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1.
Horm Behav ; 165: 105611, 2024 09.
Article in English | MEDLINE | ID: mdl-39089160

ABSTRACT

During breeding when testosterone concentrations are high, male songbirds that are open-ended vocal learners like canaries (Serinus canaria) tend to produce a stable, stereotyped song that facilitates mate attraction or territory defense. Outside breeding contexts, song becomes more variable. The neuroendocrine mechanisms controlling this vocal variability across seasons are not entirely clear. We tested whether androgen signaling within the lateral magnocellular nucleus of the anterior nidopallium (LMAN), a cortical-like brain region of the vocal control system known as a vocal variability generator, plays a role in seasonal vocal variability. We first characterized song in birds housed alone on a short day (SD) photoperiod, which simulates non-breeding conditions. Then, cannulae filled with the androgen receptor (AR) blocker flutamide or left empty as control were implanted bilaterally in LMAN. Birds were then transferred to long days (LD) to simulate the breeding season and song was analyzed again. Blocking AR in LMAN increased acoustic variability of song and the acoustic variability of syllables. However, blocking AR in LMAN did not impact the variability of syllable usage nor their sequencing in LD birds, song features that are controlled by androgen signaling in a somatosensory brain region of the vocal control system called HVC. These findings highlight the multifactorial, non-redundant actions of steroid hormones in controlling complex social behaviors such as birdsong. They also support the hypothesis that LMAN is a key brain area for the effects of testosterone on song plasticity both seasonally in adults and during the song crystallization process at sexual maturity.


Subject(s)
Androgens , Canaries , Vocalization, Animal , Animals , Male , Vocalization, Animal/physiology , Vocalization, Animal/drug effects , Canaries/physiology , Androgens/pharmacology , Stereotyped Behavior/drug effects , Stereotyped Behavior/physiology , Receptors, Androgen/metabolism , Receptors, Androgen/physiology , Flutamide/pharmacology , Photoperiod , Seasons , Signal Transduction/physiology , Signal Transduction/drug effects , Testosterone/metabolism , Testosterone/pharmacology , Androgen Antagonists/pharmacology
2.
Jpn J Clin Oncol ; 54(5): 584-591, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38305451

ABSTRACT

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.


Subject(s)
Androgen Antagonists , Benzamides , Nitriles , Phenylthiohydantoin , Prostatic Neoplasms, Castration-Resistant , Humans , Male , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/therapeutic use , Nitriles/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/blood , Aged , Prospective Studies , Androgen Antagonists/administration & dosage , Androgen Antagonists/adverse effects , Aged, 80 and over , Middle Aged , Tosyl Compounds/administration & dosage , Tosyl Compounds/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Flutamide/administration & dosage , Treatment Outcome , Anilides/administration & dosage , Anilides/adverse effects , Prostate-Specific Antigen/blood
3.
Acta Radiol ; 65(8): 940-949, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38751050

ABSTRACT

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.


Subject(s)
Flutamide , Radiopharmaceuticals , Technetium Tc 99m Pentetate , Animals , Mice , Rabbits , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution , Technetium Tc 99m Pentetate/pharmacokinetics , Flutamide/pharmacokinetics , Rhabdomyosarcoma/diagnostic imaging , Disease Models, Animal , Cell Line, Tumor , Tomography, Emission-Computed, Single-Photon/methods
4.
Sensors (Basel) ; 24(3)2024 Feb 02.
Article in English | MEDLINE | ID: mdl-38339702

ABSTRACT

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.


Subject(s)
Antineoplastic Agents , Nanoparticles , Flutamide/chemistry , Nanoparticles/chemistry , Carbon/chemistry , Water , Electrochemical Techniques/methods , Electrodes
5.
Prostate ; 83(2): 179-189, 2023 02.
Article in English | MEDLINE | ID: mdl-36262059

