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1.
J Steroid Biochem Mol Biol ; 241: 106515, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38554981

RESUMO

The development of antiprogestins was initially a gynecological purpose. However, since mifepristone was developed, its application for breast cancer treatment was immediately proposed. Later, new compounds with lower antiglucocorticoid and antiandrogenic effects were developed to be applied to different pathologies, including breast cancer. We describe herein the studies performed in the breast cancer field with special focus on those reported in recent years, ranging from preclinical biological models to those carried out in patients. We highlight the potential use of antiprogestins in breast cancer prevention in women with BRCA1 mutations, and their use for breast cancer treatment, emphasizing the need to elucidate which patients will respond. In this sense, the PR isoform ratio has emerged as a possible tool to predict antiprogestin responsiveness. The effects of combined treatments of antiprogestins together with other drugs currently used in the clinic, such as tamoxifen, CDK4/CDK6 inhibitors or pembrolizumab in preclinical models is discussed since it is in this scenario that antiprogestins will be probably introduced. Finally, we explain how transcriptomic or proteomic studies, that were carried out in different luminal breast cancer models and in breast cancer samples that responded or were predicted to respond to the antiprogestin therapy, show a decrease in proliferative pathways. Deregulated pathways intrinsic of each model are discussed, as well as how these analyses may contribute to a better understanding of the mechanisms involved.


Assuntos
Neoplasias da Mama , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Feminino , Receptores de Progesterona/metabolismo , Animais , Mifepristona/uso terapêutico , Mifepristona/farmacologia , Antagonistas de Hormônios/uso terapêutico
2.
Endocr Relat Cancer ; 31(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37962553

RESUMO

Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.


Assuntos
Neoplasias da Mama , Mifepristona , Humanos , Camundongos , Animais , Feminino , Mifepristona/uso terapêutico , Mifepristona/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptores de Progesterona , Antagonistas de Hormônios/uso terapêutico , Antagonistas de Hormônios/farmacologia , Prognóstico
3.
Pharmaceuticals (Basel) ; 16(10)2023 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-37895808

RESUMO

Although cisplatin is an effective chemotherapy drug used against many types of cancer, it has poor bioavailability, produces severe adverse effects, and frequently leads to tumor resistance. Consequently, more effective formulations are needed. The co-administration of cisplatin with mifepristone, which counters an efflux pump drug-resistance mechanism in tumor cells, has shown important synergism, but without resolving the problem of poor bioavailability. Specificity to tumor tissue and bioavailability have been improved by co-encapsulating cisplatin and mifepristone in a liposomal formulation (L-Cis/MF), which needs further research to complete pre-clinical requirements. The aim of this current contribution was to conduct a pharmacokinetic study of cisplatin and mifepristone in male Wistar rats after administration of L-Cis/MF and the conventional (unencapsulated) formulation. Additionally, the capacity of L-Cis/MF to reduce tumor growth in male nude mice was evaluated following the implantation of xenografts of non-small-cell lung cancer. The better pharmacokinetics (higher plasma concentration) of cisplatin and mifepristone when injected in the liposomal versus the conventional formulation correlated with greater efficacy in controlling tumor growth. Future research on L-Cis/MF will characterize its molecular mechanisms and apply it to other types of cancer affected by the synergism of cisplatin and mifepristone.

4.
Rev. chil. obstet. ginecol. (En línea) ; Rev. chil. obstet. ginecol;88(5): 329-334, oct. 2023. ilus
Artigo em Espanhol | LILACS | ID: biblio-1530021

