the preclinical stage or in clinical trials and hence not available to the general population. Particularly in cachexia there is a massive problem of recruiting patients for trials and also with the follow-up, due to the seriousness of the disease. This underlines the importance of well-characterized animal models. Obviously, most of the widely used cachexia and sarcopenia animal models have limitations in reproducibility of the condition and novel models are warranted in this context. The key findings of developing models in the field of cachexia and sarcopenia are that more types of the conditions have been taken into the researchers' interest. In cardiac cachexia, technical issues, which limit the preciseness and reproducibility in surgical heart failure models, have been overcome by a combination of surgery and the use of transgenic mouse models or salt sensitive rat models. Fatigue is the most pronounced symptom of cachexia and may be caused by reduced cardiac function independent of the underlying disease. Sarcopenia models often suffer from the use of young animals, due to the limited availability and very high costs of using aged animals. This review will focus on rodent models designed to mimic cachexia and sarcopenia including co-morbidities such as cancer, heart failure, as well as other diseases and conditions.
Article
To highlight the problems associated with nutrition that occur in patients with squamous cell carcinoma of the head and neck (SCCHN). SCCHN is associated with weight loss before, during and after radiotherapy or concurrent chemoradiotherapy. Because of serious consequences of malnutrition and cachexia on treatment outcome, mortality, morbidity, and quality of life, it is important to identify SCCHN patients with increased risk for the development of malnutrition and cachexia. Critical review of the literature. This review describes pathogenesis, diagnosis and treatment of malnutrition and cancer cachexia. Treatment of malnutrition and cancer cachexia includes nutritional interventions and pharmacological therapy. Advantages and disadvantages of different nutritional interventions and their effect on the nutritional status, quality of life and specific oncological treatment are presented. Nutritional management is an essential part of care of these patients, including early screening, assessment of nutritional status and appropriate intervention.
Article
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Atrophy occurs in specific muscles with inactivity (for example, during plaster cast immobilization) or denervation (for example, in patients with spinal cord injuries). Muscle wasting occurs systemically in older people (a condition known as sarcopenia); as a physiological response to fasting or malnutrition; and in many diseases, including chronic obstructive pulmonary disorder, cancer-associated cachexia, diabetes, renal failure, cardiac failure, Cushing syndrome, sepsis, burns and trauma. The rapid loss of muscle mass and strength primarily results from excessive protein breakdown, which is often accompanied by reduced protein synthesis. This loss of muscle function can lead to reduced quality of life, increased morbidity and mortality. Exercise is the only accepted approach to prevent or slow atrophy. However, several promising therapeutic agents are in development, and major advances in our understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting. Here, we discuss these new insights and the rationally designed therapies that are emerging to combat muscle wasting.
Article
ABSTRACT Muscle loss and wasting occurs with aging and in multiple disease states including cancer, heart failure, chronic obstructive pulmonary disease, end-stage liver disease, end-stage renal disease and HIV. Cachexia is defined as a multifactorial syndrome that is associated with anorexia, weight loss and increased catabolism, with increased morbidity and mortality. Currently no therapy is approved for the treatment or prevention of cachexia. Different treatment options have been suggested but many have proven to be ineffective or associated with adverse events. Nonsteroidal selective androgen receptor modulators (SARMs) are a new class of anabolic agents that bind the androgen receptor and exhibit tissue selectivity. Enobosarm (GTx-024, S-22) is a recently developed SARM, developed by GTx, Inc. (TN, USA), which has been tested in Phase I, II and III trials with promising results in terms of improving lean body mass and measurements of physical function and power. Enobosarm has received fast track designation by the US FDA and results from the Phase III trials POWER1 and POWER2 will help determine approval for use in the prevention and treatment of muscle wasting in patients with non-small-cell lung cancer. This article provides an introduction to enobosarm as a new therapeutic strategy for the prevention and treatment of cachexia. A review of the literature was performed using search terms 'cachexia', 'sarcopenia', 'SARM', 'enobosarm' and 'GTx-024' in September 2013 using multiple databases as well as online resources.
Article
Current evidence suggests that functional status is an important outcome of pharmacologic treatments in older people. At the moment, studies have shown diverse effects of medications on functional status. For example, some have shown potentially detrimental effects, while others have found improvements on physical function in elders. Overall, suboptimal prescribing and the occurrence of adverse drug reactions (ADRs) may negatively affect functional status. The use of selected drugs acting on central nervous system (CNS), e.g. benzodiazepines and antipsychotics, is generally associated with an increased risk of functional decline. The greater sensitivity of older people to these drugs, together with age-related changes in pharmacokinetics and pharmacodynamics, account for the observed detrimental effect and suggests a cautious approach to older and frail patients when prescribing CNS agents. On the other hand, selected drugs may slow or delay functional decline in older people. In particular, drugs aimed at targeting sarcopenia (loss in muscle mass and strength), such as testosterone in androgen deficiency, ACE-inhibitors, vitamin D and β-hydroxy β-methyl butyrate (HMB), as well as the recently developed selective androgen receptor modulators (SARMs) may hold extreme importance. This review will provide available evidence of the diverse impacts of drug medications on functional status in older persons.
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Sex steroid receptors are ligand-triggered transcription factors. Oestrogen, progesterone and androgen receptors form, together with the glucocorticoid and mineralocorticoid receptors, a subgroup of the superfamily of nuclear receptors. They share a common mode of action, namely translating a hormone—i.e. a small-molecule signal—from outside to changes in gene expression and cell fate, and thereby represent “natural” pharmacological targets. For pharmacological therapy, these receptors have originally been addressed by hormones and synthetic hormone analogues in order to overcome pathologies related to deficiencies in the natural ligands. Another major use for female sex hormone receptor modulators is oral contraception, i.e. birth control. On the other side, blocking the activity of sex steroid receptors has become an established way to treat hormone-dependent malignancies, such as breast and prostate cancer. In this review, we will discuss how the experience gained from the classical pharmacology of these receptors and their molecular similarities led to new options for the treatment of gender-specific diseases and highlight recent progress in medicinal chemistry of sex hormone-modulating drugs.
