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Xenobiotica; the Fate of Foreign... Oct 20181. There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for...
1. There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for identifying specific drug-metabolizing enzymes. We determined the cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) that metabolize MA, identified oxidative metabolites and determined pharmacologic activity at the progesterone, androgen and glucocorticoid receptors (PR, AR and GR, respectively). 2. Oxidative metabolites were produced using human liver microsomes (HLMs), and isolated for mass spectral (MS) and nuclear magnetic resonance (NMR) analyses. We screened recombinant P450s using MA at 62 μM (HLM K for metabolite 1; M1) and 28 μM (HLM K for metabolite 2; M2). UGT isoforms were simultaneously incubated with UDPGA, nicotinamide adenine dinucleotide phosphate (NADPH), CYP3A4 and MA. Metabolites were evaluated for pharmacologic activity on the PR, AR and GR. CYP3A4 and CYP3A5 are responsible for oxidative metabolism of 62 μM MA. 3. At 28 μM substrate concentration, CYP3A4 was the only contributing enzyme. Mass spectral and NMR data suggest metabolism of MA to two alcohols. After oxidation, MA is converted into two secondary glucuronides by UGT2B17 among other UGTs. MA, M1 and M2 had significant pharmacologic activity on the PR while only MA showed activity on the AR and GR.
Topics: Cell Line, Tumor; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Glucuronides; Humans; Ketoconazole; Kinetics; Megestrol Acetate; Metabolome; Microsomes, Liver; Oxidation-Reduction; Prostate-Specific Antigen; Proton Magnetic Resonance Spectroscopy; Receptors, Cytoplasmic and Nuclear; Recombinant Proteins; Substrate Specificity; Troleandomycin
PubMed: 29050522
DOI: 10.1080/00498254.2017.1386335 -
Journal of Pain and Symptom Management Apr 2004This study aimed to assess the efficacy and safety of megestrol acetate (MA) in anorexia-cachexia syndrome (ACS). Literature and relevant databases were searched for... (Review)
Review
This study aimed to assess the efficacy and safety of megestrol acetate (MA) in anorexia-cachexia syndrome (ACS). Literature and relevant databases were searched for randomized controlled trials of MA to treat ACS in patients with cancer, AIDS, or other pathologies. Data were extracted by two independent reviewers, and meta-analyses were performed where possible. Twenty-six studies were included (n=3,887). Compared to placebo, MA increased appetite in oncology patients [RR=2.31 (95% CI 1.52-3.59)], led to weight gain [RR=1.88 (95% CI 1.43-2.47)] and improved HRQOL [RR=1.52 (95% CI 1.00-2.30)]. In AIDS patients, it increased weight [RR=2.16 (95% CI 1.45-3.21)]. MA showed significant benefits over dronabinol in improving appetite, but no statistically significant advantages over other drugs for treating ACS were observed. There were no appreciable differences between lower (<800 mg/day) and higher (>800 mg/day) doses of MA. Few serious adverse events were recorded. MA is an effective and safe treatment for ACS in cancer and AIDS patients, particularly in terms of improvement in appetite and weight gain.
