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Cancer Chemotherapy and Pharmacology Dec 2021Megestrol acetate is a synthetic progestogen used to treat some cancers and cancer-associated cachexia, but its potential interactions with other drugs are not well...
PURPOSE
Megestrol acetate is a synthetic progestogen used to treat some cancers and cancer-associated cachexia, but its potential interactions with other drugs are not well known. This study aims to determine the regulation of drug metabolizing enzymes by megestrol acetate.
METHODS
Primary human hepatocytes were treated and analyzed by PCR array to identify genes involved in drug metabolism that are impacted by megestrol acetate. P450 3A4 (CYP3A4) reporter gene assay and HPLC analyses of nifedipine metabolites were used to determine CYP3A4 gene expression and activities. Competitive ligand binding assay was used to determine the affinity of megestrol acetate toward human pregnane x receptor (hPXR). Electrophoretic mobility shift assay and mammalian two hybrid assay were used to determine the mechanism of megestrol to activate hPXR.
RESULTS
The levels and activities of CYP3A4 were significantly induced (> 4-folds) by megestrol acetate in human hepatocytes and HepG2 cells. Megestrol treatment induced CYP3A4 through the activation of hPXR, a ligand-activated transcription factor that plays a role in drug metabolism and transport. Other tested nuclear receptors showed no response. The mechanism studies showed that megestrol activated hPXR by binding to the ligand binding domain (LBD) of hPXR and increasing the recruitment of the cofactors such as steroid receptor cofactor (SRC-1).
CONCLUSION
The results suggest that megestrol acetate is a specific inducer of CYP3A4 mediated by hPXR and therefore has the potential to cause drug interactions, especially in the co-administration with drugs that are substrates of CYP3A4.
Topics: Antineoplastic Agents, Hormonal; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Drug Interactions; Hep G2 Cells; Hepatocytes; Humans; Megestrol Acetate; Pregnane X Receptor
PubMed: 34524495
DOI: 10.1007/s00280-021-04352-9 -
Clinical Nutrition (Edinburgh, Scotland) Feb 2024Cancer cachexia (CC) syndrome, a feature of cancer-associated muscle wasting, is particularly pronounced in older patients, and is characterised by decreased energy... (Review)
Review
Cancer cachexia (CC) syndrome, a feature of cancer-associated muscle wasting, is particularly pronounced in older patients, and is characterised by decreased energy intake and upregulated skeletal muscle catabolic pathways. To address CC, appetite stimulants, anabolic drugs, cytokine mediators, essential amino acid supplementation, nutritional counselling, cognitive behavioural therapy, and enteral nutrition have been utilised. However, pharmacological treatments that have also shown promising results, such as megestrol acetate, anamorelin, thalidomide, and delta-9-tetrahydrocannabinol, have been associated with gastrointestinal and cardiovascular complications. Emerging evidence on the efficacy of probiotics in modulating gut microbiota also presents a promising adjunct to traditional therapies, potentially enhancing nutritional absorption and systemic inflammation control. Additionally, low-dose olanzapine has demonstrated improved appetite and weight management in older patients undergoing chemotherapy, offering a potential refinement to current therapeutic approaches. This review aims to elucidate the molecular mechanisms underpinning CC, with a particular focus on the role of anorexia in exacerbating muscle wasting, and to propose pharmacological and non-pharmacological strategies to mitigate this syndrome, particularly emphasising the needs of an older demographic. Future research targeting CC should focus on refining appetite-stimulating drugs with fewer side-effects, specifically catering to the needs of older patients, and investigating nutritional factors that can either enhance appetite or minimise suppression of appetite in individuals with CC, especially within this vulnerable group.
