Antiandrogenic Agents Research Articles

Development and Validation of Androgen-induced Hair Loss and Anagen Induction Mouse Models for Pharmacological Evaluation of Anti-Androgenic Agents

Development and Validation of Androgen-induced Hair Loss and Anagen Induction Mouse Models for Pharmacological Evaluation of Anti-Androgenic Agents

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), Randić (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.

Strategies to Re-Sensitize Castration-Resistant Prostate Cancer to Antiandrogen Therapy

Since prostate cancer (PCa) was described as androgen-dependent, the androgen receptor (AR) has become the mainstay of its systemic treatment: androgen deprivation therapy (ADT). Although, through recent years, more potent drugs have been incorporated, this chronic AR signaling inhibition inevitably led the tumor to an incurable phase of castration resistance. However, in the castration-resistant status, PCa cells remain highly dependent on the AR signaling axis, and proof of it is that many men with castration-resistant prostate cancer (CRPC) still respond to newer-generation AR signaling inhibitors (ARSis). Nevertheless, this response is limited in time, and soon, the tumor develops adaptive mechanisms that make it again nonresponsive to these treatments. For this reason, researchers are focused on searching for new alternatives to control these nonresponsive tumors, such as: (1) drugs with a different mechanism of action, (2) combination therapies to boost synergies, and (3) agents or strategies to resensitize tumors to previously addressed targets. Taking advantage of the wide variety of mechanisms that promote persistent or reactivated AR signaling in CRPC, many drugs explore this last interesting behavior. In this article, we will review those strategies and drugs that are able to resensitize cancer cells to previously used treatments through the use of "hinge" treatments with the objective of obtaining an oncological benefit. Some examples are: bipolar androgen therapy (BAT) and drugs such as indomethacin, niclosamide, lapatinib, panobinostat, clomipramine, metformin, and antisense oligonucleotides. All of them have shown, in addition to an inhibitory effect on PCa, the rewarding ability to overcome acquired resistance to antiandrogenic agents in CRPC, resensitizing the tumor cells to previously used ARSis.

Antiandrogenic treatment of obsessive compulsive neurosis: A case review

IntroductionObsessive-compulsive disorder (OCD) is a mental disorder in which patients who suffer from it have repetitive and undesirable thoughts, feelings, ideas, sensations (obsessions) and behaviors that drive them to do something over and over again (compulsions).Often the person tries to get rid of the obsessive thoughts through compulsions, but this only provides short-term relief. Not carrying out the obsessive rituals can cause enormous anxiety and suffering.ObjectivesTo describe a 23-year-old male patient, who suffers from anxiety and mood symptoms, reacts to ego-dystonic obsessive ideas and sexual content, of months of evolution, and who manages to calm down through compulsive masturbation or watching sexual videos on the internet. All this clinic negatively interferes with their quality of life, asking the patient for medical help to calm these ideas.MethodsWe carried out a review in Pubmed with the terms Antiandrogens and TOC, in order to make a better description of the clinical case.ResultsAfter several treatment attempts (Sertraline, Paroxetine, Clomipramine, Clomipramine + SSRI), reaching maximum doses according to clinical guidelines, and with poor therapeutic response, it was decided to discuss the case with the endocrinology department of our hospital, deciding to start treatment with antiandrogens, in order to alleviate the persistent intrusive ideas of a sexual nature. The administration of antiandrogens in men can cause a decrease or increase in the development or involution of secondary sexual characteristics in men, reducing the activity or function of accessory sexual organs, and hyposexuality, with decreased sexual desire or libido.After several weeks, there was improvement in the obsessive symptoms with a decrease in compulsive rituals. However, after the 3rd mo, some symptoms reappeared, but not with the same severity and intensity as before treatment. In addition, we cannot ignore the adverse effects that have occurred, such as involution of secondary sexual characteristics. However, and taking into account the negative repercussion that this clinic had on the patient’s quality of life, the benefit obtained exceeded the risk, having noted clear improvement with this therapy, and maintaining evolutionary controls by both psychiatry and endocrinology.ConclusionsPatients suffering from obsessive-compulsive disorder can be effectively treated with anti-androgenic pharmacological agents with various modes of action. The most effective group of such agents is the long-acting analogues of the gonadotropin-releasing hormone. The objective of this review is to elucidate the possibility of using such powerful anti-androgenic agents in the treatment of obsessive-compulsive disorder.Disclosure of InterestNone Declared

