A thiophene functionalized Hf(IV) organic framework for the detection of anti-neoplastic drug flutamide and biomolecule hemin and catalysis of Friedel-Crafts alkylation.

Development, rapid detection and quantification of anticancer drugs in biological samples are crucial for effective drug monitoring. The present work describes the design of a metal-organic framework (MOF) between Hf(IV) ion and 2-(thiophene-2-carboxamido)terephthalic acid linker (surface area = 571 m² g-1). Desolvated 1' displayed highly discriminative fluorescence sensing property for the anti-neoplastic drug flutamide and biomolecule hemin in aqueous medium in the presence of co-exiting biomolecules and ions. The MOF's response time for sensing flutamide and hemin was less than 5 s with low detection limits 1.5 and 0.08 nM respectively. Additionally, the MOF also demonstrated recyclability up to five cycles and maintained its sensing ability across different pH media, various water samples, and biological fluids. Experimental and theoretical analyses suggested photoinduced electron transfer and inner-filter effect in the presence of flutamide and Förster resonance energy transfer in the presence of hemin are most likely reasons behind the fluorescence quenching of MOF. Furthermore, the MOF demonstrated catalytic activity in Friedel-Crafts alkylation reactions, providing a 96% yield with slight decay in its activity over four uses. The enhanced activity of 1' is due to the functionalized thiophene moities through hydrogen bond donating sites, confirmed by series of control experiments.

Radiolabeling and preclinical animal model evaluation of DTPA coupled 99mTc-labelled flutamide complex ([99mTc]DTPA-FLUT) as a potential radiotracer for cancer imaging.

BACKGROUND: Advances in molecular imaging strategies have had an effect on precise diagnosis and treatment. Research has been intensified to develop more effective and versatile radiopharmaceuticals to uplift diagnostic efficiency and, consequently, the treatment. PURPOSE: To label the flutamide (FLUT) coupled with diethylenetriamine pentaacetate (DTPA) with technetium-99 m (99mTc) and to evaluate its binding efficiency with rhabdomyosarcoma (RMS) cancer cells. MATERIAL AND METHODS: Radiolabeling of FLUT with 185 MBq freshly eluted 99mTcO4-1 was carried out via DTPA bifunctional chelating agent using stannous chloride reducing agent at pH 5. The labeled compound was assessed for its purity using chromatography analysis, stability in saline and blood serum, AND charge using paper electrophoresis. Normal biodistribution was studied using a mouse model, while binding affinity with RMS cancer cells was studied using an internalization assay. The in vivo accumulation of RMS cancer cells in a rabbit model was monitored using a SPECT gamma camera. RESULTS: Radiolabeling reaction displayed a pharmaceutical yield of 97% and a stability assay showed >95% intact radiopharmaceutical up to 6 h in saline and blood serum. In vitro internalization studies showed the potential of [99mTc]DTPA-FLUT to enter into cancer cells. This biodistribution study showed rapid blood clearance and minimum uptake by body organs, and scintigraphy displayed the [99mTc]DTPA-FLUT uptake by lesion, induced by RMS cancer cell lines in rabbit. CONCLUSION: Stable, newly developed [99mTc]DTPA-FLUT seeks its way to internalize into RMS cancer cells, indicating it could be a potential candidate for the diagnosis of RMS cancer.

Spermatocytes are the terminals of germ cell differentiation in plateau zokor (Eospalax baileyi) during the non-breeding season.

Plateau zokor (Eospalax baileyi) is a subterranean rodent and seasonal breeder. During the non-breeding season, the testicles regress, leading to the arrest of spermatogenesis and loss of fertility. The identification of the specific germ cell type at which spermatogenesis is arrested, as well as potential regulatory factors during the non-breeding season, is important for understanding seasonal spermatogenesis in subterranean species. This study analyzed genes in spermatocytes of plateau zokor by referring to single-cell RNA results in mice. We discovered that spermatogenesis is arrested at the spermatocyte during the non-breeding season, which was corroborated via immunofluorescence staining results. The analysis of gene expression during different stages of meiotic prophase I has revealed that germ cell development may be arrested, starting from zygonema, during the non-breeding season. Meanwhile, we discovered that the apoptosis genes were up-regulated, leading to apoptosis in spermatocytes. To confirm that the germ cell differentiation was blocked during the non-breeding season due to a decrease in the androgen level, we used androgen receptor antagonist (flutamide) to intervene in the breeding season and found that the inner diameter of the seminiferous tubules was significantly reduced, spermatogenesis was arrested, and spermatocytes underwent apoptosis. This study revealed that spermatocytes are the terminal of germ cell differentiation in plateau zokor during the non-breeding season and that the arrest of differentiation is attributed to a decline in androgen levels. Our results complement the theoretical basis of seasonal reproduction in plateau zokor.

