Propensity score-matching analysis comparing safety outcomes of appetite-stimulating medications in oncology patients.

PURPOSE: Anorexia and weight loss are common complications in the elderly, advanced cancer population. Appetite stimulants are commonly used therapies for oncology patients with weight loss, yet their safety comparison remains unknown. METHODS: This was a two-center, retrospective, study conducted in New York City at Mount Sinai Beth Israel and New York University Langone from January 2016 to July 2019 in adult patients with histologic evidence of malignancy who were taking either megestrol acetate or mirtazapine as an appetite-stimulating medication. Endpoints included safety concerns of mortality, QTc prolongation, venous thromboembolism, fall, somnolence, xerostomia, and hallucinations. Effectiveness of weight gain or maintenance of weight was not assessed. A propensity score-matching analysis was performed using a logistic regression analysis to assess the two comparable groups. RESULTS: The study included 350 patients (69.56 ± 13.31 years) with the most common malignancies being gastrointestinal, breast, and hematologic with metastasis present in over half the patients. Adverse events were commonly seen in the oncology population. After a propensity score-matched analysis, all safety outcomes associated with mirtazapine compared to megestrol acetate were similar; all-cause mortality (7%, n = 7 vs. 12%, n = 12, p = 0.23), QTc prolongation (31%, n = 31 vs. 31%, n = 31, p = 1.00), thromboembolism (11%, n = 11 vs. 11%, n = 11, p = 1.00), somnolence (29%, n = 30 vs. 22%, n = 23, p = 0.34), xerostomia (27%, n = 28 vs. 18%, n = 19, p = 0.24), and hallucinations (17%, n = 18 vs. 8%, n = 8, p = 0.06), respectfully. CONCLUSION: There were no safety differences seen when evaluating both agents.

Randomized double-blind clinical trial of combined treatment with megestrol acetate plus celecoxib versus megestrol acetate alone in cachexia-anorexia syndrome induced by GI cancers.

PURPOSE: Previous studies reported promising efficacy for celecoxib in the treatment of cancer cachexia. We designed this study to test the hypothesis that combination therapy with megestrol acetate (MA) plus celecoxib is superior to MA alone. METHODS: Ninety eligible gastrointestinal cancer patients randomly received either MA 320 mg/day plus placebo (arm1) or MA 320 mg/day plus celecoxib 200 mg/day (arm2). Patients were evaluated at baseline, then 1 and 2 months after starting interventions. The primary outcome was body weight. Secondary outcomes were quality of life, grip strength, appetite score, performance status, plasma albumin, CRP, IL-6, and Glasgow Prognostic Score. RESULTS: Patients were comparable at baseline. Sixty patients were assessable for the first month and 33 patients for the second month. After 2 months, patients in arm1 (MA + placebo) and arm2 (MA + celecoxib) experienced 4.0 ± 3.4 and 2.2 ± 3.6Kg of weight gain respectively (P = 0.163). Changes relative to baseline were statistically significant in both arms of the study (P = 0.001). Regarding secondary outcomes, comparisons between groups did not show any statistically significant difference, but within-group changes were significant in both arms of the study. CONCLUSION: Since both MA alone and MA plus celecoxib are associated with improvement of cachexia in GI cancer patients, this study failed to show that adding celecoxib (200 mg/day) to megestrol (320 mg/day) could enhance anti-cachexic effects of megestrol.

Pharmacy Report: Megestrol Acetate-Induced Adrenal Insufficiency.

A man aged 65 years with metastatic renal cell carcinoma presented for evaluation after a recent fall. A thorough workup of the case was performed and secondary adrenal insufficiency induced by the administration of megestrol acetate was determined to be the cause. Adrenal insufficiency is a serious disorder that is a potential adverse event of megestrol acetate, a medication used to help patients with cancer cachexia increase their appetite and gain weight. This association is not well recognized in clinical practice, so this case highlights the importance of distinguishing possible endocrine complications induced by the long-term administration or sudden discontinuation of megestrol acetate.