Topics: Humans; Aged; Cachexia; Anorexia; Megestrol Acetate; Neoplasms; Appetite Stimulants
PubMed: 38237369
DOI: 10.1016/j.clnu.2024.01.009 -
International Journal of Women's Health 2014Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and affects predominantly postmenopausal women. It is estimated, however, that... (Review)
Review
Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and affects predominantly postmenopausal women. It is estimated, however, that 15%-25% of women will be diagnosed before menopause. As more women choose to defer childbearing until later in life, the feasibility and safety of fertility-sparing EC management have been increasingly studied. Definitive treatment of total hysterectomy and bilateral salpingo-oophorectomy precludes future fertility and may thus be undesirable by women who wish to maintain their reproductive potential. However, the consideration of conservative management carries the oncologic risks of unstaged EC and the risk of missing a synchronous ovarian cancer. It is further complicated by the lack of consensus regarding the initial assessment, treatment, and surveillance. Conservative treatment with progestins has been shown to be a feasible and safe fertility-sparing approach for women with low grade, early stage EC with no myometrial invasion. The two most commonly adopted regimens are medroxyprogesterone acetate at 500-600 mg daily and megestrol acetate at 160 mg daily for a minimum of 6-9 months, with initial response rates commonly reported between 60% and 80% and recurrence rates between 25% and 40%. Photodynamic therapy and hysteroscopic EC excision have recently been reported as alternative approaches to progestin therapy alone. However, limited efficacy and safety data exist. Live birth rates after progestin therapy have typically been reported around 30%; however, when focusing only on those who do pursue fertility after successful treatment, the live birth rates were found to be higher than 60%. Assisted reproductive technology has been associated with a higher live birth rate compared with spontaneous conception, most likely reflecting the presence of infertility at baseline. Close follow-up is of paramount importance, and definitive treatment after completion of childbearing is advised.
PubMed: 25114594
DOI: 10.2147/IJWH.S47232 -
Gynecologic Oncology Research and... 2017Endometrial cancer is the most common gynecologic malignancy in the United States, accounting for 6% of cancers in women. In 2017, an estimated 61,380 women were... (Review)
Review
Endometrial cancer is the most common gynecologic malignancy in the United States, accounting for 6% of cancers in women. In 2017, an estimated 61,380 women were diagnosed with endometrial cancer, and approximately 11,000 died from this disease. From 1987 to 2008, there was a 50% increase in the incidence of endometrial cancer, with an approximate 300% increase in the number of associated deaths. Although there are many chemotherapeutic and targeted therapy agents approved for ovarian, fallopian tube and primary peritoneal cancers, since the 1971 approval of megestrol acetate for the palliative treatment of advanced endometrial cancer, only pembrolizumab has been Food and Drug Administration (FDA)-approved for high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) endometrial cancer; this highlights the need for new therapies to treat advanced, recurrent, metastatic endometrial cancer. In this review, we discuss current and emerging treatment options for endometrial cancer, including chemotherapy, targeted therapy, and immunotherapy. The National Cancer Institute (NCI) and others are now focusing their efforts on the design of scientifically rational targeted therapy and immunotherapy trials for specific molecular phenotypes of endometrial cancer. This is essential for the advancement of cancer care for women, which is threatened by a severe enrollment decline of approximately 80% for gynecologic oncology clinical trials.
PubMed: 29214032
DOI: 10.1186/s40661-017-0056-7 -
The Journal of Nutrition, Health & Aging Feb 2012The objective of this review was to investigate the range of pharmacological interventions that have been studied for treatment of geriatric cachexia, and to evaluate... (Review)
Review
OBJECTIVE
The objective of this review was to investigate the range of pharmacological interventions that have been studied for treatment of geriatric cachexia, and to evaluate their effect on selected clinical outcomes in this population.
METHODS
Databases including Medline and Cochrane Central Register of Controlled Trials were searched up to March 2010 with search terms including "cache*", "intervention", "megestrol acetate" and "cytokine inhibitors". Studies investigating subjects with mean age <60y or disease-related cachexia were excluded. Outcomes assessed were weight or BMI, body composition, appetite and laboratory parameters indicative of cachexia.