RESUMO

Introducción: El embarazo ectópico intersticial es una forma de presentación poco frecuente, con una incidencia del 2-4% de los embarazos ectópicos; sin embargo, a pesar de su baja incidencia la mortalidad es cinco veces mayor, impactando en las cifras de mortalidad materna y representando en torno al 10-15% de los casos. Objetivo: Presentar un caso de embarazo ectópico intersticial, cuya ocurrencia es poco frecuente, así como el abordaje satisfactorio del manejo médico con mifepristona y metotrexato. Caso clínico: Mujer de 28 años con antecedente de resección tubárica por quiste paraovárico derecho, quien acudió a urgencias por hallazgo en ecografía obstétrica de sospecha de embarazo intersticial izquierdo y se le administró manejo farmacológico con dosis de metotrexato y mifepristona, con éxito. Conclusiones: El manejo médico con metotrexato y mifepristona para el embarazo ectópico intersticial parece ser una elección eficaz en los casos con estabilidad hemodinámica y deseo de conservación de la fertilidad.


Background: Interstitial ectopic pregnancy represents a rare form of presentation, with an incidence of 2-4% of all ectopic pregnancies. However, despite its low incidence, it is associated with a five-fold increase in mortality, significantly impacting maternal mortality rates, accounting for approximately 10-15% of cases. Objective: To present a case of interstitial ectopic pregnancy, which is a rare occurrence, as well as the successful medical management approach with mifepristone and methotrexate. Case report: A 28-year-old women with a history of right paraovarian cyst tubal resection presented to the emergency department due to suspected left interstitial pregnancy identified on obstetric ultrasound. The patient was successfully managed with pharmacological treatment using doses of methotrexate and mifepristone. Conclusions: Medical management with methotrexate and mifepristone for interstitial ectopic pregnancy appears to be an effective choice in cases with hemodynamic stability and a desire for fertility preservation.


Assuntos
Humanos , Feminino , Gravidez , Adulto , Mifepristona/uso terapêutico , Metotrexato/uso terapêutico , Gravidez Intersticial/tratamento farmacológico , Gravidez Ectópica , Ultrassonografia , Preservação da Fertilidade , Gravidez Intersticial/diagnóstico por imagem
5.
Peptides ; 163: 170975, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36791916

RESUMO

Melanin-concentrating hormone (MCH) is a peptide related to the reproductive function by interacting with the hypothalamus-pituitary-gonadal axis. In addition to the MCH central production, it is also found in the blood with a putative role as a neurohormone. Thereby, our focus is on steroid hormones' role in regulating centrally produced MCH in the incerto-hypothalamic area (IHy) and the peripheral MCH in the serum. For this, we investigated the effect of estradiol and/or progesterone injection on the number of MCH immunoreactive (MCH-ir) neurons at the IHy and serum levels. For further study of the role of progesterone, we analyzed the effect of blockade of progesterone receptors by its antagonist on MCH-ir neurons at the IHy and serum. To identify whether such regulation over MCH is established before sexual maturation, we assessed the effect of peripubertal removal of steroid hormones on MCH-ir neurons at the IHy and serum levels at adult age. Our results show that injecting estradiol in ovariectomized female rats reduces the number of MCH-ir neurons in the IHy, in addition to its serum levels. Blockade of progesterone receptors in intact females increases the number of MCH-ir neurons in the IHy and its serum concentration. The regulation of these hormones over the MCH peptidergic system is established before sexual maturation, once the peripubertal removal of the ovaries changes the serum levels of MCH and the number of MCH-ir neurons in the IHy of adult females. Such results support the inhibitory role of steroid hormones over the MCH system.


Assuntos
Hormônios Hipotalâmicos , Progesterona , Feminino , Ratos , Animais , Estradiol , Receptores de Progesterona , Hormônios Hipofisários , Hipotálamo/metabolismo , Hormônios Hipotalâmicos/metabolismo , Melaninas
6.
Front Reprod Health ; 4: 1040640, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36560973