ABSTRACT

BACKGROUND: The aim of this study was to evaluate modifications in proteoglycan morphology and composition in the prostatic stroma of 18-month-old gerbils after surgical castration, in association or not with an androgenic blockade. METHODS: The animals (n = 5) were sorted into groups subjected or not to antiandrogen treatment (flutamide 10 mg/kg/day) administered for the total postsurgery period and euthanized at 7- or 30-day postcastration; the control group consisted of intact animals. Tissue analysis included immunohistochemical assessment (perlecan and chondroitin sulfate) and proteoglycan morphology was analyzed by transmission electron microscopy. RESULTS: Chondroitin sulfate frequency was increased 7 days postcastration with an androgenic blockade. The presence of these carbohydrates was rare after 30 days of androgenic blockade treatment. There was a significant increase in the amount of perlecan in the prostate stroma from groups subjected to castration plus flutamide for 7 or 30 days. Ultrastructural analysis showed that the incidence of areas occupied by proteoglycans and basement membrane was altered by treatment. In addition, androgenic blockade results in changes in the amount, thickness, and morphology of these structures. At 30 days postcastration, with or without flutamide treatment, larger proteoglycans were common. CONCLUSIONS: In this study, in particular, the decrease in chondroitin sulfate after the longer period might be understood as a prostatic response to androgenic deprivation, while the high frequency and permanence of perlecan led to the assumption that its modulation could be androgen-independent. Length and form alterations in proteoglycans as well as associations among them and with the basement membrane were dynamic events in the prostate microenvironment.


Subject(s)
Flutamide , Prostate , Male , Animals , Flutamide/pharmacology , Gerbillinae , Androgens/pharmacology , Chondroitin Sulfates/pharmacology , Orchiectomy
6.
BMC Cancer ; 23(1): 1102, 2023 Nov 13.
Article in English | MEDLINE | ID: mdl-37957639

ABSTRACT

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.


Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Humans , Prognosis , Flutamide , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , RNA , Biomarkers , Gene Expression Regulation, Neoplastic , Protocadherins , Pancreatic Neoplasms
7.
Environ Res ; 238(Pt 2): 117261, 2023 12 01.
Article in English | MEDLINE | ID: mdl-37775004

ABSTRACT

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.


Subject(s)
Antineoplastic Agents , Prostatic Neoplasms , Humans , Male , Flutamide , Reproducibility of Results , Follow-Up Studies , Carbon
8.
J Cutan Med Surg ; 27(5): 472-475, 2023.
Article in English | MEDLINE | ID: mdl-37571839

ABSTRACT

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.


Subject(s)
Acne Vulgaris , Exanthema , Humans , Flutamide/therapeutic use , Acne Vulgaris/drug therapy , Acne Vulgaris/pathology , Gels/therapeutic use , Treatment Outcome
9.
Int J Mol Sci ; 24(21)2023 Oct 26.
Article in English | MEDLINE | ID: mdl-37958610

ABSTRACT

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.


Subject(s)
Flutamide , Prostatic Neoplasms , Male , Humans , Flutamide/pharmacology , Down-Regulation , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Androgen Antagonists/pharmacology , Cell Line, Tumor , Transferases/metabolism
10.
Reprod Biomed Online ; 45(2): 191-201, 2022 08.
Article in English | MEDLINE | ID: mdl-35725534

ABSTRACT

RESEARCH QUESTION: Polycystic ovary syndrome (PCOS) alters oocyte developmental competence and so the treatment of PCOS patients with assisted reproductive techniques is a major challenge for an infertility specialist. Does ovulation induction therapy with clomiphene citrate, metformin and flutamide affect abnormal PCOS follicle gene expression, its quality, and nuclear and cytoplasmic maturation in the oocyte matured in vitro? DESIGN: Fifty NMRI mice (7-8 weeks old) were randomly divided into five groups, including non-PCOS, PCOS and PCOS groups treated with clomiphene citrate (18 mg/kg body weight for 2 days), metformin (50 mg/100 g body weight for 30 days) and flutamide (10 mg/kg body weight injection for 15 days). The oocytes were collected for quantitative real-time polymerase chain reaction analysis (the evaluation of genes associated with oocyte maturation), transmission electron microscopy (the evaluation of cytoplasmic maturation) and in-vitro maturation (IVM) and IVF outcomes. RESULTS: The dysregulated expression of some genes of insulin-like growth factor (IGF) families involved in oocyte competence and steroid metabolism (e.g. Cyp19a1 and Cyp11a1), transforming growth factor beta (TGF-ß) family (e.g. Tgfb1, Gdf9, Bmp15, Inhbb and Bmpr1a), and oestrogen receptor signalling (e.g. Ncoa3, Pgr) was, to some extent, restored in the PCOS follicles following their with clomiphene citrate, metformin and flutamide. The improved cytoplasmic maturation was observed particularly in the PCOS mice treated with clomiphene citrate. The better IVM-IVF outcomes were also observed in the clomiphene citrate and metformin groups compared with the PCOS group. CONCLUSIONS: This study opens up a new perspective on knowing the effect of ovulation induction therapy on not only nuclear maturation but also ultrastructural characteristics, IVM-IVF outcomes and PCOS oocyte developmental competence.


