Effectiveness of low dose cyproterone acetate compared to standard dose in feminizing hormone treatment: a single institutional retrospective pilot study.

Background: Data regarding the effectiveness of low-dose cyproterone acetate (CPA) in testosterone suppression as feminizing hormone therapy (FHT) in individuals assigned male at birth (AMAB) are sparse. Aim: To assess the effectiveness in testosterone suppression using low-dose CPA (<25 mg/day) compared to standard-dose CPA (25-50 mg/day) in FHT. Methods: A retrospective cohort study of 59 individuals AMAB using CPA was done at a tertiary care center in Bangkok, Thailand between January 2014 and July 2022. Outcomes: The main outcomes included a median time when the testosterone was suppressed (<50 ng/dL), the proportion of individuals AMAB who achieved the targeted testosterone level at 3 months, and the testosterone level at each follow-up. Changes in clinical data were assessed. Results: Among 59 individuals AMAB, 37 initiated CPA with available testosterone levels at the 3-month follow-up. Twenty-two individuals AMAB started with low-dose CPA (12.5 mg/day), and 15 individuals AMAB started with standard-dose CPA. The median time to reach targeted testosterone was 3 months in both groups (adjusted hazard ratio 0.60, P = .489). At 3 months, 72.7% of those on low-dose CPA and 86.7% of those on standard-dose CPA achieved targeted testosterone (adjusted relative risk 0.85, P = .606). Testosterone levels at all follow-up visits were not significantly different. The standard dose group had higher high-density lipoprotein cholesterol (HDL-C) but lower low-density lipoprotein cholesterol (LDL-C) and alanine aminotransferase (ALT). Clinical Translation: This study supports a paradigm shift toward using lower-dose CPA in FHT. Strengths and Limitations: This is one of a few studies showing the effectiveness of low-dose CPA in testosterone suppression within 3 months. Limitations include a small sample size and missing data. Conclusions: Testosterone suppression is comparable between CPA 12.5 mg/day and the standard dose in FHT.

AOP Report: An Upstream Network for Reduced Androgen Signaling Leading to Altered Gene Expression of Androgen Receptor-Responsive Genes in Target Tissues.

Adverse outcome pathways (AOPs) can aid with chemical risk assessment by providing plausible links between chemical activity at the molecular level and effect outcomes in intact organisms. Because AOPs can be used to infer causality between upstream and downstream events in toxicological pathways, the AOP framework can also facilitate increased uptake of alternative methods and new approach methodologies to help inform hazard identification. However, a prevailing challenge is the limited number of fully developed and endorsed AOPs, primarily due to the substantial amount of work required by AOP developers and reviewers. Consequently, a more pragmatic approach to AOP development has been proposed where smaller units of knowledge are developed and reviewed independent of full AOPs. In this context, we have developed an upstream network comprising key events (KEs) and KE relationships related to decreased androgen signaling, converging at a nodal KE that can branch out to numerous adverse outcomes (AOs) relevant to androgen-sensitive toxicological pathways. Androgen signaling represents an extensively studied pathway for endocrine disruption. It is linked to numerous disease outcomes and can be affected by many different endocrine-disrupting chemicals. Still, pathways related to disrupted androgen signaling remain underrepresented in the AOP-wiki, and endorsed AOPs are lacking. Given the pivotal role of androgen signaling in development and function across vertebrate taxa and life stages of both sexes, this upstream AOP network serves as a foundational element for developing numerous AOPs. By connecting the upstream network with various downstream AOs, encompassing different species, it can also facilitate cross-species extrapolations for hazard and risk assessment of chemicals. Environ Toxicol Chem 2024;00:1-9. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

"One a Day Keeps the Prison Away": Understanding the Experiences of Individuals Convicted of Sexual Offences Receiving Anti-Androgens for the Treatment of Problematic Sexual Arousal.