Sophorin mitigates flutamide-induced hepatotoxicity in wistar rats.

Flutamide is frequently used in the management of prostate cancer, hirsutism, and acne. It is a non-steroidal anti-androgenic drug and causes hepatotoxicity. The current study's objective is to evaluate sophorin's hepatoprotective effectiveness against flutamide-induced hepatotoxicity in Wistar rats. Sophorin is a citrus flavonoid glycoside, also known as rutin, which is a low molecular weight polyphenolic compound with natural antioxidant properties and reported to have promising hepatoprotective efficacy. In this study, sophorin was used at a dose of 100 mg/kg body weight in purified water via oral route for 4 week daily whereas, flutamide was used at a dose of 100 mg kg/b.wt for 4 weeks daily in 0.5% carboxy methyl cellulose (CMC) through the oral route for the induction of hepatotoxicity. Flutamide administration leads to enhanced reactive oxygen species (ROS) generation, an imbalance in redox homeostasis and peroxidation of lipid resulted in reduced natural antioxidant level in liver tissue. Our result demonstrated that sophorin significantly abrogate flutamide induced lipid peroxidation, protein carbonyl (PC), and also significantly increasesed in enzymatic activity/level of tissue natural antioxidant such as reduced glutathione(GSH), glutathione reductase(GR), catalase, and superoxide dismutase(SOD). Additionally, sophorin reduced the activity of cytochrome P450 3A1 in liver tissue which was elevated due to flutamide treatment. Furthermore, sophorin treatment significantly decreased the pro-inflammatory cytokines (TNF-α and IL-6) level. Immunohistochemical analysis for the expression of inflammatory proteins (iNOS and COX-2) in hepatic tissue was decreased after sophorin treatment against flutamide-induced hepatotoxicity. Moreover, sophorin suppressed the infiltration of mast cells in liver tissue which further showed anti-inflammatory potential of sophorin. Our histological investigation further demonstrated sophorin's hepatoprotective function by restoring the typical histology of the liver. Based on the aforementioned information, we are able to come to the conclusion that sophorin supplementation might benefit wistar rats with flutamide-induced hepatic damage by reducing oxidative stress and hepatocellular inflammation.

Antiandrogen Flutamide-Induced Restoration of miR-449 Expression Mitigates Functional Biomarkers Associated with Ovarian Cancer Risk.

Background: The involvement of the androgen and androgen receptor (AR) pathway in the development of epithelial ovarian cancer is increasingly recognized. However, the specific mechanisms by which anti-androgen agents, such as flutamide, may prevent ovarian cancer and their efficacy remain unknown. We examined the effects of flutamide on the miRNA expression profile found in women at high risk (HR) for ovarian cancer. Methods: Ovarian and tubal tissues, free from ovarian, tubal, peritoneal cancers, and serous tubal intraepithelial carcinoma (STIC), were collected from untreated and flutamide-treated HR women. Low-risk (LR) women served as controls. Transcriptomic miRNA sequencing was performed on these 3 sample cohorts. The miRNAs that showed the most notable differential expression were subjected to functional assays in primary ovarian epithelial cells and ovarian cancer cells. Results: Flutamide treatment demonstrated a normalization effect on diminished miRNA levels in HR tissues compared to LR tissues. Particularly, the miR-449 family was significantly upregulated in HR ovarian tissues following flutamide treatment, reaching levels comparable to those in LR tissues. MiR-449a and miR-449b-5p, members of the miR-449 family, were computationally predicted to target the mRNAs of AR and colony-stimulating factor 1 receptor (CSF1R, also known as c-fms), both of which are known contributors to ovarian cancer progression, with emerging evidence also supporting their roles in ovarian cancer initiation. These findings were experimentally validated in primary ovarian epithelial cells and ovarian cancer cell lines (SKOV3 and Hey): flutamide treatment resulted in elevated levels of miR-449a and miR-449b-5p, and introducing mimics of these miRNAs reduced the mRNA and protein levels of CSF1R and AR. Furthermore, introducing miR-449a and miR-449b-5p mimics showed inhibitory effects on the migration and proliferation of ovarian cancer cells. Conclusion: Flutamide treatment restored the reduced expression of miR-449a and miR-449b-5p in HR tissues, thereby decreasing the expression of CSF1R and AR, functional biomarkers associated with an increased risk of ovarian cancer. In addition to the known direct binding of flutamide to the AR, we found that flutamide also suppresses AR expression via miR-449a and miR-449b-5p upregulation, revealing a novel dual-inhibitory mechanism on the AR pathway. Taken together, our study highlights mechanisms supporting the chemopreventive potential of flutamide in ovarian cancer, particularly in HR patients with reduced miR-449 expression.