Subject(s)
Infertility, Female , Metformin , Polycystic Ovary Syndrome , Animals , Body Weight , Clomiphene/pharmacology , Female , Fertility Agents, Female/pharmacology , Fertility Agents, Female/therapeutic use , Flutamide/pharmacology , Humans , Infertility, Female/chemically induced , Metformin/pharmacology , Mice , Oocytes , Ovulation Induction/methods , Polycystic Ovary Syndrome/drug therapy
11.
AAPS PharmSciTech ; 23(1): 62, 2022 Jan 26.
Article in English | MEDLINE | ID: mdl-35080685

ABSTRACT

Flutamide which is used to treat prostate cancer and other diseases induces liver damage during and after the therapy. The aim of this study was to develop a flutamide/piperineco-loaded self-emulsifying drug delivery system (FPSEDDS) to inhibit flutamide-induced liver injury by utilizing piperine as a metabolic inhibitor. The development of SEDDS was carried out following a quality by design (QbD) approach. The risk assessment study was performed to identify critical quality attributes (CQAs) and critical material attributes (CMAs)/critical process parameters (CPPs). I-optimal mixture design was executed with three CMAs as the independent variables and CQAs as the dependable variables. The effectiveness of optimized SEDDS to circumvent flutamide-induced hepatotoxicity was assessed in mice. The numerical optimization suggested an optimal formulation with a desirability value of 0.621, using CQAs targets as optimization goals with 95% prediction intervals (α = 0.05). The optimal formulation exhibited the grade A SEDDS characteristics with the guarantee of high payloads in self-formed oily droplets. The design space was also obtained from the same optimization goals. All CQA responses of verification points were found within the 95% prediction intervals of the polynomial models, indicating a good agreement between actual versus predicted responses within the design space. These obtained responses also passed CQAs acceptance criteria. Finally, hematoxylin-eosin staining revealed the minimal flutamide-induced hepatotoxicity from the optimal SEDDS formulation as compared to the control and flutamide/piperine normal suspension. We demonstrate that the piperine containing optimized SEDDS formulation developed by QbD significantly reduces the flutamide-induced liver injury in mice.


Subject(s)
Drug Delivery Systems , Flutamide , Animals , Emulsions , Flutamide/toxicity , Liver , Male , Mice
12.
Am J Physiol Lung Cell Mol Physiol ; 320(5): L803-L818, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33719566

ABSTRACT

Epidemiological studies demonstrate an apparent sex-based difference in the prevalence of asthma, with a higher risk in boys than girls, which is reversed postpuberty, where women become more prone to asthma than men, suggesting a plausible beneficial role for male hormones, especially androgens as a regulator of pathophysiology in asthmatic lungs. Using a murine model of asthma developed with mixed allergen (MA) challenge, we report a significant change in airway hyperresponsiveness (AHR), as demonstrated by increased thickness of epithelial and airway smooth muscle layers and collagen deposition, as well as Th2/Th17-biased inflammation in the airways of non-gonadectomized (non-GDX) and gonadectomized (GDX) male mice. Here, compared with non-GDX mice, MA-induced AHR and inflammatory changes were more prominent in GDX mice. Activation of androgen receptor (AR) using 5α-dihydrotestosterone (5α-DHT, AR agonist) resulted in decreased Th2/Th17 inflammation and remodeling-associated changes, resulting in improved lung function compared with MA alone challenged mice, especially in GDX mice. These changes were not observed with Flutamide (Flut, AR antagonist). Overall, we show that AR exerts a significant and beneficial role in asthma by regulating AHR and inflammation.