New Biopolymer Nanoparticles Improve the Solubility of Lipophilic Megestrol Acetate.

As many substances are poorly soluble in water and thus possess decreased bioavailability, creating orally administered forms of these substances is a challenge. The objective of this study was to determine whether the solubility of megestrol acetate, a Biopharmaceutical Classification System (BCS) class II drug, can be improved by using a newly-synthesized surfactant (Rofam 70: a rapeseed methyl ester ethoxylate) and compare it with two references surfactants (Tween 80, Pluronic F68) at three different pH values. Spectrophotometry was used to compare the solubility profiles in the presence of three tested surfactants at pH 5.0, 7.4 and 9.0. Rapeseed methyl ester ethoxylate was found to improve the solubility of the BCS Class II drug and increase its bioavailability; It increased drug solubility more effectively than Pluronic F68. Its cytotoxicity results indicate its possible value as a surfactant in Medicine and Pharmacy.

Dose-dependent effect of megestrol acetate supplementation in cancer patients with anorexia-cachexia syndrome: A meta-analysis.

There is inconsistent evidence relating to the effects of megestrol acetate (MA) supplementation on cancer patients suffering from anorexia-cachexia syndrome. This review aimed to examine the dose-response effect of MA supplementation in patients with cancer-associated anorexia/cachexia. Relevant keywords were searched in PubMed, Scopus and ISI Web of Science from inception to June 2023 for randomized controlled trials (RCTs) examining the effect of MA on pathologies in patients with cancer-associated cachexia. Our primary outcomes were changes in body weight and appetite. However, fatigue and quality of life were secondary outcomes. The mean difference (MD) and 95% confidence interval (95% CI) were estimated using the random-effects method. Thirteen trials comprising 1229 participants (mean age 60 years) were identified. The results of our highest versus lowest analysis revealed that MA supplementation was not associated with any increase in body weight (MD: 0.64 kg, 95% CI [-0.11, 1.38], P = 0.093, I2 = 69.1%; GRADE = very low certainty). Twelve trials, including 14 effect sizes derived from 1369 patients (intervention = 689, control = 680), provided data on the effect of MA on body weight. Subgroup analyses showed a significant increase in body weight following short-term intervention (≤8 weeks) and a combination of radiation/chemotherapy as concurrent treatment. A linear dose-response meta-analysis indicated that each 200 mg/day increment in MA consumption had a significant increase in weight gain (MD: 0.44; 95% CI [0.13, 0.74], P = 0.005; I2 = 97.1%); however, the magnitude of the effect was small. MA administration significantly affected the quality of life based on pooled effect sizes (MD: 1.15, 95% CI [0.76, 1.54], P < 0.001, I2 = 0%; n = 2 RCTs including 176 patients; GRADE = very low certainty). However, no significant effect of MA supplementation was observed on appetite (MD: 0.29, 95% CI [-0.05, 0.64], P = 0.096, I2 = 18.3%; n = 3 RCTs including 163 patients; GRADE = very low certainty) and fatigue (MD: 0.14, 95% CI [-0.09, 0.36], P = 0.236, I2 = 0%; n = 2 RCTs including 300 patients; GRADE = very low certainty). With very low certainty of the evidence, MA supplementation may not lead to a significantly increased weight gain and other outcomes.

Sterol regulatory element-binding protein-1/fatty acid synthase involvement in proliferation inhibition and apoptosis promotion induced by progesterone in endometrial cancer.