Problematic sexual arousal (PSA) is an umbrella term to describe a range of clinical presentations related to excessive sexual thinking (e.g., sexual preoccupation) and sexual behavior (e.g., hypersexuality). Although such concepts are known to affect sexual recidivism among individuals convicted of sexual offences, PSA is not routinely or directly targeted in offending behavior programs in England and Wales. However, in recent years, there have been moves to incorporate pharmacological interventions for addressing this among people with sexual offence histories. Although some work to understand the experiences of those taking SSRI medication for this purpose has emerged, little is known about the experiences of service users taking anti-androgen medication. In this study, we interviewed all individuals in prison taking anti-androgens for the treatment of problematic sexual arousal following convictions for sexual offences in England at the time of data collection (N = 10). Using a phenomenologically oriented thematic analysis, we established themes pertaining to "Differing needs: Motivations for treatment," "Medication as a risk management strategy," and how the medication helped the men in their pursuit of "Discovering a 'new me'." This work contributes important knowledge to inform the development of ethical and effective prescribing of anti-androgen medication with this population and offer recommendations for both future research and the development of clinical practice.

Case Series: "Silent" Spinal Epidural Metastases in Metastatic Castrate-Resistant Prostate Cancer.

Introduction: Spinal epidural metastases (SEM) are an uncommon phenomenon and traditionally occur as a preterminal event in heavily pre-treated patients. The introduction of novel anti-androgen therapies, such as enzalutamide and abiraterone acetate, has greatly improved the survival of patients with metastatic prostate cancer but may be changing the pattern of disease. Case Presentation: Four patients diagnosed with metastatic castrate-resistant prostate cancer (CRPC) were commenced on enzalutamide prior to chemotherapy. Baseline scans in all patients demonstrated extensive bony disease and lymph node involvement. All patients experienced a moderate initial PSA response to treatment (median PSA at baseline 53.5 ng/mL to median nadir 24.5 ng/mL). In all four cases, clinical presentation of spinal cord compression was unexpected with no prodromal neurological symptoms, PSA levels either stable or slowly rising, and CT scans and whole-body bone scans showing stable disease at other metastatic sites. Whole-spine MRI on presentation of neurological deficits showed epidural and dural metastases on the background of stable bone disease. Spinal cord compression occurred at a median of 11.4 months after starting enzalutamide. Conclusion: Clinicians should be aware of this change in the pattern of CRPC in patients treated with novel anti-androgen therapy. Onset of "silent" spinal cord compression due to SEM rather than bone metastases, can occur relatively early with minimal warning despite stable disease on PSA and standard imaging. Differential progression in nontraditional sites suggests that research into the androgen microenvironment in a wide range of tissue sites should be undertaken, and may explain why prostate cancer metastasizes preferentially to bone and lymph nodes.

Efficacy and safety of anti-androgens in the management of polycystic ovary syndrome: a systematic review and meta-analysis of randomised controlled trials.

Background: Anti-androgens and combined oral contraceptive pills (COCPs) may mitigate hyperandrogenism-related symptoms of polycystic ovary syndrome (PCOS). However, their efficacy and safety in PCOS remain unclear as previous reviews have focused on non-PCOS populations. To inform the 2023 International Evidence-based Guideline in PCOS, we conducted the first systematic review and meta-analysis investigating the efficacy and safety of anti-androgens in the management of hormonal and clinical features of PCOS. Methods: We systematically searched MEDLINE, Embase, PsycInfo, All EBM reviews, and CINAHL up to 28th June 2023 for randomised controlled trials (RCTs) examining oral anti-androgen use, alone or in combination with metformin, COCPs, lifestyle, or other interventions, in women of any age, with PCOS diagnosed by Rotterdam, National Institutes of Health or Androgen Excess & PCOS Society criteria, and using a form of contraception. Non-English studies and studies of less than 6 months duration or which used the same anti-androgen regimen in both/all groups were excluded in order to establish efficacy for the clinical outcomes of interest. Three authors screened articles against selection criteria and assessed risk of bias and quality using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Critical outcomes (prioritised during guideline development for GRADE purposes) included weight, body mass index (BMI), irregular cycles, hirsutism, liver function, and quality of life. Random effects meta-analyses were conducted where appropriate. This study is registered with PROSPERO, CRD42022345640. Findings: From 1660 studies identified in the search, 27 articles comprising 20 unique studies were included. Of these, 13 studies (n = 961) were pooled in meta-analysis. Seven studies had a high risk of bias, nine moderate and four low. Anti-androgens included finasteride, flutamide, spironolactone, or bicalutamide. In meta-analysis, anti-androgens + lifestyle were superior to metformin + lifestyle for hirsutism (weighted mean difference [WMD] [95% CI]: -1.59 [-3.06, -0.12], p = 0.03; I2 = 74%), SHBG (7.70 nmol/l [0.75, 14.66], p = 0.03; I2 = 0%), fasting insulin and fasting insulin: glucose ratio (-2.11 µU/ml [-3.97, -0.26], p = 0.03; I2 = 0% and -1.12 [-1.44, -0.79], p < 0.0001, I2 = 0%, respectively), but were not superior to placebo + lifestyle for hirsutism (-0.93, [-3.37, 1.51], p = 0.45; I2 = 76%) or SHBG (9.72 nmol/l [-0.71, 20.14], p = 0.07; I2 = 31%). Daily use was more effective for hirsutism than use every three days (-3.48 [-4.58, -2.39], p < 0.0001, I2 = 1%), and resulted in lower androstenedione levels (-0.30 ng/ml [-0.50, -0.10], p = 0.004; I2 = 0%). Combination treatment with anti-androgens + metformin + lifestyle resulted in lower testosterone compared with metformin + lifestyle (-0.29 nmol/l [-0.52, -0.06], p = 0.01; I2 = 61%), but there were no differences in hirsutism when anti-androgens + metformin + lifestyle were compared with either anti-androgens + lifestyle or metformin + lifestyle. In limited meta-analyses (n = 2 trials), combining anti-androgens with COCP resulted in poorer lipid profiles compared with COCP ± placebo, with no differences in other outcomes. Interpretation: Current evidence does not support the use of anti-androgens preferentially to COCPs to treat hyperandrogenism in PCOS. Anti-androgens could be considered to treat hirsutism in PCOS, where COCPs are contraindicated, poorly tolerated, or present a sub-optimal response after a minimum 6-month period, with consideration of clinical context and individual risk factors and characteristics. Funding: National Health and Medical Research Council (NHMRC) of Australia Monash University.

