Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Androgen deprivation therapy is part of the initial treatment of patients with metastatic prostate cancer. Nevertheless, after an initial response and despite maintaining an effective testosterone suppression, the tumor is able to continue growing.Enzalutamide is an oral second generation pure antiandrogen that acts at various levels in the signal activation cascade of the androgen receptor and has demonstrated being effective in this phase of the disease. In the clinical trials completed, it has demonstrated benefits in overall patient survival in patients with the diagnosis of metastatic castration resistant prostate cancer. Recent studies have also demonstrated benefits in progression free survival in patients with non-metastatic castration resistant prostate cancer. Enzalutamide has an excellent toxicity profile, but we have to avoid it in patients with history of seizure episodes, mainly if they are under anti-epileptic drug therapy. Enzalutamide is rapidly metabolized by the liver, mainly through the CYP2C8 and to a lesser extent by CYP3A4/5 so that its metabolism may be altered when cytochrome isoenzyme inductor or inhibitor drugs are given concomitantly. Moreover, enzalutamide may require dose adjustment for other drugs since it is a potent inductor of CYP3A4 and a moderate inductor of CYP2C9 y el CYP2C19. Even though treatment with enzalutamide has significantly altered the natural history of the disease, in most cases it will progress by development of resistance mechanisms, among which we may emphasize androgen receptor mutations, overexpression, amplification and variants, as well as the intracrine production of androgens. Enzalutamide must be considered as first line therapy in patients with castration resistant prostate cancer.
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PMID:[Enzalutamide in castration resistant prostate cancer.] 3031 26

Men treated with androgen deprivation therapy for rising PSA after failed local therapy will often develop castrate resistance, and the appearance of metastases predicts a poor prognosis. Thus, researchers have long sought to prolong the onset of metastasis in patients with nonmetastatic castration-resistant prostate cancer (CRPC). Until 2018, patients in this group had no FDA-approved treatment options. They were typically managed with androgen-deprivation therapy (ADT) to maintain castrate systemic testosterone levels and given approved therapies for metastatic CRPC once metastases appeared. However, third-generation androgen receptor inhibitors (ARIs) have dramatically changed the treatment paradigm, having shown the ability to extend metastasis-free survival (MFS) significantly over ADT alone in Phase 3 trials. The newest of these, darolutamide, prolonged MFS 22 months over placebo while also improving a host of secondary and exploratory endpoints such as overall survival (OS), prostate-specific antigen (PSA) progression and time to pain progression, chemotherapy initiation, and symptomatic skeletal events. Among third-generation ARIs, darolutamide is unique in that it incorporates two pharmacologically active diastereomers and has demonstrated resistance to all known androgen receptor (AR) mutations. Additionally, patients taking darolutamide appear to experience comparatively few central nervous system-related adverse events (AEs) such as fatigue and falls, and no increases in seizures have been reported in the drug's clinical or preclinical development. Various authors attribute the low incidence of CNS-related AEs to darolutamide's minimal penetration of the blood-brain barrier (BBB). Other side effects ranging from hot flashes to hypothyroidism also occurred at rates similar to those of the placebo arm in Phase 3. As ADT in itself raises cardiovascular risk, the cardiovascular safety of third-generation antiandrogens as a category warrants continued scrutiny. In total, however, published data suggest that darolutamide provides a reasonable option for patients with nonmetastatic CRPC. Ongoing research will determine darolutamide's potential role in additional disease states such as localized and castration-sensitive PCa.
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PMID:Darolutamide: An Evidenced-Based Review of Its Efficacy and Safety in the Treatment of Prostate Cancer. 3276 70

Prostate cancer (PC) is known as the most frequent cancer among men in the world. Androgen Deprivation Therapy (ADT) is one of the initial treatment approaches in the PC therapy and various drugs can be used in routine Hormonal therapy for PC therapy. Nevertheless, PC cells can survive and continue their growth via different mechanisms which lead to their resistance to common treatments i.e., Enzalutamide. Darolutamide (ODM-201) is a second-generation androgen receptor (AR) inhibitor with a new chemical structure and has a high affinity to the AR. Darolutamide doesn't cross the bloodbrain barrier, for this reason, reduces the possibility of seizures. Darolutamide also can inhibit the transcriptional activity of several AR mutant variants (F877L, F877L/T878A, and H875Y/T878A) which are Enzalutamide resistant. In this review we reviewed the results of different studies: in vitro, animal model and phase 1, 2 and 3 clinical trials (ARADES, ARAFOR and ARAMIS). We shall discuss worldwide phase 2 and 3 clinical trials (ARASENS and ODENZA) that are in progress, in order to demonstrate the advantages of Darolutamide consumption in different groups of patients. Darolutamide has shown high potential in inhibiting the growth of MR49F (Enzalutamide resistant PC cells) and VCaP (Castration-resistant PC cells) cell lines and transcriptional activities of AR. Fewer doses of Darolutamide is needed compared to Enzalutamide. The drug had significant anti-tumor activity and had no effect on serum testosterone levels in animal models. Darolutamide demonstrates its safety and efficacy in different studies and was well tolerated nearly in all of the patients.
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PMID:Darolutamide as a second-generation Androgen receptor inhibitor in the treatment of prostate cancer. 3288 69


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