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1.
Breast Cancer Res Treat ; 160(1): 101-109, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27663436

RESUMO

PURPOSE: The purpose of this study is to evaluate survival outcome in patients with hormone receptor (HR)-positive (+) metastatic breast cancer (MBC) who received fluoxymesterone after disease progression while receiving contemporary hormonal therapy, as well as the association between estrogen receptor (ER)/androgen receptor (AR) status and survival outcome in these patients. METHODS: We retrospectively identified 103 patients treated with fluoxymesterone for HR + MBC from 2000 to 2014 and with at least one previous hormonal therapy in a metastatic setting. RESULTS: A median of 3 (range 1-10) hormonal therapies (aromatase inhibitors, tamoxifen, and/or fulvestrant) were received before fluoxymesterone; 33 patients discontinued fluoxymesterone before progression because of physician decision or adverse events including toxicity in 14 patients. Of the remaining 70 patients, 2 (3 %) had complete response, 7 (10 %) partial response, and 21 (30 %) stable disease for at least 6 months, yielding a clinical benefit rate of 43 %. The median PFS was 3.9 months (95 % CI 3.2-5.3 months). Multivariate analysis revealed no significant association between PFS and the type or number of prior systemic treatments. All 39 patients who had archived tumor slides available for AR staining had ER + carcinoma; 10 had ≥1 % but <10 %, 18 had ≥10 %, and 11 had no AR nuclear expression. AR positivity with various cutoffs (i.e. any AR + cells, ≥1 % AR + cells, or ≥10 % AR + cells) was not significantly associated with survival outcome. CONCLUSIONS: Fluoxymesterone can be considered for patients whose ER + MBC progresses on contemporary hormonal therapy, regardless of the level of AR expression.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Fluoximesterona/uso terapêutico , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Receptores Androgênicos/genética , Receptores Estrogênicos/genética , Estudos Retrospectivos , Resultado do Tratamento
2.
BMJ Case Rep ; 20152015 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-25948845

RESUMO

Gynaecomastia is a benign condition characterised by enlargement of the male breast. Drug-induced gynaecomastia merits deep consideration as it may account for as many as 25% of all cases of gynaecomastia in adults. Although the mechanism is not fully clear, some mechanisms include oestrogen-like activities, stimulation of testicular production of oestrogens, inhibition of testosterone synthesis or blockade of androgen action. Anabolic steroids, in particular when used during the pubertal stage, may cause significant irreversible gynaecomastia. We report a case of 28-year-old Filipino man with persistent gynaecomastia from fluoxymesterone used for aplastic anaemia during his prepubertal stage. Hormonal work ups for gynaecomastia all turned out normal, thus isolating the drug as the cause. The patient was unable to undergo breast reconstruction surgery due to haematological contraindications, but eventually referred to psychiatry for counselling. This case will highlight the paradoxical effect of androgenic steroid used during childhood on male breast proliferation during puberty.


Assuntos
Anabolizantes/efeitos adversos , Anemia Aplástica/tratamento farmacológico , Aconselhamento Diretivo , Fluoximesterona/efeitos adversos , Ginecomastia/induzido quimicamente , Adulto , Anabolizantes/administração & dosagem , Anemia Aplástica/sangue , Fluoximesterona/administração & dosagem , Ginecomastia/psicologia , Humanos , Masculino , Maturidade Sexual , Resultado do Tratamento
3.
Steroids ; 77(8-9): 871-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22521423

RESUMO

In this study fluoxymesterone urinary profiles were investigated by liquid chromatography quadrupole time-of-flight tandem mass spectrometry (LC-QTOFMS) with accurate mass measurement. Twelve metabolites including the parent drug were detected in two fluoxymesterone positive control urine samples. Three parameters were employed for evaluation of the accuracy of the chemical formulae in positive full scan experiment, which contained error between actual and calculated mass weights of prontonated and isotopic molecules together with abundance match between prontonated and isotopic molecules. The 13 analytes were determined with mass accuracy less than 1.1 ppm and isotopic abundance match more than 94 marks. Based on the ionization, CID fragmentation, the accurate mass of the product ion and comparison of the accurate mass weight and retention time with reference standard, fluoxymesterone and its 12 metabolites containing three unreported ones were detected. The chemical structures of three unreported metabolites were identified as: 9-fluro-17ß-ol-17-methyl-11-en-5α-androstan-3-one (F13), 9-fluro-17ß-ol-17-methyl-11-en-5ß-androstan-3-one (F8) and 9-fluro-17ß-ol-17-methyl-5-androstan-3,6,11-trione, and meanwhile a dihydroxylated metabolite (F12), 6,16-dihydroxylated fluoxymesterone, was also detected in human urine, which was previously reported to be available only in equine urine.