RESULTS
Fifteen publications met the selection criteria, reporting on ten studies. Seven studies investigated use of megestrol acetate (MA): two randomised controlled trials, one case control study, two pre-test/post-test studies and two retrospective chart reviews. Weight/BMI was common amongst outcomes and these studies showed an improvement in weight compared with baseline. MA studies which investigated body composition, appetite and/or laboratory parameters provided some evidence for improvement in these outcomes. Three randomised controlled trials investigated the use of other interventions: ghrelin, growth hormone and vitamin supplementations. All demonstrated a significant increase in lean body mass. The only other outcome of interest in these three trials was weight in one study with a significant increase demonstrated.
CONCLUSION
Little investigation has been conducted in this population and the diagnosis of cachexia is problematic however these trials provide preliminary evidence for beneficial outcomes in older adults likely to have cachexia. Further high quality adequately powered prospective studies are necessary to provide effective treatment for geriatric cachexia.
Topics: Aged; Aged, 80 and over; Aging; Appetite; Appetite Stimulants; Body Composition; Body Mass Index; Body Weight; Cachexia; Cytokines; Female; Humans; Male; Megestrol Acetate; Nutritional Physiological Phenomena; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 22323350
DOI: 10.1007/s12603-011-0083-8 -
Kidney International Aug 2006Anorexia, defined as the loss of the desire to eat, is relatively common in hemodialysis (HD) patients, occurring in one-third of cases. The pathogenesis is essentially... (Review)
Review
Anorexia, defined as the loss of the desire to eat, is relatively common in hemodialysis (HD) patients, occurring in one-third of cases. The pathogenesis is essentially unknown. It has been proposed that uremic toxins as middle molecules, inflammation, altered amino-acid pattern, leptin, ghrelin, and neuropeptide Y are involved. Anorexia reduces oral energy and protein intakes, thus contributing to the development of malnutrition and cachexia. Unquestionably, it contributes to poor quality of life. The clinical relevance of anorexia as an independent prognostic factor in HD patients is a matter of debated issue. The treatment of this debilitating condition is based on a therapeutic strategy which may include daily dialysis sessions and nutritional counseling. Normalization of plasma branched-chain amino acids through branched-chain amino acids supplementation may decrease anorexia and improve energy and protein intake. The role of megestrol acetate as appetite stimulant needs to be validated through adequate randomized trials. Subcutaneous ghrelin administration and melanocortin-receptor antagonists appear promising therapeutic interventions.
Topics: Anorexia; Humans; Kidney Failure, Chronic; Renal Dialysis
PubMed: 16775598
DOI: 10.1038/sj.ki.5001572 -
The Cochrane Database of Systematic... Oct 2009Endocrine therapy removes the influence of oestrogen on breast cancer cells and so hormonal treatments such as tamoxifen, megestrol acetate and medroxyprogesterone... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Endocrine therapy removes the influence of oestrogen on breast cancer cells and so hormonal treatments such as tamoxifen, megestrol acetate and medroxyprogesterone acetate have been in use for many years for advanced breast cancer. Aromatase inhibitors (AIs) inhibit oestrogen synthesis in the peripheral tissues and have a similar tumour-regressing effect to other endocrine treatments. Aminoglutethimide was the first AI in clinical use and now the third generation AIs, anastrozole, exemestane and letrozole, are in current use. Randomised trial evidence on response rates and side effects of these drugs is still limited.
OBJECTIVES
To compare AIs to other endocrine therapy in the treatment of advanced breast cancer in postmenopausal women.
SEARCH STRATEGY
For this update, the Cochrane Breast Cancer Group Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL) and relevant conference proceedings were searched (to 30 June 2008).
SELECTION CRITERIA
Randomised controlled trials in postmenopausal women comparing the effects of any AI versus other endocrine therapy, no endocrine therapy, or a different AI in the treatment of advanced (metastatic) breast cancer. Non-English language publications, comparisons of the same AI at different doses, AIs used as neoadjuvant treatment, or outcomes not related to tumour response were excluded.