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We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rationalize the structure-activity relationship of the new fragment, we used molecular modeling to design a molecular library containing over 40 cycloalkane[d]isoxazole derivatives. The most potent compound, 4-(3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3-yl)-2-(trifluoromethyl)benzonitrile (6a), exhibits antiandrogenic activity significantly greater than that of the most widely used antiandrogenic prostate cancer drugs bicalutamide (1) and hydroxyflutamide (2) in reporter gene assays measuring the transcriptional activity of AR (decreasing approximately 90% of the total AR activity) and in competitive AR ligand-binding assays (showing over four times higher potency to inhibit radioligand binding in comparison to bicalutamide). Notably, 6a maintains its antiandrogenic activity with AR mutants W741L and T877A commonly observed and activated by bicalutamide and hydroxyflutamide, respectively, in prostate cancer patients.
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According to a recent consensus, cachexia is a complex metabolic syndrome associated with underlying illness and characterised by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss. Cachexia occurs in the majority of terminal cancer patients and it is responsible for the deaths of 22% of cancer patients. Although body weight is, indeed, an important factor to be taken into consideration in any cachexia treatment, body composition, physical performance and quality of life should be monitored. From the results presented here, one can speculate that a single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. The objectives of any therapeutical combination are two: an anticatabolic aim directed towards both fat and muscle catabolism and an anabolic objective leading to the synthesis of macromolecules such as contractile proteins.
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A chronic inflammatory state (CIS) commonly accompanies advanced cancers. Elements of a CIS include aberrant immune system activity and changes in hypothalamic-neuroendocrine control mechanisms. The end result is stimulation of tumour growth and metastases. In addition to tumour stimulation, cancer symptoms may be enhanced. While for most symptoms correlation with a CIS remains tenuous, clearly a CIS is linked to the aetiology of the cancer anorexia-cachexia syndrome. To date clinical studies aimed at a CIS are modest, but the increased understanding of the partnership of a CIS, cancer progression and anorexia-cachexia must lead to targeting a CIS in concert with conventional efforts to directly destroy tumour tissue.
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Drugs that promote anabolic processes with limited undesirable effects are of considerable therapeutic interest; some notable examples include those for the treatment of cancer cachexia and muscle-wasting diseases. Anabolic properties are not only therapeutically beneficial to critically ill and debilitated patients, but are also desirable to athletes seeking artificial enhancements in endurance, strength and accelerated recovery. The use of anabolic agents in the clinical setting is being reconsidered with the emergence of a new class of drugs referred to as SARMs (selective androgen receptor modulators). SARMs have the potential to complement or even replace anabolic androgenic steroidal use with the benefit of a reduction of the undesirable side effects associated with steroid administration alone. Arylpropionamide-based SARMs such as andarine (S-4) and S-22 have shown promising therapeutic properties and have attracted the interest of elite and amateur athletes despite the absence of clinical approval, and evidence for trafficking and misuse in sport has been obtained by doping control authorities.
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The androgens testosterone and dihydrotestosterone play an essential role in the development and maintenance of primary and secondary male characteristics. Androgens bind to a specific androgen receptor (AR), a ligand-dependent transcription factor which controls the expression of a large number of downstream target genes. The AR is an essential player in early and late prostate cancer, and may also be involved in some forms of breast cancer. It also represents a drug target for the treatment of hypogonadism. Recent studies furthermore indicate that targeting the AR in pathologies such as frailty syndrome, cachexia or polycystic ovary syndrome may have clinical benefit. Numerous AR ligands with very different pharmacological properties have been identified in the last 40 years and helped to treat several of these diseases. However, progress still needs to be made in order to find compounds with an improved profile with regard to efficacy, differentiation and side-effects. This will only be achieved through a better understanding of the mechanisms involved in normal and aberrant AR signaling.
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Cancer cachexia is a complex metabolic condition characterized by loss of skeletal muscle. Common clinical manifestations include muscle wasting, anemia, reduced caloric intake, and altered immune function, which contribute to increased disability, fatigue, diminished quality of life, and reduced survival. The prevalence of cachexia and the impact of this disorder on the patient and family underscore the need for effective management strategies. Dietary supplementation and appetite stimulation alone are inadequate to reverse the underlying metabolic abnormalities of cancer cachexia and have limited long-term impact on patient quality of life and survival. Therapies that can increase muscle mass and physical performance may be a promising option; however, there are currently no drugs approved for the prevention or treatment of cancer cachexia. Several agents are in clinical development, including anabolic agents, such as selective androgen receptor modulators and drugs targeting inflammatory cytokines that promote skeletal muscle catabolism.
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Glucocorticoids are the most widely used antiinflammatory drugs in the world. However, prolonged use of glucocorticoids results in undesirable side effects such as muscle wasting, osteoporosis, and diabetes. Skeletal muscle wasting, which currently has no approved therapy, is a debilitating condition resulting from either reduced muscle protein synthesis or increased degradation. The imbalance in protein synthesis could occur from increased expression and function of muscle-specific ubiquitin ligases, muscle atrophy F-box (MAFbx)/atrogin-1 and muscle ring finger 1 (MuRF1), or decreased function of the IGF-I and phosphatidylinositol-3 kinase/Akt kinase pathways. We examined the effects of a nonsteroidal tissue selective androgen receptor modulator (SARM) and testosterone on glucocorticoid-induced muscle atrophy and castration-induced muscle atrophy. The SARM and testosterone propionate blocked the dexamethasone-induced dephosphorylation of Akt and other proteins involved in protein synthesis, including Forkhead box O (FoxO). Dexamethasone caused a significant up-regulation in the expression of ubiquitin ligases, but testosterone propionate and SARM administration blocked this effect by phosphorylating FoxO. Castration induced rapid myopathy of the levator ani muscle, accompanied by up-regulation of MAFbx and MuRF1 and down-regulation of IGF-I, all of which was attenuated by a SARM. The results suggest that levator ani atrophy caused by hypogonadism may be the result of loss of IGF-I stimulation, whereas that caused by glucocorticoid treatment relies almost solely on up-regulation of MAFbx and MuRF1. Our studies provide the first evidence that glucocorticoid- and hypogonadism-induced muscle atrophy are mediated by distinct but overlapping mechanisms and that SARMs may provide a more effective and selective pharmacological approach to prevent glucocorticoid-induced muscle loss than steroidal androgen therapy.