Evaluation of the Usefulness of Topological Indices for Predicting Selected Physicochemical Properties of Bioactive Substances with Anti-Androgenic and Hypouricemic Activity.

Due to the observed increase in the importance of computational methods in determining selected physicochemical parameters of biologically active compounds that are key to understanding their ADME/T profile, such as lipophilicity, there is a great need to work on accurate and precise in silico models based on some structural descriptors, such as topological indices for predicting lipophilicity of certain anti-androgenic and hypouricemic agents and their derivatives, for which the experimental lipophilicity parameter is not accurately described in the available literature, e.g., febuxostat, oxypurinol, ailanthone, abiraterone and teriflunomide. Therefore, the following topological indices were accurately calculated in this paper: Gutman (M, Mν), Randic (0χ, 1χ, 0χν, 1χν), Wiener (W), Rouvray-Crafford (R) and Pyka (A, 0B, 1B) for the selected anti-androgenic drugs (abiraterone, bicalutamide, flutamide, nilutamide, leflunomide, teriflunomide, ailanthone) and some hypouricemic compounds (allopurinol, oxypurinol, febuxostat). Linear regression analysis was used to create simple linear correlations between the newly calculated topological indices and some physicochemical parameters, including lipophilicity descriptors of the tested compounds (previously obtained by TLC and theoretical methods). Our studies confirmed the usefulness of the obtained linear regression equations based on topological indices to predict ADME/T important parameters, such as lipophilicity descriptors of tested compounds with anti-androgenic and hypouricemic effects. The proposed calculation method based on topological indices is fast, easy to use and avoids valuable and lengthy laboratory experiments required in the case of experimental ADME/T studies.

Detection of anti-androgenic activity of chemicals in fish studies: a data review.

A systematic review was conducted on the sensitivity of fish testing guidelines to detect the anti-androgenic activity of substances. Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) was used to investigate the conservation of the androgen receptor (AR) between humans and fish, and among fish species recommended in test guidelines. The AR is conserved between fish species and humans (i.e. ligand binding domain [LBD] homology ≥70%) and among the recommended fish species (LBD homology >85%). For model anti-androgens, we evaluated literature data on in vitro anti-androgenic activity in fish-specific receptor-based assays and changes in endpoints indicative of endocrine modulation from in vivo studies. Anti-androgenic activity was most consistently and reliably detected in in vitro and in vivo mechanistic studies with co-exposure to an androgen (spiggin in vitro assay, Rapid Androgen Disruption Activity Reporter [RADAR] Assay, and Androgenised Female Stickleback Screen). Regardless of study design (Fish Short-Term Reproduction Assay [FSTRA], Fish Sexual Development Test [FSDT], partial or full life-cycle tests), or endpoint (vitellogenin, secondary sexual characteristics, gonadal histopathology, sex ratio), there was no consistent evidence for detecting anti-androgenic activity in studies without androgen co-exposure, even for the most potent substances (while less potent substances may induce no (clear) response). Therefore, based on studies without androgen co-exposure (35 FSTRAs and 22 other studies), the other studies (including the FSDT) do not outperform the FSTRA for detecting potent anti-androgenic activity, which if suspected, would be best addressed with a RADAR assay. Overall, fish do not appear particularly sensitive to mammalian anti-androgens.