Assuntos
Cromatografia Líquida/métodos , Fluoximesterona/urina , Espectrometria de Massas em Tandem/métodos , Fluoximesterona/química , Humanos , Estrutura Molecular
4.
Toxicol Sci ; 126(2): 353-61, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22273746

RESUMO

Anabolic androgenic steroids (AAS) are testosterone derivatives used either clinically, in elite sports, or for body shaping with the goal to increase muscle size and strength. Clinically developed compounds and nonclinically tested designer steroids often marketed as food supplements are widely used. Despite the considerable evidence for various adverse effects of AAS use, the underlying molecular mechanisms are insufficiently understood. Here, we investigated whether some AAS, as a result of a lack of target selectivity, might inhibit 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2)-dependent inactivation of glucocorticoids. Using recombinant human 11ß-HSD2, we observed inhibitory effects for several AAS. Whereas oxymetholone, oxymesterone, danazol, and testosterone showed medium inhibitory potential, fluoxymesterone was a potent inhibitor of human 11ß-HSD2 (half-maximal inhibitory concentration [IC(50)] of 60-100nM in cell lysates; IC(50) of 160nM in intact SW-620, and 530nM in MCF-7 cells). Measurements with rat kidney microsomes and lysates of cells expressing recombinant mouse 11ß-HSD2 revealed much weaker inhibition by the AAS tested, indicating that the adverse effects of AAS-dependent 11ß-HSD2 inhibition cannot be investigated in rats and mice. Furthermore, we provide evidence that fluoxymesterone is metabolized to 11-oxofluoxymesterone by human 11ß-HSD2. Structural modeling revealed similar binding modes for fluoxymesterone and cortisol, supporting a competitive mode of inhibition of 11ß-HSD2-dependent cortisol oxidation by this AAS. No direct modulation of mineralocorticoid receptor (MR) function was observed. Thus, 11ß-HSD2 inhibition by fluoxymesterone may cause cortisol-induced MR activation, thereby leading to electrolyte disturbances and contributing to the development of hypertension and cardiovascular disease.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Anabolizantes/toxicidade , Inibidores Enzimáticos/farmacologia , Fluoximesterona/toxicidade , Glucocorticoides/antagonistas & inibidores , Animais , Linhagem Celular , Humanos , Camundongos
5.
Artigo em Inglês | MEDLINE | ID: mdl-22217702

RESUMO

This study was designed to examine the interaction of two anti-breast cancer drugs, i.e., fluoxymesterone (FLU) and cyclophosphamide (CYC), with human serum albumin (HSA) using different kinds of spectroscopic, zeta potential and molecular modeling techniques under imitated physiological conditions. The RLS technique was utilized to investigate the effect of the two anticancer drugs on changes of the protein conformation, both separately and simultaneously. Our study suggested that the enhancement in RLS intensity was attributed to the formation of a new complex between the two drugs and the protein. Both drugs demonstrated a powerful ability to quench the fluorescence of HSA, and the fluorescence quenching action was much stronger when the two drugs coexisted. The quenching mechanism was suggested to be static as confirmed by time-resolved fluorescence spectroscopy results. The effect of both drugs on the conformation of HSA was analyzed using synchronous fluorescence spectroscopy. Our results revealed that the fluorescence quenching of HSA originated from the Trp and Tyr residues, and demonstrated a conformational change of HSA with the addition of both drugs. The binding distances between HSA and the drugs were estimated by the Förster theory, and it was revealed that nonradiative energy transfer from HSA to both drugs occurred with a high probability. According to CD measurements, the influence of both drugs on the secondary structure of HSA in aqueous solutions was also investigated and illustrated that the α-helix content of HSA decreased with increasing drug concentration in both systems. Moreover, the zeta-potential experiments revealed that both drugs induced conformational changes on HSA. Docking studies were also performed and demonstrated that a reduction of the binding affinity between the drugs and HSA occurred in the presence of both drugs.