The High Stability and Selectivity of Electrochemical Sensor Using Low-Cost Diamond Nanoparticles for the Detection of Anti-Cancer Drug Flutamide in Environmental Samples.

In this study, a novel electrochemical sensor was created by fabricating a screen-printed carbon electrode with diamond nanoparticles (DNPs/SPCE). The successful development of the sensor enabled the specific detection of the anti-cancer drug flutamide (FLT). The DNPs/SPCE demonstrated excellent conductivity, remarkable electrocatalytic activity, and swift electron transfer, all of which contribute to the advantageous monitoring of FLT. These qualities are critical for monitoring FLT levels in environmental samples. Various structural and morphological characterization techniques were employed to validate the formation of the DNPs. Remarkably, the electrochemical sensor demonstrated a wide linear response range (0.025 to 606.65 µM). Additionally, it showed a low limit of detection (0.023 µM) and high sensitivity (0.403 µA µM-1 cm-2). Furthermore, the practicability of DNPs/SPCE can be successfully employed in FLT monitoring in water bodies (pond water and river water samples) with satisfactory recoveries.

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Characteristics of adverse drug reactions induced by flutamide and bicalutamide: a real-world pharmacovigilance study using FAERS.

BACKGROUND: Flutamide and bicalutamide are indicated for the management of prostate metastatic carcinoma. The current study evaluated the adverse drug reactions related to flutamide and bicalutamide in a real-world setting. METHODS: To quantify the signals of flutamide and bicalutamide associated adverse events (AEs), we used the US Food and Drug Administration Adverse Event Reporting System (FAERS) for this pharmacovigilance study using established pharmacovigilance methods. RESULTS: A total of 2711 AEs of flutamide were investigated as the primary suspected; 522 AEs were related to prostate cancer. A total of 4459 AEs were investigated as the primary suspected for bicalutamide; 2251 AEs were related to prostate cancer. The analysis demonstrated 29 signals for flutamide and 84 for bicalutamide. Liver function test was the most common AEs for flutamide, and malignant neoplasm progression was the most common for bicalutamide. The signal strength of Dementia Alzheimer's type was 26.53 (17.89-39.35) and 26.33 (607.34), which had the highest strength for flutamide. Anti-androgen withdrawal syndrome exhibited the strongest signal for bicalutamide. Generating awareness of rare AEs that were not listed on the label is critical. CONCLUSIONS: The analysis of the AE signals may provide support for prescribing flutamide and bicalutamide.

The Effect of Mesenchymal Stem Cells Derived-Conditioned Media in Combination with Oral Anti-Androgenic Drugs on Male Pattern Baldness: An Animal Study.