Clinical characteristics of patients with metastatic castration-resistant prostate cancer after treatment with combined androgen blockade.

BACKGROUND: Although the second-generation androgen receptor inhibitors and taxanes have recently been recommended for the initial treatment of metastatic prostate cancer, bicalutamide and flutamide are still used in a large number of cases. Therefore, it is important to elucidate the clinical characteristics of these treated CRPC cases and their sensitivity to the currently used therapeutic agents. We aimed to examine the outcomes of metastatic castration-resistant prostate cancer following combined androgen blockade as initial therapy at our institution. METHODS: Ninety-four patients who developed metastatic castration-resistant prostate cancer after hormonal treatment with combined nonsteroidal androgen receptor antagonists and continuous androgen deprivation therapy between January 2015 and December 2020 were included. The presence of visceral metastases, duration of efficacy of each treatment, and overall survival after castration-resistant prostate cancer were evaluated. RESULTS: Patients with a longer duration of castration-resistant prostate cancer tended to have a longer response duration to subsequent enzalutamide administration (p = 0.003). Patients who achieved a 90% reduction in prostate-specific antigen levels with enzalutamide had a significantly better castration-resistant prostate cancer prognosis (p = 0.002). Meanwhile, those with visceral metastases at the time of castration-resistant prostate cancer diagnosis had a significantly poorer prognosis (p < 0.001). A positive correlation was observed between the treatment efficacy of abiraterone and taxanes for castration-resistant prostate cancer. CONCLUSION: The study provides scientific evidence to support that patients with longer time to castration-resistant prostate cancer are more sensitive to enzalutamide, and the use of abiraterone between docetaxel and cabazitaxel has favorable prognostic impact. These findings provide instrumental evidence that can enable better treatment selection for prostate cancer patients.

Visceral Metastasis Predicts Response to New Hormonal Agents in Metastatic Castration-Sensitive Prostate Cancer.

Visceral metastasis (VM) and a higher number of bone metastasis generally define high volume/risk in patients with metastatic castration-sensitive prostate cancer (mCSPC). Subgroup analysis of pivotal trials did not show a clear benefit of second-generation non-steroidal anti-androgens (NSAAs) in patients with VM. However, subgroup analysis of the trial assessing abiraterone acetate, a CYP 17 inhibitor, plus prednisone (AAP) showed an improved overall survival (OS) in patients with mCSPC with VM. We searched MEDLINE, Web of Science, and congress abstracts for the phase III randomized controlled trials of second-generation NSAAs and AAP in patients with mCSPC. In this pooled analysis, we included 6485 patients from the 6 phase III trials. The rate of patients with VM was 15.2%. Interestingly, in contrast to NSAAs, AAP seems to be effective in improving OS among patients with VM (hazard ratio, HR: 0.89, 95% CI, 0.72-1.11, P = .30 for second-generation NSAAs; HR: 0.58, 95% CI, 0.40-0.84, P = .004 for AAP). In contrast, both second-generation NSAAs (HR: 0.63, 95% CI, 0.57-0.70, P < .001) and AAP (HR: 0.68, 95% CI, 0.57-0.81, P < .001) improved OS in patients without VM. In this pooled analysis, we demonstrate that while AAP provided an OS improvement in patients with VM, second-generation NSAAs did not demonstrate a similar OS benefit in this population.

Successful restoration of spermatogenesis following gender-affirming hormone therapy in transgender women.