Topics: Anorexia; Cachexia; Humans; Megestrol Acetate; Randomized Controlled Trials as Topic; Syndrome; Treatment Outcome
PubMed: 15050664
DOI: 10.1016/j.jpainsymman.2003.09.007 -
Journal of Cancer Research and... 2020Anorexia and cachexia are major clinical problems seen in a large proportion of patients with advanced cancer. Weight loss has also been identified as an indicator of... (Review)
Review
Anorexia and cachexia are major clinical problems seen in a large proportion of patients with advanced cancer. Weight loss has also been identified as an indicator of poor prognosis in cancer patients. Around 20% of patients with advanced cancer present mortality from the effects of malnutrition rather than from cancer itself. Early nutrition intervention has seen to improve outcomes in cancer patients such as weight gain, treatment tolerance, and improved quality of life (QoL). Effective therapies for addressing these threatening conditions are lacking. Pharmacotherapeutic agents such as corticosteroids, megestrol acetate, and cyproheptadine have several adverse reactions and also lack satisfactory results. Rasayana therapy is known to prevent loss of body mass and at the same time help to improve appetite and increase patient's QoL. The Rasayana compound used by us to prevent cachexia mainly includes swarna sindoor, Hirak bhasma, and suvarna bhasma. To evaluate benefits of Rasayana therapy on these variables, we maintain complete documentation of different clinical variables in all cancer patients. Here, in this observational study, we analyzed the data collected from a group of stage IV breast cancer patients (n = 30) receiving Rasayana therapy. Patients were followed at an interval of every 15 days from baseline for 3 months. Furthermore, at each visit, there weight was recorded on calibrated digital weight balance. QoL in these patients was recorded at quarterly interval using functional assessment of cancer therapies questionnaire. It was seen that in the duration of 3 months patients appetite increased significantly (P = 0.03). Significant weight gain was seen in patients (P = 0.04). Significant improvement was also seen in QoL especially related to QoL subdomains of physical wellbeing (P = 0.01), emotional wellbeing (P < 0.04), and functional wellbeing (P < 0.001). Rasayana therapy was seen to be well tolerated by all patients.
Topics: Anorexia; Appetite; Breast Neoplasms; Cachexia; Female; Humans; Medicine, Ayurvedic; Middle Aged; Quality of Life; Retrospective Studies; Surveys and Questionnaires; Weight Gain
PubMed: 33342775
DOI: 10.4103/jcrt.JCRT_96_20 -
Breast Cancer Research : BCR Apr 2012While metastatic breast cancer (MBC) remains incurable, a vast array of active therapeutic agents has provided the opportunity for long-term disease control while... (Review)
Review
While metastatic breast cancer (MBC) remains incurable, a vast array of active therapeutic agents has provided the opportunity for long-term disease control while maintaining quality of life and physical function. Optimal management of MBC balances a multitude of factors, including a woman's performance status, social support, symptoms, disease burden, prior therapies, and surrogates for tumor biology. Choosing the most appropriate initial therapy and subsequent sequence of treatments demands flexibility as goals and patient preferences may change. Knowledge of the estrogen receptor (ER), progesterone receptor (PR), and Her2 receptor status of the metastatic tumor has become critical to determining the optimal treatment strategy in the metastatic setting as targeted therapeutic approaches are developed. Patients with ER+ or PR+ breast cancer or both have a wide array of hormonal therapy options that can forestall the use of cytotoxic therapies, although rapidly progressive phenotypes and the emergence of resistance may ultimately lead to the need for chemotherapy in this setting. So-called 'triple-negative' breast cancer - lacking ER, PR, and Her2 overexpression - remains a major challenge. These tumors have an aggressive phenotype, and clear targets for therapy have not yet been established. Chemotherapy remains the mainstay of treatment in this group, but biologically based clinical trials of new agents are critical to developing a more effective set of therapies for this patient population.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Deoxycytidine; Doxorubicin; Estradiol; Female; Fulvestrant; Humans; Megestrol; Ovary; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; TOR Serine-Threonine Kinases; Tamoxifen; Gemcitabine
PubMed: 22429313
DOI: 10.1186/bcr3064 -
Breast (Edinburgh, Scotland) Apr 2013The proportion of elderly women in the population is rising, and in tandem, the incidence of breast cancer rises with age. Because of health and tolerability concerns,... (Review)
Review
The proportion of elderly women in the population is rising, and in tandem, the incidence of breast cancer rises with age. Because of health and tolerability concerns, as well as life expectancy, physicians may be reluctant to advise a standard treatment regimen for elderly patients with metastatic breast cancer. To elucidate this issue, we performed a literature review of clinical studies that included women with metastatic breast cancer who were over the age of 65. Our results show that although little clinical evidence exists, what is available suggests that standard treatment is tolerated and beneficial for patients meeting certain criteria. A geriatric assessment may identify specific patient groups (independent, dependent, or frail) and thereby guide treatment. Treatment recommendations for elderly patients with metastatic breast cancer are sparse, although first-line endocrine treatment, usually aromatase inhibitors or tamoxifen, is recommended for hormone-sensitive disease. In general, the evidence from clinical studies suggests that aromatase inhibitors are more effective than either tamoxifen or megestrol acetate as first- or second-line treatment in postmenopausal women with metastatic breast cancer. Ultimately, quality of life, treatment effects, and comorbidities are important aspects in this population and may guide treatment choice. To provide evidence-based treatment guidance, future clinical trials should include more patients over the age of 65 years.