Subject(s)
Airway Remodeling , Asthma/complications , Disease Models, Animal , Gene Expression Regulation , Inflammation/prevention & control , Receptors, Androgen/metabolism , Respiratory Hypersensitivity/prevention & control , Animals , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Receptors, Androgen/genetics , Respiratory Hypersensitivity/etiology , Respiratory Hypersensitivity/metabolism , Respiratory Hypersensitivity/pathology , Signal Transduction
13.
Arch Toxicol ; 95(4): 1335-1347, 2021 04.
Article in English | MEDLINE | ID: mdl-33585966

ABSTRACT

Mitochondrial DNA (mtDNA) is highly polymorphic and encodes 13 proteins which are critical to the production of ATP via oxidative phosphorylation. As mtDNA is maternally inherited and undergoes negligible recombination, acquired mutations have subdivided the human population into several discrete haplogroups. Mitochondrial haplogroup has been found to significantly alter mitochondrial function and impact susceptibility to adverse drug reactions. Despite these findings, there are currently limited models to assess the effect of mtDNA variation upon susceptibility to adverse drug reactions. Platelets offer a potential personalised model of this variation, as their anucleate nature offers a source of mtDNA without interference from the nuclear genome. This study, therefore, aimed to determine the effect of mtDNA variation upon mitochondrial function and drug-induced mitochondrial dysfunction in a platelet model. The mtDNA haplogroup of 383 healthy volunteers was determined using next-generation mtDNA sequencing (Illumina MiSeq). Subsequently, 30 of these volunteers from mitochondrial haplogroups H, J, T and U were recalled to donate fresh, whole blood from which platelets were isolated. Platelet mitochondrial function was tested at basal state and upon treatment with compounds associated with both mitochondrial dysfunction and adverse drug reactions, flutamide, 2-hydroxyflutamide and tolcapone (10-250 µM) using extracellular flux analysis. This study has demonstrated that freshly-isolated platelets are a practical, primary cell model, which is amenable to the study of drug-induced mitochondrial dysfunction. Specifically, platelets from donors of haplogroup J have been found to have increased susceptibility to the inhibition of complex I-driven respiration by 2-hydroxyflutamide. At a time when individual susceptibility to adverse drug reactions is not fully understood, this study provides evidence that inter-individual variation in mitochondrial genotype could be a factor in determining sensitivity to mitochondrial toxicants associated with costly adverse drug reactions.


Subject(s)
Blood Platelets/drug effects , DNA, Mitochondrial/drug effects , Flutamide/analogs & derivatives , Tolcapone/toxicity , Adolescent , Adult , DNA, Mitochondrial/genetics , Female , Flutamide/toxicity , Genotype , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Young Adult
14.
Mikrochim Acta ; 188(6): 196, 2021 05 26.
Article in English | MEDLINE | ID: mdl-34036435

ABSTRACT

The one-step synthesis of heteroatom-doped porous carbons is reported with the in situ formation of cobalt oxide nanoparticles for dual electrochemical applications (i.e., electrochemical sensor and supercapacitor). A single molecular template of zeolitic imidazole framework-67 (ZIF-67) was utilized for the solid-state synthesis of cobalt oxide nanoparticle-decorated nitrogen-doped porous carbon (Co3O4@NPC) nanocomposite through a facile calcination treatment. For the first time, Co3O4@NPC nanocomposite derived from ZIF-67 has been applied as an electrode material for the efficient electrochemical detection of anticancer drug flutamide (FLU). The cyclic voltammetry studies were performed in the operating potential from 0.15 to - 0.65 V (vs. Ag/AgCl). Interestingly, the fabricated drug sensor exhibited a very low reduction potential (- 0.42 V) compared to other  reported sensors. The fabricated sensor exhibited good analytical performance in terms of low detection limit (12 nM), wide linear range (0.5 to 400 µM), and appreciable recovery results (~ 98%, RSD 1.7% (n = 3)) in a human urine sample. Hereafter, we also examined the supercapacitor performance of the Co3O4@NPC-modified Ni foam in a 1M KOH electrolyte, and noticeable a specific capacitance of 525 F g-1 at 1.5 A g-1 was attained, with long-term cycling stability. The Co3O4@NPC nanocomposite supercapacitor experiments outperform the associated MOF-derived carbons and the Co3O4-based nanostructure-modified electrodes.


Subject(s)
Antineoplastic Agents/urine , Electric Capacitance , Electrochemical Techniques/methods , Flutamide/urine , Metal Nanoparticles/chemistry , Nanocomposites/chemistry , Carbon/chemistry , Catalysis , Cobalt/chemistry , Electrochemical Techniques/instrumentation , Electrodes , Humans , Limit of Detection , Metal-Organic Frameworks/chemistry , Oxides/chemistry , Porosity , Reproducibility of Results
15.
Mikrochim Acta ; 188(11): 371, 2021 10 08.
Article in English | MEDLINE | ID: mdl-34625854

