Pharmacokinetics, pharmacodynamics and clinical efficacy of abiraterone acetate for treating metastatic castration-resistant prostate cancer

Han, Christopher; Patel, Rutveej; Kim, Isaac Yi

doi:10.1517/17425255.2015.1041918

“…1 ). Importantly, the used precursor P1, is known as abiraterone acetate (brand name Zytiga), which inhibits androgen biosynthesis and is used for treating prostate cancer 25 , with documented pharmacokinetics 26 . The fluorophores attached on a precursor P1 via 3-hydroxy group produced fluorescent probes FP-1 ‒ FP-4 or on pyridyl group via quaternization generated probes FP-5 ‒ FP-8 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Heterocyclic sterol probes for live monitoring of sterol trafficking and lysosomal storage disorders

Králová

¹

,

Jurášek

²

,

Krčová

³

et al. 2018

Sci Rep

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The monitoring of intracellular cholesterol homeostasis and trafficking is of great importance because their imbalance leads to many pathologies. Reliable tools for cholesterol detection are in demand. This study presents the design and synthesis of fluorescent probes for cholesterol recognition and demonstrates their selectivity by a variety of methods. The construction of dedicated library of 14 probes was based on heterocyclic (pyridine)-sterol derivatives with various attached fluorophores. The most promising probe, a P1-BODIPY conjugate FP-5, was analysed in detail and showed an intensive labelling of cellular membranes followed by intracellular redistribution into various cholesterol rich organelles and vesicles. FP-5 displayed a stronger signal, with faster kinetics, than the commercial TF-Chol probe. In addition, cells with pharmacologically disrupted cholesterol transport, or with a genetic mutation of cholesterol transporting protein NPC1, exhibited strong and fast FP-5 signal in the endo/lysosomal compartment, co-localizing with filipin staining of cholesterol. Hence, FP-5 has high potential as a new probe for monitoring cholesterol trafficking and its disorders.

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“…Additionally, a minimal inhibitory effect on Pglycoprotein (P-gp) has been shown. 5,6 • A recent analysis at our institution revealed that 39% of men undergoing abiraterone+prednisone therapy used anticoagulants and/or antiaggregatory medications. 7 Cancer associated thrombosis is a leading cause of death in ambulatory cancer patients receiving chemotherapy, second only to progression of disease.…”

Section: Resultsmentioning

confidence: 99%

Management of anticoagulation in patients with metastatic castration–resistant prostate cancer receiving abiraterone + prednisone

Dubinsky

¹

,

Thawer

²

,

Ag

³

et al. 2019

Support Care Cancer

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Monitor INR 3 days after initiation and then once weekly for 4 weeks, as INR becomes stable the interval may increased slowly.Figure 1.0. Anticoagulation management for atrial fibrillation in a patient receiving abiraterone + prednisone. Abbreviations: CAD; coronary artery disease. ASA; acetylsalicylic acid. CHADS 2 ; congestive heart failure, hypertension, age >65, diabetes, prior stroke or transient attack. CrCl; creatinine clearance. INR; international normalized ratio. * -Close monitoring of INR Abbreviations: ASA, acetylsalicylic acid; CAD; coronary artery disease. CHADS 2 , Congestive heart failure, hypertension, age, diabetes, prior stroke or transient attack; LMWH, low-molecular weight heparin. Table 2.0. Recommended management strategies for anticoagulation in patients receiving abiraterone + prednisone. References Ŧ Dose adjust for renal function and body weight * -Dose adjust for renal function; not recommended if CrCl < 30 ml/min ** -Monitor INR 3 days after initiation and then once weekly for 4 weeks, as INR becomes stable the interval may be increased slowly.

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“…1). Importantly, the used precursor P1, is known as abiraterone acetate (brand name Zytiga), which inhibits androgen biosynthesis and is used for treating prostate cancer (25), with documented pharmacokinetics (26). The fluorophores attached on a precursor P1 via 3-hydroxy group produced fluorescent probes FP-1-FP-4 or on pyridyl group via quaternization generated probes FP-5-8 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Heterocyclic sterol probes for live monitoring of sterol trafficking and lysosomal storage disorders

Králová

¹

,

Jurášek

²

,

Krčová

³

et al. 2018

Preprint

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The monitoring of intracellular cholesterol homeostasis and trafficking is of great importance because their imbalance leads to many pathologies. Reliable tools for cholesterol detection are in demand. This study presents the design and synthesis of fluorescent probes for cholesterol recognition and demonstrates their selectivity by a variety of methods. The construction of dedicated library of 14 probes was based on heterocyclic (pyridine)-sterol derivatives with various attached fluorophores. The most promising probe, a P1-BODIPY conjugate FP-5, was analyzed in detail and showed an intensive labeling of cellular membranes followed by intracellular redistribution into various cholesterol rich organelles and vesicles. FP-5 displayed a stronger signal, with faster kinetics, than the commercial TF-Chol probe. In addition, cells with pharmacologically disrupted cholesterol transport, or with a genetic mutation of cholesterol transporting protein NPC1, exhibited strong and fast FP-5 labeling in the endo/lysosomal compartment, co-localizing with filipin staining of cholesterol. Hence, FP-5 has high potential as a new probe for monitoring cholesterol trafficking and its disorders.Significance statementCholesterol is a vital steroid molecule with many important functions in animal cells. Although its dysregulation is associated with an expanding list of clinically important pathologies, the study of its role is limited by a lack of reliable tools for live intracellular monitoring. This study demonstrates the applicability of a novel class of heterocyclic sterol probes. These probes exhibit fast cellular uptake with effective fluorescence labeling of sterol species in a variety of living cells, without a need for artificial carriers. When applied to Niemann-Pick disease type C1 cells, they identified massive accumulation of cholesterol in the endosome/lysosome compartment. Thus, several probes from the same series can also be used for visualizing lysosomal storage disorders and sterol transporting pathologies.

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Pharmacokinetics, pharmacodynamics and clinical efficacy of abiraterone acetate for treating metastatic castration-resistant prostate cancer

Cited by 20 publications

References 38 publications

Heterocyclic sterol probes for live monitoring of sterol trafficking and lysosomal storage disorders

Heterocyclic sterol probes for live monitoring of sterol trafficking and lysosomal storage disorders

Management of anticoagulation in patients with metastatic castration–resistant prostate cancer receiving abiraterone + prednisone

Heterocyclic sterol probes for live monitoring of sterol trafficking and lysosomal storage disorders

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