Topics: Aged, 80 and over; Anastrozole; Androstadienes; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Comorbidity; Disease Management; Disease Progression; Drug Therapy, Combination; Female; Geriatric Assessment; Health Status; Humans; Letrozole; Life Expectancy; Nitriles; Prognosis; Quality of Life; Treatment Outcome; Triazoles
PubMed: 23321585
DOI: 10.1016/j.breast.2012.12.015 -
ESC Heart Failure Jun 2015As life expectancy increases, muscle wasting is becoming a more and more important public health problem. This review summarizes the current knowledge of... (Review)
Review
PURPOSE
As life expectancy increases, muscle wasting is becoming a more and more important public health problem. This review summarizes the current knowledge of pathophysiological mechanisms underlying muscle loss in ageing and chronic diseases such as heart failure and discusses evolving interventional strategies.
RECENT FINDINGS
Loss of skeletal muscle mass and strength is a common phenomenon in a wide variety of disorders associated with ageing and morbidity-associated catabolic conditions such as chronic heart failure. Muscle wasting in ageing but otherwise healthy human beings is referred to as sarcopenia. Unlike cachexia in advanced stages of chronic heart failure, muscle wasting per se is not necessarily associated with weight loss. In this review, we discuss pathophysiological mechanisms underlying muscle loss in sarcopenia and cachexia, highlight similarities and differences of both conditions, and discuss therapeutic targets and possible treatments, such as exercise training, nutritional support, and drugs. Candidate drugs to treat muscle wasting disease include myostatin antagonists, ghrelin agonists, selective androgen receptor molecules, megestrol acetate, activin receptor antagonists, espindolol, and fast skeletal muscle troponin inhibitors.
SUMMARY
Present approaches to muscle wasting disease include exercise training, nutritional support, and drugs, although particularly the latter remain currently restricted to clinical studies. Optimizing skeletal muscle mass and function in ageing and chronic illness including heart failure is one of the chapters that are far from finished and gains future potential for new therapeutic interventions to come.
PubMed: 28834653
DOI: 10.1002/ehf2.12033 -
Breast (Edinburgh, Scotland) Dec 2012To determine the variable burden of disease of patients with advanced estrogen receptor-positive (ER+) breast cancer and assess the current treatment landscape after... (Review)
Review
OBJECTIVE
To determine the variable burden of disease of patients with advanced estrogen receptor-positive (ER+) breast cancer and assess the current treatment landscape after failure of first-line endocrine therapy.
METHODS
A comprehensive literature review was performed (2000-2011) by searching Medline via PubMed, and Embase and Cochrane databases, to assess disease burden (i.e. societal, humanistic, and/or economic burden) and treatment landscape for second-line therapy of ER+ advanced breast cancer in postmenopausal women.
RESULTS
Only 1 study was identified that evaluated burden of disease based on ER status (ER+, ER-negative, or ER-unknown); this study was a subgroup analysis assessing the impact of breast cancer recurrence over 10 years. The investigators reported that only minor differences in survival and medical costs were noted based on ER status in relapsing patients. Regardless of ER status, patients with breast cancer recurrence consumed more healthcare resources and were associated with more costly care than those without recurrence. A total of 7 studies were identified related to treatment outcomes of second-line therapy in ER+ patients. A combined international population totaled >3800 patients who had progressed on prior hormonal therapy, including tamoxifen and aromatase inhibitors. Three trials performed a comparative efficacy/safety assessment of an ER antagonist vs. aromatase inhibitor, 1 trial compared an aromatase inhibitor to megestrol acetate, and 1 trial compared 2 aromatase inhibitors. Among each of the studies evaluated, no significant differences were observed in the primary efficacy endpoint, and the safety profiles were similar. Two additional studies demonstrated a similar or better efficacy and safety profile based on different dosing evaluations.