Phytochemical Characterization of Vitex negundo Leaves: a Potent Antiandrogenic and Antioxidant Agent

This study was conducted to characterise phytochemicals and to explore the biological activities of Vitex negundo leaves. The washed, course powder of V. negundo leaves were extracted with different solvents of increasing polarity. All the extracts were characterized and biological activities were compared. The results revealed that the ethanolic and cold water extracts showed the presence of all phytochemicals studied except protein compared to other extracts. Further, the quantitative estimation of phytochemicals showed that the ethanolic extract had highest yield and maximum amount of total polyphenols, flavonoids, and alkaloids with the least amount of tannins compared to other extracts studied. Furthermore, the highest total polyphenol content corresponds with the potent biological activities. Indeed, in vitro antioxidant and antisteroidogenic activities were highest in the ethanolic extract than others. To conclude, the present study is the first to report the characterization and antiandrogenic property of V. negundo leaf extracts. The ethanolic extract of V. negundo leaves can be used as an antioxidant and antiandrogenic agent. Hence, it can be considered for the treatment of hyperandrogenic conditions like polycystic ovary syndrome, etc.

Effects of Transcutol P and Precirol ATO-5 on Percutaneous Absorption of Flutamide from Emulgels

Background: Flutamide is a non-steroidal anti-androgenic agent which is not only used in treating prostate cancer but also can be effective in some disorders such as androgenic alopecia and male pattern baldness. Several serious side effects for systemic administration of flutamide can be overcome by emulgel dosage form. Absorption enhancers can promote permeation of flutamide through skin. Percutaneous absorption of Flutamide emulgels with different concentrations of Transcutol P and Precirol ATO5 was studied. Methods: Various emulgel formulations using different concentration of Transcutol P and Precirol ATO5 with 0.5 to 5 % w/w were prepared. Percutaneous absorption was tested with standard Franz Diffusion Cell equipment using full thickness rat skin. Drug concentrations in the samples were analyzed by High-Performance Liquid Chromatography (HPLC) equipped with UV-Vis detector at 305 nm. Results: The percutaneous absorption of flutamide emulgels formulated with enhancers was higher than control formulations. Enhancement ratio increased from 1.218 to 3.670 and 1.346 to3.900 for Precirol ATO5 and Transcutol P, respectively. Area under the Curve (AUC) increased by increase the enhancers’ concentration and a significant upsurge was seen in the concentration 1% for both enhancers. Conclusion: The flutamide emulgel containing 1% Transcutol P showed more appropriate percutaneous absorption through the skin compared to others.

Medicinal Use of Testosterone and Related Steroids Revisited.

Testosterone derivatives and related compounds (such as anabolic-androgenic steroids—AAS) are frequently misused by athletes (both professional and amateur) wishing to promote muscle development and strength or to cover AAS misuse. Even though these agents are vastly regarded as abusive material, they have important pharmacological activities that cannot be easily replaced by other drugs and have therapeutic potential in a range of conditions (e.g., wasting syndromes, severe burns, muscle and bone injuries, anemia, hereditary angioedema). Testosterone and related steroids have been in some countries treated as controlled substances, which may affect the availability of these agents for patients who need them for therapeutic reasons in a given country. Although these agents are currently regarded as rather older generation drugs and their use may lead to serious side-effects, they still have medicinal value as androgenic, anabolic, and even anti-androgenic agents. This review summarizes and revisits the medicinal use of compounds based on the structure and biological activity of testosterone, with examples of specific compounds. Additionally, some of the newer androgenic-anabolic compounds are discussed such as selective androgen receptor modulators, the efficacy/adverse-effect profiles of which have not been sufficiently established and which may pose a greater risk than conventional androgenic-anabolic agents.

Effect of phthalates exposure during perinatal period on hormonal profile in Mexican males during their first months of life.

Phthalates affect development of male reproductive system acting as an antiandrogenic agents. We sought to explore if perinatal exposure to phthalates could alter male hormone levels in humans during the first months of life. A cohort of 83 pregnant women and their male infants were studied. Five phthalate metabolites were measured in the mother's urine during the first, second, and third trimesters of pregnancy and during the first, third, and sixth months of life in the infants. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and inhibin B were analyzed. Association between phthalate exposure and hormone variation was assessed using regression models for longitudinal data. Mono-butyl phthalate reduced FSH concentration (ß = -0.0012 international units [IU]/L, p < 0.01), mono-ethylhexyl phthalate reduced inhibin B (ß = -0.0094 pg/mL, p = 0.02), monoethyl phthalate reduced testosterone (ß = -0.0071 ng/L, p = 0.07), mono-ocytl phthalate reduced LH (ß = -0.0041 IU/L, p = 0.13). No effects were observed for exposure to mono-methyl phthalate. Our results are consistent with the findings in animal and human studies. Special precaution should be taken when measuring phthalate exposure in susceptible populations such as pregnant women and infants.

