Xtandi

Organic molecules containing fluorine and sulfur atoms represent a large percentage of approved pharmaceuticals. Those with combination of both S and F atoms in their structure such as Xtandi, approved in 2012 for prostate cancer, indicates the importance of synthetic methods that accommodates both atoms in an organic moiety. In this study, a novel aspect of sulfoxonium ylide reactivity was explored, unveiling a streamlined and mild synthesis method for gem-difluorinated keto-sulfoxides. Our protocol offers a direct and practical approach to prepare these compounds in 14-80% chemical yields, that were represented by 21 examples...

The purpose of this study is to develop and evaluate a self-nanoemulsifying drug delivery system (SNEDDS) to improve the oral absorption of poorly water-soluble enzalutamide (ENZ). Considering the rapid recrystallization of the drug, based on solubility and crystallization tests in various oils, surfactants and co-surfactants, Labrafac PG 10%, Solutol HS15 80%, and Transcutol P 10%, which showed the most stable particle size and polydispersity index (PDI) without drug precipitation, were selected as the optimal SNEDDS formulation...

The median survival time of patients with an aggressive brain tumor, glioblastoma, is still poor due to ineffective treatment. The discovery of androgen receptor (AR) expression in 56% of cases offers a potential breakthrough. AR antagonists, including bicalutamide and enzalutamide, induce dose-dependent cell death in glioblastoma and glioblastoma-initiating cell lines (GIC). Oral enzalutamide at 20 mg/kg reduces subcutaneous human glioblastoma xenografts by 72% ( p = 0.0027). We aimed to further investigate the efficacy of AR antagonists in intracranial models of human glioblastoma...

Enzalutamide is a new potent inhibitor of the signaling pathway for the androgen receptor with a half-life of 5.8 days. It has been on the market for the treatment of metastatic castration-resistant prostate cancer since November 2013. We report a case of acute generalized exanthematous maculopapular rash induced by enzalutamide. In summary, newer androgen receptor blockers have a propensity to cause skin related adverse effects. Most common among these are apalutamide. Enzalumatamide, per se, is a safe drug and has not been associated frequently in causing maculopapular rash...

No abstract text is available yet for this article.

Galeterone, 3β-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Gal, 1) and VNPP433-3β, 3β-(1H-imidazole-1-yl-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (2) are potent molecular glue degrader modulators of AR/AR-V7 and Mnk1/2-eIF4E signaling pathways, and are promising Phase 3 and Phase 1 drug candidates, respectively. Because appropriate salts can be utilized to create new chemical entities with enhanced aqueous solubility, in vivo pharmacokinetics, and enhanced in vitro and in vivo efficacies, the monohydrochloride salt of Gal (3) and the mono- and di-hydrochlorides salts of compound 2, compounds 4 and 5, respectively, were synthesized...

No abstract text is available yet for this article.

This study systematically compared enzalutamide (ENZ) nanocrystals and amorphous formulation (Xtandi® Tablets) and proposed an effective method for predicting pharmacokinetic behavior. ENZ nanosuspensions were prepared by anti-solvent precipitation (ENZ/NS-AS) and wet milling (ENZ/NS-WM) under optimal conditions and were solidified by spray drying and further tableting. Spray dried ENZ/NS-WM was confirmed to exist in crystalline state by DSC and PXRD, while spray dried ENZ/NS-AS was amorphous form. The dissolution testing revealed that ENZ/NS-WM tablets exhibited significantly faster dissolution rate than the physical mixture of untreated ENZ and HPMCAS-HG (1:1) prepared by gently grinding with a mortar and pestle for 2 min and were comparable to Xtandi® Tablets...

Background: PARP inhibitors have been recently approved by the FDA for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Their effectiveness is seen when used with androgen deprivation therapy in patients with or without deleterious germline and somatic genetic mutations. Objectives: To identify all the randomized controlled trials (RCTs) in which PARP inhibitors have been assessed in the treatment of mCRPC, and to compare the efficacy of PARP inhibitors in these patients with standard-of-care (S/nonhormonal therapies like abiraterone acetate (Zytiga) or enzalutamide (Xtandi) in terms of progression-free survival (PFS) and overall survival (OS)...