CONCLUSIONS
Currently, there is insufficient evidence on the economic and humanistic burden associated with ER status, and this gap warrants further research. With increasing drug resistance and greater economic burden associated with breast cancer recurrence, there is an unmet medical need for improved treatment in this patient population.
Topics: Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Breast Neoplasms; Cost of Illness; Female; Health Care Costs; Humans; Postmenopause; Receptors, Estrogen; Treatment Outcome; United States
PubMed: 23092824
DOI: 10.1016/j.breast.2012.09.005 -
TheScientificWorldJournal 2013Muscle wasting has long been recognized as a major clinical problem in hemodialysis (HD) patients. In addition to its impact on quality of life, muscle wasting has been... (Review)
Review
Muscle wasting has long been recognized as a major clinical problem in hemodialysis (HD) patients. In addition to its impact on quality of life, muscle wasting has been proven to be associated with increased mortality rates. Identification of the molecular mechanisms underlying muscle wasting in HD patients provides opportunities to resolve this clinical problem. Several signaling pathways and humeral factors have been reported to be involved in the pathogenic mechanisms of muscle wasting in HD patients, including ubiquitin-proteasome system, caspase-3, insulin/insulin-like growth factor-1 (IGF-1) signaling, endogenous glucocorticoids, metabolic acidosis, inflammation, and sex hormones. Targeting the aforementioned crucial signaling and molecules to suppress protein degradation and augment muscle strength has been extensively investigated in HD patients. In addition to exercise training, administration of megestrol acetate has been proven to be effective in improving anorexia and muscle wasting in HD patients. Correction of metabolic acidosis through sodium bicarbonate supplements can decrease muscle protein degradation and hormone therapy with nandrolone decanoate has been reported to increase muscle mass. Although thiazolidinedione has been shown to improve insulin sensitivity, its role in the treatment of muscle wasting remains unclear. This review paper focuses on the molecular pathways and potential new therapeutic approaches to muscle wasting in HD patients.
Topics: Exercise Therapy; Humans; Megestrol Acetate; Models, Biological; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Renal Dialysis; Signal Transduction
PubMed: 24382946
DOI: 10.1155/2013/643954 -
Cancers Mar 2023Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for... (Review)
Review
Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for which other treatment types may be too toxic. Hormonal therapy is well tolerated and has response rates ranging from 9 to 33%. Hormonal treatment options take advantage of the estrogen-dependent molecular pathways in endometrial cancers. Current options for hormonal therapies include progesterone therapy (medroxyprogesterone acetate and megestrol acetate) as a single agent or in combination and agents that target the estrogen pathway. Aromatase inhibitors have had modest single-agent activity, but synergistic effects have been found when used in combination with targeted therapy including mTOR inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Molecular profiling of endometrial cancers has begun to help individualize treatments. This review will report on existing data and ongoing trials investigating novel hormonal therapy agents.
PubMed: 36980685
DOI: 10.3390/cancers15061799 -
CA: a Cancer Journal For Clinicians 2002Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a... (Review)
Review
Cachexia is among the most debilitating and life-threatening aspects of cancer. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cachexia should be suspected in patients with cancer if an involuntary weight loss of greater than five percent of premorbid weight occurs within a six-month period. The two major options for pharmacological therapy have been either progestational agents, such as megestrol acetate, or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome has led to, and continues to lead to, effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide--all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life.
Topics: Anorexia; Cachexia; Carbohydrate Metabolism; Digestive System; Humans; Leptin; Lipid Metabolism; Neoplasms; Neuropeptide Y; Proteins; Syndrome
PubMed: 11929007
DOI: 10.3322/canjclin.52.2.72