Abstract 4362: Combination of conventional therapies and antiandrogenic treatments as a succesful tool for triple negative breast cancer (TNBC) treatment

Abstract Triple negative breast cancer (TNBC) patients do not benefit from conventional hormonal therapies due to the loss of expression of ER, PR, and HER2. Therefore, the usual adjuvant treatments for breast cancer, are not applied to TNBC. Recently, it has been found that approximately one third of TNBC tumours express androgen receptor (AR) and it is associated with better response to endocrine therapies. However, the prognostic value of AR expression in TNBC is still unclear. Therefore, in this preliminary study we evaluate the effectiveness of an anti-androgen treatment (bicalutamide) respect to conventional treatments (doxorubicin and lapatinib) in TNBC human cell lines and their corresponding xenografts. Briefly, SUM149, SUM159 and MDAMB231 TNBC cell lines were cultured in supplemented medium. Cells were plated in 96-well plates and a serial dilution of Doxorubicin, Lapatinib, Bicatulamide and respective combinations were added. In addition, 106 cells were implanted subcutaneosly into five female mice (Balb/C SCID). When tumors developed, mice were treated with doxorubicin, bicalutamide, doxorubicin + bicalutamide and doxorubicin + bicalutamide + lapatinib. Every treatment was perfomed every 3 days during 15 days and tumor reduction and appearance of metastases were evaluated. Results from cell culture showed that neoplasic cells from each cell line were high sensitive to bicalutamide treatment (SUM149 EC50: 9,860e009; MDAMB231 EC50: 9,454e009; SUM159 EC50: 2,170e009). Also, viability decreased when we added an anti-androgen (bicalutamide) to the conventional treatments (doxorubicin + lapatinib). In vivo experiments revealed a greater percentage of tumour reduction (around 70%) in mice treated with combination of treatments and a lower appearance of metastasis was observed in this group respect to control group (SUM149: 40% vs 60%; MDA-MB-231: 20% vs 75%; SUM159: 20% vs 60%). Therefore, our preliminary findings suggest that the addition of an anti-androgenic agent to treatments currently in use can reduce the tumour considerably, defining anti-androgenic treatments as a novel effective therapeutic target. Citation Format: Sara Caceres, Angela Alonso Diez, Gema Silvan, Maria J. Illera, Juan C. Illera. Combination of conventional therapies and antiandrogenic treatments as a succesful tool for triple negative breast cancer (TNBC) treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4362.

Abstract B082: Association of CXCR6/CXCL16 axis in triple-negative breast cancer and racial disparity

Abstract Breast cancer (BrCa) is the most common cancer in women worldwide and remains an important global health issue. The American Cancer Society recorded 252,710 new cases of BrCa in the United States in 2017, with 40,610 deaths. Though the incidence of BrCa is higher in Caucasian American (CA), African American (AA) women are often diagnosed with more aggressive TNBC at a younger age. Also, in absence of targeted therapies, cytotoxic chemotherapy remains the backbone of treatment for TNBC. But the median survival of women with advanced TNBC remains dismal. Androgen receptor (AR) has emerged as a potential target for treating TNBC; higher AR expression is a favorable prognostic factor associated with a lower clinical stage, lower histologic grade, and lower mitotic score. Several novel anti-androgenic agents alone or in combination with other agents are currently under investigation. Unfortunately, anti-AR therapies are not as beneficial in AA since AR is often low or missing in AA TNBC. Also, outcome of TNBC in AA is worse than CA, which suggests racial differences in the molecular landscape of TNBC between the two races. Hence, defining the molecular differences in TNBC between racial/ethnic groups is vital in order to effectively reduce the observed disparity in BrCa outcome. There are strong indications of a positive linkage between chemokine, cancer and metastasis. Chemokine receptor CXCR6 and its natural ligand CXCL16 are overexpressed in many cancer cells. We have shown that CXCR6 and CXCL16 axis promotes cancer by cytoskeleton rearrangement and its significance in etiopathogenesis of BrCa is well established. Goal of this study was to establish the association of CXCR6/CXCL16 axis in BrCa disparity using TCGA data and BrCa cell lines. We show overexpression of CXCR6 and CXCL16 in BrCa tissues and cell lines. Expression was higher in AA TNBC compared to CA TNBC cell lines. TCGA data confirms higher CXCR6 and CXCL16 expression in AA compared to CA BrCa and inverse association between androgen receptor (AR) and CXCR6 expression. Low AR expression was found in TNBC expressing high CXCR6 and CXCL16. In addition to this, differential phosphorylation status of signaling molecules down stream of CXCR6 in AA and CA TNBC cells was observed. In conclusion, our work highlights association of CXCR6/CXCL16 in race specific biological differences and emphasizes the potential of CXCR6/CXCL16 as a target to reduce the racial gap in TNBC outcome. Citation Format: Hina Mir, Jeronay K Thomas, Neeraj Kapur, Anita T Johnson, Shailesh Singh. Association of CXCR6/CXCL16 axis in triple-negative breast cancer and racial disparity [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B082.