BACKGROUND: The number of endometrial cancer (EC) cases is escalating rapidly, with no evident improvements in survival rates. The downregulation of progesterone receptor, resulting in progestin resistance, is presently a major problem regarding the therapeutic aspect. On the basis of this, we can focus more on the downstream signaling pathways that are controlled by progesterone. Lipid biosynthesis mediated by sterol regulatory element-binding protein-1/fatty acid synthase (SREBP-1/FASN) is of utmost importance to the growth and the proliferation of EC cells, so we hypothesize that SREBP-1/FASN might be involved in suppressing the proliferation and promoting apoptosis in EC cells through the effects induced by progesterone. MATERIAL AND METHODS: The Cell Counting Kit-8 was used to analyze the growth inhibition ratio of Ishikawa cells upon treatment with megestrol acetate (MA; MA is a progesterone derivative, also known as 17α-acetoxy-6-dehydro-6-methylprogesterone) and to determine the 50% inhibitory concentration. Apoptosis ratio was analyzed by treatment of the cells with MA at 50% inhibitory concentration at different time intervals using Annexin V-FITC/propidium iodide. The protein and messenger RNA levels of SREBP-1 and FASN were compared between the experimental and control groups (MA-treated Ishikawa cells were considered to be the experimental group). RESULTS: The experimental group showed obvious growth inhibition that was time and concentration dependent. The apoptosis ratio was also significantly higher in the experimental group compared with the control group (P < 0.01). The protein and messenger RNA levels of SREBP-1 and FASN were significantly reduced by MA too. CONCLUSIONS: Sterol regulatory element-binding protein-1/FASN is involved in the proliferation suppression and apoptosis promotion brought about by MA in Ishikawa cells.

Successful treatment for subinvolution of placental sites in the bitch with low oral doses of progestagen.

Subinvolution of placental sites (SIPS) is the major cause of persistent sanguineous vaginal discharge after parturition in the bitch. Spontaneous remission is common but may take several months, and hence, medical therapy to end the discharge is often requested. In this retrospective study, we evaluated the effect of treatment for SIPS with low oral doses of a progestagen. Nine bitches with SIPS, but otherwise clinically healthy, were found in the computer database of the Department of Clinical Sciences of Companion Animals. Seven of these bitches were treated with low oral doses of a progestagen (megestrol acetate, 0.1 mg/kg body weight (bw) once daily for the 1st week, then 0.05 mg/kg bw once daily for the 2nd week). The other two bitches were untreated. Treatment results were evaluated by a telephone questionnaire. Progestagen treatment was successful in all of the treated dogs; sanguineous vaginal discharge stopped within the treatment period. One of the two untreated dogs remained symptomatic until the next oestrus, approximately 120 days after parturition, and the other remained symptomatic until 6 weeks before the start of the next pro-oestrus, 270 days after parturition. No side effects of the progestagen treatment were observed. Subsequent gestations, parturitions and puerperal periods of 5 mated bitches were uneventful. One bitch did not become pregnant after mating. In conclusion, the results of this study indicate that oral administration of low doses of progestagen for 2 weeks is effective in stopping persistent sanguineous vaginal discharge in bitches with SIPS, with neither side effects nor reduced subsequent fertility.

A review of the efficacy of appetite stimulating medications in hospitalized adults.

BACKGROUND: The majority of evidence on efficacy of appetite-stimulating medications is limited to specific populations and the outpatient treatment setting. However, hospitalized adults remain at risk for poor appetite and inadequate intake. METHOD: The purpose of this review was to assess recent evidence on the efficacy of dronabinol, megestrol acetate, and mirtazapine (used to stimulate appetite) on promoting change in intake; somatic symptoms, such as appetite and nausea; and weight change during hospital stay. The population was limited to hospitalized adults or adults who demonstrated a need for appetite stimulation during hospitalization. RESULTS: Of the 382 articles screened, four met inclusion criteria (one randomized control trial, two retrospective cohort studies, and one retrospective case series). Based on the studies included, these appetite stimulants have limited efficacy on improving appetite and meal intake. There was no significant change in weight. CONCLUSION: Current data lack standardization, generalizability, and comparability, and higher quality evidence is needed before conclusions can be identified on the efficacy of dronabinol, megestrol acetate, and mirtazapine in the inpatient setting.