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Limited proteolysis of in vitro produced human androgen receptor was used to probe the different conformations of the receptor after binding of androgens and several antiandrogens. The results provide evidence for five different conformations of the receptor, as detected by the formation of proteolysis resisting fragments: 1) an initial conformation of the unoccupied receptor not resisting proteolytic attack; and receptor conformations characterized by 2) a 35-kDa proteolysis resisting fragment spanning the ligand binding domain and part of the hinge region, obtained with most antagonists, and in an initial step after agonist binding; 3) a 29-kDa proteolysis resisting fragment spanning the ligand binding domain, obtained in the presence of agonists after an activation process; 4 and 5) 30- and 25-kDa fragments, derived from 2 and 3, but missing part of the C terminus, obtained with RU486 (RU486 has antiandrogenic properties, besides its effects as an antiprogestagen/antiglucocorticoid). Concomitantly with the change from 2 to 3 (and of 4 to 5 for RU486), dissociation of the 8 S complex of receptor with associated proteins occurred. With a mutant receptor (LNCaP cell mutation in C-terminal region), some antagonists activated transcription analogous to agonists, and induced the activated receptor conformation 3. A mutant lacking the C-terminal 12 amino acids bound RU486 but not androgens, and formed with RU486 conformation 5. These data imply that, after the initial rapid binding of ligand, androgens induce a conformational change of the receptor, a process that also involves release of associated proteins. RU486 induces an inappropriate conformation of the C-terminal end, similar as found for its effect on the progesterone receptor. In contrast, the other antiandrogens act at a different step in the mechanism of action: they do not induce an abnormal conformation, but act earlier and prevent a conformation change by stabilizing a complex with associated proteins.
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Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.
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Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.
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The aim of the present study was to summarise evidence from scientific studies on cancer anorexia-cachexia syndrome in order to assess and highlight the efficacy of high-dose progestins (megestrol acetate and medroxyprogesterone acetate) compared with placebo in patients with hormone-independent tumors. A systematic review of published randomised clinical trials was carried out by an extensive electronic and hand search through databases, relevant journals and books, congress, proceedings, reference lists, without any language or year of publication restriction. The research was conducted by two independent operators who collected the data in a form specifically designed for this review. Among the several possible outcomes, appetite and body weight were chosen. Fifteen randomised clinical trials (more than 2000 patients) were retrieved for the review. There was a statistically significant advantage for high-dose progestins as regards improved appetite: pooled odds ratio (OR) = 4.23, 95% confidence interval (CI): 2.53-7.04. Although the effect of high-dose progestins on body weight was less impressive, statistical significance was also reached for this outcome: pooled OR = 2.66, 95% CI: 1.80-3.92. Treatment morbidity was very low, due to the brief period of the treatment in most of the studies. The effects of high-dose progestins on appetite and body weight were clearly demonstrated. However, further studies are undoubtedly warranted to investigate other aspects of progestin activity, especially as regards dosage, duration and timing with best therapeutic index.
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Evidence for the effectiveness of corticosteroids in palliative care is anecdotal, and more information is required. From January to December 1999 a total of 376 consecutive patients admitted to a home palliative care program were longitudinally surveyed. Patients who started a corticosteroid treatment after admission on the basis of common indications prescribed by their home care physicians were selected. Fifty patients were enrolled in the study. Dexamethasone, in doses ranging from 4 to 16 mg, was the drug of choice. Corticosteroids were found to be effective in anorexia, weakness, headache, and nausea and vomiting. The reduction of symptom intensity was achieved in less than 3 days on average. However, no great advantages were found in terms of controlling drowsiness or confusional states associated with advanced illness because of cerebral involvement. It can be concluded from this study that: (a) corticosteroids may be effective in controlling anorexia, weakness, headache, and nausea and vomiting associated with cerebral involvement or bowel obstruction; (b) they should be stopped if no therapeutic effect has become evident within 3-5 days; (c) the treatment is not useful when given in the presence of severe neurological impairment resulting from the advanced stage of disease; (d) the range of adverse effects was acceptable for limited periods and in the circumstances in which the preparations were used in this study; and (e) corticosteroids may have an adjuvant role in potentiation of analgesic drugs. These findings will be very useful in the planning of future controlled studies designed to yield evidence-based data on the role of corticosteroids in the relief of specific symptoms.
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To determine whether dronabinol administered alone or with megestrol acetate was more, less, or equal in efficacy to single-agent megestrol acetate for palliating cancer-associated anorexia. Four hundred sixty-nine assessable advanced cancer patients were randomized to (1) oral megestrol acetate 800 mg/d liquid suspension plus placebo, (2) oral dronabinol 2.5 mg twice a day plus placebo, or (3) both agents. Eligible patients acknowledged that loss of appetite or weight was a problem and reported the loss of 5 pounds or more during 2 months and/or a daily intake of less than 20 calories/kg of body weight. Groups were comparable at baseline in age, sex, tumor type, weight loss, and performance status. A greater percentage of megestrol acetate-treated patients reported appetite improvement and weight gain compared with dronabinol-treated patients: 75% versus 49% (P =.0001) for appetite and 11% versus 3% (P =.02) for > or = 10% baseline weight gain. Combination treatment resulted in no significant differences in appetite or weight compared with megestrol acetate alone. The Functional Assessment of Anorexia/Cachexia Therapy questionnaire, which emphasizes anorexia-related questions, demonstrated an improvement in quality of life (QOL) among megestrol acetate-treated and combination-treated patients. The single-item Uniscale, a global QOL instrument, found comparable scores. Toxicity was also comparable, with the exception of an increased incidence of impotence among men who received megestrol acetate. In the doses and schedules we studied, megestrol acetate provided superior anorexia palliation among advanced cancer patients compared with dronabinol alone. Combination therapy did not appear to confer additional benefit.
