• MeSH
• adjuvantní chemoterapie metody   využití   MeSH
• anastrozol MeSH
• lidé MeSH
• nádory prsu farmakoterapie   MeSH
• nitrily aplikace a dávkování   terapeutické užití   MeSH
• postmenopauza účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

Anastrozol je vysoce selektivní nesteroidní inhibitor aromatáz. Léčivo je schváleno pro léčbu karcinomu prsu s pozitivními hormonálními receptory u postmenopauzálních žen. Inhibitory aromatáz jsou nicméně mnoho let používány off­‐label i u mužů. Tento článek přibližuje empirická neonkologická využití anastrozolu u mužů a stručně přibližuje některá aktuální klinická hodnocení zahrnující mužskou populaci.

Anastrozole is a highly selective nonsteroidal aromatase inhibitor. It is approved for the treatment of hormone receptor-positive breast cancer in postmenopausal women. Nonetheless, aromatase inhibitors have also been used off-label for many years in men. This article outlines empirical non-oncological anastrozole uses in men and briefly presents some current clinical trials involving the male population.

• MeSH
• anastrozol * farmakologie   terapeutické užití   MeSH
• hodnocení léčiv MeSH
• inhibitory aromatasy farmakologie   terapeutické užití   MeSH
• lidé MeSH
• off-label použití léčivého přípravku MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

The mitochondrial permeability transition pore (mtPTP) plays a vital role in altering the structure and function of mitochondria. Cyclophilin D (CypD) is a mitochondrial protein that regulates mtPTP function and a known drug target for therapeutic studies involving mitochondria. While the effect of aromatase inhibition on the mtPTP has been studied previously, the effect of anastrozole on the mtPTP has not been completely elucidated. The role of anastrozole in modulating the mtPTP was evaluated by docking, molecular dynamics and network-guided studies using human CypD data. The peripheral blood mononuclear cells (PBMCs) of patients with mitochondrial disorders and healthy controls were treated with anastrozole and evaluated for mitochondrial permeability transition pore (mtPTP) function and apoptosis using a flow cytometer. Spectrophotometry was employed for estimating total ATP levels. The anastrozole-CypD complex is more stable than cyclosporin A (CsA)-CypD. Anastrozole performed better than cyclosporine in inhibiting mtPTP. Additional effects included inducing mitochondrial membrane depolarization and a reduction in mitochondrial swelling and superoxide generation, intrinsic caspase-3 activity and cellular apoptosis, along with an increase in ATP levels. Anastrozole may serve as a potential therapeutic agent for mitochondrial disorders and ameliorate the clinical phenotype by regulating the activity of mtPTP. However, further studies are required to substantiate our preliminary findings.Communicated by Ramaswamy H. Sarma.

• MeSH
• adenosintrifosfát metabolismus   MeSH
• anastrozol farmakologie   metabolismus   MeSH
• cyklofiliny genetika   metabolismus   MeSH
• leukocyty mononukleární metabolismus   MeSH
• lidé MeSH
• mitochondriální nemoci * metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• peptidylprolylisomerasa F MeSH
• přechodový pór mitochondriální permeability * metabolismus   farmakologie   MeSH
• transportní proteiny mitochondriální membrány metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• antagonisté estrogenu MeSH
• aromatasa MeSH
• inhibitory aromatasy MeSH
• inhibitory enzymů terapeutické užití   MeSH
• klinická farmakologie MeSH
• nádory prsu farmakoterapie   MeSH
• Publikační typ
• kongresy MeSH
• sborníky MeSH

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• farmacie a farmakologie
• onkologie

PURPOSE: To compare overall survival (OS) for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer. PATIENTS AND METHODS: The Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) was a phase II, randomized, open-label, multicenter trial. Postmenopausal women with estrogen receptor-positive, locally advanced/metastatic breast cancer who had no previous therapy for advanced disease received either fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or anastrozole 1 mg (daily). The primary end point (clinical benefit rate [72.5% and 67.0%]) and a follow-up analysis (median time to progression [23.4 months and 13.1 months]) have been reported previously for fulvestrant 500 mg and anastrozole, respectively. Subsequently, the protocol was amended to assess OS by unadjusted log-rank test after approximately 65% of patients had died. Treatment effect on OS across several subgroups was examined. Tolerability was evaluated by adverse event monitoring. RESULTS: In total, 205 patients were randomly assigned (fulvestrant 500 mg, n = 102; anastrozole, n = 103). At data cutoff, 61.8% (fulvestrant 500 mg, n = 63) and 71.8% (anastrozole, n = 74) had died. The hazard ratio (95% CI) for OS with fulvestrant 500 mg versus anastrozole was 0.70 (0.50 to 0.98; P = .04; median OS, 54.1 months v 48.4 months). Treatment effects seemed generally consistent across the subgroups analyzed. No new safety issues were observed. CONCLUSION: There are several limitations of this OS analysis, including that it was not planned in the original protocol but instead was added after time-to-progression results were analyzed, and that not all patients participated in additional OS follow-up. However, the present results suggest fulvestrant 500 mg extends OS versus anastrozole. This finding now awaits prospective confirmation in the larger phase III FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast Cancer) trial (ClinicalTrials.gov identifier: NCT01602380).