RESUMO

The disruption caused by the COVID-19 pandemic on health services around the world boosted interest over telehealth models of care. In Brazil, where abortion is heavily restricted, abortion seekers have long relied on international telehealth services to access abortion pills. We conducted a cross-sectional multilevel study to assess the effect of individual and contextual social factors on utilization of one such service. For the individual-level, we analyzed data from the records of abortion seekers contacting this feminist international telehealth organization during 2019 (n = 25,920). Individual-level variables were age, race, education level and pregnancy length. Contextual-level units were states, for which we used data from the national Demographic Census and Household Surveys. Contextual-level variables were household income per capita, adjusted net school attendance rate, percentage of racialized women and income Gini Index. We fitted five multilevel Poisson Mixed-effects models with robust variance to estimate prevalence ratios (PR) of service utilization, which was defined as receiving abortion pills through the service. We found that only 8.2% of requesters got abortion pills through the service. Utilization was higher among women who were older, white, more educated and 5-8-weeks pregnant. Independently of this, service utilization was higher in states with higher income and education access, with lower proportions of racialized women, and located in the South, Southeast and Central-West regions. We concluded that while feminist telehealth abortion initiatives provide a life-saving service for some abortion seekers, they are not fully equipped to overcome entrenched social inequalities in their utilization, both at individual and contextual levels.

7.
Am J Obstet Gynecol ; 227(5): 737.e1-737.e11, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35780811

RESUMO

BACKGROUND: Early pregnancy loss, also referred to as miscarriage, is common, affecting approximately 1 million people in the United States annually. Early pregnancy loss can be treated with expectant management, medications, or surgical procedures-strategies that differ in patient experience, effectiveness, and cost. One of the medications used for early pregnancy loss treatment, mifepristone, is uniquely regulated by the Food and Drug Administration. OBJECTIVE: This study aimed to compare the cost-effectiveness from the healthcare sector perspective of medical management of early pregnancy loss, using the standard of care medication regimen of mifepristone and misoprostol, with that of office uterine aspiration. STUDY DESIGN: We developed a decision analytical model to compare the cost-effectiveness of early pregnancy loss treatment with medical management with that of office uterine aspiration. Data on medical management came from the Pregnancy Failure Regimens randomized clinical trial, and data on uterine aspiration came from the published literature. The analysis was from the healthcare sector perspective with a 30-day time horizon. Costs were in 2018 US dollars. Effectiveness was measured in quality-adjust life-years gained and the rate of complete gestational sac expulsion with no additional interventions. Our primary outcome was the incremental cost per quality-adjust life-year gained. Sensitivity analysis was performed to identify the key uncertainties. RESULTS: Mean per-person costs were higher for uterine aspiration than for medical management ($828 [95% confidence interval, $789-$868] vs $661 [95% confidence interval, $556-$766]; P=.004). Uterine aspiration more frequently led to complete gestational sac expulsion than medical management (97.3% vs 83.8%; P=.0001); however, estimated quality-adjust life-years were higher for medical management than for uterine aspiration (0.082 [95% confidence interval, 0.8148-0.08248] vs 0.079 [95% confidence interval, 0.0789-0.0791]; P<.0001). Medical management dominated uterine aspiration, with lower costs and higher confidence interval. The probability that medical management is cost-effective relative to uterine aspiration is 97.5% for all willingness-to-pay values of ≥$5600/quality-adjust life-year. Sensitivity analysis did not identify any thresholds that would substantially change outcomes. CONCLUSION: Although office-based uterine aspiration more often results in treatment completion without further intervention, medical management with mifepristone pretreatment costs less and yields similar quality-adjust life-years, making it an attractive alternative. Our findings provided evidence that increasing access to mifepristone and eliminating unnecessary restrictions will improve early pregnancy care.