GCMS analysis &amp; assessment of antimicrobial potential of rhizospheric Actinomycetes of AIA3 isolate

Plants have been used for medicine to support human health in many regions in the world by researchers since ancient times. Plants and soil organisms have been found to have very high therapeutic potential as they produce many natural products. Evolving drug resistance towards nearly all anti-infection drugs, lead to the fast development of new drugs. Many natural products or secondary metabolites have been used for animal and human health. Recently, many new secondary metabolites from actinomycetes have been isolated and reported as important compounds with different activities like anti-microbial, anti-oxidant, anti-inflammatory, anti-androgenic and anticancer agents, etc. In this study isolation of actinomycetes was carried out on actinomycetes isolation agar media (AIA). Characterization and biochemical tests were performed and followed by fermentation and solvent extraction by four solvents for example- Benzene, pet ether, ethyl acetate, chloroform. GCMS was performed for identification of compounds present in culture broth. Major compounds present were Octanal,Pyrrolo[1,2-a]pyrazine-1,4-dione,hexahydro-3-(2-methylpropyl), Dibutyl phthalate, N-hexadecanoic acid, 1-nonadecene, Heptadecane, Octadecanoic acid, 3,7,11,15-tetramethyl-2-hexadecene, Dihydroergotamine, Hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester, Octadecanoic acid, 2,3-dihydroxypropyl ester, 13-docosenamide, and 4-tert-butylcalix[4]arene. Crude obtained was checked for their antimicrobial activity and inhibition zones (IZ) were noted on Mullar Hinton agar (MHA) media against indicator organisms like Staphylococcus aureus (MTCC-3160) (IZ=Ben-18 mm, E.A-25 mm), Pseudomonas aeruginosa (MTCC 1688) (IZ=Ben-11 mm, Chl-14 mm, E.A-24 mm), Klebsiella pneumonia (MTCC-432) (IZ=Ben-19 mm, Chl-20 mm, E.A-34 mm), Proteus vulgaris (MTCC-7306) (IZ=Benzene-10 mm, E.A-30 mm), Bacillus subtilis (MTCC-441). Identification of compounds was carried out by NIST 14 library.

The effect of low-dose isotretinoin therapy on serum androgen levels in women with acne vulgaris.

BackgroundAcne vulgaris is a common dermatologic disease that causes significant social and psychological morbidity. Isotretinoin, as a vitamin A derivative, is the most effective agent in the treatment of acne. Evidence suggests that isotretinoin’s therapeutic function is independent of hormonal mediation; however, the effect of isotretinoin on serum androgens and precursor androgen levels in humans remains unclear.ObjectiveHerein, we aim to investigate the effect of low-dose isotretinoin on androgen levels in women and postulate the role of concomitant anti-androgen therapy (e.g., spironolactone).MethodsA total of 36 women, age 18 to 30 years, with moderate-to-severe nodulocystic acne were treated with 20 mg isotretinoin (Roaccutane) daily for 3 months. A hormone panel was obtained at baseline and after completion of the treatment course. The panel included dehydroepiandrosterone (DHEA), 17-hydroxyprogestrone, testosterone, free testosterone, dihydrotestosterone (DHT), luteinizing hormone, follicle stimulating hormone, and prolactin.ResultsSerum levels of testosterone (p = .015), prolactin (p = .001), and DHT (p = .001) were significantly decreased, while serum levels of DHEA (p = .001) significantly increased after isotretinoin treatment. No significant change was found in the other hormones evaluated.LimitationsThe distribution of acne was not assessed in our patient population. We did not directly evaluate for associations between elevated DHEA levels and clinical response rates.ConclusionIsotretinoin alone can decrease androgen levels, but increase an important driver of acne pathogenesis (i.e., DHEA). The co-administration of an anti-androgenic agent (e.g., spironolactone) may optimize the therapeutic efficacy of isotretinoin by limiting iatrogenic increases in DHEA and perhaps allow for more widespread use of low-dose isotretinoin.