OBJECTIVE: Androgenetic alopecia (AGA) is a prevalent form of hair loss, mainly caused by follicular sensitivity to androgens. Despite developing different anti-androgen treatment options, the success rate of these treatments has been limited. Using animal models, this study evaluated the therapeutic effects of umbilical cord (UC) stem cell conditioned media (CM) combined with oral anti-androgens for hair regeneration. MATERIALS AND METHODS: In this experimental study, Poloxamer 407 (P407) was used as a drug carrier for subcutaneous testosterone injection. AGA models were treated with oral finasteride, oral flutamide, and CM injections. Samples were thoroughly evaluated and compared using histological, stereological, and molecular analyses. RESULTS: Injecting CM-loaded hydrogel alone or combined with oral intake of anti-androgens improved hair regeneration. These treatments could promote hair growth by inducing hair follicles in the anagen stage and shortening the telogen and catagen phases. Furthermore, the combination treatment led to an upregulation of hair induction gene expression with a downregulation of inflammation genes. CONCLUSION: Through a reduction in inflammation, injection of CM-loaded hydrogel alone or combined with oral intake of anti-androgens induces the hair cell cycle with regeneration in damaged follicles. Hence, this could be a promising therapeutic method for AGA patients.

PCDH1, a poor prognostic biomarker and potential target for pancreatic adenocarcinoma metastatic therapy.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is an aggressive solid tumour characterised by few early symptoms, high mortality, and lack of effective treatment. Therefore, it is important to identify new potential therapeutic targets and prognostic biomarkers of PAAD. METHODS: The Cancer Genome Atlas and Genotype-Tissue Expression databases were used to identify the expression and prognostic model of protocadherin 1 (PCDH1). The prognostic performance of risk factors and diagnosis of patients with PAAD were evaluated by regression analysis, nomogram, and receiver operating characteristic curve. Paraffin sections were collected from patients for immunohistochemistry (IHC) analysis. The expression of PCDH1 in cells obtained from primary tumours or metastatic biopsies was identified using single-cell RNA sequencing (scRNA-seq). Real-time quantitative polymerase chain reaction (qPCR) and western blotting were used to verify PCDH1 expression levels and the inhibitory effects of the compounds. RESULTS: The RNA and protein levels of PCDH1 were significantly higher in PAAD cells than in normal pancreatic ductal cells, similar to those observed in tissue sections from patients with PAAD. Aberrant methylation of the CpG site cg19767205 and micro-RNA (miRNA) hsa-miR-124-1 may be important reasons for the high PCDH1 expression in PAAD. Up-regulated PCDH1 promotes pancreatic cancer cell metastasis. The RNA levels of PCDH1 were significantly down-regulated following flutamide treatment. Flutamide reduced the percentage of PCDH1 RNA level in PAAD cells Panc-0813 to < 50%. In addition, the PCDH1 protein was significantly down-regulated after Panc-0813 cells were incubated with 20 µM flutamide and proves to be a potential therapeutic intervention for PAAD. CONCLUSION: PCDH1 is a key prognostic biomarker and promoter of PAAD metastasis. Additionally, flutamide may serve as a novel compound that down-regulates PCDH1 expression as a potential treatment for combating PAAD progression and metastasis.

Resistance to 2-Hydroxy-Flutamide in Prostate Cancer Cells Is Associated with the Downregulation of Phosphatidylcholine Biosynthesis and Epigenetic Modifications.

In this study, we examined the metabolic adaptations of a chemoresistant prostate cancer cell line in comparison to a sensitive cell line. We utilized prostate cancer LNCaP cells and subjected them to a stepwise increase in the antiandrogen 2-hydroxy-flutamide (FLU) concentration to generate a FLU-resistant cell line (LN-FLU). These LN-FLU cells displayed characteristics of cancer stem cells, exhibited drug resistance, and showed a significantly reduced expression of Cyclin D1, along with the overexpression of p16, pointing to a proliferation arrest. In comparing the cancer stem-like LN-FLU cells to the LNCaP cells, we observed a decrease in the expression of CTP-choline cytidylyl transferase α (CCTα), as well as a decline in choline kinase, suggesting altogether a downregulation of the phosphatidylcholine biosynthetic pathway. In addition, we found decreased levels of the protein methyl transferase PRMT2 and the upregulation of the histone deacetylase Sirtuin1 (Sirt1). Analysis of the human prostate cancer samples revealed similar results in a population with high expressions of the stem cell markers Oct4 and ABCB1A1. Our findings suggest that the adaptation of prostate cancer cells to antiandrogens could induce reprogramming into stem cells that survive in a low phosphocholine metabolism and cell cycle arrest and display drug resistance.