Assuntos
Aborto Espontâneo , Misoprostol , Gravidez , Feminino , Humanos , Aborto Espontâneo/tratamento farmacológico , Mifepristona/uso terapêutico , Análise Custo-Benefício , Misoprostol/uso terapêutico , Quimioterapia Combinada
8.
Brain Res Bull ; 178: 29-36, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34798218

RESUMO

The benign prostatic hyperplasia (BPH) is the main source of lower urinary tract symptoms. The BPH is a common age-dependent disease and tamsulosin is an α1-adrenoceptor blocker widely prescribed for BPH. Beyond the common adverse effects of tamsulosin, increased diagnosis of dementia after prescription was observed. Importantly, a clinical study suggested that tamsulosin may exert antidepressant effects in BPH patients. Considering the expression of α1-adrenoceptors in the brain, this study aimed to investigate the effects of tamsulosin in the forced swimming and open field tests in mice. For this, tamsulosin (0.001-1 mg/kg) was orally administered subacutely (1, 5 and 23 hr) and acutely (60 min) before tests. Mifepristone (10 mg/kg), a glucocorticoid receptor antagonist, and aminoglutethimide (10 mg/kg), a streoidogenesis inhibitor, were intraperitoneally injected before tamsulosin to investigate the role of the hypothalamic-pituitary-adrenal axis in the mediation of tamsulosin-induced effects. Subacute and acute administrations of tamsulosin increased the immobility time in the first exposition to an inescapable stressful situation. In the re-exposition to the swim task, controls displayed a natural increase in the immobility time, and the treatment with tamsulosin further increased this behavioral parameter. Tamsuslosin did not affect spontaneous locomotion neither in naïve nor in stressed mice. Our findings also showed that mifepristone and aminoglutethimide prevented the tamsulosin-induced increase in the immobility time in the first and second swimming sessions, respectively. In conclusion, tamsulosin may contribute to increased susceptibility to depressive-like behaviors, by facilitating the acquisition of a passive stress-copying strategy. These effects seem to be dependent on endogenous glucocorticoids.


Assuntos
Adaptação Psicológica/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Inibidores da Aromatase/farmacologia , Depressão/induzido quimicamente , Antagonistas de Hormônios/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Receptores de Glucocorticoides/antagonistas & inibidores , Tansulosina/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Aminoglutetimida/farmacologia , Animais , Inibidores da Aromatase/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas de Hormônios/administração & dosagem , Camundongos , Mifepristona/farmacologia , Tansulosina/administração & dosagem
9.
Sex Reprod Health Matters ; 29(3): 1948953, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34252017

RESUMO

Self-managed abortion is a common self-care practice that enables pregnant people to exercise their rights to health, bodily autonomy and to benefit from the advances of science even when living in contexts that do not guarantee these rights. In this interpretative qualitative study, we aimed to understand women's abortion trajectories, experiences with self-managed abortion and assessments of the quality of care provided by Women Help Women (WHW, an international activist non-profit organisation working on abortion access). Grounded in feminist epistemology and health inequalities approaches, we conducted eleven semi-structured interviews in Santiago, Chile. We found that illegality, stigma and expectations surrounding motherhood and abortion determined women's experiences. Participants perceived the WHW service as good, trustworthy, fast and affordable, and valued confidentiality and privacy; the quantity and quality of information; having direct, personalised and timely communication with service staff; being treated with respect; and feeling safe, cared for and supported in their decisions. Most participants considered self-managed abortion appropriate and acceptable given their circumstances. Fear was the dominant feeling in women's narratives. Some participants mentioned missing instant communication, in-person support and professional care. We conclude that support, information and company are key to improving abortion seekers' experiences and enabling their decisions, particularly in legally restrictive settings. Centring care in pregnant people's needs and autonomy is fundamental to ensure safe, appropriate and accessible self-care interventions in reproductive health. Social and legal changes, such as public funding for abortion, destigmatisation and decriminalisation, are needed to realise people's right to higher standards of healthcare.


