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1.
Gynecol Oncol ; 153(1): 55-62, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30674421

RESUMO

OBJECTIVE: This study aimed to evaluate the efficacy of comprehensive hysteroscopic evaluation and lesion resection combined with progestin therapy in young patients with endometrial atypical hyperplasia (EAH) and early stage endometrial cancer (EEC) who wished to preserve their fertility. METHODS: Patients with EAH (n = 120) or well-differentiated EEC (n = 40, FIGO stage IA, without myometrial invasion) were retrospectively included. All patients received constant oral progestin combined with hysteroscopic evaluation every 3 months until achieving complete response (CR). The location, number and size of each suspected lesion or cluster were detailly recorded during the hysteroscopy. RESULTS: The median age was 32.0 year-old (range, 22-47 year-old). Totally 148 patients (97.4%) achieved CR while 3 EAH and 1 EEC patients presented with disease progression, and 8 patients were still in treatment. The mean treatment duration for achieving CR was 6.7 ±â€¯0.3 months (range, 1-18 months). After adjusting for patient age, body mass index (BMI), history of pregnancy and type of conservative therapies, lesion size ≤2 cm (OR, 0.701; 95% CI, 0.496-0.991; P = 0.045) was significantly correlated with shorter treatment time to achieve CR. Among 60 patients attempted to conceive after achieving CR, 45.0% (15/60) had been pregnant, 25.0% (15/60) delivered live birth, 13.3% (8/60) are still in pregnancy, while 6.7% experienced spontaneous abortion. CONCLUSION: Comprehensive hysteroscopic evaluation and lesion resection plus progestin therapy seem to be an effective and safe fertility sparing therapy for patients with EAH or EEC. Endometrial lesion size ≤2 cm correlated with a shorter treatment period to achieve CR.


Assuntos
Hiperplasia Endometrial/tratamento farmacológico , Hiperplasia Endometrial/cirurgia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/cirurgia , Preservação da Fertilidade/métodos , Progestinas/administração & dosagem , Administração Oral , Adulto , Hiperplasia Endometrial/diagnóstico , Hiperplasia Endometrial/patologia , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Feminino , Humanos , Histeroscopia/métodos , Acetato de Megestrol/administração & dosagem , Metformina/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
2.
Dement Geriatr Cogn Disord ; 46(3-4): 186-192, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30286455

RESUMO

BACKGROUND: The effects of the glucocorticoid and progesterone receptor agonist megestrol on declarative memory, and the ability of phenytoin to block these effects, were assessed. METHODS: Healthy volunteers received each medication combination (placebo and megestrol, phenytoin and megestrol, and placebo and placebo) using a randomized, crossover design. The Rey Auditory Verbal Learning Test assessed declarative memory. RESULTS: Megestrol was associated with a significant reduction in declarative memory (p = 0.0008), which was attenuated by phenytoin, and was associated with significant cortisol suppression compared to placebo (p < 0.001). CONCLUSION: Changes in memory and cortisol suppression were found in healthy volunteers given megestrol.


Assuntos
Hidrocortisona/sangue , Acetato de Megestrol , Memória/efeitos dos fármacos , Adulto , Estimulantes do Apetite/administração & dosagem , Estimulantes do Apetite/efeitos adversos , Cognição/efeitos dos fármacos , Estudos Cross-Over , Monitoramento de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Acetato de Megestrol/administração & dosagem , Acetato de Megestrol/efeitos adversos , Fenitoína/administração & dosagem , Fenitoína/efeitos adversos , Receptores de Progesterona/agonistas , Resultado do Tratamento
4.
Pharm Dev Technol ; 23(4): 407-413, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29095656