DATA COLLECTION AND ANALYSIS
Data from published trials were extracted independently by two review authors and cross-checked by a third. Hazard ratios (HR) were derived for analysis of time-to-event outcomes (overall and progression-free survival). Odds ratios (OR) were derived for objective response, clinical benefit, and toxicity.
MAIN RESULTS
Thirty-seven trials were identified, 31 of which were included in the main analysis of any AI versus any other treatment (11,403 women). No trials were excluded due to inadequate allocation concealment. The pooled estimate showed a significant survival benefit for treatment with an AI over other endocrine therapies (HR 0.90, 95% CI 0.84 to 0.97). A subgroup analysis of the three commonly prescribed AIs (anastrozole, exemestane, letrozole) also showed a similar survival benefit (HR 0.88, 95% CI 0.80 to 0.96). There were very limited data to compare one AI with a different AI, but these suggested an advantage for letrozole over anastrozole.AIs have a different toxicity profile to other endocrine therapies. For those currently prescribed, and for all AIs combined, they had similar levels of hot flushes and arthralgia; increased risks of rash, nausea, diarrhoea and vomiting; but a 71% decreased risk of vaginal bleeding and 47% decrease in thromboembolic events compared with other endocrine therapies.
AUTHORS' CONCLUSIONS
In women with advanced (metastatic) breast cancer, aromatase inhibitors including those in current clinical use show a survival benefit when compared to other endocrine therapy.
Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Neoplasms, Hormone-Dependent; Postmenopause; Randomized Controlled Trials as Topic
PubMed: 19821307
DOI: 10.1002/14651858.CD003370.pub3 -
The Cochrane Database of Systematic... Dec 2010Endometrial cancer is a cancer of the lining of the womb and worldwide is the seventh most common cancer in women. Treatment with hormones is thought to be beneficial in... (Review)
Review
BACKGROUND
Endometrial cancer is a cancer of the lining of the womb and worldwide is the seventh most common cancer in women. Treatment with hormones is thought to be beneficial in patients with endometrial cancer.
OBJECTIVES
To assess the indications, effectiveness and safety of hormone therapy for advanced or recurrent epithelial endometrial cancer.
SEARCH STRATEGY
We searched the Cochrane Gynaecological Cancer Group Trials Register, MEDLINE, EMBASE up to May 2009 and and CENTRAL (Issue 2, 2009). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies, and contacted experts in the field.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that studied hormonal therapy in adult women diagnosed with advanced or recurrent endometrial cancer.
DATA COLLECTION AND ANALYSIS
Two review authors independently abstracted data and assessed risk of bias. Comparisons were restricted to single-trial analyses so we did not synthesise data in meta-analyses.
MAIN RESULTS
We found six trials (542 participants) that met our inclusion criteria. These trials assessed the effectiveness of hormonal therapy in women with advanced or recurrent endometrial cancer as a single agent, as part of combination therapy and as low versus high dose. All comparisons were restricted to single-trial analyses, where we found no evidence that hormonal therapy as a single agent or as a combination treatment prolonged overall or five-year disease-free survival of women with advanced or recurrent endometrial cancer. However, low-dose hormonal therapy may have had a benefit in terms of overall and progression-free survival (PFS) compared to high-dose hormonal therapy (HR 1.31, 95% CI 1.04 to 1.66 and HR 1.35, 95% CI 1.07 to 1.71 for overall and PFS, respectively).
AUTHORS' CONCLUSIONS
We found insufficient evidence that hormonal treatment in any form, dose or as part of combination therapy improves the survival of patients with advanced or recurrent endometrial cancer. However, a large number of patients would be needed to demonstrate an effect on survival and none of the included RCTs had a sufficient number of patients to demonstrate a significant difference. In the absence of a proven survival advantage and the heterogeneity of patient populations, the decision to use any type of hormonal therapy should be individualised and with the intent to palliate the disease. It is debatable whether outcomes such as quality of life, treatment response or palliative measures such as relieving symptoms should take preference over overall and PFS as the major objectives of future trials.