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Androgens are involved in the development of prostate cancer. Finasteride, an inhibitor of 5alpha-reductase, inhibits the conversion of testosterone to dihydrotestosterone, the primary androgen in the prostate, and may reduce the risk of prostate cancer. In the Prostate Cancer Prevention Trial, we randomly assigned 18,882 men 55 years of age or older with a normal digital rectal examination and a prostate-specific antigen (PSA) level of 3.0 ng per milliliter or lower to treatment with finasteride (5 mg per day) or placebo for seven years. Prostate biopsy was recommended if the annual PSA level, adjusted for the effect of finasteride, exceeded 4.0 ng per milliliter or if the digital rectal examination was abnormal. It was anticipated that 60 percent of participants would have prostate cancer diagnosed during the study or would undergo biopsy at the end of the study. The primary end point was the prevalence of prostate cancer during the seven years of the study. Prostate cancer was detected in 803 of the 4368 men in the finasteride group who had data for the final analysis (18.4 percent) and 1147 of the 4692 men in the placebo group who had such data (24.4 percent), for a 24.8 percent reduction in prevalence over the seven-year period (95 percent confidence interval, 18.6 to 30.6 percent; P<0.001). Tumors of Gleason grade 7, 8, 9, or 10 were more common in the finasteride group (280 of 757 tumors [37.0 percent], or 6.4 percent of the 4368 men included in the final analysis) than in the placebo group (237 of 1068 tumors [22.2 percent], P<0.001 for the comparison between groups; or 5.1 percent of the 4692 men included in the final analysis, P=0.005 for the comparison between groups). Sexual side effects were more common in finasteride-treated men, whereas urinary symptoms were more common in men receiving placebo. Finasteride prevents or delays the appearance of prostate cancer, but this possible benefit and a reduced risk of urinary problems must be weighed against sexual side effects and the increased risk of high-grade prostate cancer.
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N-3 fatty acids, especially eicosapentaenoic acid (EPA), may possess anticachectic properties. This trial compared a protein and energy dense supplement enriched with n-3 fatty acids and antioxidants (experimental: E) with an isocaloric isonitrogenous control supplement (C) for their effects on weight, lean body mass (LBM), dietary intake, and quality of life in cachectic patients with advanced pancreatic cancer. A total of 200 patients (95 E; 105 C) were randomised to consume two cans/day of the E or C supplement (480 ml, 620 kcal, 32 g protein +/- 2.2 g EPA) for eight weeks in a multicentre, randomised, double blind trial. At enrolment, patients' mean rate of weight loss was 3.3 kg/month. Intake of the supplements (E or C) was below the recommended dose (2 cans/day) and averaged 1.4 cans/day. Over eight weeks, patients in both groups stopped losing weight (delta weight E: -0.25 kg/month versus C: -0.37 kg/month; p = 0.74) and LBM (Delta LBM E: +0.27 kg/month versus C: +0.12 kg/month; p = 0.88) to an equal degree (change from baseline E and C, p<0.001). In view of evident non-compliance in both E and C groups, correlation analyses were undertaken to examine for potential dose-response relationships. E patients demonstrated significant correlations between their supplement intake and weight gain (r = 0.50, p<0.001) and increase in LBM (r = 0.33, p = 0.036). Such correlations were not statistically significant in C patients. The relationship of supplement intake with change in LBM was significantly different between E and C patients (p = 0.043). Increased plasma EPA levels in the E group were associated with weight and LBM gain (r = 0.50, p<0.001; r = 0.51, p = 0.001). Weight gain was associated with improved quality of life (p<0.01) only in the E group. Intention to treat group comparisons indicated that at the mean dose taken, enrichment with n-3 fatty acids did not provide a therapeutic advantage and that both supplements were equally effective in arresting weight loss. Post hoc dose-response analysis suggests that if taken in sufficient quantity, only the n-3 fatty acid enriched energy and protein dense supplement results in net gain of weight, lean tissue, and improved quality of life. Further trials are required to examine the potential role of n-3 enriched supplements in the treatment of cancer cachexia.
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1: S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (also known as S-4) is a non-steroidal selective androgen receptor modulator demonstrating tissue-selective androgenic and anabolic effects. The purpose of the present study was to examine the systemic pharmacokinetics, elimination and oral bioavailability of S-4 in rats. 2: Thirty-five male Sprague-Dawley rats weighing approximately 250 g were randomly assigned to one of seven treatment groups. Intravenous doses of 0.5, 1, 10, and 30 mg kg(-1) were given via a jugular catheter. Oral doses of 1, 10 and 30 mg kg(-1) were administered via gavage. Plasma concentrations were determined using a validated high-performance liquid chromatography or by a high-performance liquid chromatography/mass spectrometry method. 3: Clearances ranged between 1.0 and 2.1 ml min(-1) kg(-1) and varied with dose. The volume of distribution was approximately 0.448 l kg(-1) in all treatment groups. Oral bioavailability was also dose dependent, with the lower doses showing complete oral bioavailability. The half-life of S-4 over the dose range tested was between 2.6 and 5.3 h. 4: It was demonstrated that S-4 is rapidly absorbed, slowly cleared, and has a moderate volume of distribution in rats. The pharmacokinetics and oral bioavailability of S-4 indicate that it is an excellent candidate for clinical development.
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Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5alpha-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5alpha-reductase (Ki, >20 microm) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5alpha-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH.
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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.