Altered claudin-4 expression in progesterone-treated endometrial adenocarcinoma cell line Ishikawa.

OBJECTIVE: To detect the expression change of claudin-4 in Ishikawa endometrial adenocarcinoma cell line in response to progesterone. To determine whether claudin-4 is involved in the anticancer effect of progesterone. METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine the 50% inhibitory concentration (IC50) of megestrol acetate (MA) in treating Ishikawa cells. After the Ishikawa cells were treated with MA at IC50, cell apoptosis was examined by flow cytometry and transmission electron microscopy. The messenger RNA and protein expression levels of claudin-4 were further quantified by real-time polymerase chain reaction and Western blot. The localization of claudin-4 was examined by immunofluorescent staining. RESULTS: The IC50 of MA on Ishikawa cells was 15 mg/L incubated for 72 hours. Apoptosis percentage was elevated from 0.07% ± 0.02% to 3.93% ± 0.81% after MA treatment. The expression of claudin-4 at both protein and messenger RNA levels was significantly decreased after the treatment of MA (P < 0.05). The localization of claudin-4 transferred from cytomembrane to cytoplasm and nucleus. CONCLUSION: Megestrol acetate can inhibit the growth of Ishikawa cells. It may work through decreasing claudin-4 expression and cell apoptosis. The localization change of claudin-4 may also be involved in the anticancer effect of progesterone.

AZA Wildlife Contraception Center programme for wild felids and canids.

North American zoos began using melengestrol acetate (MGA) implants to control reproduction in wild felids in the mid-1970s. Research linking MGA and other progestin-based contraceptives to uterine and mammary pathology in canids as well as felids resulted in a shift to GnRH agonist implants (Suprelorin(®): deslorelin, Peptech Animal Health, Australia). However, a recent study revealed an association between Suprelorin(®) and uterine pathology in canids, but that pathology was not found in canids treated with oral megestrol acetate (MA) for 2 weeks around the time of implant insertion to prevent the initial agonist stimulation phase. Thus, the AZA Wildlife Contraception Center (WCC) currently recommends Suprelorin(®) plus the 2-week MA regimen for wild canids and felids. WCC research is now focusing on factors affecting Suprelorin(®) reversibility.

[Regulation of claudin-4 gene expression in endometrial adenocarcinoma Ishikawa cell line by progesterone].

OBJECTIVE: To explore the regulation of claudin-4 expression in endometrial adenocarcinoma cell lines by progesterone. METHODS: Ishikawa cells were treated with various concentrations of megestrol acetate (MA: 2, 5, 10, 15, 20 mg/L). After cultured for 24, 48 and 72 hours, cells growth were measured by methyl thiazolyl tetrazolium (MTT). The group of Ishikawa cells incubated with MA at the 50% inhibitory concentration (IC(50)) was selected for cell apoptosis assay by using transmission electron microscopy and flow cytometry method. Real-time PCR and western blot were used for detecting the mRNA and protein expression levels of claudin-4. The localization of claudin-4 was examined by immunofluorescent staining. RESULTS: The inhibitory effects of megestrol acetate on the growth of Ishikawa cells were dose-dependent and time-dependent. IC(50) of MA on Ishikawa cells was 15 mg/L after incubated for 72 hours. After MA treatment, Ishikawa cells showed shrinkage, nuclear chromatin condensation, fractures of nuclear membrane and endoplasmic reticulum expansion, even round apoptotic bodies were found. The apoptosis rate of cells before MA treatment was (0.076 ± 0.024)%, and the rate was (3.934 ± 0.816)% by MA treated for 72 hours, in which there were signicant difference (P < 0.05). The relative quantification of claudin-4 mRNA and protein of the cells before MA treatment were 0.64 ± 0.20 and 0.94 ± 0.18, while they were 0.47 ± 0.15 and 0.62 ± 0.15 after MA treated. The expression of claudin-4 was significantly decreased after MA treatment (P < 0.05). The localization of claudin-4 transferred from cytomembrane to cytoplasm and nucleus after MA treatment. CONCLUSIONS: MA could inhibite the growth of Ishikawa cells, in which the mechanism may be decrease the expression of claudin-4 and the apoptosis of cells. The distribution change of claudin-4 may be related to the anti-cancer effect of progesterone.