Increasing numbers of transgender individuals are presenting for gender-affirming medical care. For trans women, gender-affirming hormone therapy (GAHT) promotes feminization but also inhibits spermatogenesis. There is a common untested assumption that this inhibition is permanent, resulting in infertility. In this longitudinal study, we report the recovery of viable spermatozoa in nine trans women who stopped GAHT for reproductive purposes. Our preliminary findings suggest that the negative impact of GAHT on spermatogenesis can be reversed, casting doubt on previous claims that GAHT in trans women inevitably leads to permanent infertility. Larger studies are needed to confirm our findings, which have implications not only for fertility counseling and the reproductive options of transgender individuals but also efforts to restrict access to GAHT based on fertility grounds.

Long-Lasting Effects of Spironolactone after its Withdrawal in Patients with Hyperandrogenic Skin Disorders.

OBJECTIVE: Hyperandrogenic skin disorders, such as hirsutism, acne and alopecia, affect approximately 10-20% of women of reproductive age, reducing quality of life and causing psychological impairment. Spironolactone is a commonly used antiandrogen, especially in women who are not sexually active or have contraindications to hormonal contraceptives. The aim of this study was to evaluate the effects of spironolactone, especially after its withdrawal, in patients with hyperandrogenic skin disorders. METHODS: Retrospective analysis of 63 women with hyperandrogenic skin symptoms due to polycystic ovary syndrome (PCOS), treated with spironolactone for at least 6 months as first-line treatment. RESULTS: After a mean time of treatment of 25.7 months, all patients reported a significant improvement in hyperandrogenic skin disorders; only 5 patients were dissatisfied and required the addition of an oral contraceptive. The therapy was well tolerated and the most frequent side-effect was intermestrual bleeding in 68.2% of cases, affecting mainly classic PCOS phenotype. Thirthyeight patients showed prolonged effects 33.7 months after spironolactone withdrawal, whereas 20 relapsed 17.5 months after discontinuation. No significant difference in clinical and biochemical parameters was observed between these two groups both at baseline and after spironolactone treatment. Ovulatory PCOS patients were treated for a shorter time and reported earlier relapse than classic PCOS patients. CONCLUSION: Spironolactone is an effective and safe treatment for hyperandrogenic skin disorders, showing long-lasting effects even several months after its discontinuation.

Exposure to the pesticides linuron, dimethomorph and imazalil alters steroid hormone profiles and gene expression in developing rat ovaries.

Inhibition of androgen signaling during critical stages of ovary development can disrupt folliculogenesis with potential consequences for reproductive function later in life. Many environmental chemicals can inhibit the androgen signaling pathway, which raises the question if developmental exposure to anti-androgenic chemicals can negatively impact female fertility. Here, we report on altered reproductive hormone profiles in prepubertal female rats following developmental exposure to three pesticides with anti-androgenic potential: linuron (25 and 50 mg/kg bw/d), dimethomorph (60 and 180 mg/kg bw/d) and imazalil (8 and 24 mg/kg bw/d). Dams were orally exposed from gestational day 7 (dimethomorph and imazalil) or 13 (linuron) until birth, then until end of dosing at early postnatal life. Linuron and dimethomorph induced dose-related reductions to plasma corticosterone levels, whereas imazalil mainly suppressed gonadotropin levels. In the ovaries, expression levels of target genes were affected by linuron and dimethomorph, suggesting impaired follicle growth. Based on our results, we propose that anti-androgenic chemicals can negatively impact female reproductive development. This highlights a need to integrate data from all levels of the hypothalamic-pituitary-gonadal axis, as well as the hypothalamic-pituitary-adrenal axis, when investigating the potential impact of endocrine disruptors on female reproductive development and function.

Selective Sensing of Darolutamide and Thalidomide in Pharmaceutical Preparations and in Spiked Biofluids.

Selective spectrofluorometric sensing is introduced for the analysis of non-steroidal anti-androgens, darolutamide, and thalidomide in pharmaceutical preparations and biofluids. An organic fluorophore, 2,4,8,10-tetramethylpyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine 2 was synthesized in our laboratories by new simple methods to act as a fluorescent reagent for the analysis of the studied drugs. Elemental and spectral analyses were performed to approve the fluorophore structure. The fluorophore possesses a fluorescence at λem 422 nm when excited at 328 nm. The interaction between the studied drugs and the fluorophore was found to be quenching. The quenching mechanisms were studied and interpreted through the Stern-Volmer relationship. Moreover, the Stern-Volmer constants were calculated for the quenching interactions of both drugs. The introduced method was validated for the estimation of darolutamide and thalidomide in dosage forms, plasma, and urine, offering good percentage recoveries.