Fertility Preservation Outcomes and Considerations in Transgender and Gender-Diverse Youth.

* Abbreviations: MAI — : medical affirming intervention TGD-AYA — : transgender and gender-diverse adolescents and young adults Transgender and gender-diverse adolescents and young adults (TGD-AYA) increasingly present to health care providers seeking medical affirming interventions (MAIs) to induce physiologic changes aligned with their gender identity. MAIs include gonadotropin-releasing hormone agonists to temporarily suppress puberty, testosterone to induce masculine characteristics among those assigned female at birth, and estrogen (often combined with an antiandrogenic agent) to induce feminine characteristics among those assigned male at birth. There is considerable concern that these MAIs impact gonadal structures and function, thereby decreasing future fertility potential.1 Little research has explored reversibility or thresholds (amount and/or duration) of MAIs in impacting TGD-AYA fertility. Therefore, multiple professional organizations recommend fertility counseling before MAI initiation.2–4 In this month’s issue of Pediatrics, Barnard et al5 provide the first study of semen cryopreservation outcomes among TGD-AYA assigned male at birth who assert a female gender identity. They conducted retrospective chart reviews on 11 TGD-AYA referred for fertility preservation over a nearly 4-year period. One patient did not provide a sample. The 8 samples obtained from patients before MAI initiation were all viable. One patient … Address correspondence to Jason Rafferty, MD, MPH, EdM, Department of Pediatrics, Thundermist Health Centers, 450 Clinton St, Woonsocket, RI 02895. E-mail: jason_rafferty{at}mail.harvard.edu

Co-crystallization for enhanced dissolution rate of bicalutamide: preparation and evaluation of rapidly disintegrating tablets

Objectives: Enhance the dissolution rate of bicalutamide via co-crystallization with sucralose (sweetener), with the aim to develop rapidly disintegrating tablets with subsequent prompt dissolution.Significance: Bicalutamide is antiandrogenic agent for the treatment of prostate cancer but has low and variable oral bioavailability, mainly attributed to poor dissolution. Co-crystallization with benign excipients is promising for dissolution enhancement with the additive serving dual functions. The benefit will become greater if dissolution enhancement is associated with the development of orodispersible tablets which is suitable for elderly patients who are the most vulnerable for prostate cancer.Methods: Bicalutamide was dissolved in acetone in the presence of increasing molar ratios of sucralose. The solvent was evaporated while mixing to deposit crystals that were subjected to wet co-grinding until drying. The developed solids were characterized using Fourier transform infrared spectroscopy, differential thermal analysis and X-ray diffraction in addition to monitoring bicalutamide dissolution.Results: Instrumental analysis provided evidences for co-crystallization which was initiated at 1:1 molar ratio of bicalutamide to sucralose with complete co-crystallization at 1:4 molar ratio. The co-crystals provided faster bicalutamide dissolution compared with the unprocessed drug and that recrystalized from acetone in the absence of sucralose. The formulation containing bicalutamide with sucralose at 1:4 molar ratio was selected for tablet formulation into which superdisintegrants were included. The developed tablets exhibited flash disintegration with subsequent fast dissolution of bicalutamide.Conclusions: The study introduced co-crystallization of bicalutamide with sucralose as an efficient tool to enhance the dissolution rate and to develop rapidly dissolving tablets for intraoral administration.

Species differences in the developmental toxicity of procymidone-Placental transfer of procymidone in pregnant rats, rabbits, and monkeys.