Assuntos
Aborto Induzido , Telemedicina , Chile , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Percepção , Gravidez
11.
Front Oncol ; 11: 606907, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33680961

RESUMO

Glioma is the most common and aggressive primary tumor of the central nervous system. The standard treatment for malignant gliomas is surgery followed by chemoradiotherapy. Unfortunately, this treatment has not produced an adequate patient response, resulting in a median survival time of 12-15 months and a 5-year overall survival of <5%. Although new strategies have been sought to enhance patient response, no significant increase in the global survival of glioma patients has been achieved. The option of developing new drugs implies a long and costly process, making drug repurposing a more practical alternative for improving glioma treatment. In the last few years, researchers seeking more effective cancer therapy have pursued the possibility of using anti-hormonal agents, such as mifepristone. The latter drug, an antagonist for progesterone and glucocorticoid receptors, has several attractive features: anti-tumor activity, low cytotoxicity to healthy cells, and modulation of the chemosensitivity of several cancer cell lines in vitro. Hence, the addition of mifepristone to temozolomide-based glioblastoma chemotherapy may lead to a better patient response. The mechanisms by which mifepristone enhances glioma treatment are not yet known. The current review aims to discuss the potential role of mifepristone as an adjuvant drug for the treatment of high-grade gliomas.

12.
Health Serv Res Manag Epidemiol ; 8: 23333928211068919, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34993274

RESUMO

BACKGROUND: As part of the accelerated approval of mifepristone as an abortifacient in 2000, the Food and Drug Administration (FDA) required prescribers to report all serious adverse events (AEs) to the manufacturer who was required to report them to the FDA. This information is included in the FDA Adverse Event Reporting System (FAERS) and is available to the public online. The actual Adverse Event Reports (AERs) can be obtained through the Freedom of Information Act (FOIA). METHODS: We compared the number of specific AEs and total AERs for mifepristone abortions from January 1, 2009 to December 31, 2010 from 1. Planned Parenthood abortion data published by Cleland et al. 2. FAERS online dashboard, and 3. AERs provided through FOIA and analyzed by Aultman et al. RESULTS: Cleland identified 1530 Planned Parenthood mifepristone cases with specific AEs for 2009 and 2010. For this period, FAERS online dashboard includes a total (from all providers) of only 664, and the FDA released only 330 AERs through FOIA. Cleland identified 1158 ongoing pregnancies in 2009 and 2010. FAERs dashboard contains only 95, and only 39 were released via FOIA. CONCLUSIONS: There are significant discrepancies in the total number of AERs and specific AEs for 2009 and 2010 mifepristone abortions reported in 1. Cleland's documentation of Planned Parenthood AEs, 2. FAERS dashboard, and 3. AERs provided through FOIA. These discrepancies render the FAERS inadequate to evaluate the safety of mifepristone abortions.

13.
Front Oncol ; 10: 581814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123485

RESUMO

Glioblastoma, the most common primary central nervous system tumor, is characterized by extensive vascular neoformation and an area of necrosis generated by rapid proliferation. The standard treatment for this type of tumor is surgery followed by chemotherapy based on temozolomide and radiotherapy, resulting in poor patient survival. Glioblastoma is known for strong resistance to treatment, frequent recurrence and rapid progression. The aim of this study was to evaluate whether mifepristone, an antihormonal agent, can enhance the effect of temozolomide on C6 glioma cells orthotopically implanted in Wistar rats. The levels of the vascular endothelial growth factor (VEGF), and P-glycoprotein (P-gp) were examined, the former a promoter of angiogenesis that facilitates proliferation, and the latter an efflux pump transporter linked to drug resistance. After a 3-week treatment, the mifepristone/temozolomide regimen had decreased the level of VEGF and P-gp and significantly reduced tumor proliferation (detected by PET/CT images based on 18F-fluorothymidine uptake). Additionally, mifepristone proved to increase the intracerebral concentration of temozolomide. The lower level of O6-methylguanine-DNA-methyltransferase (MGMT) (related to DNA repair in tumors) previously reported for this combined treatment was herein confirmed. After the mifepristone/temozolomide treatment ended, however, the values of VEGF, P-gp, and MGMT increased and reached control levels by 14 weeks post-treatment. There was also tumor recurrence, as occurred when administering temozolomide alone. On the other hand, temozolomide led to 100% mortality within 26 days after beginning the drug treatment, while mifepristone/temozolomide enabled 70% survival 60-70 days and 30% survived over 100 days, suggesting that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide.