Enzalutamide, a second-generation antiandrogen, is commonly prescribed for the therapy of advanced prostate cancer, but enzalutamide-resistant, lethal, or incurable disease invariably develops. To understand the molecular mechanism(s) behind enzalutamide resistance, here, we comprehensively analyzed a range of prostate tumors and clinically relevant models by gene expression array, immunohistochemistry, and Western blot, which revealed that enzalutamide-resistant prostate cancer cells and tumors overexpress the pseudokinase, Tribbles 2 (TRIB2)...

Enzalutamide (XTANDI®), an antiandrogen, is used for the treatment of advanced-stage prostate cancer. Approximately, 60% of patients receiving enzalutamide show initial remission followed by disease relapse with the emergence of highly aggressive castration-resistant prostate cancer. Solute carrier (SLC) proteins play a critical role in the development of drug resistance by altering cellular metabolism. Transcriptome analysis revealed the predominance of SLC25A17 and SLC27A6 in enzalutamide-resistant prostate cancer cells; however, their role in antiandrogen resistance has not been elucidated...

Androgen deprivation therapy (ADT) is standard-of-care for advanced-stage prostate cancer, and enzalutamide (Xtandi® , Astellas, Northbrook, IL, USA), a second generation antiandrogen, is prescribed in this clinical setting. The response to this medication is usually temporary with the rapid emergence of drug resistance. A better understanding of gene expression changes associated with enzalutamide resistance will facilitate circumventing this problem. We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-2B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation...

No abstract text is available yet for this article.

Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line antiandrogen therapies, including bicalutamide (CASODEX® ) and enzalutamide (XTANDI® )...

The next generation anti-androgen drugs, XTANDI® (Enzalutamide), ZYTIGA® (Abiraterone acetate), ERLEADA™ (Apalutamide) and NUBEQA (Darolutamide) extend survival times and improve quality of life in advanced prostate cancer patients. Despite these advances, resistance occurs frequently and there is currently no definitive cure for Castration-Resistant Prostate Cancer (CRPC). Our previous studies identified that similar mechanisms of resistance to enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer...

Drugs used for the treatment of castration resistant prostate cancer (CRPC) include Abiraterone acetate (Zytiga®) and Enzalutamide (XTANDI®). However, these drugs provide clinical benefit in metastatic disease for only a brief period before drug resistance emerges. One mechanism of drug resistance involves the overexpression of type 5 17-β-hydroxysteroid dehydrogenase (aldo-keto reductase 1C3 or AKR1C3), a major enzyme responsible for the formation of intratumoral androgens that activate the androgen receptor (AR)...

Oral enzalutamide (Xtandi® ), a second generation androgen receptor inhibitor, is indicated for the treatment of castration-resistant prostate cancer (CRPC) in numerous countries worldwide, with specific indications in this patient population varying between individual countries. Based on extensive experience in the clinical trial and/or real-world settings, oral enzalutamide 160 mg once daily is an effective and generally well tolerated treatment in a broad spectrum of patients with CRPC, including in nonmetastatic and metastatic disease and in chemotherapy-naive and -experienced metastatic CRPC...

Objective: We report two cases of elevated digoxin plasma levels in patients receiving enzalutamide. Cases reported: The first patient, an 84-year-old male treated with enzalutamide, was hospitalized due to deterioration in his general state. Atrial fibrillation was discovered and treatment with digoxin was initiated. Supratherapeutic digoxin concentrations (4 µg/L and 3.5 µg/L 3 days later) led to treatment being stopped despite the lack of clinical or biological signs of overdose. The second patient, an 84-year-old male treated with digoxin and enzalutamide, was hospitalized for the same reasons...

Understanding and targeting the mechanisms of resistance to enzalutamide in castration resistant prostate cancer. BACKGROUND: Enzalutamide (MDV3100, XTANDI) is a second generation androgen receptor inhibitor that is designed for the treatment of castration-resistant prostate cancer (CRPC) and has prolonged survival time. The mechanisms of mdv3100 resistance have not yet been clearly clarified and the majority of treated patients, innate or acquiring resistance invariably arises. OBJECTIVE: The purpose of this review is to summarize the main data available on the mechanisms of resistance to mdv3100...

No abstract text is available yet for this article.