RESUMO

Megestrol acetate (MGA) is used as a progestagen to treat advanced cancers in the breast or uterus and anorexia-cachexia syndrome in cancer patients. Due to its low solubility (BCS class II), MGA bioavailability needs to be enhanced for efficacy and safety. We developed MGA-encapsulated Eudragit® L100 (EUD) nanoparticles (MGA-EUD (1:1) and MGA-EUD (2:1)) using an ultrasonic nebulization method. MGA-EUD (1:1) and MGA-EUD (2:1) consisted of MGA and EUD at the mass ratios of 1:1 and 2:1. Their physicochemical properties, i.e. particle size, loading efficiency, morphology, and crystallinity were determined. Dissolution tests were performed using USP method II. For pharmacokinetics, they were orally administered at 50 mg/kg to mice. Microcrystalline MGA suspension (MGA-MC, Megace®, BMS) was used as control. MGA-EUD (1:1) and MGA-EUD (2:1) had a smooth and spherical shape of 0.70 and 1.05 µm in diameter with loading efficiencies of 93 and 95% showing amorphous states of MGA. They significantly enhanced the dissolution potential of MGA. Oral bioavailability of MGA-EUD (1:1) and MGA-EUD (2:1) increased 2.0- and 1.7-fold compared to that of MGA-MC. It suggests that ultrasonic nebulization method for the fabrication of polymeric nanoparticles is a promising approach to improve the bioavailability of poorly soluble drugs.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Estimulantes do Apetite/administração & dosagem , Acetato de Megestrol/administração & dosagem , Nanopartículas/química , Ácidos Polimetacrílicos/química , Administração Oral , Animais , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacocinética , Estimulantes do Apetite/química , Estimulantes do Apetite/farmacocinética , Disponibilidade Biológica , Masculino , Acetato de Megestrol/química , Acetato de Megestrol/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Transição de Fase , Solubilidade , Sonicação , Suspensões , Ultrassom
5.
Gynecol Endocrinol ; 34(1): 15-19, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28650773

RESUMO

Estrogen-dependent early stage endometrial cancer is relatively common in young women of reproductive age. The standard treatment is hysterectomy and bilateral salpingo-oophorectomy (BSO), even in early stage well-differentiated endometrial cancer patients. This surgical option results in permanent loss of fertility. There have been some reports of live births using in vitro fertilization after conservative management of endometrial cancer with high-dose progestin for the purpose of fertility preservation. However, most were not recurrent cases and pregnancy was achieved through conventional in vitro fertilization, which usually raises serum estradiol levels and may lead to the recurrence of endometrial cancer. To date, it is hard to find a case that can be referred for any possible different approach needed for the patients who experience recurrence. Here we report a successful live birth with in vitro fertilization using letrozole to maintain physiological levels of estradiol, and subsequent thawed embryo transfer after elective cryopreservation of embryos in a patient with recurrent endometrial cancer. There has been no evidence of disease recurrence at one year after delivery.


Assuntos
Tratamento Conservador , Transferência Embrionária/métodos , Neoplasias do Endométrio/tratamento farmacológico , Fertilização In Vitro/métodos , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado da Gravidez , Adulto , Antineoplásicos Hormonais/administração & dosagem , Criopreservação , Neoplasias do Endométrio/patologia , Feminino , Preservação da Fertilidade/métodos , Humanos , Letrozol , Levanogestrel/administração & dosagem , Nascimento Vivo , Acetato de Megestrol/administração & dosagem , Recidiva Local de Neoplasia/patologia , Nitrilos/uso terapêutico , Gravidez , Triazóis/uso terapêutico
6.
Int J Gynecol Cancer ; 27(9): 1919-1925, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28885274

RESUMO

OBJECTIVE: This study aims to explore the feasibility of a hysteroscopic procedure combined with progestin therapy in young patients with stage Ia endometrioid carcinoma (EC) to avoid sterilization. MATERIALS AND METHODS: Eleven young women with stage Ia EC (International Federation of Gynecology and Obstetrics grade 1) who were treated with a hysteroscopic approach combined with progestin from July 2004 to June 2016 were retrospectively analyzed and followed up to monitor their general recovery and pregnancy outcome. RESULTS: The patients' median age was 27.3 years (range, 25-39 years). Comorbidities consisted of primary infertility in 8 patients, polycystic ovary syndrome in 4, uterine fibroids in 2, and diabetes in 1. The results of immunohistochemical analysis were positive for all estrogen and progestin receptors. After treatment, 9 patients attained complete remission, and 2 patients achieved partial remission. The results of peritoneal cytology in 4 patients were negative. As of this writing, 6 of the 11 patients have given birth to 7 infants, and 1 patient had an ectopic pregnancy. Two patients ultimately underwent radical resection. The average follow-up time was 82.3 months (range, 15 to 152 months), and all patients remain disease-free. CONCLUSIONS: Hysteroscopic surgery combined with progestin treatment for stage Ia EC in young patients to avoid sterilization was practical and may represent a new option for patients with stage Ia EC who wish to preserve their fertility.