Exploring the potential of single-metals (Cu, Ni, Zn) decorated Al12N12 nanostructures as sensors for flutamide anticancer drug.

In recent years, scientists have been actively exploring and expanding biosensor technologies and materials to meet the growing societal demands in healthcare and other fields. This study aims to revolutionize biosensors by using density functional theory (DFT) at the cutting-edge B3LYP-GD3BJ/def2tzsvp level to investigate the sensing capabilities of (Cu, Ni, and Zn) doped on Aluminum nitride (Al12N12) nanostructures. Specifically, we focus on their potential to detect, analyze, and sense the drug flutamide (FLU) efficiently. Through advanced computational techniques, we explore molecular interactions to pave the way for highly effective and versatile biosensors. The adsorption energy values of -38.76 kcal/mol, -39.39 kcal/mol, and -39.37 kcal/mol for FLU@Cu-Al12N12, FLU@Ni-Al12N12, and FLU@Zn-Al12N12, respectively, indicate that FLU chemically adsorbs on the studied nanostructures. The reactivity and conductivity of the system follow a decreasing pattern: FLU@Cu-Al12N12 > FLU@Ni-Al12N12 > FLU@Zn-Al12N12, with a band gap of 0.267 eV, 2.197 eV, and 2.932 eV, respectively. These results suggest that FLU preferably adsorbs on the Al12N12@Cu surface. Natural bond orbital analysis reveals significant transitions in the studied system. Quantum theory of atom in molecule (QTAIM) and Non-covalent interaction (NCI) analysis confirm the nature and strength of interactions. Overall, our findings indicate that the doped surfaces show promise as electronic and biosensor materials for detection of FLU in real-world applications. We encourage experimental researchers to explore the use of (Cu, Ni, and Zn) doped on Aluminum nitride (Al12N12), particularly Al12N12@Cu, for biosensor applications.

Androgenetic alopecia: An update.

Androgenetic alopecia (AGA) is the most common nonscarring alopecia and is characterised by distinct gradual patterned hair loss. AGA is mediated by genetic predisposition and excessive follicular sensitivity to androgens, mainly in males, leading to the progressive conversion of scalp terminal hair into vellus hair. Although highly prevalent, it is not fatal but may have a severe psychosocial impact, especially on females and younger males. Significant advances have been made in understanding AGA's epidemiology and pathophysiology, but only 2 drugs remain approved by the FDA - finasteride and minoxidil. Prolonged use of these drugs, is a prerequisite for enhanced treatment response. However, this leads to poor medication adherence and adverse effects from extended use eg, the "postfinasteride syndrome" which persists beyond stopping the drug. Hence, there is a need for research on more effective alternative treatments for AGA, with fewer side effects. This paper reviewed recent advances in AGA pathophysiology and its treatment options. The recently characterized structure of type 2, 5-alpha reductase holds significance in comprehending present and prospective treatments of AGA.

Follow up of the prostate cancer treatment based on a novel sensing method for anti-prostate cancer drug (flutamide).

In this work, novel modified electrode (MXene/MIL-101(Cr)/GCE) are manufactured through simple layer-by-layer immobilization procedure. The fabricated electrochemical sensor was utilized for electrochemical sensing of flutamide in biological fluids. The immobilization of both MXene and metal-organic framework (MOF) materials on the electrode surface could improve the electrochemical performance of the modified glassy carbon electrode (GCE) towards flutamide due to the synergic effects. The established sensor illustrated the significant sensing ability for the determination of flutamide. The influence of solution pH and volume ratio of MXene/MIL-101(Cr) on electrochemical performance of the modified GCE was researched and optimized. The sensor demonstrated a favorable detection limit of 0.009 µM and a linear range of 0.025-100 µM using differential pulse voltammetry (DPV) technique. The suggested assay illustrated an excellent sensing efficiency towards flutamide in body fluids with recoveries ranging from 97.7% to 102.5%, which indicates its potential in real matrices. In addition, the MXene/MIL-101(Cr)/GCE was illustrated some advantages including simple preparation, good selectivity and reproducibility, and rapid flutamide detection.