14.
Pharmaceutics ; 12(9)2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32971785

RESUMO

Cervical cancer is usually diagnosed in the later stages despite many campaigns for early detection and continues to be a major public health problem. The standard treatment is cisplatin-based chemotherapy plus radiotherapy, but patient response is far from ideal. In the research for new drugs that enhance the activity of cisplatin, different therapeutic agents have been tested, among them the antiprogestin mifepristone. Nevertheless, the efficacy of cisplatin is limited by its low specificity for tumor tissue, which causes severe side effects. Additionally, cervical tumors often become drug resistant. These problems could possibly be addressed by the use of liposome nanoparticles to encapsulate drugs and deliver them to the target. The aim of this study was to prepare liposome nanoparticles that co-encapsulate cisplatin and mifepristone, evaluate their cytotoxicity against HeLa cells and in vivo with subcutaneous inoculations of xenografts in nu/nu mice, and examine some plausible mechanisms of action. The liposomes were elaborated by the reverse-phase method and characterized by physicochemical tests. The nanoparticles had a mean particle size of 109 ± 5.4 nm and a Zeta potential of -38.7 ± 1.2 mV, the latter parameter indicating a stable formulation. These drug-loaded liposomes significantly decreased cell viability in vitro and tumor size in vivo, without generating systemic toxicity in the animals. There was evidence of cell cycle arrest and increased apoptosis. The promising results with the co-encapsulation of cisplatin/mifepristone warrant further research.

15.
Steroids ; 163: 108708, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32730775

RESUMO

Glioblastomas (GBMs) are the most common and deadliest intracranial tumors. Steroid hormones, such as progesterone (P4), at physiological concentrations, promote proliferation, and migration of human GBM cells in vivo and in vitro. Neuronal and glial cells, but also GBMs, metabolize P4 and synthesize different active metabolites such as 5α-dihydroprogesterone (5α-DHP). However, their contribution to GBM malignancy remains unknown. Here, we determined the 5α-DHP effects on the number of cells, proliferation, and migration of the U87 and U251 human GBM-derived cell lines. Of the tested concentrations (1 nM-1 µM), 5α-DHP 10 nM significantly increased the number of U87 and U251 cells from day 2 of treatment, and proliferation (at day 3) in a similar manner as P4 (10 nM). The treatment with the progesterone receptor (PR) antagonist RU486 (mifepristone), blocked the effects of 5α-DHP on the number of cells and proliferation. Besides, in U251 and LN229 GBM cells, 5α-DHP promoted cell migration (from 12 to 24 h). We also determined that GBM cells expressed the 3α-hydroxysteroid oxidoreductases (3α-HSOR), which reversibly reduce 5α-DHP to allopregnanolone (3α-THP). These data indicate that 5α-DHP induces proliferation and migration of human GBM through the activation of PR.


Assuntos
5-alfa-Di-Hidroprogesterona/farmacologia , Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Glioblastoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Receptores de Progesterona/metabolismo
16.
Exp Eye Res ; 190: 107854, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669405