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The partial agonist activity of a selective androgen receptor modulator (SARM) in the prostate was demonstrated in orchidectomized rats. In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (a structurally related SARM referred to in other publications and hereafter as S-4) in skeletal muscle, bone, and pituitary of castrated male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 wk. S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were also observed in DHT-treated (3 mg/kg) animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights more than 2-fold greater than that observed in intact controls, whereas S-4 (3 mg/kg) returned these androgenic organs to only 16 and 17%, respectively, of the control levels. S-4 (3 and 10 mg/kg) and DHT (3 mg/kg) restored castration-induced loss in lean body mass. Furthermore, S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. S-4 (3 and 10 mg/kg) also demonstrated agonist activity in the pituitary and significantly decreased plasma LH and FSH levels in castrated animals in a dose-dependent manner. In summary, the strong anabolic effects of S-4 in skeletal muscle, bone, and pituitary were achieved with minimal pharmacologic effect in the prostate. The tissue-selective pharmacologic activity of SARMs provides obvious advantages over steroidal androgen therapy and demonstrates the promising therapeutic utility that this new class of drugs may hold.
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Cancer cachexia is characterized by skeletal muscle wasting that is mainly supported by hypercatabolism. Muscle atrophy has been suggested to depend on impaired IGF-1 signal transduction pathway. The present study has been aimed at investigating the IGF-1 system in rats bearing the AH-130 hepatoma, a well-characterized model of cachexia. IGF-1 mRNA expression in the gastrocnemius of tumor hosts progressively decreases to approximately 50% of controls. By contrast, both IGF-1 receptor and insulin receptor mRNA levels increase in day 7 AH-130 hosts. IGF-1 and insulin circulating levels, as well as IGF-1 expression in the liver, are reduced. Muscle wasting in the AH-130 bearers is associated with hyperactivation of the ubiquitin-proteasome system. Consistently, the mRNA levels of ubiquitin and of the ubiquitin ligases atrogin-1 and MuRF1 are significantly increased in the gastrocnemius of day 7 AH-130 hosts. Exogenous IGF-1 administered to tumor bearers does not prevent cachexia. IGF-1 mRNA levels also have been evaluated in the gastrocnemius of AH-130 hosts treated with pentoxifylline, an inhibitor of TNF-alpha synthesis, alone or combined with formoterol, a beta(2)-adrenergic agonist. Both treatments partially correct muscle atrophy without modifying IGF-1 and atrogin-1 mRNA levels, whereas MuRF1 hyperexpression is reduced by the combination of pentoxifylline with formoterol. These results demonstrate for the first time that the IGF-1 system is downregulated in cancer cachexia, although the underlying mechanism remains unknown. Moreover, no simple relation linking IGF-1 and/or atrogin-1 mRNA levels and muscle atrophy could be observed in these experimental conditions. Further studies are thus needed to clarify both issues.
Article
Background: Cancer cachexia is a multifactorial syndrome that is poorly defined. Objective: Our objective was to evaluate whether a 3-factor profile incorporating weight loss (≥10%), low food intake (≤1500 kcal/d), and systemic inflammation (C-reactive protein ≥ 10 mg/L) might relate better to the adverse functional aspects of cachexia and to a patient’s overall prognosis than will weight loss alone. Design: One hundred seventy weight-losing (≥5%) patients with advanced pancreatic cancer were screened for nutritional status, functional status, performance score, health status, and quality of life. Patients were followed for a minimum of 6 mo, and survival was noted. Patients were characterized by using the individual factors, ≥2 factors, or all 3 factors. Results: Weight loss alone did not define a population that differed in functional aspects of self-reported quality of life or health status and differed only in objective factors of physical function. The 3-factor profile identified both reduced subjective and objective function. In the overall population, the 3 factors, ≥2 factors, and individual profile factors (except weight loss) all carried adverse prognostic significance (P < 0.01). Subgroup analysis showed that the 3-factor profile carried adverse prognostic significance in localized (hazard ratio: 4.9; P < 0.001) but not in metastatic disease. Conclusions: Weight loss alone does not identify the full effect of cachexia on physical function and is not a prognostic variable. The 3-factor profile (weight loss, reduced food intake, and systemic inflammation) identifies patients with both adverse function and prognosis. Shortened survival applies particularly to cachectic patients with localized disease, thereby reinforcing the need for early intervention.
Article
PURPOSE: To determine whether dronabinol administered alone or with megestrol acetate was more, less, or equal in efficacy to single-agent megestrol acetate for palliating cancer-associated anorexia. PATIENTS AND METHODS: Four hundred sixty-nine assessable advanced cancer patients were randomized to (1) oral megestrol acetate 800 mg/d liquid suspension plus placebo, (2) oral dronabinol 2.5 mg twice a day plus placebo, or (3) both agents. Eligible patients acknowledged that loss of appetite or weight was a problem and reported the loss of 5 pounds or more during 2 months and/or a daily intake of less than 20 calories/kg of body weight. RESULTS: Groups were comparable at baseline in age, sex, tumor type, weight loss, and performance status. A greater percentage of megestrol acetate-treated patients reported appetite improvement and weight gain compared with dronabinol-treated patients: 75% versus 49% (P = .0001) for appetite and 11% versus 3% (P = .02) for ≥ 10% baseline weight gain. Combination treatment resulted in no significant differences in appetite or weight compared with megestrol acetate alone. The Functional Assessment of Anorexia/Cachexia Therapy questionnaire, which emphasizes anorexia-related questions, demonstrated an improvement in quality of life (QOL) among megestrol acetate–treated and combination-treated patients. The single-item Uniscale, a global QOL instrument, found comparable scores. Toxicity was also comparable, with the exception of an increased incidence of impotence among men who received megestrol acetate. CONCLUSION: In the doses and schedules we studied, megestrol acetate provided superior anorexia palliation among advanced cancer patients compared with dronabinol alone. Combination therapy did not appear to confer additional benefit.