Megestrol acetate is a specific inducer of CYP3A4 mediated by human pregnane X receptor.

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.

Megestrol acetate induced proliferation and differentiation of osteoblastic MC3T3-E1 cells: A drug repurposing approach.

AIMS: Drug repurposing or repositioning i.e.; identifying new indications for existing drugs have recently accelerated the process of drug discovery and development. Megestrol acetate (1) is a well-known progestin. It is commonly used as an appetite stimulant, and also in the treatment of breast, and endometrial cancers. The aim of this study is to investigate the effect of megestrol acetate (1) in osteoblast differentiation, and to determine the possible mechanism involved in megestrol acetate (1) induced osteoblast differentiation. MAIN METHODS: Cytotoxicity of different steroidal drugs was evaluated using MTT assay. Alkaline phosphatase (ALP) activity was also determined, and alizarin red S (ARS) staining was performed to measure extracellular mineralization. Osteogenic protein levels were determined using Western blot analysis. KEY FINDINGS: Results of the current study indicated that the megestrol acetate (1) enhanced the proliferation and differentiation of osteoblast cells at 1, 0.2, and 0.04 µM. This stimulatory effect of the megestrol acetate (1) was more prominent at 0.2 µM for cell proliferation, while the maximum cell differentiation (ALPase activity, and calcification) was observed at 0.04 µM. Western blot analysis also showed that megestrol acetate (1) altered the expression of bone morphogenic protein-2 (BMP2), p38, and pJNK proteins. Hence, only moderate doses of MGA (1) can enhance osteoblast proliferation and differentiation. SIGNIFICANCE: Our results identified that megestrol acetate (1) could be a potential lead for further research towards bone fragility related disorders.

Effect of megestrol acetate on serum albumin level in malnourished dialysis patients.

OBJECTIVE: Malnutrition is a common problem in dialysis patients, and may affect up to one third of patients. It is associated with high mortality and morbidity. Although a number of studies were performed to determine effective treatment, there is no proven medication for this condition. This study aimed to evaluate the effect of megestrol acetate (MA) on serum albumin levels in malnourished dialysis patients. DESIGN: This was a randomized, controlled clinical trial. SETTING: The setting, a dialysis center at Razi Hospital, Rasht, Iran, provides services to dialysis patients. PATIENTS: Twenty-two malnourished dialysis patients with persistent hypoalbuminemia (albumin, <3.5 g/dL for 2 months) participated, and were randomly assigned to either an experimental group or a control group. INTERVENTION: The experimental group was treated with MA, 40 mg twice daily, over 2 months, and was compared with the control group. The collected data were analyzed using SPSS (version 10; Chicago, IL). RESULTS: After 2 months, the mean (+/-SD) serum albumin level in the experimental group rose from 3.31 +/- 0.31 g/dL to 4.41 +/- 0.31 g/dL, but in the control group, it declined, from 3.35 +/- 0.21 to 3.02 +/- 0.48 g/dL. The difference between the two groups was significant (P = .002). CONCLUSION: At a dose of 40 mg twice a day, MA safely increased serum albumin in malnourished dialysis patients.

Ten years of Croatian national guidelines for use of eicosapentaenoic acid and megestrol acetate in cancer cachexia syndrome - Evaluation of awareness and implementation among Croatian oncologists.