To clarify species differences in the developmental toxicity of procymidone (Sumilex®, a fungicide for agricultural use), placental transfer studies were conducted using 14C-labeled procymidone in pregnant rats, rabbits, and monkeys. These studies demonstrated that maternal-to-fetal transfer of the parent compound and its hydroxylated metabolite, which are both weak anti-androgenic agents, occurred more easily than that of other metabolites, with much higher absolute concentrations achieved in the fetal circulation of rats than of rabbits or monkeys. Notably, in rats, the fetal plasma concentration of the hydroxylated metabolite was higher than that of procymidone, especially after repeated oral administration of procymidone. These results suggest that the hydroxylated metabolite is the most relevant metabolite involved in teratogenic activity in rats.

Pharmacokinetics of the anti-androgenic drug flutamide in healthy stallions

Alternatives to surgical castration are necessary for controlling the sexual behaviour of stallions with breeding potential in training and competition. Flutamide is a potent selective non-steroidal androgen receptor competitive antagonist that has been used in human beings as an anti-androgenic drug. In this study, the pharmacokinetics and bioavailability of flutamide and its main active metabolite, 2-hydroflutamide, were determined in seven healthy mature stallions. Single doses of flutamide (1mg/kg intravenously, 1mg/kg orally in fasted horses, 5mg/kg orally in fasted horses and 5mg/kg orally in fed horses) were administered randomly at intervals of 2 weeks. All horses had full physical examinations and blood samples were collected for pharmacokinetics, complete blood counts and biochemistry before and after drug administration. Administration of flutamide did not result in any abnormalities on physical examination or in blood parameters. After intravenous administration of flutamide, the volume of distribution was 0.83L/kg and clearance was 1.20L/h/kg. Flutamide and its metabolite had high protein binding values (93–97%). After oral administration, flutamide was rapidly transformed to 2-hydroxyflutamide, with areas under the concentration–time curve ratios of metabolite:drug ∼7. Oral bioavailability was 6.63% after 1mg/kg flutamide in fasted horses, 6.50% after 5mg/kg flutamide in fasted horses and 6.95% after 5mg/kg in fed horses. Half lives of flutamide were close to 1h after intravenous administration and 2h after oral administration. Half lives of 2-hydroxyflutamide were 4.79–6.84h for all routes and doses. After oral administration, oral flutamide reached plasma concentrations that could be effective as an anti-androgenic agent in horses, but further studies are needed to determine whether flutamide has clinical value as an alternative to castration for controlling sexual behaviour in stallions.

Neoadjuvant Therapy for Patients with Triple Negative Breast Cancer (TNBC).

Patients with triple negative breast cancer (TNBC) are characterized by an unfavorable prognosis particularly when not responding well to anthracycline-taxane chemotherapy. This is due to a more aggressive biology in some cases but most importantly to a lack of agents other than conventional chemotherapy. Hence, there is an urgent need to optimize therapy of patients with TNBC in order to improve prognosis. The objective of this review is to present the current understanding of TNBC biology and give an insight of current therapeutic concepts in the neoadjuvant treatment setting. Current literature has been selected based on a literature search and current therapeutic concepts are explained and commented on. Novel therapeutic concepts for patients with TNBC focus on a) chemotherapy optimization through alternate scheduling, dosing or alternative/additional chemotherapeutic agents, b) evaluation of novel targeted agents and c) identification of clinically relevant patient subgroups through prognostic/ predictive biomarkers to enable a more personalized treatment approach. Potential novel therapeutic targets include inhibition of Poly-A-Ribose-Polymerase (PARP), checkpoint inhibition and antiandrogenic agents. Treatment of TNBC is currently been optimized both through optimization of chemotherapy and introduction of novel targeted agents which should enhance treatment response rates in the future.

Istaroxime, a potential anticancer drug in prostate cancer, exerts beneficial functional effects in healthy and diseased human myocardium.