Article
Purpose: To determine whether high doses of fish oil, administered over 2 weeks, improve symptoms in patients with advanced cancer and decreased weight and appetite. Patients and Methods: Sixty patients were randomly assigned to fish oil capsules or placebo. Appetite, tiredness, nausea, well-being, caloric intake, nutritional status, and function were prospectively assessed at days 1 and 14. Results: The baseline weight loss was 16 ± 11 and 16 ± 8 kg in the fish oil (n = 30) and placebo (n = 30) group respectively, whereas the baseline appetite (0 mm = best and 10 mm = worst) was 58 ± 24 mm and 67 ± 19 mm, respectively (P = not significant). The mean daily dose was 10 ± 4 (fish oil group) and 9 ± 3 (placebo group) capsules, which provided 1.8 g of eicosapentaenoic acid and 1.2 g of docosahexaenoic acid in the fish oil group. No significant differences in symptomatic or nutritional parameters were found (P < .05), and there was no correlation between changes in different variables between days 1 and 14 and the fish oil doses. Finally, the majority of the patients were not able to swallow more than 10 fish oil capsules per day, mainly because of burping and aftertaste. Conclusion: Fish oil did not significantly influence appetite, tiredness, nausea, well-being, caloric intake, nutritional status, or function after 2 weeks compared with placebo in patients with advanced cancer and loss of both weight and appetite.
Article
The androgen receptor (AR) is a nuclear hormone receptor that, upon binding to testosterone, dihydrotestosterone (DHT) and other endogenous androgens, supports the development, growth and maintenance of masculine features through activation of anabolic and androgenic metabolism. The AR has been demonstrated to be a productive therapeutic target. AR ligands in clinical practice include androgenic steroids, antiandrogenic steroids and antiandrogenic nonsteroidals. Of primary importance for this review are nonsteroidal selective AR modulators (SARMs) that have tissue-specific agonist and/or antagonist activities. The AR has a myriad of peripheral and central functions that can be modulated in a pleiotropic and tissue-specific fashion using the increasingly diverse collection of SARMs discussed herein. This suggests that SARMs will have a high level of clinical utility for a wide variety of health conditions. The patent literature focusing on SARMs is reviewed and reveals multiple chemical classes in various stages of preclinical and clinical development. Emphasis is placed on selected disease states for which SARMs show potential for therapeutic use in clinical practice.
Article
Anorexia, cachexia, and resultant weight loss are major clinical problems in a substantial proportion of patients with advanced cancer. Effective means of alleviating these problematic symptoms are lacking. Extensive clinical data demonstrate a weight enhancing effect for the serotonin antagonist, cyproheptadine, in several clinical situations. In addition, sound basic research suggests that cyproheptadine may be helpful in patients with cancer anorexia/cachexia. Because of this, the authors performed a randomized, placebo-controlled, double-blinded clinical trial using cyproheptadine, 8 mg orally three times a day in 295 patients with advanced malignant disease. Patients assigned to cyproheptadine had less nausea (P = 0.02), less emesis (P = 0.11), more sedation (P = 0.07), and more dizziness (P = 0.01) than placebo patients. Patients' appetites, measured by serial patient-completed questionnaires, appeared to be mildly enhanced by cyproheptadine. Unfortunately, cyproheptadine did not significantly abate progressive weight loss in these patients with advanced malignant disease; patients assigned to cyproheptadine lost an average of 4.5 pounds per month compared to 4.9 pounds per month for patients assigned to a placebo (P = 0.72).
Article
Nonsteroidal androgens have not been reported. During studies to identify affinity ligands for the androgen receptor in our laboratory, we synthesized several electrophilic nonsteroidal ligands for the androgen receptor and examined their receptor binding affinity and ability to stimulate receptor-mediated transcriptional activation. We found that three of these ligands (1) bound the androgen receptor with affinity similar to that of dihydrotestosterone (the endogenous ligand) and (2) mimicked the effects of dihydrotestosterone on receptor-mediated transcriptional activation (i.e., they were receptor agonists). These studies demonstrate that nonsteroidal ligands can be structurally modified to produce agonist activity. These ligands thus represent the first members of a novel class of androgens with potential therapeutic applications in male fertility and hormone replacement therapy.
Article
Anabolic agents have been among the most frequently detected drugs in amateur and professional sport. A novel class of therapeutics presumably complementing anabolic steroids in the near future includes so-called selective androgen receptor modulators (SARMs) that have been under clinical investigations for several years. Although not yet commercially available, their potential for misuse in sports is high. Four aryl-propionamide-derived SARMs were synthesized in order to establish a fast and robust screening procedure using liquid chromatography/electrospray ionization tandem mass spectrometry. Synthesized compounds were characterized by high-resolution/high-accuracy mass analysis employing a linear ion trap-Orbitrap hybrid mass spectrometer while routine analyses were conducted on a triple-quadrupole mass spectrometer. Characteristic product ions obtained by collision-induced dissociation were found at m/z 289 and 261 as well as m/z 269 and 241 representing the bisubstituted aniline residues of selected model compounds. Assay validation was performed regarding lower limit of detection (1 ng/mL), recovery (85-105%), intraday precision (7.6-11.6%) and interday precision (9.9-14.4%), and precursor ion scan experiments on diagnostic product ions enabled the detection of a structurally related compound at 50 ng/mL.
Article
The past decade has witnessed an unprecedented discovery effort to develop selective androgen receptor modulators (SARMs) that improve physical function and bone health without adversely affecting the prostate and cardiovascular outcomes. This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity. Although steroidal SARMs have been around since the 1940s, a number of nonsteroidal SARMs that do not serve as substrates for CYP19 aromatase or 5alpha-reductase, act as full agonists in muscle and bone and as partial agonists in prostate are in development. The differing interactions of steroidal and nonsteroidal compounds with androgen receptor (AR) contribute to their unique pharmacologic actions. Ligand binding induces specific conformational changes in the ligand-binding domain, which could modulate surface topology and protein-protein interactions between AR and coregulators, resulting in tissue-specific gene regulation. Preclinical studies have demonstrated the ability of SARMs to increase muscle and bone mass in preclinical rodent models with varying degree of prostate sparing. Phase I trials of SARMs in humans have reported modest increments in fat-free mass. SARMs hold promise as a new class of function promoting anabolic therapies for a number of clinical indications, including functional limitations associated with aging and chronic disease, frailty, cancer cachexia, and osteoporosis.