Assuntos
Carcinoma Endometrioide/cirurgia , Neoplasias do Endométrio/cirurgia , Preservação da Fertilidade/métodos , Histeroscopia/métodos , Adulto , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Acetato de Medroxiprogesterona/administração & dosagem , Acetato de Megestrol/administração & dosagem , Estadiamento de Neoplasias , Gravidez , Estudos Retrospectivos
7.
J Am Vet Med Assoc ; 251(2): 217-223, 2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28671496

RESUMO

OBJECTIVE To evaluate the impact of oral megestrol acetate (MA) administration on adrenal function in male bottlenose dolphins (Tursiops truncatus). DESIGN Serial cross-sectional study. ANIMALS 8 adult male dolphins, all of which were receiving MA at various daily doses (range, 0 to 60 mg, PO) for the control of reproductive behavior. PROCEDURES Blood samples were collected every 2 weeks for 1 year from dolphins trained to voluntarily provide them. Cortisol, ACTH, and other hormone concentrations were measured in serum or plasma via radioimmunoassay or ELISA. Fecal samples, also provided by dolphins voluntarily, were assayed for glucocorticoid metabolite concentrations. Effects of daily MA dose on hormone concentrations were evaluated. RESULTS Daily MA doses as low as 10 mg strongly suppressed cortisol secretion in nearly all dolphins, and except for a single measurement, no dolphin had measurable serum concentrations at doses ≥ 20 mg. Variations in serum cortisol concentration were unrelated to season but were directly related to ACTH concentrations, suggesting primary effects upstream of the adrenal gland. Cessation of MA administration resulted in almost immediate restoration of measurable serum cortisol concentrations, although concentrations continued to rise in a few dolphins over the following weeks to months. CONCLUSIONS AND CLINICAL RELEVANCE Caution should be exercised when administering MA to control reproductive behavior in male dolphins. Because the hypothalamic-pituitary-adrenal axis appeared to be sensitive to even small doses of MA in dolphins, duration of treatment may be the most critical consideration.


Assuntos
Golfinho Nariz-de-Garrafa , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Acetato de Megestrol/administração & dosagem , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Animais , Golfinho Nariz-de-Garrafa/sangue , Golfinho Nariz-de-Garrafa/fisiologia , Estudos Transversais , Relação Dose-Resposta a Droga , Masculino , Reprodução/efeitos dos fármacos , Reprodução/fisiologia
8.
Gynecol Oncol ; 146(1): 39-43, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28526167

RESUMO

OBJECTIVE: To evaluate the influence of body weight change during fertility-sparing progestin therapy on oncologic and reproductive outcomes in young women with early-stage endometrial cancer who did not complete child bearing. METHODS: This multicenter, retrospective study included 154 young patients with well-differentiated, endometrium-confined endometrioid endometrial adenocarcinoma on magnetic resonance imaging who received fertility-sparing progestin therapy. RESULTS: The mean body weight and body mass index (BMI) at baseline and progestin therapy completion was 65.3±16.2 and 66.5±15.9kg (P=0.044), respectively, and 25.51±5.99 and 25.99±5.94kg/m2 (P=0.034), respectively. During progestin therapy, 51 (33.1%), 29 (18.8%), and 74 patients (48.1%) had weight loss, no weight change, and weight gain, respectively, of which 11 (7.1%) had 10% weight loss and 30 (19.5%) had 10% weight gain. A pretreatment BMI of ≥25kg/m2 was significantly associated with a lower complete response rate to progestin therapy (P=0.003) and a high recurrence rate (P=0.033). A posttreatment BMI of ≥25kg/m2 was also a significant factor for high recurrence rate (P=0.049). However, weight change during therapy was not significantly associated with complete response or recurrence rate. Pre and posttreatment BMIs and weight change were not associated with pregnancy and live birth rates. CONCLUSION: Weight change during progestin therapy has little influence on complete response, recurrence, pregnancy, and live birth rates. However, pre and posttreatment BMIs of ≥25kg/m2 were significant predictors for poor treatment response and high recurrence. Therefore, it is important to maintain patients' normal BMIs during progestin therapy.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Peso Corporal/efeitos dos fármacos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/fisiopatologia , Preservação da Fertilidade/métodos , Progestinas/administração & dosagem , Adulto , Índice de Massa Corporal , Neoplasias do Endométrio/patologia , Feminino , Humanos , Acetato de Medroxiprogesterona/administração & dosagem , Acetato de Megestrol/administração & dosagem , Estadiamento de Neoplasias , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Estudos Retrospectivos
9.
J Gynecol Oncol ; 28(1): e2, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27670256