The current gold standard for prostate cancer treatment is androgen deprivation therapy and antiandrogenic agents. However, adverse cardiovascular events including heart failure can limit therapeutic use. Istaroxime, which combines Na+-K+-ATPase (NKA) inhibition with sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) stimulation, has recently shown promising anti-neoplastic effects in prostate cancer (PC) models and may also improve cardiac function. Considering the promising anticancer effects of istaroxime, we aimed to assess its functional effects on human myocardium.ResultsIstaroxime and strophanthidin elicited dose-dependent positive inotropic effects with a decline in developed force at supraphysiological concentrations in human atrial, nonfailing, and failing ventricular (ToF) myocardium. Diastolic force and RT50% did not change after exposure to both drugs. The maximal developed force in our in-vitro model of heart failure (ToF) was significantly higher after istaroxime administration. Such a difference did not occur in atrial or nonfailing ventricular trabeculae and was not applicable to the diastolic force.Materials and MethodsHuman atrial and ventricular trabeculae were isolated from nonfailing hearts and hearts of infants with tetralogy of Fallot (ToF), which were used as an in-vitro model of heart failure. The samples were electrically stimulated and treated with increasing concentrations of istaroxime and strophanthidin (10 nM–1 μM). Systolic and diastolic force development and relaxation parameters (RT50%) were analyzed.ConclusionsCombined NKA inhibition/SERCA2a stimulation increases contractility in atrial, nonfailing, and failing myocardium. Considering that heart failure is a potential side effect of current PC treatments, especially in elderly patients, istaroxime might combine beneficial cardiac and anti-cancer properties.

A single-center study on predicting outcomes of primary androgen deprivation therapy for prostate cancer using the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score.

Japan Cancer of the Prostate Risk Assessment scores are reportedly useful for predicting progression-free survival after primary androgen deprivation therapy of prostate cancer patients. This study validated the risk assessment at a single institution. We studied 255 prostate cancer patients given primary androgen deprivation therapy. Progression-free survival, cause-specific survival and overall survival were analyzed according to Japan Cancer of the Prostate Risk Assessment score-based risk classification. Cases with lymph node or distant metastases were subdivided by the risk classification. Ages ranged from 50 to 90 years (median: 76.5). Observation periods were 2-199 (median: 46.5) months. Primary androgen deprivation therapy includes combined androgen blockade in 150 cases (58.8%), uncombined luteinizing hormone-releasing hormone agonist in 97 (38.0%) and uncombined anti-androgenic agent in 8 (3.2%). Risk classified by Japan Cancer of the Prostate Risk Assessment scores was low in 104 cases (40.8%), intermediate in 86 (33.7%) and high in 65 (25.5%). The 5-year/10-year progression-free survival rates were 100%/80.8% in the low-risk, 82.3%/69.5% in the intermediate-risk and 34.7%/16.5% in the high-risk group. The 5-year/10-year cause-specific survival rates were 100%/100% in the low-risk, 90.7%/58.2% in the intermediate-risk and 63%/30.8% in the high-risk group. The 5-year/10-year overall survival rates were 87.5%/78.5% in the low-risk, 76.2%/43.1% in the intermediate-risk and 54.9%/25.4% in the high-risk group. For lymph node metastasis, cause-specific survival differed minimally between the intermediate- and high-risk groups (P = 0.1118). For distant metastasis, cause-specific survival differed significantly between the intermediate- and high-risk groups (P = 0.0264). Japan Cancer of the Prostate Risk Assessment score-based risk classification is useful for predicting post-primary androgen deprivation therapy progression-free survival, cause-specific survival and overall survival. Subtyping patients based on Japan Cancer of the Prostate Risk Assessment scores is particularly useful for predicting cause-specific survival with distant metastasis from prostate cancer.

Mixture effects of nonylphenol and di-n-butyl phthalate (monobutyl phthalate) on the tight junctions between Sertoli cells in male rats in vitro and in vivo

The estrogenic chemical nonylphenol (NP) and the antiandrogenic agent di-n-butyl phthalate (DBP) are regarded as widespread environmental endocrine disruptors (EEDs) which at high doses in some species of laboratory animals have adverse effects on male reproduction and development. Given the ubiquitous coexistence of various classes of EEDs in the environment, their combined effects warrant investigation. In this study, we attempted to clarify the interactions of NP and DBP on tight junctions (TJs) between rat Sertoli cells. In the in vitro experiment, monobutyl phthalate (MBP), the active metabolite of DBP, was used instead of DBP. Sertoli cells were isolated from Sprague-Dawley rats, and treated with NP and MBP, singly or combined. The morphology of Sertoli cells, and structure and functionality of TJs were measured. In the in vivo experiment, rats were gavaged on postnatal day 23–35 with a single or combined NP and DBP treatment. Testicular weight and morphology of TJs were recorded. These data indicated that NP and DBP/MBP, either in single or in combination, induced the structural and function changes of Sertoli cell tight junctions, both in vivo and in vitro. The combined effect on the regulation of TJ proteins at both the protein and gene levels was correlated to the effect exerted by NP, suggesting that the structure and function of Sertoli cells were more sensitive to exposure to NP than MBP.