Article
To review current knowledge of the relationship between cytokines, the acute phase response (APR) and the development of cachexia. Cytokines important in the initiation of the APR are also important in the genesis of cachexia. The presence of an APR or high circulating levels of pro-inflammatory cytokines are known to be related to adverse outcome in cancer patients. Studies of host cytokine genotype have demonstrated that specific host cytokine polymorphisms are associated with both the development of cachexia and reduced patient survival. The desire to be able to predict accurately survival in cancer patients has led to the description of various APR-based prognostic scoring systems. Cachexia is an important clinical problem affecting up to two thirds of cancer patients. It results from anorexia and metabolic change and leads to loss of both adipose tissue and lean body mass, particularly in the skeletal muscle compartment. An APR is seen in half of cancer patients at presentation, and is most often determined clinically by raised plasma C-reactive protein concentrations. Adverse outcome and shortened survival have been linked to the presence of an APR. This article explores the cause and consequences of the APR in cancer cachexia.
Article
On December 13th and 14th a group of scientists and clinicians met in Washington, DC, for the cachexia consensus conference. At the present time, there is no widely agreed upon operational definition of cachexia. The lack of a definition accepted by clinician and researchers has limited identification and treatment of cachectic patient as well as the development and approval of potential therapeutic agents. The definition that emerged is: "cachexia, is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance and increased muscle protein breakdown are frequently associated with cachexia. Cachexia is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity. While this definition has not been tested in epidemiological or intervention studies, a consensus operational definition provides an opportunity for increased research.
Article
The short term addition of nandrolone decanoate to combination chemotherapy given to patients with unresectable non-small cell lung cancer was evaluated in a randomized, prospective trial. Patients were treated with doxorubicin 50 mg/M2 intravenously, cyclophosphamide 300 mg/M2 intravenously, CCNU 50 mg/M2 orally, vincristine 1.4 mg/M2 intravenously, with and without cisplatin 50 mg/M2 intravenously, all given every 28 days. In addition, patients were randomized to receive either nandrolone decanoate 200 mg intramuscularly weekly for 4 weeks or no additional therapy. Patient age, disease extent, performance score, and pretreatment weight loss were similar in the two treatment arms. Objective antitumor response frequency was comparable on both treatment arms with median survival somewhat longer for patients receiving the androgen (median survival 5.5 months without and 8.2 months with nandrolone decanoate). There was a trend for less severe weight loss on the nandrolone decanoate arm (average weight loss 0.8 +/- 0.15 kg versus 0.21 +/- 0.18 kg, respectively), with half as many patients experiencing weight loss on nandrolone decanoate (25% versus 12%). A separate concurrent study has demonstrated decreased free testosterone levels in 66% of patients with advanced cancer studied prior to chemotherapy treatment, therefore, further prospective studies in which pretreatment testosterone levels are used to guide androgen administration are needed to define more precisely a role for androgen replacement therapy in non-small cell lung cancer.
Article
Limited proteolysis of in vitro produced human androgen receptor was used to probe the different conformations of the receptor after binding of androgens and several antiandrogens. The results provide evidence for five different conformations of the receptor, as detected by the formation of proteolysis resisting fragments: 1) an initial conformation of the unoccupied receptor not resisting proteolytic attack; and receptor conformations characterized by 2) a 35-kDa proteolysis resisting fragment spanning the ligand binding domain and part of the hinge region, obtained with most antagonists, and in an initial step after agonist binding; 3) a 29-kDa proteolysis resisting fragment spanning the ligand binding domain, obtained in the presence of agonists after an activation process; 4 and 5) 30- and 25-kDa fragments, derived from 2 and 3, but missing part of the C terminus, obtained with RU486 (RU486 has antiandrogenic properties, besides its effects as an antiprogestagen/antiglucocorticoid). Concomitantly with the change from 2 to 3 (and of 4 to 5 for RU486), dissociation of the 8 S complex of receptor with associated proteins occurred. With a mutant receptor (LNCaP cell mutation in C-terminal region), some antagonists activated transcription analogous to agonists, and induced the activated receptor conformation 3. A mutant lacking the C-terminal 12 amino acids bound RU486 but not androgens, and formed with RU486 conformation 5. These data imply that, after the initial rapid binding of ligand, androgens induce a conformational change of the receptor, a process that also involves release of associated proteins. RU486 induces an inappropriate conformation of the C-terminal end, similar as found for its effect on the progesterone receptor. In contrast, the other antiandrogens act at a different step in the mechanism of action: they do not induce an abnormal conformation, but act earlier and prevent a conformation change by stabilizing a complex with associated proteins.
Article
Based on evidence that suggests pentoxifylline can inhibit tumor necrosis factor, we set out to evaluate the activity and toxicity of this drug in patients with cancer-associated anorexia and/or cachexia. Seventy patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 with cancer anorexia and/or cachexia (defined by a weight loss of > or = 5 lb in the preceding 2 months or a caloric intake < 20 kcal/kg/d) were stratified and then randomly assigned to receive pentoxifylline or identical-appearing placebo tablets in a double-blind fashion. Patients' weights were monitored and patient questionnaires were used to assess appetite, toxicity, and perception of benefit. Pentoxifylline failed to improve the appetites of study patients. Pentoxifylline did not appear to cause any toxicity. This study failed to demonstrate any benefit of pentoxifylline at this dose and schedule as therapy for cancer anorexia and/or cachexia.