• MeSH
• antagonisté estrogenového receptoru aplikace a dávkování   MeSH
• dospělí MeSH
• estradiol aplikace a dávkování   analogy a deriváty   MeSH
• hormonální protinádorové látky aplikace a dávkování   MeSH
• inhibitory aromatasy aplikace a dávkování   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• nitrily aplikace a dávkování   MeSH
• přežití bez známek nemoci MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• triazoly aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

• MeSH
• duktální karcinom prsu farmakoterapie   chirurgie   radioterapie   MeSH
• karcinom in situ * farmakoterapie   chirurgie   radioterapie   MeSH
• kongresy jako téma MeSH
• lidé MeSH
• nádory prsu farmakoterapie   terapie   MeSH
• nitrily * škodlivé účinky   terapeutické užití   toxicita   MeSH
• postmenopauza účinky léků   MeSH
• radioterapie metody   využití   MeSH
• randomizované kontrolované studie jako téma metody   využití   MeSH
• segmentální mastektomie metody   využití   MeSH
• statistika jako téma MeSH
• tamoxifen * terapeutické užití   toxicita   MeSH
• triazoly škodlivé účinky   terapeutické užití   toxicita   MeSH
• věkové faktory MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

Anastrozole is a selective non-steroidal aromatase inhibitor that blocks the conversion of androgens to estrogens in peripheral tissues. It is used as adjuvant therapy for early-stage hormone-sensitive breast cancer in postmenopausal women. Significant side effects of anastrozole include osteoporosis and increased levels of cholesterol. To date, seven case reports on anastrozole hepatotoxicity have been published. We report the case of an 81-year-old woman with a history of breast cancer, arterial hypertension, type 2 diabetes mellitus, hyperlipidemia, and chronic renal insufficiency. Four days after switching hormone therapy from tamoxifen to anastrozole, icterus developed along with a significant increase in liver enzymes (measured in the blood). The patient was admitted to hospital, where a differential diagnosis of jaundice was made and anastrozole was withdrawn. Subsequently, hepatic functions quickly normalized. The observed liver injury was attributed to anastrozole since other possible causes of jaundice were excluded. However, concomitant pharmacotherapy could have contributed to the development of jaundice and hepatotoxicity, after switching from tamoxifen to anastrozole since several the patient's medications were capable of inhibiting hepatobiliary transport of bilirubin, bile acids, and metabolized drugs through inhibition of ATP-binding cassette proteins. Telmisartan, tamoxifen, and metformin all block bile salt efflux pumps. The efflux function of multidrug resistance protein 2 is known to be reduced by telmisartan and tamoxifen and breast cancer resistance protein is known to be inhibited by telmisartan and amlodipine. Moreover, the activity of P-glycoprotein transporters are known to be decreased by telmisartan, amlodipine, gliquidone, as well as the previously administered tamoxifen. Finally, the role of genetic polymorphisms of cytochrome P450 enzymes and/or drug transporters cannot be ruled out since the patient was not tested for polymorphisms.