A Narrative Review of Flutamide in Juvenile Nasopharyngeal Angiofibroma.

The detection of androgen receptors within Juvenile Nasopharyngeal Angiofibroma (JNA) has prompted investigation of the role of Flutamide. The aim of this review is to evaluate Flutamide as a possible neo-adjuvant treatment for JNA. Literature searches were conducted using MEDLINE, EMBASE and Web of Science. The Joanna Briggs Institute (JBI) checklist was used to assess risk of bias. The Oxford Centre of Evidence-Based Medicine (OCEBM) Levels of Evidence was used to stratify the evidence level. Literature searches were conducted using MEDLINE, EMBASE and Web of Science. Flutamide as neo-adjuvant treatment potentially causes a reduction in JNA tumor volume by ≥ 25%. Based on the current limited evidence, Flutamide has a limited role in JNA management and further research is required. Its utilization should only follow discussion with the patient, their families, and within the multidisciplinary team.

Skeletal Muscle Function Is Altered in Male Mice on Low-Dose Androgen Receptor Antagonist or Estrogen Receptor Agonist.

In males, skeletal muscle function may be altered by shifts in either circulating testosterone or estrogen. We examined the effect of acute (2-week) exposures to 17α-ethinyl estradiol (EE2), an estrogen receptor (ER) agonist, or flutamide, an androgen receptor (AR) antagonist, on the contractile function of individual skeletal muscle fibers from slow-contracting soleus and fast-contracting extensor digitorum longus muscles from adult male mice. Single fiber specific tension (force divided by cross-sectional area) was decreased with flutamide treatment in all myosin heavy chain (MHC) fiber types examined (I, IIA, and IIB); similar effects were observed with EE2 treatment but only in the fastest-contracting MHC IIB fibers. The decreases in maximally Ca2+-activated specific tension were primarily a result of fewer strongly bound myosin-actin cross-bridges, with flutamide treatment also showing lower myofilament lattice stiffness. Myosin-actin cross-bridge kinetics were slower in MHC IIA fibers in flutamide-treated mice, but faster in EE2-treated mice, indicating that contractile velocity may be affected differently in this fiber type, which is commonly expressed in human skeletal muscle. Importantly, these effects were observed in the absence of outcomes previously used to evaluate ER agonists or AR antagonists in rodents including weight of reproductive organs or mammary gland morphology. Our findings indicate that substantial shifts in skeletal muscle function occur in male mice following acute exposures to low doses of a pharmacological ER agonist and an AR antagonist. These results suggest that countermeasures to maintain physical function may be needed early in situations that induce similar ER agonist and AR antagonist conditions.

Efficacy and Safety of Topical Flutamide 1% Gel as an Adjunctive Therapy in the Treatment of Patients With Acne Vulgaris.

BACKGROUND: Acne vulgaris is a worldwide dermatological condition that has a complex pathophysiology in which androgens play an important role. Flutamide is a first-generation non-steroidal antiandrogen that can be used for acne treatment. AIM: To evaluate the potential therapeutic efficacy and safety of topical flutamide in the treatment of acne vulgaris. METHODS: A andomized controlled study included two equal groups, each had 27 patients, with a total of 54 patients with mild to moderate acne vulgaris having inflammatory (papules and pustules) and non-inflammatory (comedones) lesions. For eight weeks, Group (A) received 1% Flutamide topical gel on the face twice daily, whereas Group (B) served as the control group. RESULT: After 8 weeks of topical Flutamide 1% gel application twice daily, there was a significant reduction in papules count, and a highly significant reduction in pustules number from baseline. LIMITATIONS: We recommend that topical Flutamide 1% gel be tried on a larger number of patients with acne vulgaris, for longer therapeutic duration and follow up periods after treatment. CONCLUSION: Patients with acne vulgaris may find topical Flutamide 1% gel to be a viable, efficient, and safe solution with few adverse effects.

Mechanism of non-steroidal anti-androgen-induced liver injury: Reactive metabolites of flutamide and bicalutamide activate inflammasomes.