Assuntos
Ciclofosfamida/metabolismo , Fluoximesterona/metabolismo , Modelos Moleculares , Albumina Sérica/metabolismo , Sítios de Ligação , Dicroísmo Circular , Ciclofosfamida/química , Transferência de Energia , Fluoximesterona/química , Humanos , Concentração de Íons de Hidrogênio , Cinética , Luz , Conformação Molecular , Estrutura Secundária de Proteína , Espalhamento de Radiação , Albumina Sérica/química , Espectrometria de Fluorescência , Eletricidade Estática , Fatores de Tempo , Triptofano/metabolismo
6.
Anal Sci ; 24(7): 911-4, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18614835

RESUMO

Fluoxymesterone, an anabolic steroid with the 17alpha-methyl,17beta-hydroxy group, has been developed as an oral formulation for therapeutic purposes. However, it is also used illegally in racehorses to enhance racing performance. In this study, we detected 9alpha-fluoro-17,17-dimethyl-18-norandrostane-4,13-dien-11beta-ol-3-one by gas chromatography/mass spectrometry (GC/MS), which has not been reported as a fluoxymesterone metabolite so far in horse. It was synthesized for use as a reference standard, and characterized on the basis of (1)H NMR and (13)C NMR spectra, as well as GC/MS EI mass spectra of TMS derivatives. It was excreted as the main metabolite in horse urine, and its reference standard could be synthesized easily. Therefore, this metabolite could be a useful target for a doping test of fluoxymesterone in racehorses.


Assuntos
Anabolizantes/urina , Doping nos Esportes , Fluoximesterona/urina , Cromatografia Gasosa-Espectrometria de Massas/métodos , Detecção do Abuso de Substâncias/métodos , Animais , Cavalos , Espectroscopia de Ressonância Magnética/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
7.
J Mass Spectrom ; 43(3): 394-408, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18035854

RESUMO

The suitability of liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography mass spectrometry (GC-MS) for the elucidation of fluoxymesterone metabolism has been evaluated. Electrospray ionization (ESI) and collision induced dissociation (CID) fragmentation in LC-MS/MS and electron impact spectra (EI) in GC-MS have been studied for fluoxymesterone and two commercially available metabolites. MS(n) experiments and accurate mass measurements performed by an ion-trap analyser and a QTOF instrument respectively have been used for the elucidation of the fragmentation pathway. The neutral loss scan of 20 Da (loss of HF) in LC-MS/MS has been applied for the selective detection of fluoxymesterone metabolites. In a positive fluoxymesterone doping control sample, 9 different analytes have been detected including the parent compound. Seven of these metabolites were also confirmed by GC-MS including 5 previously unreported metabolites. On the basis of the ionization, the CID fragmentation, the accurate mass of the product ions and the EI spectra of these analytes, a tentative elucidation as well as a proposal for the metabolic pathway of fluoxymesterone has been suggested. The presence of these compounds has also been confirmed by the analysis of five other positive fluoxymesterone urine samples.


Assuntos
Fluoximesterona/urina , Cromatografia Gasosa-Espectrometria de Massas/métodos , Detecção do Abuso de Substâncias/métodos , Espectrometria de Massas em Tandem/métodos , Anabolizantes/química , Anabolizantes/metabolismo , Anabolizantes/urina , Cromatografia Líquida/métodos , Doping nos Esportes , Fluoximesterona/metabolismo , Fluoximesterona/normas , Humanos , Redes e Vias Metabólicas , Estrutura Molecular , Padrões de Referência , Espectrometria de Massas por Ionização por Electrospray/métodos
8.
Electrophoresis ; 28(20): 3737-44, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17893945

RESUMO

ACE is a popular technique for evaluating association constants between drugs and proteins. However, ACE has not previously been applied to study the association between electrically neutral biomolecules and plasma proteins. We studied the affinity between human and bovine serum albumins (HSA and BSA, respectively) and three neutral endogenous steroid hormones (testosterone, epitestosterone and androstenedione) and two synthetic analogues (methyltestosterone and fluoxymesterone) by applying the partial-filling technique in ACE (PF-ACE). From the endocrinological point of view, the distribution of endogenous steroids among plasma components is of great interest. Strong interactions with albumins suppress the biological activity of steroids. Notable differences in the association constants were observed. In the case of the endogenous steroids, the interactions between testosterone and the albumins were strongest, and those between androstenedione and the albumins were substantially weaker. The association constants, K(b), for testosterone, epitestosterone and androstenedione and HSA at 37 degrees C were 32 100 +/- 3600, 21 600 +/- 1500 and 13 300 +/- 1300 M(-1), respectively, while the corresponding values for the steroids and BSA were 18 800 +/- 1500, 14 000 +/- 400 and 7800 +/- 900 M(-1). Methyltestosterone was bound even more strongly than testosterone, while fluoxymesterone was only weakly bound by the albumins. Finally, the steroids were separated by PF-ACE with HSA and BSA used as resolving components.