Changes in prostate-specific antigen kinetics during androgen-deprivation therapy as a predictor of response to abiraterone in chemonaïve patients with metastatic castration-resistant prostate cancer.

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) has a poor prognosis. Abiraterone acetate (AA), enzalutamide, and chemotherapy are first-line treatments for patients with mCRPC. This study examined prognostic factors for AA response in the form of prostate-specific antigen (PSA) kinetics throughout androgen-deprivation therapy (ADT) in chemonaïve patients with mCRPC. MATERIALS AND METHODS: We retrospectively included data from 34 chemonaïve patients with mCRPC who had received AA at some point between January 2017 and December 2018. We separated patients into two study arms according to the decrease in PSA percentages after use of AA for 3 months. We correlated PSA kinetics parameters with response and compared the two study groups with respect to PSA kinetics. RESULTS: The patients' median age was 77 years. In the total group of patients, 64% had a response to AA, whereas 35% did not. The ratio of the PSA level at nadir to the level during ADT was significantly higher in the AA-sensitive group (19.78 vs. 1.03, p=0.019). CONCLUSIONS: Patients who experienced a dramatic change in PSA level during ADT were more likely to be resistant to AA after progression to mCRPC. Chemotherapy rather than AA might be more suitable as a first-line treatment for these patients.

Androgen Receptor Inhibitors in the Treatment of Acne Vulgaris: Efficacy and Safety Profiles of Clascoterone 1% Cream.

The purpose of this narrative review is to provide a summary of the clinical trials on the efficacy and safety of clascoterone 1% cream (Winlevi) to grant providers an understanding of which patients will benefit most from this novel topical antiandrogen medication. Clascoterone 1% cream (Winlevi) offers a new and exciting treatment approach for a difficult and common skin condition such as acne vulgaris. This topical androgen antagonist is the first of its kind but will hopefully provoke investigations into other androgen receptor antagonists with similar or better efficacy.

Next Generation Risk Assessment of the Anti-Androgen Flutamide Including the Contribution of Its Active Metabolite Hydroxyflutamide.

In next generation risk assessment (NGRA), non-animal approaches are used to quantify the chemical concentrations required to trigger bioactivity responses, in order to assure safe levels of human exposure. A limitation of many in vitro bioactivity assays, which are used in an NGRA context as new approach methodologies (NAMs), is that toxicokinetics, including biotransformation, are not adequately captured. The present study aimed to include, as a proof of principle, the bioactivity of the metabolite hydroxyflutamide (HF) in an NGRA approach to evaluate the safety of the anti-androgen flutamide (FLU), using the AR-CALUX assay to derive the NAM point of departure (PoD). The NGRA approach applied also included PBK modelling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE). The PBK model describing FLU and HF kinetics in humans was developed using GastroPlus™ and validated against human pharmacokinetic data. PBK model-facilitated QIVIVE was performed to translate the in vitro AR-CALUX derived concentration-response data to a corresponding in vivo dose-response curve for the anti-androgenicity of FLU, excluding and including the activity of HF (-HF and +HF, respectively). The in vivo benchmark dose 5% lower confidence limits (BMDL05) derived from the predicted in vivo dose-response curves for FLU, revealed a 440-fold lower BMDL05 when taking the bioactivity of HF into account. Subsequent comparison of the predicted BMDL05 values to the human therapeutic doses and historical animal derived PoDs, revealed that PBK modelling-facilitated QIVIVE that includes the bioactivity of the active metabolite is protective and provides a more appropriate PoD to assure human safety via NGRA, whereas excluding this would potentially result in an underestimation of the risk of FLU exposure in humans.

Comparative Study of the Lipophilicity of Selected Anti-Androgenic and Blood Uric Acid Lowering Compounds.