RESUMO

Death of retinal photoreceptors is the basis of prevalent blinding diseases. Since steroids might have a therapeutic role in retinal degenerations, we compared the protective effects of dexamethasone and progesterone on photoreceptor death induced by mifepristone and light exposure. Therefore, we studied the effective protection doses for each steroid in the two models. In addition, we analyzed changes in the levels of pro- and antiapoptotic molecules, glucocorticoid receptors α and ß (GRα and GRß), and rhodopsin under conditions of successful protection and photoreceptor survival. Mifepristone and light exposure selectively damaged photoreceptors. In light exposed retinas, photoreceptors mainly disappeared in the dorsotemporal region, while mifepristone produced a uniform damage. Dexamethasone and progesterone, at the same dose of 4 mg/kg/day for 2 days, preserved over 88% photoreceptor nuclei in both models. Assessment of cell death regulators showed that, in control retinas, both steroids activated BCL-XL, a prosurvival molecule, and decreased BID, a proapoptotic regulator. After steroid treatment of damaged retinas, BCL-XL, BCL2 and BAX showed characteristic patterns depending on the use of dexamethasone or progesterone on mifepristone or light exposed retinas. By contrast, BID decreased with any injury-steroid combination. Changes in GRα or GRß levels did not correlate with survival but were consistent with a mechanism of ligand induced downregulation of receptor expression. GRß might be upregulated by progesterone. Both dexamethasone and progesterone increased retinal rhodopsin stores, suggesting a link between photoreceptor protection and transduction pathways. Results show that dexamethasone and progesterone induced comparable but not identical protection responses in each model.


Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Progesterona/farmacologia , Lesões Experimentais por Radiação/prevenção & controle , Degeneração Retiniana/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Western Blotting , Caspase 3 , Sobrevivência Celular/fisiologia , Antagonistas de Hormônios/toxicidade , Imuno-Histoquímica , Luz/efeitos adversos , Masculino , Camundongos Endogâmicos BALB C , Mifepristona/toxicidade , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/efeitos da radiação , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/metabolismo , Receptores de Glucocorticoides/metabolismo , Degeneração Retiniana/etiologia , Degeneração Retiniana/metabolismo , Rodopsina/metabolismo , Proteína bcl-X/metabolismo
17.
Inflammopharmacology ; 28(3): 773-786, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31802387

RESUMO

The treatment of cutaneous inflammation with topical corticosteroids may cause adverse effects reinforcing the need for therapeutic alternatives to treat inflammatory skin disorders. We investigated the anti-inflammatory effect of oleic acid (OA), a fatty acid of the omega-9 (ω-9) family, and we point out it as an alternative to treat inflammatory skin disorders. OA was incorporated into Lanette®- or Pemulen® TR2-based semisolid preparations and the pH, spreadability, rheological behavior and in vivo anti-inflammatory performance in a UVB radiation-induced skin inflammation model in mice were assessed. The anti-inflammatory activity was verified after single or repeated treatment of the mouse ear following the UVB. The OA action on glucocorticoid receptors was investigated. Both semisolids presented pH values compatible with the deeper skin layers, appropriate spreadability factors, and non-Newtonian pseudoplastic rheological behavior. Pemulen® 3% OA inhibited ear edema with superior efficacy than Lanette® 3% OA and dexamethasone after a single treatment. Pemulen® 3% OA and dexamethasone also reduced inflammatory cell infiltration. After repeated treatments, all formulations decreased the ear edema at 24 h, 48 h and 72 h after UVB. OA in semisolids, especially Pemulen® TR2-based ones, presented suitable characteristics for cutaneous administration and its anti-inflammatory activity seems to occur via glucocorticoid receptors. OA was also capable to reduce croton oil-induced skin inflammation. Besides, the ex vivo skin permeation study indicated that OA reaches the receptor medium, which correlates with a systemic absorption in vivo. The natural compound OA could represent a promising alternative to those available to treat inflammatory skin disorders.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Ácido Oleico/farmacologia , Receptores de Glucocorticoides/metabolismo , Pele/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Administração Cutânea , Animais , Dermatite/tratamento farmacológico , Dermatite/metabolismo , Edema/tratamento farmacológico , Edema/metabolismo , Inflamação/metabolismo , Masculino , Camundongos , Pele/metabolismo
18.
BMJ Open ; 10(11): e036800, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33444174