Assuntos
Algoritmos , Ensaio de Desvio de Mobilidade Eletroforética/métodos , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Albumina Sérica/química , Albumina Sérica/metabolismo , Androstenodiona/análise , Androstenodiona/química , Androstenodiona/urina , Animais , Bovinos , Cromatografia Capilar Eletrocinética Micelar/métodos , Epitestosterona/análise , Epitestosterona/química , Epitestosterona/urina , Fluoximesterona/análise , Fluoximesterona/química , Fluoximesterona/urina , Humanos , Masculino , Metiltestosterona/análise , Metiltestosterona/química , Metiltestosterona/urina , Progesterona/análise , Progesterona/química , Progesterona/urina , Ligação Proteica , Reprodutibilidade dos Testes , Globulina de Ligação a Hormônio Sexual/química , Globulina de Ligação a Hormônio Sexual/metabolismo , Dodecilsulfato de Sódio/química , Testosterona/análise , Testosterona/química , Testosterona/urina
10.
Endocrinology ; 148(1): 363-73, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17023534

RESUMO

A number of conditions, including osteoporosis, frailty, and sexual dysfunction in both men and women have been improved using androgens. However, androgens are not widely used for these indications because of the side effects associated with these drugs. We describe an androgen receptor (AR) ligand that maintains expected anabolic activities with substantially diminished activity in the prostate. LGD2226 is a nonsteroidal, nonaromatizable, highly selective ligand for the AR, exhibiting virtually no affinity for the other intracellular receptors. We determined that AR bound to LGD2226 exhibits a unique pattern of protein-protein interactions compared with testosterone, fluoxymesterone (an orally available steroidal androgen), and other steroids, suggesting that LGD2226 alters the conformation of the ligand-binding domain. We demonstrated that LGD2226 is fully active in cell-based models of bone and muscle. LGD2226 exhibited anabolic activity on muscle and bone with reduced impact on prostate growth in rodent models. Biomechanical testing of bones from animals treated with LGD2226 showed strong enhancement of bone strength above sham levels. LGD2226 was also efficacious in a sex-behavior model in male rats measuring mounts, intromissions, ejaculations, and copulation efficiency. These results with an orally available, nonaromatizable androgen demonstrate the important role of the AR and androgens in mediating a number of beneficial effects in bone, muscle, and sexual function independent from the conversion of androgens into estrogenic ligands. Taken together, these results suggest that orally active, nonsteroidal selective androgen receptor modulators may be useful therapeutics for enhancing muscle, bone, and sexual function.


Assuntos
Aminoquinolinas/farmacologia , Copulação/efeitos dos fármacos , Vértebras Lombares/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Próstata/efeitos dos fármacos , Quinolonas/farmacologia , Administração Oral , Aminoquinolinas/síntese química , Aminoquinolinas/metabolismo , Animais , Antineoplásicos Hormonais/farmacologia , Fenômenos Biomecânicos , Linhagem Celular Tumoral , Fluoximesterona/farmacologia , Humanos , Vértebras Lombares/fisiologia , Masculino , Orquiectomia , Osteossarcoma , Neoplasias da Próstata , Quinolonas/síntese química , Quinolonas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Spodoptera
12.
Breast Cancer Res Treat ; 98(2): 217-22, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16538529

RESUMO

PURPOSE: This clinical trial evaluated the addition of fluoxymesterone (Flu) to tamoxifen (Tam) in women with resected early stage breast cancer and attempted to corroborate the findings of superiority for the combination over Tam alone seen in a previous randomized trial in metastatic disease. PATIENTS AND METHODS: Postmenopausal women with early stage breast cancer that was known to be estrogen receptor (ER) positive were randomized to treatment with Tam (20 mg per day orally for 5 years) alone or combined with Flu (10 mg orally twice per day for 1 year). The primary endpoint was relapse-free survival (RFS) defined as local-regional or distant recurrence including ductal carcinoma in situ of the ipsilateral, but not contralateral breast, and death from any cause. RESULTS: There were 541 eligible patients entered between 1991 and 1995 and the treatment arms were balanced with respect to patient characteristics. The median follow up of patients still alive was 11.4 years. No significant difference was found between Tam plus Flu and Tam alone in terms of RFS or overall survival. The adjusted hazard ratio (Tam+Flu/Tam) for relapse or death without relapse was estimated to be 0.84 (95% CI: 0.64-1.10) and that for death was 0.89 (95% CI: 0.67-1.18). As expected there was more virilization in women who received Flu. CONCLUSIONS: This clinical trial did not demonstrate superiority of Tam plus Flu over Tam alone as adjuvant therapy for postmenopausal women with resected early breast cancer known to be ER positive.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fluoximesterona/administração & dosagem , Receptores Estrogênicos/análise , Tamoxifeno/uso terapêutico , Adulto , Idoso , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Fluoximesterona/efeitos adversos , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos
13.
J Pharm Biomed Anal ; 31(1): 201-8, 2003 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-12560066

RESUMO

Two isocratic liquid chromatographic methods (conventional and micellar) for the determination of methyltestosterone in sugar-coated pills using fluoxymesterone as internal standard have been developed and validated. In conventional liquid chromatography a mobile phase 45% water:acetonitrile 55% (v:v), a flow-rate 1 mlmin(-1) and a C(18) Hypersil ODS (250 x 4.6 mm, 5 microm) column (25 degrees C) were used. In micellar liquid chromatography the conditions were: mobile phase 40 mM sodium dodecyl sulfate: 10% propanol, flow-rate 0.5 mlmin(-1) and C(18) Hypersil ODS (150 x 3.0 mm, 5 microm) column (60 degrees C). For both methods, UV absorbance detection at 245 nm was used and a separation up to base line was achieved. Prior to HPLC analysis a simple sample preparation was required.


Assuntos
Anabolizantes/análise , Metiltestosterona/análise , Calibragem , Cromatografia Líquida de Alta Pressão , Fluoximesterona/análise , Indicadores e Reagentes , Micelas , Padrões de Referência , Reprodutibilidade dos Testes , Comprimidos
14.
Stat Med ; 20(4): 557-79, 2001 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-11223901

RESUMO

In this paper we propose formulae for calculating the expected number of events or, alternatively, the required trial duration, for clinical trials involving two treatment groups in which patients may potentially experience multiple events and the data will be analysed using a multiplicative intensity (MI) model. We use a partial likelihood-based approach and examine in detail two MI models: one that includes a binary treatment variable as the only covariate and a three-state Markov process model in which a binary time-varying covariate is added to the previous model. For the simpler model, our formula coincides with those derived by Cook using full likelihood methods. We present applications of the derived formulae to chronic granulomatous disease and breast cancer data sets.


Assuntos
Modelos Biológicos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Criança , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Fluoximesterona/uso terapêutico , Doença Granulomatosa Crônica/tratamento farmacológico , Humanos , Interferon gama/uso terapêutico , Funções Verossimilhança , Cadeias de Markov , Metotrexato/uso terapêutico , Prednisona/uso terapêutico , Tamanho da Amostra , Tamoxifeno/uso terapêutico
15.
Breast Cancer Res Treat ; 61(2): 103-10, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10942095

RESUMO

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N = 94), the TAM+AG+H (N = 83), and the TAM+FLU (N = 81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p = 0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are -9-19% and for TAM vs. TAM+FLU -4-25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM + FLU group, respectively (p = 0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG +H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Aminoglutetimida/administração & dosagem , Aminoglutetimida/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Sinergismo Farmacológico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Fluoximesterona/administração & dosagem , Fluoximesterona/efeitos adversos , Humanos , Hidrocortisona/administração & dosagem , Tábuas de Vida , Metástase Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Terapia de Salvação , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Análise de Sobrevida , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Resultado do Tratamento
16.
J Clin Oncol ; 18(2): 262-6, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10637238

RESUMO

PURPOSE: Although hormonal therapy represents standard therapy for metastatic hormone-sensitive disease, many patients receive initial chemotherapy because of the location, bulk, or aggressiveness of their disease. It is uncertain whether simultaneous hormonal therapy provides additional benefit compared with chemotherapy alone. Eastern Cooperative Oncology Group trial E3186 was initiated to explore this question. PATIENTS AND METHODS: Between January 1988 and December 1992, 231 patients with estrogen receptor (ER)-positive or ER-unknown metastatic breast cancer were randomized to receive either chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil ¿CAF) or chemohormonal therapy (CAF plus tamoxifen and Halotestin ¿fluoxymesterone; Pharmacia-Upjohn, Kalamazoo, MI ¿CAFTH) as front-line therapy for metastatic breast cancer. Patients who experienced a complete response to induction therapy either received or did not receive maintenance cyclophosphamide, methotrexate, fluorouracil, prednisone, and TH as a secondary randomization. RESULTS: The response rates (complete response and partial response) of patients who received CAF and CAFTH were similar (69.2% v 68.9%, respectively; P =.99). Time to treatment failure (TTF) was slightly longer for patients who received chemohormonal therapy compared with chemotherapy alone patients (13.4 months v 10.3 months, respectively; P =.087), and TTF was significantly longer in ER-positive compared with ER-negative patients (17.4 months v 10.3 months, respectively; P =.048). However, ER status had no effect on overall survival (30.0 months for CAF v 29.3 months for CAFTH). CONCLUSION: In patients with potentially hormone-sensitive metastatic breast cancer, chemohormonal therapy prolongs TTF for ER-positive patients without improving overall survival.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fluoximesterona/administração & dosagem , Tamoxifeno/administração & dosagem , Adulto , Idoso , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/patologia , Terapia Combinada , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptores Estrogênicos/análise , Resultado do Tratamento
17.
J Clin Oncol ; 17(10): 3299-306, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10506633

RESUMO

PURPOSE: Previous double-blind, placebo-controlled, randomized clinical trials have demonstrated that both corticosteroids and progestational agents do partially alleviate cancer anorexia/cachexia. Pilot information suggested that an anabolic corticosteroid might also improve appetite in patients with cancer anorexia/cachexia. The current trial was developed to compare and contrast a progestational agent, a corticosteroid, and an anabolic corticosteroid for the treatment of cancer anorexia/cachexia. PATIENTS AND METHODS: Patients suffering from cancer anorexia/cachexia were randomized to receive either dexamethasone 0. 75 mg qid, megestrol acetate 800 mg orally every day, or fluoxymesterone 10 mg orally bid. Patients were observed at monthly intervals to evaluate weight changes and drug toxicity. Patients also completed questionnaires at baseline and at monthly intervals to evaluate appetite and drug toxicities. RESULTS: Fluoxymesterone resulted in significantly less appetite enhancement and did not have a favorable toxicity profile. Megestrol acetate and dexamethasone caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, with nonsignificant trends favoring megestrol acetate for both of these parameters. Dexamethasone was observed to have more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate (36% v 25%; P =.03). Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone (5% v 1%; P =.06). CONCLUSION: Whereas fluoxymesterone clearly seems to be an inferior choice for treating cancer anorexia/cachexia, megestrol acetate and dexamethasone have similar appetite stimulating efficacy but differing toxicity profiles.


Assuntos
Anabolizantes/uso terapêutico , Anorexia/tratamento farmacológico , Antieméticos/uso terapêutico , Apetite/efeitos dos fármacos , Caquexia/tratamento farmacológico , Dexametasona/uso terapêutico , Fluoximesterona/uso terapêutico , Acetato de Megestrol/uso terapêutico , Neoplasias/fisiopatologia , Administração Oral , Idoso , Anabolizantes/farmacologia , Anorexia/etiologia , Peso Corporal , Caquexia/etiologia , Feminino , Fluoximesterona/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Resultado do Tratamento , Ganho de Peso
18.
Med Sci Sports Exerc ; 31(2): 243-50, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10063813