Article
The aim of this study was to demonstrate significant factors behind elevated resting energy expenditure in weight-losing cancer patients. Therefore, weight-losing cancer patients (n = 60), with normal liver and kidney function tests, were randomized to receive one of four drug treatments for 5 days: (a) Propranolol 80 mg x 2 (beta-adrenoceptor blockade); (b) Indomethacin 50 mg x 2 (prostaglandin synthesis inhibition); (c) Morphine 5 mg x 3 (pain relief) or (d) Placebo x 2. A reference group of healthy well-nourished individuals were examined outside the formal randomization protocol and they received Propranolol 80 mg x 2. The cancer patients were randomized by a computer based algorithm stratifying for measured resting energy expenditure (REE), body composition, biochemical tests, previous therapy, tumour type and tumour stage. Resting energy expenditure was measured by indirect calorimetry in the morning after an overnight fast before and after drug treatment. beta-blockade reduced REE significantly in cancer patients from 1416 +/- 95 kcal day-1 to 1160 +/- 63 kcal day-1 (P < 0.02) and from 1472 +/- 69 vs, 1398 +/- 63 kcal day-1 (P < 0.01) in the well-nourished reference individuals. The reduction found in cancer patients (10%) was significantly larger than that in the group of reference patients (5%), (P < 0.01). Indomethacin, morphine or placebo did not induce any significant alteration in energy expenditure in our cancer patients. Propranolol treatment was associated with a significant reduction in plasma concentrations of free fatty acids (FFA), but not in plasma glycerol.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Previous double-blind, placebo-controlled, randomized clinical trials have demonstrated that both corticosteroids and progestational agents do partially alleviate cancer anorexia/cachexia. Pilot information suggested that an anabolic corticosteroid might also improve appetite in patients with cancer anorexia/cachexia. The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia. Patients suffering from cancer anorexia/cachexia were randomized to receive either dexamethasone 0. 75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid. Patients were observed at monthly intervals to evaluate weight changes and drug toxicity. Patients also completed questionnaires at baseline and at monthly intervals to evaluate appetite and drug toxicities. Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P =.03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P =.06). Whereas fluoxymesterone clearly seems to be an inferior choice for treating cancer anorexia/cachexia, megestrol acetate and dexamethasone have similar appetite stimulating efficacy but differing toxicity profiles.
Article
Despite the fact that there are only a few controlled trials demonstrating the benefits associated with the use of corticosteroids in specific situations, these agents are administered frequently to patients with advanced cancer. Corticosteroids may be used alone or as adjuvants in combination with other palliative or antineoplastic treatments. For example, corticosteroids may help prevent nausea, vomiting, and hypersensitivity reactions to treatment with chemotherapy or radiation. They are also commonly used as appetite stimulants in patients with advanced cancer. In the adjuvant setting, corticosteroids help to alleviate pain in advanced cancer patients, including specific situations such as back pain related to epidural compression. This article reviews the evidence supporting the use of corticosteroids in a broad range of situations seen in patients with advanced cancer.
Article
Cachexia is common in patients with advanced cancer and has a direct impact on well-being and mortality. To test the hypothesis that thalidomide can promote weight gain and lean body mass in patients with advanced oesophageal cancer. In an open-label study, 11 patients with non-obstructing and inoperable oesophageal cancer were established on an isocaloric diet for 2 weeks, followed by 2 weeks on thalidomide, 200 mg daily. The primary end-points were weight change and lean body mass. Secondary end-points were quality of life and changes in resting energy expenditure. Ten patients completed the study protocol. The average caloric intake remained the same throughout the study period in all patients. Nine of 10 patients (95% confidence interval, 0.60, 0.98) lost weight on diet alone. The mean weight gain on thalidomide in the following 2 weeks was 1.29 kg (median, 1.25 kg). A similar trend was shown in the lean body mass. Eight of nine patients (95% confidence interval, 0.57, 0.98) initially lost lean body mass on diet alone (missing data in one patient). The mean gain in lean body mass on thalidomide in the following 2 weeks was 1.75 kg (median, 1.33 kg). Thalidomide treatment appeared to reverse the loss of weight and lean body mass over the 2-week trial period.
Article
Advanced cancer patients are polysymptomatic and often receive multiple medications for symptom relief. Common symptoms include anorexia, weight loss, delirium and depression. Olanzapine and mirtazapine may have several advantages over older agents despite increased acquisition costs. Both medications can treat several symptoms with a low risk for drug-drug interactions and with only once- or twice-daily dosing. Drug side effects are low, compared with more conventionally used agents. The pharmacokinetics and pharmacodynamics of both agents are unique and explain many of the benefits. More research and clinical experience will be necessary to define their role in the palliation of advanced cancer.
Article
In a single-blind, placebo-controlled study, the effects of a 3-month oral administration of 160 mg/day testosterone undecanoate (Andriol) on the quality of life of men with testosterone deficiency were evaluated. The subjects included ten men with primary hypogonadism and 29 with andropause with sexual dysfunction as the most common problem. The changes in subjective symptoms were evaluated by the PNUH QoL scoring system and the St. Louis University Questionnaire for androgen deficiency in aging males (ADAM). Digital rectal examination (DRE) was performed and serum testosterone, prostate-specific antigen (PSA) and liver profile were monitored. Testosterone undecanoate treatment (n = 33) significantly improved sexual dysfunction and symptom scores of metabolic, cardiopulmonary, musculoskeletal and gastrointestinal functions compared to baseline and to placebo (n = 6). ADAM score also significantly improved after 3 months of treatment. Serum testosterone was significantly increased compared to pretreatment levels only in the testosterone undecanoate group. In the placebo group, no significant changes compared to baseline were found for testosterone levels and QoL questionnaires. No abnormal findings were detected on DRE or laboratory findings in either group. Adverse events, such as gastrointestinal problems and fatigue, were mild and self-limiting. It is concluded that androgen supplement therapy with oral testosterone undecanoate (Andriol) restores the quality of life through improvement of general body functions in men with testosterone deficiency.
Article
A number of environmental and industrial chemicals are reported to possess androgenic or antiandrogenic activities. These androgenic endocrine disrupting chemicals may disrupt the endocrine system of humans and wildlife by mimicking or antagonizing the functions of natural hormones. The present study developed a low cost recombinant androgen receptor (AR) competitive binding assay that uses no animals. We validated the assay by comparing the protocols and results from other similar assays, such as the binding assay using prostate cytosol. We tested 202 natural, synthetic, and environmental chemicals that encompass a broad range of structura