RESUMO

INTRODUCTION: A range of barriers deter or prevent people from accessing facility-based abortion care. As a result, people are obtaining and using abortifacient medications to end their pregnancies outside of the formal healthcare system, without clinical supervision. One model of self-managed abortion has come to be known as the 'accompaniment' model, in which grassroots organisations provide pregnant people with evidence-based counselling and support through the medication abortion process. Data are needed to understand the safety and effectiveness of this increasingly common model of abortion care. METHODS AND ANALYSIS: This is a large, prospective, observational study in Argentina and Nigeria. All people who contact one of two accompaniment groups seeking information for their own self-managed medication abortion, are ages 13 years and older, have no contraindications for medication abortion, are within the gestational range supported by the group (up to 12 weeks' gestation for the primary outcome) and are willing to be contacted for follow-up will be recruited. Participants will respond to an interviewer-administered baseline survey at enrolment, and 1-4 additional surveys over 6 weeks to ascertain whether they obtain medications for abortion, dosing and route of administration of medications, physical and emotional experience of medication abortion self-management, and effectiveness and safety outcomes. Analyses will include estimates of the primary outcome: the proportion of participants that report a complete abortion without surgical intervention at last recorded follow-up; as well as secondary outcomes including a pseudo-experimental test of non-inferiority of the effectiveness of self-managed medication abortion as compared with clinical medication abortion. ETHICS AND DISSEMINATION: We describe the ethical considerations and protections for this study, as well the creation of a study-specific Data Monitoring and Oversight Committee. We describe dissemination plans to ensure that study results are shared widely with all relevant audiences, particularly researchers, advocates, policymakers and clinicians. TRIAL REGISTRATION NUMBER: ISRCTN95769543.


Assuntos
Aborto Induzido , Aborto Espontâneo , Adolescente , Argentina , Feminino , Humanos , Recém-Nascido , Nigéria , Gravidez , Estudos Prospectivos
19.
Rev. bras. pesqui. méd. biol ; Braz. j. med. biol. res;53(11): e10067, 2020. graf
Artigo em Inglês | LILACS, Coleciona SUS | ID: biblio-1132493

RESUMO

RU486 (mifepristone), a glucocorticoid and progesterone receptor antagonist, has been reported to exert antiproliferative effects on tumor cells. Experiments were performed to analyze the effects of RU486 on the proliferation of the human neuroblastoma, both in vitro and in vivo, using the human neuroblastoma SK-N-SH cell line. The exposure in vitro of SK-N-SH cells to RU486 revealed a dose-dependent inhibition of 3H-thymidine incorporation due to a rapid but persistent inhibition of MAPKinase activity and ERK phosphorylation. A significant decrease of SK-N-SH cell number was evident after 3, 6, and 9 days of treatment (up to 40% inhibition), without evident cell death. The inhibitory effect exerted by RU486 was not reversed by the treatment of the cells with dexamethasone or progesterone. Moreover, RU486 induced a shift in SK-N-SH cell phenotypes, with an almost complete disappearance of the neuronal-like and a prevalence of the epithelial-like cell subtypes. Finally, the treatment with RU486 of nude mice carrying a SK-N-SH cell xenograft induced a strong inhibition (up to 80%) of tumor growth. These results indicated a clear effect of RU486 on the growth of SK-N-SH neuroblastoma cells that does not seem to be mediated through the classical steroid receptors. RU486 acted mainly on the more aggressive component of the SK-N-SH cell line and its effect in vivo was achieved at a concentration already used to inhibit oocyte implantation.


Assuntos
Humanos , Animais , Coelhos , Neuroblastoma/tratamento farmacológico , Progesterona , Mifepristona/farmacologia , Glucocorticoides , Camundongos Nus
20.
Cell Mol Neurobiol ; 39(4): 471-472, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30941611

RESUMO

Steroids are complex molecules, exerting known and still unknown effects in the nervous system. Throughout this volume, the reader will find a wide spectrum of articles, giving an up-to-date account of the molecular, physiological, pharmacological, and clinical aspects of steroid action on the nervous system.


Assuntos
Sistema Nervoso/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Esteroides/farmacologia , Animais , Humanos , Camundongos , Neuroproteção/efeitos dos fármacos
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