ABSTRACT

A one-pot hydrothermal synthesis of three-dimensional (3D), large-area, bimetallic oxide NiCo2O4 (NCO) microflowers has been developed as a novel substrate for surface-enhanced Raman scattering (SERS) detection of flutamide in biological fluids. The 3D flower-like morphology of the NCO is observed via FESEM micrographs, while the orthorhombic phase formation is confirmed through XRD spectra. Due to the presence of multiple coordination cations of the 3D NCO microflowers (such as Ni2+ and Co2+), the high surface area and surface roughness, the NCO-modified indium tin oxide (NCO/ITO) SERS substrate exhibits a linear detection range from 0.5-500 nM with a low limit of detection (LOD) of 0.1 nM. The SERS substrate provides a high enhancement factor of 1.864 × 106 with an accumulation time of 30 s using a laser source of λ = 532 nm, which can be ascribed to the excellent and rapid interaction between the flutamide molecule and the NCO microflower substrate that leads to photoinduced charge transfer (PICT) resonance. The NCO/ITO substrate exhibits excellent homogeneity and high chemical stability. Besides, the substrate displays an excellent selectivity to flutamide molecules in the existence of other metabolites such as urea, ascorbic acid (AA), glucose, NaCl, KCl, CaCl2, and hydroxyflutamide. The NCO/ITO substrate is successful in the trace-level detection of flutamide in simulated blood serum samples. The strategy outlined here presents a novel strategy for the efficacy of transition metal oxides (TMOs) based electrodes useful for a wide variety of bioanalytical applications.


Subject(s)
Spectrum Analysis, Raman
16.
Drug Dev Ind Pharm ; 47(4): 579-608, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33651659

ABSTRACT

Crystallization tendencies, thermal analysis [i.e. glass transition temperature (Tg)], crystallinity, and melting point depression, along with theoretical calculations such as solubility parameter, of five different drugs [i.e. curcumin (CUR), indomethacin (IND), flutamide (FLU), dipyridamole (DIP), and griseofulvin (GRI)] in the absence and presence of four different polymers in various drug-polymer ratios were determined and analyzed. Physical states of the drug in the solid dispersions (SDs) and their stability were characterized by X-ray diffraction and modulated differential scanning calorimetry. Infrared (IR) and Raman were used in selected systems (i.e. CUR, DIP, and GRI systems) to explore the role of drug-polymer interactions in the amorphization of SDs. The crystallization tendencies of pure drugs were categorized as low (CUR, IND), moderate (FLU), and high (DIP, GRI). In the presence of selected polymers, the crystallization tendency of the drugs changed, though a high polymer concentration was required for high crystallization-tendency drugs [i.e. DIP and GRI (>50% w/w)]. Polymers showing a greater effect on the crystallization tendency of drugs were found to have higher drug-polymer miscibility and stronger molecular interactions. Drug-polymer systems selected from the investigation of physical mixtures formed stable amorphous solid dispersions (ASD). Furthermore, the rank order of the crystallization tendency of drug-polymer systems correlated well with those on miscibility and molecular interactions. Those rank orders also correlated well with the stability of prepared/reported SDs. Hence, the developed approach has significant potential to be a rational screening method for the development of amorphous SDs.


Subject(s)
Pharmaceutical Preparations , Polymers , Calorimetry, Differential Scanning , Crystallization , Drug Stability , Solubility
17.
Biol Reprod ; 102(1): 76-83, 2020 02 12.
Article in English | MEDLINE | ID: mdl-31403160

ABSTRACT

Efferent duct ligation (EDL) induces epithelial cell degeneration followed by regeneration in the epididymal initial segment. We tested here the role of androgens in the recovery phase. EDL was performed at post-natal weeks (PNW) 3, 4, 5, 6, and 7, and apoptotic and proliferating epithelial cells were quantified 24 h, and at days 2 and 2.5 post-EDL, respectively. A progressive increase in the number of apoptotic basal cells (BCs) and principal cells (PCs) was detected from PNW3 to 6, 24 h after EDL. Two days after EDL, no increase in proliferating BCs and PCs was observed at PNW3 and 4, despite the induction of apoptosis by EDL. A progressive increase in the number of proliferating BCs was then observed from PNW5 to 6, while the number of proliferating PCs remained low. 2.5 days after EDL, the number of proliferating BCs and PCs remained low at PNW3, 4, and 5, but a marked increase in the number of proliferating PCs was observed at PNW6. Flutamide pretreatment for 3 weeks followed by EDL at PNW7 dramatically decreased the number of proliferating BCs on EDL day 2, and the number of proliferating PCs on EDL day 2.5, compared to controls. We conclude that (1) BCs are the first to show recovery after EDL, followed by PCs; (2) androgens are essential for BC and PC repair after injury in the postpubertal epididymis; and (3) the prepubertal epididymis lacks repair ability following injury.