Flutamide is a non-steroidal anti-androgen agent, which is mainly used for the treatment of prostate cancer. Flutamide is known to cause severe adverse events, which includes idiosyncratic liver injury. However, details of the mechanism of these adverse reactions have not been elucidated. We investigated whether flutamide induces the release of damage-associated molecular patterns (DAMPs) that activate inflammasomes. We also tested bicalutamide, enzalutamide, apalutamide, and darolutamide for their ability to activate inflammasomes in differentiated THP-1 cells. The supernatant from the incubation of flutamide and bicalutamide with human hepatocarcinoma functional liver cell-4 (FLC-4) cells increased caspase-1 activity and production of IL-1ß by differentiated THP-1 cells. In the supernatant of FLC-4 cells with flutamide and bicalutamide, the heat shock protein (HSP) 40 or 60 was significantly increased. Addition of a carboxylesterase or a CYP inhibitor to the FLC-4 cells prevented release of HSPs from the FLC-4 cells. These results suggested that the reactive metabolites of flutamide and bicalutamide can cause the release of DAMPs from hepatocytes and activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by flutamide or bicalutamide, which in some patients, can cause immune-related adverse events.

Androgen receptor blockade by flutamide down-regulates renal fibrosis, inflammation, and apoptosis pathways in male rats.

AIM: this study aims to explore the effect of androgen receptor (AR) blockade by flutamide on some renal pathologic changes such as inflammation, apoptosis, and fibrosis in male rats. MAIN METHODS: Firstly, we investigated the potential effect of AR blockade on renal inflammatory intermediates including IL-1ß, IL-6, TNF-α, NF-Òšß proteins, and the renal gene expression of NF-Қß. Besides inflammation, we also assessed the apoptosis pathways including the caspases 3 & 9, mTOR, pAKT proteins, and BAX gene expression. Besides inflammation and apoptosis pathways, we also investigated the effect of androgen blockade on renal fibrosis intermediates including vimentin, TGFß-1, α-SMA, MMP-9, collagen type-III, collagen type-IV, and the renal expression of the col1A1 gene. Besides previous pathological pathways, we assessed the expression of chloride channel protein-5 (ClC-5), as an important regulator of many renal pathological changes. Finally, we assessed the impact of previous pathological changes on renal function at biochemical and pathological levels. KEY FINDINGS: We found that AR blockade by flutamide was associated with the down-regulation of renal inflammation, apoptosis, and fibrosis markers. It was associated with expression down-regulation of IL-1ß & IL-6, TNF-α, NF-Қß, caspases 3 & 9, mTOR, MMP-9, collagens, TGFß-1, and α-SMA. Away from down-regulation, we also found that AR blockade has upregulated ClC-5 and pAKT proteins. SIGNIFICANCE: AR is a major player in androgens-induced nephrotoxicity. AR blockade downregulates renal fibrosis, inflammation, and apoptosis pathways. It may be helpful as a strategy for alleviation of renal side effects associated with some drugs. However; this needs further investigations.

The effects of conformation and intermolecular hydrogen bonding on the structure and IR spectra of flutamide; a study based on the matrix isolation technique, ab initio and DFT calculations.

In this study, stable conformers of flutamide referred to as an anticancer drug were searched through a relaxed potential energy surface scan carried out at the B3LYP/6-31G(d) level of theory. This was followed by geometry optimization and thermochemistry calculations performed with the HF-SCF, MP2, B3LYP methods and the 6-31G(d), 6-311++G(d,p), aug-cc-pvTZ basis sets for each of the determined minimum energy conformers. The results revealed that flutamide has at least five stable conformers and two of them provide the major contribution to the observed matrix isolation infrared (IR) spectra of the molecule. The effects of conformational variety and intermolecular hydrogen bonding interactions on the observed IR spectra of flutamide were interpreted in the light of the vibrational spectral data obtained for the most stable monomer and dimer forms of the molecule at the same levels of theory. Pulay's "Scaled Quantum Mechanical-Force Field (SQM-FF)" method was used in the refinement of the calculated harmonic wavenumbers, IR intensities and potential energy distributions. This scaling method which proved its superiority to both anharmonic frequency calculations and other scaling methods helped us to correctly interpret the remarkable differences between the matrix IR spectra of flutamide in argon and the condensed phase IR spectra of the molecule in solvents such as KBr, H2O, D2O, ethanol and methanol.