• Publikační typ
• kazuistiky MeSH

Little data exist on whether efficacy benefits or side-effects persist after 5 years of adjuvant treatment with an aromatase inhibitor. We aimed to study long-term outcomes in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial that compares anastrozole with tamoxifen after a median follow-up of 100 months. METHODS: We analysed postmenopausal women with localised invasive breast cancer. The primary endpoint disease-free survival (DFS), and the secondary endpoints time to recurrence (TTR), incidence of new contralateral breast cancer (CLBC), time to distant recurrence (TTDR), overall survival (OS), and death after recurrence were assessed in the total population (intention to treat; ITT: anastrozole, n=3125; tamoxifen, n=3116; total 6241) and the hormone-receptor-positive subpopulation, the clinically important subgroup for which endocrine treatment is now known to be effective (84% of ITT: anastrozole, n=2618; tamoxifen, n=2598; total 5216). After treatment completion, fractures and serious adverse events continued to be collected blindly (safety population: anastrozole, n=3092; tamoxifen, n=3094; total 6186). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. FINDINGS: At a median follow-up of 100 months (range 0-126), DFS, TTR, TTDR, and CLBC were improved significantly in the ITT and hormone-receptor-positive populations. For hormone-receptor-positive patients: DFS hazard ratio (HR) 0.85 (95% CI 0.76-0.94), p=0.003; TTR HR 0.76 (0.67-0.87), p=0.0001; TTDR HR 0.84 (0.72-0.97), p=0.022; and CLBC HR 0.60 (0.42-0.85), p=0.004. Absolute differences in time to recurrence increased over time (TTR 2.8% [anastrozole 9.7%vs tamoxifen 12.5%] at 5 years and 4.8% [anastrozole 17.0%vs tamoxifen 21.8%] at 9 years) and recurrence rates remained significantly lower on anastrozole compared with tamoxifen after treatment completion (HR 0.75 [0.61-0.94], p=0.01). The fewer deaths after recurrence (anastrozole 245 vs tamoxifen 269) was not significant (HR 0.90 [0.75-1.07], p=0.2), and no effect was noted for OS (anastrozole 472 vs tamoxifen 477) HR 0.97 [0.86-1.11], p=0.7). Fracture rates were higher in patients receiving anastrozole than in those receiving tamoxifen during active treatment (number [annual rate]: 375 [2.93%] vs 234 [1.90%]; incidence rate ratio [IRR] 1.55 [1.31-1.83], p<0.0001), but were not different after treatment was completed (off treatment: 146 [1.56%] vs 143 [1.51%]; IRR 1.03 [0.81-1.31], p=0.79). We did not note any significant difference in risk of cardiovascular morbidity or mortality between anastrozole and tamoxifen treatment groups. INTERPRETATION: These data show long-term safety findings and establish clearly the long-term efficacy of anastrozole compared with tamoxifen as initial adjuvant treatment for postmenopausal women with hormone-sensitive, early breast cancer, and provide statistically significant evidence of a larger carryover effect after 5 years of adjuvant treatment with anastrozole compared with tamoxifen.

• MeSH
• alkylační protinádorové látky škodlivé účinky   terapeutické užití   MeSH
• časové faktory MeSH
• fraktury kostí chemicky indukované   MeSH
• inhibitory aromatasy škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• nádory prsu farmakoterapie   mortalita   MeSH
• následné studie MeSH
• nitrily škodlivé účinky   terapeutické užití   MeSH
• postmenopauza MeSH
• přežití bez známek nemoci MeSH
• tamoxifen škodlivé účinky   terapeutické užití   MeSH
• triazoly škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

For more than 20 years, tamoxifen has been the mainstay of adjuvant endocrine therapy for women with hormone-sensitive early-stage breast cancer. However, not only does tamoxifen have potential side-effects such as an increased risk of endometrial cancer and thromboembolic events, but patients can also develop resistance to the drug. We aimed to investigate whether switching treatment of postmenopausal women with such breast cancer to anastrozole after 2-3 years of tamoxifen would be more effective than continuing on tamoxifen for a total of 5 years. METHODS: We did a meta-analysis of three clinical trials--the Austrian Breast and Colorectal Cancer Study Group (ABCSG 8), Arimidex-Nolvadex (ARNO 95), and the Italian Tamoxifen Anastrozole (ITA) studies--in which postmenopausal women with histologically confirmed, hormone-sensitive early-stage breast cancer were randomised to 1 mg/day anastrozole (n=2009) after 2-3 years of tamoxifen treatment or to continued 20 or 30 mg/day tamoxifen (n=1997). We analysed the data with a stratified Cox proportional hazards model with the covariates of age, tumour size, nodal status, grade, surgery, and chemotherapy. FINDINGS: Patients who switched to anastrozole had fewer disease recurrences (92 vs 159) and deaths (66 vs 90) than did those who remained on tamoxifen, resulting in significant improvements in disease-free survival (hazard ratio 0.59 [95% CI 0.48-0.74]; p<0.0001), event-free survival (0.55 [0.42-0.71]; p<0.0001), distant recurrence-free survival (0.61 [0.45-0.83]; p=0.002), and overall survival (0.71 [0.52-0.98]; p=0.04). INTERPRETATION: Our results show that the clinical benefits in terms of event-free survival seen in individual trials for those patients who switched to anastrozole translate into a benefit in overall survival. These findings confirm that clinicians should consider switching postmenopausal women who have taken adjuvant tamoxifen for 2-3 years to anastrozole.

• MeSH
• hormonální protinádorové látky terapeutické užití   MeSH
• lidé MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• nitrily MeSH
• postmenopauza MeSH
• přežití bez známek nemoci MeSH
• progrese nemoci MeSH
• randomizované kontrolované studie jako téma MeSH
• receptory pro estrogeny metabolismus   MeSH
• tamoxifen terapeutické užití   MeSH
• triazoly terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

• Klíčová slova
• Arimidex, Novaldex,
• MeSH
• adjuvantní chemoterapie metody   škodlivé účinky   využití   MeSH
• finanční podpora výzkumu jako téma MeSH
• interpretace statistických dat MeSH
• karcinom terapie   MeSH
• lidé MeSH
• nádory prsu diagnóza   terapie   MeSH
• nitrily aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• tamoxifen aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH