RESUMO
INTRODUCTION: Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy. METHODS/DESIGN: We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation. RESULTS/DISCUSSION: With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S. TRIAL REGISTRATION: NCT04496739.
Assuntos
Neoplasias da Mama , Quimioprevenção , Humanos , Feminino , Neoplasias da Mama/prevenção & controle , Quimioprevenção/métodos , Educação de Pacientes como Assunto/métodos , Técnicas de Apoio para a Decisão , Pessoa de Meia-Idade , Adulto , Tomada de Decisões , Conhecimentos, Atitudes e Prática em Saúde , Comportamento de Redução do Risco , Projetos de Pesquisa , Antagonistas de Estrogênios/uso terapêutico , Antagonistas de Estrogênios/administração & dosagem , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: This AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer. METHODS: In this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed. RESULTS: No DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported. CONCLUSIONS: Amcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer. TRIAL REGISTRATION: Clinical trial registration NCT03816839.
Assuntos
Neoplasias da Mama , Antagonistas de Estrogênios , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , População do Leste Asiático , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/farmacocinética , Antagonistas de Estrogênios/uso terapêutico , Dose Máxima Tolerável , Receptores de Estrogênio/genética , Genes erbB-2/genética , Administração Oral , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/farmacocinética , Moduladores Seletivos de Receptor Estrogênico/uso terapêuticoRESUMO
Breast cancer remains the most common cancer in women in the United States. For certain women at high risk for breast cancer, endocrine therapy (ET) can greatly decrease the risk. Tools such as the Breast Cancer Risk Assessment Tool (or Gail Model) and the International Breast Cancer Intervention Study risk calculator are available to help identify women at increased risk for breast cancer. Physician awareness of family history, reproductive and lifestyle factors, dense breast tissue, and history of benign proliferative breast disease are important when identifying high-risk women. The updated US Preventive Services Task Force and American Society of Clinical Oncology guidelines encourage primary care providers to identify at-risk women and offer risk-reducing medications. Among the various ETs, which include tamoxifen, raloxifene, anastrozole, and exemestane, tamoxifen is the only one available for premenopausal women aged 35 years and older. A shared decision-making process should be used to increase the usage of ET and must be individualized. This individualized approach must account for each woman's medical history and weigh the benefits and risks of ET in combination with the personal values of the patient.
Assuntos
Anastrozol/administração & dosagem , Neoplasias da Mama/prevenção & controle , Antagonistas de Estrogênios/administração & dosagem , Pessoal de Saúde/educação , Medicina Preventiva/educação , Cloridrato de Raloxifeno/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Tamoxifeno/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Currículo , Tomada de Decisão Compartilhada , Educação Médica Continuada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medicina Preventiva/métodos , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
The present work describes the systematic development of paclitaxel and naringenin-loaded solid lipid nanoparticles (SLNs) for the treatment of glioblastoma multiforme (GBM). So far only temozolomide therapy is available for the GBM treatment, which fails by large amount due to poor brain permeability of the drug and recurrent metastasis of the tumor. Thus, we investigated the drug combination containing paclitaxel and naringenin for the treatment of GBM, as these drugs have individually demonstrated significant potential for the management of a wide variety of carcinoma. A systematic product development approach was adopted where risk assessment was performed for evaluating the impact of various formulation and process parameters on the quality attributes of the SLNs. I-optimal response surface design was employed for optimization of the dual drug-loaded SLNs prepared by micro-emulsification method, where Percirol ATO5 and Dynasan 114 were used as the solid lipid and surfactant, while Lutrol F188 was used as the stabilizer. Drug loaded-SLNs were subjected to detailed in vitro and in vivo characterization studies. Cyclic RGD peptide sequence (Arg-Gly-Asp) was added to the formulation to obtain the surface modified SLNs which were also evaluated for the particle size and surface charge. The optimized drug-loaded SLNs exhibited particle size and surface charge of 129 nm and 23 mV, drug entrapment efficiency >80% and drug loading efficiency >7%. In vitro drug release study carried out by micro dialysis bag method indicated more than 70% drug was release observed within 8 h time period. In vivo pharmacokinetic evaluation showed significant improvement (p < 0.05) in drug absorption parameters (Cmax and AUC) from the optimized SLNs over the free drug suspension. Cytotoxicity evaluation on U87MG glioma cells indicated SLNs with higher cytotoxicity as compared to that of the free drug suspension (p < 0.05). Evaluation of uptake by florescence measurement indicated superior uptake of SLNs tagged with dye over the plain dye solution. Overall, the dual drug-loaded SLNs showed better chemoprotective effect over the plain drug solution, thus construed superior anticancer activity of the developed nanoformulation in the management of glioblastoma multiforme.
Assuntos
Neoplasias Encefálicas , Sistemas de Liberação de Medicamentos/métodos , Flavanonas/administração & dosagem , Glioblastoma , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/metabolismo , Feminino , Flavanonas/síntese química , Flavanonas/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Lipídeos , Masculino , Nanopartículas/química , Paclitaxel/síntese química , Paclitaxel/metabolismo , Tamanho da Partícula , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/síntese química , Ratos , Ratos WistarRESUMO
BACKGROUND: We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial (MONALEESA-7) data to evaluate the cost-effectiveness of ribociclib (RIB) as a first-line treatment for premenopausal women with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from the United States healthcare payer perspective. In addition, because RIB has not been marketed in China, we identified the range of drug costs for which RIB could be considered cost effective from a Chinese healthcare system perspective. PATIENTS AND METHODS: A Markov model was developed to evaluate the cost-effectiveness of adding RIB to endocrine therapy over a lifetime. The clinical outcomes and utility data were obtained from published literature. Costs data were obtained from United States and Chinese official websites, and we determined the potential price for RIB in China based on its price in the United States. The main outcomes of this study were the incremental cost-effectiveness ratio (ICER) and quality-adjusted life-years (QALYs). RESULTS: The model projected that mean outcome was better with RIB and endocrine combined (3.83366 QALYs) than with endocrine therapy alone (2.71203 QALYs). In the United States, RIB and endocrine therapy cost an additional $604,960.06, resulting in an ICER of $539,357.95/QALY compared with endocrine monotherapy. Subgroup analyses indicated that, in China, the projected mean outcomes were better for RIB and endocrine therapy (6.37 QALYs) than for endocrine monotherapy (2.71 QALYs). The corresponding incremental costs were $224,731.88943. Thus, the ICER comparing RIB and endocrine therapy with endocrine therapy alone represented a $61,454.96/QALY gain. CONCLUSION: Additional use of RIB is estimated to not be cost effective as a first-line treatment for premenopausal women with HR-positive, HER2-negative ABC in the United States. A value-based price for the cost of RIB is less than $31.74/200 mg for China.
Assuntos
Aminopiridinas/administração & dosagem , Aminopiridinas/economia , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/economia , Neoplasias da Mama/tratamento farmacológico , Custos de Medicamentos , Purinas/administração & dosagem , Purinas/economia , Neoplasias da Mama/patologia , China , Análise Custo-Benefício , Quimioterapia Combinada , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/economia , Moduladores de Receptor Estrogênico/administração & dosagem , Moduladores de Receptor Estrogênico/economia , Feminino , Humanos , Cadeias de Markov , Pré-Menopausa , Anos de Vida Ajustados por Qualidade de Vida , Receptor ErbB-2 , Estados UnidosRESUMO
We report a case of ischaemic stroke in a 34-year-old male recreational bodybuilder following a 3-month period of anabolic androgenic steroid (AAS) use and 1-month period of 'post-cycle therapy' (tamoxifen and clomiphene citrate), the latter treatments aimed at restoring normal endogenous testosterone production after initial AAS use. We hypothesise a transient drug-related prothrombotic state with paradoxical embolisation via an atrial septal defect which was later found on bubble echocardiogram. We highlight a rare but important cause of stroke in younger patients which is relevant given the increasing use of AAS misuse among casual fitness enthusiasts. We explore the various possible mechanisms by which AAS use can increase ischaemic stroke risk in such patients.
Assuntos
Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/diagnóstico por imagem , Dopagem Esportivo , Exercício Físico/fisiologia , AVC Isquêmico/induzido quimicamente , AVC Isquêmico/diagnóstico por imagem , Congêneres da Testosterona/efeitos adversos , Administração Intravenosa , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aspirina/uso terapêutico , Atorvastatina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Clomifeno/administração & dosagem , Clomifeno/efeitos adversos , Ecocardiografia , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/efeitos adversos , Comunicação Interatrial/cirurgia , Humanos , AVC Isquêmico/tratamento farmacológico , Masculino , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversosRESUMO
Programmed cell death protein 1 immune checkpoint inhibitor is an effective treatment for non-small cell lung cancer. Although hematological immune-related adverse events induced by antiprogrammed-cell-death-protein-1 immunotherapy have been reported, they are rare, and there remain many unknowns. We report the case of a 77-year-old woman with non-small cell lung cancer and pembrolizumab-induced danazol-dependent aplastic anemia. Sixteen days after she received pembrolizumab with carboplatin and pemetrexed as first-line treatments, she developed pancytopenia, including severe thrombocytopenia (1â¯×â¯109/L) with oral bleeding, epistaxis, and systemic purpura. We initially diagnosed immune-related thrombocytopenia based on an elevated level of platelet-associated immunoglobulin G (922ng/107 cells), but her thrombocytopenia was refractory to prednisolone (1mg/kg) and thrombopoietin receptor agonists. We eventually diagnosed aplastic anemia based on the findings of bone marrow hypoplasia. Treatment with cyclosporine and danazol 300mg (7.5mg/kg) was initiated. Eighteen days later, her blood cell count increased, and we reduced danazol to 100mg. Twenty-four days after the reduction of danazol, her platelet count dropped again to 14â¯×â¯109/L; subsequently, increasing danazol improved her platelet count in a few days. Although aplastic anemia was recovered, she died owing to lung cancer progression. In this case, the thrombocytopenia was noticeable initially; however, pancytopenia appeared a month later, and we diagnosed her with aplastic anemia. Platelet counts improved rapidly with the use of danazol. No effective treatment has yet been established for aplastic anemia induced by antiprogrammed-cell-death-protein-1 immunotherapy, but our case suggests that danazol is an effective therapy.
Assuntos
Anemia Aplástica/induzido quimicamente , Anemia Aplástica/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Danazol/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Evolução Fatal , Feminino , Humanos , Neoplasias Pulmonares/patologia , Metástase Linfática/patologiaRESUMO
Estrogen receptor-alpha (ERα) is the target of endocrine therapies for the treatment of more than 70 % of ERα-positive breast cancers. Selective estrogen receptor degraders (SERDs) antagonize estrogen binding and target the receptor for degradation, representing the last line of treatment for resistant metastatic breast cancer patients. However, the clinical efficacy of the lone clinically approved SERD (Fulvestrant) is limited by its poor oral bioavailability. Recently, several analogues of GW5638, an acrylic acid-based ERα ligand developed by Glaxo Research Institute in 1994, have been reported as promising orally bioavailable SERDs. Some of these compounds are currently in clinical trials, while various other structurally novel SERDs have also been reported by pharma as well as academic research groups. This review provides a critical analysis of the recent developments in orally available SERDs, with a focus on the structure-activity relationships, binding interactions and pharmacokinetic properties of these compounds.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/química , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Estrutura MolecularRESUMO
PURPOSE: Perivascular epithelioid cell tumors (PEComa) are rare mesenchymal neoplasms. mTOR inhibitors are the most active agents in PEComa and in patients progressing to mTOR inhibitors, other available therapies have limited benefit. Preclinical evidences showed a cross-talk between the mTOR pathway and estrogen receptor signaling. This provided a rationale for adding an antiestrogen treatment in female patients becoming resistant to mTOR inhibitors. EXPERIMENTAL DESIGN: Since April 2018, female patients with advanced/metastatic PEComa progressing to mTOR inhibitors were treated with a combination of sirolimus and exemestane with or without LHRH analogue (based on menopausal status). This case series was retrospectively reviewed. Survival analyses were performed using the Kaplan-Meier method. RESULTS: A total of seven consecutive patients treated with the combination of sirolimus and antiestrogen treatment were retrospectively reviewed. Six (86%) received a combination of sirolimus and exemestane, whereas one patient (14%) received a combination of sirolimus, exemestane, and triptorelin since in premenopausal status. After a median follow-up of 13.1 months, three patients (43%) experienced a partial response, three patients (43%) experienced a stabilization of disease, and one patient (14%) had disease progression with an overall response rate of 43% and a disease control rate of 86%. CONCLUSIONS: In this small retrospective case series, the addition of antiestrogen treatment in female patients with advanced PEComa progressing to mTOR inhibitors resulted in a remarkable clinical benefit in a setting where no other options are available.
Assuntos
Everolimo/administração & dosagem , Neoplasias de Células Epitelioides Perivasculares/tratamento farmacológico , Sarcoma/tratamento farmacológico , Sirolimo/administração & dosagem , Serina-Treonina Quinases TOR/genética , Idoso , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/efeitos adversos , Everolimo/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patologia , Intervalo Livre de Progressão , Sarcoma/genética , Sarcoma/patologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/efeitos adversos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Pamoato de Triptorrelina/administração & dosagem , Pamoato de Triptorrelina/efeitos adversosRESUMO
Breast cancer is the most common cancer in women and is the second most common cause of death in women. Estrogen plays an important role in breast tumor etiopathogenesis. Tamoxifen and other anti-estrogen drugs are used in breast cancer patients who have a positive estrogen receptor (ER). While angiotensin II plays a key role in breast cancer etiology and causes tamoxifen resistance, angiotensin 1-7 has been reported to may reduce the spread and invasion of breast cancer. During the COVID-19 infection, the virus blocks ACE2, and angiotensin 1-7 production discontinued. Angiotensin III production may increase as angiotensin II destruction is reduced. Thus, aminopeptidase upregulation may occur. Increased aminopeptidase may develop resistance to chemotherapy in breast cancer patients receiving chemotherapy. Estrogen can have a protective effect against COVID-19. Estrogen increase causes ER-α upregulation in T lymphocytes. Thus, estrogen increases the release of interferon I and III from T lymphocytes. Increasing interferon I and III alleviates COVID-19 infection. Tamoxifen treatment causes down-regulation, mutation, or loss in estrogen receptors. In the long-term use of tamoxifen, its effects on estrogen receptors can be permanent. Thus, since estrogen receptors are damaged or downregulated, estrogen may not act by binding to these receptors. Tamoxifen is a P-glycoprotein inhibitor, independent of its effect on estrogen receptors. It suppresses T cell functions and interferon release. We think tamoxifen may increase the COVID-19 risk due to its antiestrogen and P-glycoprotein inhibitory effects.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Infecções por Coronavirus/complicações , Resistencia a Medicamentos Antineoplásicos , Pneumonia Viral/complicações , Tamoxifeno/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Betacoronavirus , Neoplasias da Mama/complicações , COVID-19 , Suscetibilidade a Doenças , Antagonistas de Estrogênios/administração & dosagem , Feminino , Humanos , Interferons , Pandemias , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores de Estrogênio/metabolismo , Risco , SARS-CoV-2RESUMO
BACKGROUND: This study aims to assess the efficacy and safety of clomifene citrate (CC) for the treatment of patients with polycystic ovary syndrome (PCOS). METHODS: In this study, we will comprehensively search MEDLINE, EMBASE, The Cochrane Library, Web of Science, CINAHL, ACMD, PsycINFO, and China National Knowledge Infrastructure for original articles published from their inceptions to the January 1, 2020 without language restrictions. All studies will undergo relevance and a design selecting process. Data from qualified studies will be collected by 2 independent authors. Additionally, we will conduct a risk of bias evaluation using a Cochrane risk of bias tool. We will undertake statistical analysis utilizing RevMan 5.3 software. RESULTS: This study will summarize the up-to-date evidence to investigate the efficacy and safety of CC for the treatment of patients with PCOS. CONCLUSION: The findings of this study will provide helpful evidence of CC for the treatment of patients with PCOS, as well as may help develop treatment guidelines. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42020162818.
Assuntos
Clomifeno/administração & dosagem , Antagonistas de Estrogênios/administração & dosagem , Síndrome do Ovário Policístico/tratamento farmacológico , Clomifeno/efeitos adversos , Antagonistas de Estrogênios/efeitos adversos , Feminino , Humanos , Revisões Sistemáticas como AssuntoAssuntos
Neurônios Adrenérgicos/metabolismo , Regulação Enzimológica da Expressão Gênica , Glicogênio Fosforilase/biossíntese , Norepinefrina/administração & dosagem , Receptores de Estrogênio/metabolismo , Núcleo Hipotalâmico Ventromedial/metabolismo , Neurônios Adrenérgicos/efeitos dos fármacos , Animais , Antagonistas de Estrogênios/administração & dosagem , Feminino , Glicogênio Fosforilase/genética , Infusões Intraventriculares , Isoenzimas/biossíntese , Isoenzimas/genética , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/antagonistas & inibidores , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacosRESUMO
Breast cancer is one of the leading causes of mortality specifically for the women. The existing therapy is not sufficient due to the lack of target specificity and drug resistance. Carbon nanotubes (CNTs) are one of the promising formulation approaches that show a promising effect to target specifically the cancer cells, with better cellular internalization. CNTs were prepared based on the modified Staudenmaier process, where temperature and stirring speed were found to be the most influencing factor for particle size and entrapment of the drug raloxifene hydrochloride (RLX). The optimized formulation was produced with drug loading of about 74.2 ± 4.67% and the average particle size of 234.2 ± 1.7 nm. The surface of the CNTs was functionalized by folic acid (FA), which helps to deliver the drug on the site of the cancer cells only in a target-specific manner. in vitro drug-release studies indicated that the drug release was dependent on the pH of the system. Cytotoxicity study clearly indicated the efficacy of the FA physically conjugated CNTs with affectivity induces apoptosis in the cancer cell line with the IC50 value of 43.57305 µg/ml. The fluorescence imagining study showed higher cellular internalization of the RLX compared with the pure drug and the RLX-CNT formulation.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Ácido Fólico/química , Nanotubos de Carbono , Cloridrato de Raloxifeno/administração & dosagem , Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Química Farmacêutica , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Concentração Inibidora 50 , Tamanho da Partícula , Cloridrato de Raloxifeno/farmacologia , TemperaturaRESUMO
Systemic sclerosis primarily affects women. This sex bias raises the question on the role female hormones could play in the development of fibrosis, which is largely unknown. Our aim was to evaluate the effects of estrogens in the development of experimental dermal fibrosis, in the mouse models of bleomycin-induced dermal fibrosis and tight skin (Tsk-1) mice, and on the activation of dermal fibroblasts by transforming growth factor-ß (TGF-ß). Estrogen inhibition, obtained through gene inactivation for the estrogen receptor-αknockout or treatment with tamoxifen, exacerbated skin fibrosis in the bleomycin model and in the Tsk-1 mice. In the dermal fibroblasts, treatment with 17-ß-estradiol significantly decreased the stimulatory effects of TGF-ß on collagen synthesis and myofibroblast differentiation, decreased the activation of canonical TGF-ß signaling, and markedly reduced the expression of the TGF-ß target genes. Tamoxifen reversed the inhibitory effects of estrogens by restoring Smad2/3 phosphorylation and TGF-ß-induced collagen synthesis. Our results demonstrate a beneficial effect of estrogens in dermal fibrosis. Estrogens reduce the TGF-ß-dependent activation of dermal fibroblasts, and estrogen inhibition leads to a more severe experimental dermal fibrosis. These findings are consistent with the prominent development of systemic sclerosis in postmenopausal women and the greater severity of the disease in men.
Assuntos
Receptor alfa de Estrogênio/antagonistas & inibidores , Estrogênios/metabolismo , Escleroderma Sistêmico/patologia , Pele/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Biópsia , Bleomicina/toxicidade , Células Cultivadas , Colágeno/biossíntese , Modelos Animais de Doenças , Antagonistas de Estrogênios/administração & dosagem , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios/administração & dosagem , Feminino , Fibroblastos , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Cultura Primária de Células , Escleroderma Sistêmico/diagnóstico , Índice de Gravidade de Doença , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Tamoxifeno/administração & dosagemRESUMO
BACKGROUND: Clomiphene citrate (CC) has been shown to restore the hypothalamic-pituitary-gonadal (HPG) axis by increasing testosterone (T) levels to physiological levels in patients with dysmetabolic conditions such as obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). However, the data are unclear regarding the effects on Sertoli cell (SC) function. AIM: To study SC function by assessing Inhibin B (IB) and anti-Mullerian hormone (AMH) levels at baseline and after 3 months of CC treatment. MATERIALS AND METHODS: This is an ancillary study of a cross-over, randomised, double-blind, placebo-controlled trial performed to evaluate androgen response to CC treatment in dysmetabolic obese subjects with low T levels treated with metformin. We evaluated SC function by assessing IB and AMH levels at baseline and after 3 months of each treatment in ten dysmetabolic obese subjects with low T levels. In all subjects, the influence of the clinical characteristics, metabolic and hormonal baseline parameters on SC and Leydig (LC) function, evaluated respectively with AMH, IB, follicle-stimulating hormone (FSH) and T levels, was tested. RESULTS: No significant changes were observed for IB and AMH concentrations after each treatment period. Whereas T and oestradiol (E2) levels were shown to be significantly higher in the CC plus metformin phase (CC/Met) only. No clinical, metabolic or hormonal parameters showed significant effects on serum AMH at baseline or after treatments. However, baseline T, dihydrotestosterone (DHT) and E2 positively affected IB levels during CC/Met therapy (P = .003, P = .038 and P = .049, respectively). Baseline leptin and FSH had a negative (P = 031) and positive (P = .048) respectively role on T levels during CC/Met, as they were statistically significant compared to the placebo period (Plac/Met). CONCLUSION: Unlike the LC activity, CC was unable to influence SC function, as shown by the lack of IB and AMH serum modifications, thus suggesting an intrinsic nonreversible defect of SC cells in patients with dysmetabolic conditions.
Assuntos
Hormônio Antimülleriano/sangue , Clomifeno/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Antagonistas de Estrogênios/farmacologia , Hipoglicemiantes/farmacologia , Hipogonadismo/tratamento farmacológico , Inibinas/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Metformina/farmacologia , Obesidade/tratamento farmacológico , Células de Sertoli/efeitos dos fármacos , Testosterona/sangue , Adulto , Clomifeno/administração & dosagem , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Di-Hidrotestosterona/sangue , Método Duplo-Cego , Quimioterapia Combinada , Estradiol/sangue , Antagonistas de Estrogênios/administração & dosagem , Seguimentos , Humanos , Hipogonadismo/sangue , Hipogonadismo/etiologia , Inibinas/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicaçõesRESUMO
Alternaria molds can produce a variety of different mycotoxins, often resulting in food contamination with chemical mixtures, posing a challenge for risk assessment. Some of these metabolites possess estrogenic properties, an effect whose toxicological relevance is questioned in the light of the strong genotoxic and cytotoxic properties of co-occurring toxins. Thus, we tested a complex extract from A. alternata for estrogenic properties in Ishikawa cells. By assessing alkaline phosphatase activity, we did not observe estrogen receptor (ER) activation at non-cytotoxic concentrations (≤ 10 µg/ml). Furthermore, an extract stripped of highly genotoxic perylene quinones also did not mediate estrogenic effects, despite diminished genotoxic properties in the comet assay (≥ 10 µg/ml). Interestingly, both extracts impaired the estrogenicity of 17ß-estradiol (E2) at non-cytotoxic concentrations (5-10 µg/ml), indicating anti-estrogenic effects which could not be explained by the presence of known mycoestrogens. A mechanism for this unexpected result might be the activation of the aryl hydrocarbon receptor (AhR) by Alternaria metabolites, as indicated by the induction of CYP1A1 transcription. While a direct influence on the metabolism of E2 could not be confirmed by LC-MS/MS, literature describing a direct interplay of the AhR with estrogenic pathways points to a corresponding mode of action. Taken together, the present study indicates AhR-mediated anti-estrogenic effects as a novel mechanism of naturally co-occurring Alternaria toxin mixtures. Furthermore, our results confirm their genotoxic activity and raise questions about the contribution of still undiscovered metabolites to toxicological properties.
Assuntos
Alternaria/metabolismo , Antagonistas de Estrogênios/toxicidade , Micotoxinas/toxicidade , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Estradiol/metabolismo , Antagonistas de Estrogênios/administração & dosagem , Antagonistas de Estrogênios/isolamento & purificação , Humanos , Mutagênicos/administração & dosagem , Mutagênicos/isolamento & purificação , Mutagênicos/toxicidade , Micotoxinas/administração & dosagem , Micotoxinas/isolamento & purificação , Receptores de Hidrocarboneto Arílico/metabolismoAssuntos
Sistemas de Liberação de Medicamentos , Antagonistas de Estrogênios/administração & dosagem , Fosfolipídeos/administração & dosagem , Cloridrato de Raloxifeno/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Eritrócitos/efeitos dos fármacos , Antagonistas de Estrogênios/química , Antagonistas de Estrogênios/farmacocinética , Feminino , Hemólise/efeitos dos fármacos , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Fosfolipídeos/química , Fosfolipídeos/farmacocinética , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacocinética , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoAssuntos
Clomifeno/administração & dosagem , Disfunção Erétil/etiologia , Antagonistas de Estrogênios/administração & dosagem , Fadiga/etiologia , Hipogonadismo , Adulto , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/tratamento farmacológico , Masculino , Obesidade/terapia , Apneia Obstrutiva do Sono/terapiaRESUMO
Menopause is an important physiological event associated with structural and functional changes in the kidneys. An animal model of bilateral ovariectomy was used to study the effects of estrogen depletion, replacement and antiestrogen on renal structure and endocrine function. Sixty female rats were divided into six groups; group I was the control group, the remaining five groups underwent ovariectomy: group II received no treatment. The other groups received estradiol in group III, tamoxifen in group IV, estradiol followed by tamoxifen in group V and tamoxifen followed by estradiol in group VI. Serum creatinine, blood urea nitrogen, and endocrine functions of kidney were measured. Tissue samples were examined both microscopically for beta estrogen receptors and ultrastructurally for cell changes. Groups II, IV & VI showed a significant increase in creatinine, blood urea nitrogen, renal malondialdehyde, renal erythropoietin, plasma renin and plasma prostaglandin E2 and a significant decrease in renal antioxidants and serum vitamin D3. Groups III &V had a significant decrease in creatinine, blood urea nitrogen, renal malondialdehyde and renal erythropoietin with an increase in renal antioxidants, plasma prostaglandin E2 and serum vitamin D3. Histopathological and ultrastructural examinations revealed atrophic tubular changes in group II. The changes were less marked in groups III &V and more extensive in groups IV & VI. Estrogen receptor beta staining showed progressively increased expression in the absence of estrogen. Structural and most endocrine functions of the kidney were significantly affected by estradiol deficiency. Estradiol replacement exhibited a protective effect on renal tissue and endocrine functions.
Assuntos
Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios/métodos , Rim/metabolismo , Menopausa/efeitos dos fármacos , Animais , Antagonistas de Estrogênios/administração & dosagem , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Menopausa/metabolismo , Modelos Animais , Ovariectomia/efeitos adversos , Ratos , Tamoxifeno/administração & dosagemRESUMO
OBJECTIVE: Determine whether gestational age of 17-hydroxyprogesterone caproate (17-OHPC) initiation is associated with preterm birth (PTB) risk. STUDY DESIGN: We performed a retrospective cohort study using MarketScan® data. The primary outcome was PTB < 37 weeks. Rates of PTB were compared between medication initiation at 16-21 weeks versus 21-29 weeks. The association between compliance with weekly 17-OHPC injections and preterm birth rate was tested after adjusting for potential confounding variables. RESULT: In all 3374 pregnancies met inclusion criteria. Women with an early 17-OHPC start were less likely to deliver preterm than those with a late start (aRR 0.88; 95%CI 0.79-0.97; p = 0.02). Less compliant patients receiving <25% of recommended doses had a higher PTB rate than those receiving >85% of recommended doses (aRR 1.5; 95%CI 1.2-1.7; p < 0.01). CONCLUSION: There is an association between both early 17-OHPC initiation and compliance with reduced rates of PTB.