Topics: 17 alpha-Hydroxyprogesterone Caproate; Adult; Antineoplastic Agents, Hormonal; Disease-Free Survival; Drug Therapy, Combination; Endometrial Neoplasms; Female; Humans; Hydroxyprogesterones; Medroxyprogesterone Acetate; Megestrol; Neoplasm Recurrence, Local; Neoplasm Staging; Progestins
PubMed: 21154390
DOI: 10.1002/14651858.CD007926.pub2 -
The management strategies of cancer-associated anorexia: a critical appraisal of systematic reviews.BMC Complementary and Alternative... Aug 2018Cancer-related anorexia remains one of the most prevalent and troublesome clinical problems experienced by patients with cancer during and after therapy. To ensure... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cancer-related anorexia remains one of the most prevalent and troublesome clinical problems experienced by patients with cancer during and after therapy. To ensure high-quality care, systematic reviews (SRs) are seen as the best guide. Considering the methodology quality of SRs varies, we undertook a comprehensive overview, and critical appraisal of pertinent SRs.
METHODS
Eight databases (between the inception of each database and September 1, 2017) were searched for SRs on the management of cancer-related anorexia. Two researchers evaluated the methodological quality of each SR by using the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR) checklist. Characteristics of the "high quality" SRs were abstracted, included information on relevant studies numbers, study design, population, intervention, control, outcome and result.
RESULTS
Eighteen SRs met the inclusion criteria. The R-AMSTAR scores of methodological quality ranged from 18 to 41 out of 44, with an average score of 30. Totally eight SRs scored ≥31 points, which showed high methodological quality, and would be used for data extraction to make summaries. Anamorelin had some positive effects to relieve cancer anorexia-cachexia syndrome (CACS) and improve the quality of life (QoL). Megestrol Acetate (MA) could improve appetite, and was associated with slight weight gain for CACS. Oral nutritional interventions were effective in increasing nutritional intake and improving some aspects of QoL in patients with cancer who were malnourished or at nutritional risk. The use of thalidomide, Eicosapentaenoic Acid, and minerals, vitamins, proteins, or other supplements for the treatment of cachexia in cancer were uncertain, and there was inadequate evidence to recommend it to clinical practices, the same situation in Chinese Herb Medicine and acupuncture (acupuncture and related therapies were effective in improving QoL) for treating anorexia in cancer patients, warranting further RCTs in these areas.
CONCLUSIONS
Anamorelin, MA, oral nutrition interventions, and acupuncture could be considered to be applied in patients with cancer-related anorexia. Future RCTs and SRs with high quality on the pharmaceutical or non-pharmaceutical interventions of anorexia in cancer patients are warranted.
Topics: Acupuncture Therapy; Adult; Anorexia; Cachexia; Dietary Supplements; Evidence-Based Medicine; Humans; Hydrazines; Medicine, Chinese Traditional; Neoplasms; Oligopeptides; Plant Extracts
PubMed: 30092794
DOI: 10.1186/s12906-018-2304-8 -
Acta Crystallographica. Section E,... Apr 2012The title compound, C(24)H(34)O(4), is a precursor of Megestrol acetate. Ring A has a half-chair conformation [Q = 0.446 (3) Å, θ = 54.6 (4)° and ϕ =...
The title compound, C(24)H(34)O(4), is a precursor of Megestrol acetate. Ring A has a half-chair conformation [Q = 0.446 (3) Å, θ = 54.6 (4)° and ϕ = 9.5 (4)°]. Ring D adopts a 13β-envelope conformation [Q = 0.463 (2) Å and ϕ = 188.2 (3)°].
PubMed: 22590046
DOI: 10.1107/S1600536812008665