RESUMO

OBJECTIVE: To report our 15-year institutional experience of fertility-sparing treatment in young patients with early endometrial cancer (EC) treated by combined hysteroscopic resection and progestin therapy. METHODS: Twenty-eight patients (stage IA, G1 and 2 endometrioid EC) wishing to preserve their fertility were enrolled into this prospective study. Hysteroscopic resection was used to resect the tumor, endometrium adjacent to the tumor and myometrium underlying the tumor. Adjuvant hormonal therapy consisted of oral megestrol acetate or levonorgestrel intrauterine device for 6 months or more. RESULTS: After 3 months from the progestin start date, 25 patients (89.3%) showed a complete regression (median time to complete regression, 3 months [range, 3-9 months]), two (7.1%) showed persistent disease, while one patient (3.6%) presented with progressive disease and underwent definitive surgery (stage IA, G3 endometrioid). At 6 months, one of the two patients with persistent disease underwent definitive surgery (stage IA, G1 endometrioid), while the other one was successfully re-treated. Two recurrences were observed (7.7%) both involving the endometrium and synchronous ovarian cancer. The median duration of complete response was 94.5 months (range, 8-175 months). More than half of the responders (57.7%) attempted to conceive with 93.3% and 86.6% pregnancy and live birth rates, respectively. CONCLUSION: The addition of a standardized three-step resectoscopy to progestin would seem to improve the efficacy of progestin alone. High pregnancy and live birth rates were observed in women attempting to conceive.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias do Endométrio/terapia , Preservação da Fertilidade/métodos , Histeroscopia , Acetato de Megestrol/administração & dosagem , Progestinas/uso terapêutico , Adulto , Quimioterapia Adjuvante , Terapia Combinada , Neoplasias do Endométrio/patologia , Feminino , Humanos , Dispositivos Intrauterinos , Levanogestrel/administração & dosagem , Gravidez , Estudos Prospectivos , Adulto Jovem
10.
Basic Clin Pharmacol Toxicol ; 120(3): 270-277, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27639080

RESUMO

Megestrol acetate, an appetite stimulant with low bioavailability, shows increased bioavailability when taken together with food. However, the pharmacokinetic characteristics of megestrol acetate and its relation with food are not well understood. This study aimed to investigate the food effect on the pharmacokinetics (PK) of the recently developed nano-crystallized megestrol acetate (NCMA), using a model-based approach. Data were obtained from an NCMA PK study consisting of a single dose in fasting (39 individuals) and fed conditions (40 individuals). Plasma concentrations were measured up to 120 hr after dosing. With the incorporation of body-weight via allometry, NONMEM 7.3 was used to develop a PK model, which was then used to simulate an optimal fasting dose yielding an area under concentration (AUC) and maximum concentration (Cmax ) of NCMA close to those obtained with the fed dose. NCMA concentrations were best characterized by a two-compartment model with first-order absorption linked to a recycling compartment to account for the multiple concentration peaks observed. Food increased bioavailability 2.2 times and decreased the absorption rate constant 0.58 times. Recycling event times were estimated to be 3.56, 7.99 and 24.0 hr. The optimal fast dose was 2.0 times higher than the fed dose, and the resulting difference in drug exposure between the fasting and fed dose was 7.5%. This work suggests that the PK model developed can be applied to an optimal dosage regimen design for NCMA treatment.


Assuntos
Estimulantes do Apetite/administração & dosagem , Estimulantes do Apetite/farmacocinética , Interações Alimento-Droga , Acetato de Megestrol/administração & dosagem , Acetato de Megestrol/farmacocinética , Modelos Biológicos , Administração Oral , Adulto , Estimulantes do Apetite/uso terapêutico , Disponibilidade Biológica , Caquexia/tratamento farmacológico , Estudos Cross-Over , Sistemas de Liberação de Medicamentos/métodos , Cálculos da Dosagem de Medicamento , Ingestão de Alimentos , Jejum , Voluntários Saudáveis , Humanos , Masculino , Acetato de Megestrol/uso terapêutico , Nanopartículas , República da Coreia , Adulto Jovem
11.
Int J Clin Pharmacol Ther ; 54(9): 698-704, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27191767