RESUMO

PURPOSE: The aim of this study was to examine the separate and combined effects of an 8-wk treatment with high doses of 17alpha-alkylated anabolic-androgenic steroids (AAS) and exercise training on selected lysosomal and mitochondrial enzyme activities in rat liver. METHODS: Sedentary and treadmill-trained (25 m x min(-1), 45 min x d(-1), 5 d x wk(-1)) male rats were treated with fluoxymesterone, methylandrostanolone, or stanozolol (2 mg x kg body weight(-1), 5 d x wk(-1)) for 8 wk. RESULTS: Acid phosphatase, arylsulfatase, beta-glucuronidase, and beta-galactosidase activities were increased in liver homogenates of sedentary and trained AAS-treated rats. The mitochondrial respiratory chain activities rotenone-sensitive NADH-cytochrome c reductase (NCCR), succinate cytochrome c reductase (SCCR), and cytochrome oxidase (COX) showed a significant decrease in steroid-administered rats, whereas citrate synthase (CS), a matrix enzyme, exhibited no changes in activity, pointing to a selective effect of AAS on mitochondrial membrane complexes. In vitro studies in mitochondrial fractions isolated from the liver of control rats showed that COX and CS activities were insensitive to the AAS, whereas NCCR and SCCR activities were partly inhibited. On the other hand, the mean values of serum parameters related to hepatic function were within normal ranges in all the experimental groups of animals. CONCLUSIONS: The present data show that 8-wk ingestion of three different anabolic-androgenic steroids, either with or without concurrent exercise training, affects lysosomal hydrolases and mitochondrial respiratory chain electron transport in rat liver without modifying classical serum indicators of hepatic function.


Assuntos
Anabolizantes/farmacologia , Di-Hidrotestosterona/análogos & derivados , Fluoximesterona/farmacologia , Lisossomos/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Condicionamento Físico Animal , Estanozolol/farmacologia , Análise de Variância , Animais , Di-Hidrotestosterona/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Lisossomos/enzimologia , Masculino , Mitocôndrias Hepáticas/enzimologia , Distribuição Aleatória , Ratos , Ratos Wistar
19.
Harefuah ; 134(3): 178-80, 247, 1998 Feb 01.
Artigo em Hebraico | MEDLINE | ID: mdl-9662906

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder of blood cells which originate from an abnormal hematopoietic stem cell. The condition is characterized by nocturnal hemoglobinuria, chronic hemolytic anemia, and thrombosis. We describe a 60-year-old woman with PNH admitted with abdominal pain and jaundice, who had dark urine on arising after a night's sleep. The diagnosis was established by the typical clinical story and a positive Ham test. She was successfully treated with Halotestin and folic acid. Although PNH is rare, it should be considered in the differential diagnosis of hemolytic anemia. Early diagnosis and treatment are important.


Assuntos
Hemoglobinúria Paroxística/diagnóstico , Diagnóstico Diferencial , Feminino , Fluoximesterona/uso terapêutico , Ácido Fólico/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/fisiopatologia , Humanos , Icterícia , Pessoa de Meia-Idade , Dor , Sono
20.
J Clin Oncol ; 16(5): 1669-76, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9586877

RESUMO

PURPOSE: To investigate the value of maintenance treatment for patients with metastatic breast cancer whose disease is in complete remission (CR). PATIENTS AND METHODS: One hundred ninety-five women (141 eligible) whose disease was in CR or in CR except for bone metastases following six cycles (6 months) of doxorubicin-containing induction treatment were randomized to receive cyclophosphamide, methotrexate, fluorouracil, prednisone, tamoxifen, and halotestin [CMF(P)TH] or observation. In a previous pilot study, patients in CR after 24 months of induction treatment were randomized to continue chemotherapy for 4 more years or stop chemotherapy. RESULTS: Among patients randomized to CMF(P)TH, life-threatening toxicity included leukopenia in 3%, thrombocytopenia in 3%, cardiac in 2%, and diabetes in 1%. The median time to relapse from randomization was 18.7 months on CMF(P)TH and only 7.8 months on observation (P < .0001). The median time to death was 32.2 months on CMF(P)TH and 28.7 months on observation (P=.74). Similar results were seen in the pilot study (median time to relapse, 12.6 and 6.4 months; median survival, 37.7 and 24.2 months; study too small for statistical significance). Maintenance treatment was always the most significant covariate in time-to-relapse models. CONCLUSION: There is definite toxicity associated with CMF(P)TH maintenance treatment. When CR was obtained on induction, maintenance treatment with CMF(P)TH was never significant in survival models. However, maintenance treatment was always the most significant covariate in the time-to-relapse models, which motivates its consideration for appropriately informed patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/secundário , Neoplasias da Mama/mortalidade , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoximesterona/administração & dosagem , Fluoximesterona/efeitos adversos , Humanos , Neoplasias Hepáticas/secundário , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Indução de Remissão , Taxa de Sobrevida , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos
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