Subject(s)
Androgens/metabolism , Apoptosis/physiology , Cell Proliferation/physiology , Epididymis/metabolism , Epithelial Cells/metabolism , Androgen Antagonists/pharmacology , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Epididymis/drug effects , Epithelial Cells/drug effects , Flutamide/pharmacology , Ligation , Male , Mice
18.
Mol Pharm ; 17(10): 3730-3739, 2020 10 05.
Article in English | MEDLINE | ID: mdl-32790413

ABSTRACT

In this work, we proposed the method to maintain the desired level of drug's solubility within the polymer matrix by adjusting conditions to uphold the same molecular dynamics of the system (e.g., temperature for set elevated pressure or vice versa). Namely, we observed, that recrystallization of the drug from the supersaturated drug-polymer system, initiated for the same structural relaxation time of the sample (τα-1) ceases when certain, different than the initial, molecular mobility of the systems is reached (τα-2)-regardless of a given combination of temperature and pressure conditions. Based on the presented results, one can conclude that the molecular dynamics seem to control the process of recrystallization of the excess amount of solute from the supersaturated solution (e.g., small molecules dissolved within the polymer). Therefore, it appears that the elevated pressure compensates the effect of solubility enhancement caused by the elevated temperature. Such information not only is of fundamental relevance in science but also, from a much broader perspective, could be potentially very useful considering extrusion-based manufacturing methods.


Subject(s)
Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Polymers/chemistry , Crystallization , Feasibility Studies , Pressure , Solubility , Temperature
19.
J Exp Biol ; 223(Pt 11)2020 06 01.
Article in English | MEDLINE | ID: mdl-32291320

ABSTRACT

Performance trade-offs can dramatically alter an organism's evolutionary trajectory by making certain phenotypic outcomes unattainable. Understanding how these trade-offs arise from an animal's design is therefore an important goal of biology. To explore this topic, we studied how androgenic hormones, which regulate skeletal muscle function, influence performance trade-offs relevant to different components of complex reproductive behaviour. We conducted this work in golden-collared manakins (Manacus vitellinus), a neotropical bird in which males court females by rapidly snapping their wings together above their back. Androgens help mediate this behavior by radically increasing the twitch speed of a dorsal wing muscle (scapulohumeralis caudalis, SH), which actuates the bird's wing-snap. Through hormone manipulations and in situ muscle recordings, we tested how these positive effects on SH speed influence trade-offs with endurance. Indeed, this latter trait impacts the display by shaping signal length. We found that androgen-dependent increases in SH speed incur a cost to endurance, particularly when this muscle performs at its functional limits. Moreover, when behavioural data were overlaid on our muscle recordings, displaying animals appeared to balance display speed with fatigue-induced muscle fusion (physiological tetanus) to generate the fastest possible signal while maintaining an appropriate signal duration. Our results point to androgen action as a functional trigger of trade-offs in sexual performance - these hormones enhance one element of a courtship display, but in doing so, impede another.


Subject(s)
Androgens , Passeriformes , Animals , Courtship , Female , Male , Muscle, Skeletal , Sexual Behavior, Animal
20.
Bioorg Med Chem Lett ; 30(21): 127507, 2020 11 01.
Article in English | MEDLINE | ID: mdl-32866675

ABSTRACT

In this paper, we designed and extended modification basing on the flutamide structure. A series of flutamide-conjugates were obtained with methyl bromoacetate and ethylenediamine. Through the synthesis of two conjugates with 3,5-bis(dodecyloxy)benzoate derivatives, these flutamide conjugates were tested for anticancer activity. Among the compounds tested, the flutamide-conjugates showed good inhibition activity against cancer cell lines U-251, PC-3 and K-562. The conjugates showed a better inhibitory effect than free flutamide and did not show activity against normal COS-7 monkey kidney fibroblast cells. It was also observed that the flutamide conjugates had an inhibitory effect against human colorectal adenocarcinoma HCT-15.


Subject(s)
Antineoplastic Agents/pharmacology , Flutamide/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Flutamide/chemical synthesis , Flutamide/chemistry , Humans , Molecular Structure , Structure-Activity Relationship
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