RESUMO

UNLABELLED: OBJECTIVE: The conventional suspension of megestrol acetate contains micronized megestrol acetate, which was recently discovered to have a disadvantage of decreasing bioavailability when taken in a fasting state. Since megestrol acetate is taken to increase appetite, this property becomes a discouraging factor. To improve upon this, an advanced formulation was developed using a nanocrystal drug-delivery system. This study was conducted to compare the safety and pharmacokinetic characteristics between the conventional formulation of megestrol acetate and a generic version of the advanced formulation containing nanocrystals. METHODS: This was a randomized, open-label, 2-period, 2-treatment, crossover, single-dose, 2-part study (part 1 fasting and part 2 fed), conducted in healthy males aged between 20 and 50 years with weight within ± 20% of ideal body weight having no congenital abnormalities or chronic diseases. Different subjects were used in part 1 and part 2, but subjects received a single dose of the reference and test drugs separated by a 14-day washout period. Blood sampling was performed up to 120 hours after dosing using a pre-specified sampling time scheme. Primary pharmacokinetic parameters were Cmax and AUClast of the test and reference formulations of megestrol acetate. Bioequivalence evaluation was based on the standard criterion of 80 - 125% for the 90% confidence interval of geometric mean ratios of test to reference drugs calculated for the pharmacokinetic parameters. To monitor adverse events, both subject interviews and physical examinations were done on a regular time basis. RESULTS: 80 subjects (n = 40 each part) were enrolled, and 79 completed the study. The 90% CIs of the geometric mean ratios of Cmax and AUClast were 4.4625 - 5.6018 and 1.3602 - 1.6418, respectively, for part 1, and 0.9793 - 1.1327 and 0.7721 - 0.8431, respectively, for part 2. No significant difference was discovered in the incidence of adverse events (AEs) when test and reference treated groups were compared. CONCLUSIONS: Our findings suggest that the test formulation of megestrol-acetate-containing nanocrystals is better absorbed and has higher bioavailability compared to the reference formulation in a fasting state. This should allow for a lower dose and better patient compliance.

ClinicalTrials.gov identifier: NCT02446353.


Assuntos
Estimulantes do Apetite/farmacocinética , Medicamentos Genéricos/farmacocinética , Acetato de Megestrol/farmacocinética , Nanopartículas , Adulto , Estimulantes do Apetite/administração & dosagem , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Disponibilidade Biológica , Estudos Cross-Over , Sistemas de Liberação de Medicamentos , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/efeitos adversos , Jejum , Humanos , Masculino , Acetato de Megestrol/administração & dosagem , Acetato de Megestrol/efeitos adversos , Pessoa de Meia-Idade , Equivalência Terapêutica , Adulto Jovem
12.
Vet Ophthalmol ; 19 Suppl 1: 86-90, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26938779

RESUMO

OBJECTIVE: To evaluate a compounded ophthalmic formulation of 0.5% megestrol acetate to treat eosinophilic keratitis in cats. STUDY DESIGN: Prospective study. ANIMALS STUDIED: Seventeen client owned cats with eosinophilic keratitis in one or both eyes. METHODS: Eosinophilic keratitis was confirmed by cytology. At each visit, fluorescein staining and photography were performed. Cats were initially treated q 8-12 h with 0.5% megestrol acetate in an aqueous base. Serum glucose was measured at the first or second reexamination. RESULTS: Fifteen of 17 (88%) cats had a positive response to treatment, with 6 of 17 (35%) having complete resolution at the first reexamination (2-4 weeks). Two of 17 (12%) cats did not respond to treatment. Most cats required a treatment frequency of once daily to once weekly to maintain remission of disease. No ocular irritation or systemic side effects were noted in any cat. CONCLUSIONS AND CLINICAL RELEVANCE: The use of an ophthalmic formulation of 0.5% megestrol acetate is a viable option for treating feline eosinophilic keratitis.