BACKGROUND & AIMS: Cancer cachexia (CC) syndrome and anorexia-cachexia syndrome are common terms used to describe changes in metabolism with increased inflammatory activity and can progressively develop through various stages such as pre-cachexia; cachexia; and refractory cachexia. Therefore in year 2007 Croatian guidelines for use of eicosapentaenoic acid and megestrol acetate in cancer cachexia syndrome were published. Aim of this study was to assess the awareness and implementation of Croatian guidelines for use of eicosapentaenoic acid (EPA) and megestrol acetate (MA) into clinical practice among Croatian oncologists approximately 10 years after the publication, but also to point out the importance of adequate recognition and treatment of CC. METHODS: Survey with questions was designed to assess the awareness and implementation of Croatian guidelines for use of EPA and MA into clinical practice and was distributed among all Croatian oncologists in secondary and tertiary hospital centers. Survey was conducted in January 2011 (40 months following release of the guidelines), February 2013 and June 2018, and were formed in a way of yes/no answers. Additional multiple choice questions that focus on the implementation of guidelines were added in June 2018. RESULTS: A total of 128 oncologists completed a questionnaire. There was no statistically significant difference in follow up period (2011-2018) of percentage of oncologists that are familiar with Croatian guidelines for use of EPA and MA in CC, percentage of oncologists in which Croatian national guidelines changed their approach in treating patients with CC syndrome and proportion of oncologists that are using MA, enteral nutrition formulas with EPA or their combination. Most of the oncologists 38% (N = 44) are using >2.2 g of EPA per day. Nutritional support is prescribed in 25-50% of patients by 42% (N = 48) of oncologists and most of the oncologists (35%, N = 41) start with nutritional support when a body mass loss is >5%. Oncologists mostly recommend patients to use nutritional support during 1 year or more (43%, N = 49) or two months to 1 year (42%, N = 48). Compliance of patients with malignant diseases for using nutritional support was mostly evaluated as medium (69%, N = 60). CONCLUSIONS: Results have shown that majority of oncologists who filled the questionnaire believe that the Croatian national guidelines for use of EPA and MA in CC syndrome changed their approach in treating patients with CC, but also that there are several targeted issues that can be significantly improved. The awareness of and adherence to national guidelines was maintained at high level even 11 years after the guidelines were published.

Nutritional and anti-inflammatory interventions in chronic heart failure.

Currently, there are 5 million individuals with chronic heart failure (CHF) in the United States who have poor clinical outcomes, including high death rates. Observational studies have indicated a reverse epidemiology of traditional cardiovascular risk factors in CHF; in contrast to trends seen in the general population, obesity and hypercholesterolemia are associated with improved survival. The temporal discordance between the overnutrition (long-term killer) and undernutrition (short-term killer) not only can explain some of the observed paradoxes but also may indicate that malnutrition, inflammation, and oxidative stress may play a role that results in protein-energy wasting contributing to poor survival in CHF. Diminished appetite or anorexia and nutritional deficiencies may be both a cause and a consequence of this so-called malnutrition-inflammation-cachexia (MIC) or wasting syndrome in CHF. Neurohumoral activation, insulin resistance, cytokine activation, and survival selection-resultant genetic polymorphisms also may contribute to the prominent inflammatory and oxidative characteristics of this population. In patients with CHF and wasting, nutritional strategies including amino acid supplementation may represent a promising therapeutic approach, especially if the provision of additional amino acids, protein, and energy includes nutrients with anti-inflammatory and antioxidant properties. Regardless of the etiology of anorexia, appetite-stimulating agents, especially those with anti-inflammatory properties such as megesterol acetate or pentoxyphylline, may be appropriate adjuncts to dietary supplementation. Understanding the factors that modulate MIC and body wasting and their associations with clinical outcomes in CHF may lead to the development of nutritional strategies that alter the pathophysiology of CHF and improve outcomes.

GnRH mediates estrous behavior induced by ring A reduced progestins and vaginocervical stimulation.