This study aimed to evaluate the lipophilicity of a series substances lowering the concentration of uric acid in blood and anti-androgen drugs by thin-layer chromatography in reversed-phase systems (RP-TLC, RP-HPTLC) and computational methods. The chromatographic parameter of lipophilicity (RMW) of tested compounds was determined on three stationary phases, i.e., RP18F254, RP18WF254 and RP2F254, using ethanol-water, propan-2-ol-water and acetonitrile-water in various volume compositions as mobile phases. The chromatographic analysis led to determining the experimental value of the lipophilicity parameter for each of the tested compounds, including those for which the experimental value of the partition coefficient (logPexp) as a measure of lipophilicity is not well described in available databases, such as febuxostat, oxypurinol, ailanthone, abiraterone and teriflunomide. The chromatographic parameters of lipophilicity were compared with the logP values obtained with various software packages, such as AClogP, AlogPs, AlogP, MlogP, XlogP2, XlogP3, ACD/logP and logPKOWWIN. The obtained results indicate that, among selected chromatographic parameters of lipophilicity, both experimental and calculated logP values gave similar results, and these RP-TLC or RP-HPTLC systems can be successfully applied to estimate the lipophilicity of studied heterocyclic compounds belonging to two different pharmacological groups. This work also illustrates the similarity and difference existing between the tested compounds under study using the chemometric methods, such as principal component analysis (PCA) and cluster analysis (CA). In addition, a relatively new approach based on the sum of ranking differences (SRD) was used to compare the chromatographically obtained and theoretical lipophilicity descriptors of studied compounds.

Impact of New Systemic Therapies in Overall Survival in Non-Metastatic Castration Resistant Prostate Cancer: Systematic Review and Meta-Analysis.

There was a high medical need for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) when several next-generation anti-androgens (apalutamide, enzalutamide, and darolutamide) demonstrated clinically relevant delays in metastasis onset. However, to date, few publications have assessed the pooled effect of these treatments on overall survival (OS). We performed a systematic review and meta-analysis of all randomized, placebo-controlled studies investigating a systemic treatment in nmCRPC. Publications were identified by searching several databases on April 7, 2021. The primary objective of this analysis was to determine the OS benefit. Secondary outcomes included the relative risk (RR) of adverse events (AEs) and grade 3-4 AEs. A sensitivity analysis with simulated data was also conducted to examine the influence of the study designs on the results. Three randomized controlled studies (SPARTAN, PROSPER, ARAMIS) met our inclusion criteria. Pooled meta-analyses showed a significant benefit in OS with the active agents versus placebo (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.65-0.83), as well as increased risk of any grade (RR 1.09, 95% CI 1.01-1.17) and grade 3-4 AEs (RR 1.50, 95% CI 1.23-1.83). The sensitivity analysis with SPARTAN-like simulated populations demonstrated that when using ARAMIS statistical design, OS would be statistically significant in 98.1% of the cases, at a shorter follow-up and with lower number of events. First-line treatment of nmCRPC patients with anti-androgens increased OS with an acceptable safety profile. In light of the different study designs and follow-up, results should be interpreted separately.

Treatment Landscape of Nonmetastatic Castration-Resistant Prostate Cancer: A Window of Opportunity.

The treatment for nonmetastatic castration-resistant prostate cancer (nmCRPC) is a highly unmet medical need. The classic treatment approach for these patients-androgen deprivation therapy (ADT) alone-until metastatic progression is now considered suboptimal. Several randomized phase III clinical trials have demonstrated significant clinical benefits-including significantly better overall survival (OS)-for treatments that combine ADT with apalutamide, enzalutamide, and darolutamide. As a result, these approaches are now included in treatment guidelines and are considered a standard of care. In the present article, we discuss the changing landscape of the management of patients with nmCRPC.

UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications.

The UHRF1 and CDC6, oncogenes play critical roles in therapeutic resistance. In the present study, we found that UHRF1 mediates androgen receptor (AR)-regulated CDC6 transcription in prostate cancer cells. In prostate cancer tissues and cell lines, levels of UHRF1 and CDC6 were simultaneously upregulated, and this was associated with worse survival. UHRF1 silencing significantly promoted the cytotoxicity and anti-prostate cancer efficacy of bicalutamide in mouse xenografts by inhibiting CDC6 gene expression. UHRF1 promoted AR-regulated CDC6 transcription by binding to the CCAAT motif near the androgen response element (ARE) in the CDC6 promoter. We further found that UHRF1 promoted androgen-dependent chromatin occupancy of AR protein by recruiting the H3K9me2/3-specific demethyltransferase KDM4C and modifying the intense heterochromatin status. Altogether, we found for the first time that UHRF1 promotes AR-regulated CDC6 transcription through a novel chromatin modification mechanism and contributes to anti-AR drug resistance in prostate cancer. Targeting AR and UHRF1 simultaneously may be a novel and promising therapeutic modality for prostate cancer.