Assuntos
Doenças do Gato/tratamento farmacológico , Ceratite/veterinária , Acetato de Megestrol/uso terapêutico , Soluções Oftálmicas/uso terapêutico , Progestinas/uso terapêutico , Administração Oftálmica , Animais , Doenças do Gato/patologia , Gatos , Eosinófilos , Feminino , Ceratite/tratamento farmacológico , Ceratite/patologia , Masculino , Acetato de Megestrol/administração & dosagem , Acetato de Megestrol/efeitos adversos , Soluções Oftálmicas/efeitos adversos , Progestinas/efeitos adversos , Estudos Prospectivos
13.
Gynecol Oncol ; 141(1): 43-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27016228

RESUMO

OBJECTIVE: Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development. METHODS: Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next-generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored. RESULTS: Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01-0.78) and RR (response difference 0.83; 95% CI 0.03-0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20-0.97) but not RR (response difference 0.00, 95% CI -0.34-0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR. CONCLUSIONS: Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus.


Assuntos
Neoplasias do Endométrio/genética , Acetato de Megestrol/administração & dosagem , Mutação , Sirolimo/análogos & derivados , Tamoxifeno/administração & dosagem , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-akt/genética , Sirolimo/administração & dosagem , Sirolimo/uso terapêutico , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética
16.
Int J Gynaecol Obstet ; 132(1): 34-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26493012

RESUMO

OBJECTIVE: To investigate the oncologic and reproductive outcomes after progestin treatment of complex endometrial hyperplasia (CEH) and grade 1 endometrial carcinoma (EC). METHODS: In a retrospective study, data were obtained for patients aged 20-42years with CEH or grade 1 EC at presumed stage IA (without myometrial invasion) who wished to preserve fertility and were treated at the Peking Union Medical College Hospital, China, between January 1, 2000, and December 31, 2011. Patients had received oral medroxyprogesterone acetate (250-500mg/day) or megestrol acetate (160-480mg/day) for at least 6months. Response to progestin treatment was assessed histologically. RESULTS: Among 53 included patients, 39 (74%) achieved complete response after a median period of 6 (3-24) months. Complete response was less frequent among obese than nonobese patients (4/12 [33%] vs 35/41 [85%]; P=0.001). Disease recurrence was recorded in 10 (26%) patients with complete response; the 5-year recurrence-free survival rate was 71%. Among the 33 patients who retained a desire to conceive, 17 (52%) became pregnant. CONCLUSION: Fertility-sparing management with oral progestin is effective. Obesity is associated with a lower probability of long-term success.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Hiperplasia Endometrial/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Preservação da Fertilidade/métodos , Progestinas/administração & dosagem , Adulto , China , Intervalo Livre de Doença , Feminino , Fertilidade/efeitos dos fármacos , Humanos , Acetato de Medroxiprogesterona/administração & dosagem , Acetato de Megestrol/administração & dosagem , Recidiva Local de Neoplasia , Obesidade/complicações , Gravidez , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
17.
Oncologist ; 20(12): 1432-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26463869

RESUMO

BACKGROUND: In a previous pilot study, adrenal suppression was found to be common after antiemetic dexamethasone therapy in cancer patients. The objective of this large prospective multicenter study was to confirm the incidence and factors associated with secondary adrenal suppression related to antiemetic dexamethasone therapy in cancer patients receiving chemotherapy. METHODS: Chemotherapy-naïve patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Patients with a suppressed adrenal response before chemotherapy or those administered corticosteroids within 6 months of enrollment in the study were excluded. RESULTS: Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid adrenocorticotropic hormone (ACTH) stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the start of the first chemotherapy. The incidence of adrenal suppression was affected by age, performance status, stage, and use of megestrol acetate in univariate analysis. Multivariate analysis revealed that secondary adrenal suppression associated with antiemetic dexamethasone therapy was significantly associated with megestrol acetate treatment (odds ratio: 3.06; 95% confidence interval: 1.60 to 5.86; p < .001). CONCLUSION: This large prospective study indicates that approximately 15% of cancer patients receiving chemotherapy with a normal adrenal response show suppressed adrenal responses after antiemetic dexamethasone therapy. This result was particularly significant for patients cotreated with megestrol acetate.