The present study was designed to assess the participation of gonadotropin-releasing hormone (GnRH) in the display of estrous behavior induced by application of vaginal-cervical stimulation (VCS) and by the intracerebroventricular (icv) administration of progesterone and its ring A-reduced metabolites to ovariectomized (ovx), estradiol benzoate (E2B) primed rats. Icv injection of Antide, a GnRH-1 receptor antagonist, significantly depressed lordosis behavior in ovx, E2B-primed rats treated with icv GnRH. Application of VCS to ovx, E2B-primed rats facilitated both lordosis and proceptivity. These behavioral responses were significantly depressed by the icv administration of Antide. Similarly, icv Antide blocked the stimulatory effect on both lordosis and proceptive behaviors elicited by progesterone and its ring A-reduced metabolites: 5alpha-pregnandione (5alpha-DHP), 5alpha-pregnan-3alpha-ol-20-one (5alpha,3alpha-Pgl) and 5beta-pregnan-3beta-hydroxy-20-one (5beta,3beta-Pgl) in ovx, E2B-primed rats. By contrast, icv injection of Antide failed to interfere with the facilitatory effect of the synthetic progestin megestrol acetate on lordosis and proceptive behaviors. This progestin is not reduced in ring A. The results suggest that GnRH release is an important process in the chain of events leading to the display of estrous behavior in response to progesterone, its ring A-reduced metabolites, and VCS in female rats.

Randomized phase III clinical trial of five different arms of treatment for patients with cancer cachexia: interim results.

OBJECTIVE: In April 2005 a phase III randomized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints: increase of lean body mass, decrease of resting energy expenditure (REE), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-alpha, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). METHODS: All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients. RESULTS: By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes. CONCLUSION: The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data.

Megestrol acetate for cachexia-anorexia syndrome. A systematic review.

In 1993, megestrol acetate (MA) was approved by the US Food and Drug Administration for the treatment of anorexia, cachexia, or unexplained weight loss in patients with acquired immunodeficiency syndrome. The mechanism by which MA increases appetite is unknown, and its effectiveness for anorexia and cachexia in neoplastic, elderly, and acquired immunodeficiency syndrome patients is under investigation. This is an updated version of a Cochrane systematic review first published in 2005 and later updated in 2013 entitled 'Megestrol acetate for the treatment of anorexia-cachexia syndrome'. MA vs. placebo: in studies where MA was compared with placebo, the overall results showed that MA patients gained weight (mean difference, MD 2.25 kg, 95% CI [1.19, 3.3]) but did not gain quality of life (QOL) (standarized mean difference, SMD 0.5, 95% CI [-0.13, 1.13]), with more adverse events (relative risk, RR 1.46, 95% CI [1.05, 2.04]), but no difference in deaths (RR 1.26, 95% CI [0.70, 2.27]). MA vs. no treatment: MA patients gained weight (MD 1.45 kg, 95% CI [0.15, 2.75]) but did not gain QOL (standardized mean difference 3.89 95% CI [-14, 6.28]). There was no increase in adverse events (RR 0.90, 95% CI [0.39, 2.08]) or deaths (RR 1.01, 95% CI [0.42, 2.45]). MA vs. active drugs: MA patients gained weight (MD 2.5 kg, 95% CI [0.37, 4.64]) but did not gain QOL (MD 0.20 95% CI [-0.02, 0.43]) and did not report an increase in adverse events (RR 1.05 95% CI [0.95, 1.16]) or in deaths (RR 1.53, 95% CI [1.02, 2.29]) Different doses of MA: in studies where lower doses of MA were compared with higher doses of MA, we did not find differences either in weight gain (MD -0.94 kg, 95% CI [-3.33, 1.45]), QOL (MD 0.31 95% CI [-0.19, 0.81]), or adverse events (RR 1.34, 95% CI [0.65, 2.76]). Thus, we cannot reach a conclusion for an optimal dose of MA.