Assuntos
Insuficiência Adrenal/induzido quimicamente , Antieméticos/efeitos adversos , Dexametasona/efeitos adversos , Neoplasias/tratamento farmacológico , Insuficiência Adrenal/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Acetato de Megestrol/administração & dosagem , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
18.
Drug Des Devel Ther ; 9: 4269-77, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26345723

RESUMO

In the present study, solid dispersion nanoparticles with a hydrophilic polymer and surfactant were developed using the supercritical antisolvent (SAS) process to improve the dissolution and oral absorption of megestrol acetate. The physicochemical properties of the megestrol acetate solid dispersion nanoparticles were characterized using scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction, and a particle-size analyzer. The dissolution and oral bioavailability of the nanoparticles were also evaluated in rats. The mean particle size of all solid dispersion nanoparticles that were prepared was <500 nm. Powder X-ray diffraction and differential scanning calorimetry measurements showed that megestrol acetate was present in an amorphous or molecular dispersion state within the solid dispersion nanoparticles. Hydroxypropylmethyl cellulose (HPMC) solid dispersion nanoparticles significantly increased the maximum dissolution when compared with polyvinylpyrrolidone K30 solid dispersion nanoparticles. The extent and rate of dissolution of megestrol acetate increased after the addition of a surfactant into the HPMC solid dispersion nanoparticles. The most effective surfactant was Ryoto sugar ester L1695, followed by D-α-tocopheryl polyethylene glycol 1000 succinate. In this study, the solid dispersion nanoparticles with a drug:HPMC:Ryoto sugar ester L1695 ratio of 1:2:1 showed >95% rapid dissolution within 30 minutes, in addition to good oral bioavailability, with approximately 4.0- and 5.5-fold higher area under the curve (0-24 hours) and maximum concentration, respectively, than raw megestrol acetate powder. These results suggest that the preparation of megestrol acetate solid dispersion nanoparticles using the supercritical antisolvent process is a promising approach to improve the dissolution and absorption properties of megestrol acetate.


Assuntos
Cromatografia com Fluido Supercrítico , Acetato de Megestrol/administração & dosagem , Nanopartículas , Congêneres da Progesterona/administração & dosagem , Tecnologia Farmacêutica/métodos , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cristalografia por Raios X , Derivados da Hipromelose/química , Absorção Intestinal , Masculino , Acetato de Megestrol/química , Acetato de Megestrol/farmacocinética , Microscopia Eletrônica de Varredura , Nanotecnologia , Polietilenoglicóis/química , Povidona/química , Difração de Pó , Congêneres da Progesterona/química , Congêneres da Progesterona/farmacocinética , Ratos Sprague-Dawley , Solubilidade , Tensoativos/química , Vitamina E/análogos & derivados , Vitamina E/química
19.
J Biomed Nanotechnol ; 11(3): 392-402, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26307823

RESUMO

This study aims at the targeted delivery of 5-fluorouracil (5-FU) and Megestrol acetate (Meg) loaded fibrinogen-graft-poly(N-Vinyl caprolactam) nanogels (5-FU/Meg-fib-graft-PNVCL NGs) toward α5ß1-integrins receptors expressed on breast cancer cells to have enhanced anti-cancer effect in vitro. To achieve this aim, we developed biocompatible thermoresponsive fib-graft-PNVCL NGs using fibrinogen and carboxyl terminated PNVCL via EDC/NHS amidation reaction. The Lower Critical Solution Temperature (LCST) of fib-graft-PNVCL could be tuned according to PNVCL/fibrinogen compositions. The 100-120 nm sized nanogels of fib-graft-PNVCL (LCST = 35 ?1 'C) was prepared using CaCl2 cross-linker. The 5-FU/Meg-fib-graft-PNVCL NGs showed a particle size of 150-170 nm size. The drug loading efficiency with 5-FU was 62% while Meg showed 74%. The 5-FU and Meg release was prominent above LCST than below LCST. The multi drug loaded fib-graft-PNVCL NGs showed enhanced toxicity, apoptosis and uptake by breast cancer (MCF-7) cells compared to their individual doses above their LCST. The in vivo assessment in Swiss albino mice showed sustained release of Meg and 5-FU as early as 3 days, confirming the therapeutic efficiency of the formulation. These results demonstrate an enhanced platform for the future animal studies on breast tumor xenograft model.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Caprolactama/análogos & derivados , Preparações de Ação Retardada/administração & dosagem , Fibrinogênio/farmacocinética , Nanocápsulas/administração & dosagem , Polímeros/química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caprolactama/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/síntese química , Difusão , Fibrinogênio/química , Fluoruracila/administração & dosagem , Fluoruracila/química , Humanos , Hidrogéis/síntese química , Acetato de Megestrol/administração & dosagem , Acetato de Megestrol/química , Nanocápsulas/química , Nanocápsulas/ultraestrutura , Tamanho da Partícula , Receptores de Vitronectina/metabolismo , Temperatura Ambiente
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