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1.
Expert Rev Clin Pharmacol ; 12(10): 953-963, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31526281

RESUMO

Introduction: This is an overview of the recently FDA-approved silicone elastomer combined hormonal contraceptive vaginal ring (CVR), which is used cyclically for up to 1 year, eliminating resupply challenges. This ring requires no refrigeration, simplifying the supply chain. Developed by the Population Council, this CVR will soon be marketed in the United States as Annovera™ by TherapeuticsMD. Areas Covered: The composition of the elastomer ring and the chemical, pharmacokinetic and pharmacodynamic properties of both hormonal components are discussed. Results of the clinical trials of its efficacy, tolerability, safety, and acceptability follow. Finally, subanalyses from the clinical trials are presented to guide clinicians in counseling potential users. Expert Opinion: This CVR introduces a new progestin - segesterone acetate (SA) - that has no androgenic or estrogenic action in vitro or in vivo, but has the highest anti-ovulatory potential of all available progestins. SA is paired with EE in an intravaginal elastomer ring, that is used cyclically (21 days in place/7 days removed) to provide 12 months (13 cycles) of contraception. This once-a-month, self-applied CVR offers a convenient, rapidly reversible, year-long contraception with efficacy and side effect profiles similar to other combined hormonal methods, for women with BMI < 29 kg/m2.


Assuntos
Dispositivos Anticoncepcionais Femininos , Etinilestradiol/administração & dosagem , Contracepção Reversível de Longo Prazo , Pregnenodionas/administração & dosagem , Animais , Aprovação de Drogas , Etinilestradiol/efeitos adversos , Feminino , Humanos , Pregnenodionas/efeitos adversos , Elastômeros de Silicone/química , Estados Unidos , United States Food and Drug Administration
2.
Food Chem Toxicol ; 132: 110728, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31365888

RESUMO

We report the data from the guideline-compliant two-year toxicology study conducted as part of the Consortium Linking Academic and Regulatory Insights on Bisphenol A Toxicity (CLARITY-BPA). BPA (0, 2.5, 25, 250, 2,500, and 25,000 µg/kg body weight (bw)/day) was administered daily by gavage in 0.3% carboxymethylcellulose vehicle to NCTR Sprague-Dawley rats from gestation day 6 through the start of parturition and then directly to pups from the day after birth until postnatal day 21 (stop-dose arm) or continuously until termination at one or two years. The stop-dose arm was included to assess the potential for any BPA effects that were due to developmental exposure. No BPA-related effects were evident in the in-life and non-histopathology data. Neoplastic and nonneoplastic lesions diagnosed in both females and males were common age-associated lesions that were variable across control and BPA-treated groups. The lack of consistent responses within the continuous- and stop-dose arms within and across tissues brought into question the plausible relationship of most of these lesions to BPA treatment. There was a possible relationship between the increased incidences of lesions in the female reproductive tract and the male pituitary and exposure to the 25,000 µg BPA/kg bw/day dose level.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Fenóis/toxicidade , Animais , Relação Dose-Resposta a Droga , Etinilestradiol/administração & dosagem , Feminino , Genitália Feminina/efeitos dos fármacos , Masculino , Exposição Materna , Gravidez , Ratos , Ratos Sprague-Dawley
3.
Drugs Today (Barc) ; 55(7): 449-457, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31347613

RESUMO

The Food and Drug Administration (FDA) approved on August 10, 2018, a soft, reusable, flexible silicone ring (56 mm diameter) containing segesterone acetate and ethinyl estradiol as the first contraceptive vaginal ring (CVR) that can be used for a year and that is totally under the control of the woman using it. The vaginal ring releases segesterone and ethinyl estradiol at estimated rates of 150 mcg/day and 13 mcg/day, respectively. The CVR is inserted into the upper two-thirds of the vagina and left in place for 21 days, then removed for 7 days. The same ring can be used for 13 cycles for a total of a year's contraception. The CVR was found to be 97.5% effective in preventing pregnancy with a Pearl Index of 2.98. The adverse effects in women using the ring were similar in nature and frequency to those reported during the use of other hormonal contraceptives. The one exception was the occurrence of venous thromboembolism, which was reported more often than expected. Because of this, the FDA has required a postmarketing study to determine the true incidence of this adverse effect. The CVR was developed by the Population Council, is known as Annovera, and will be marketed by TherapeuticsMD in the U.S.


Assuntos
Anticoncepcionais/administração & dosagem , Dispositivos Anticoncepcionais Femininos , Etinilestradiol/administração & dosagem , Anticoncepção , Feminino , Humanos , Gravidez , Estados Unidos , Vagina
5.
Rev Bras Ginecol Obstet ; 41(3): 203-205, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30939605

RESUMO

INTRODUCTION: Autoimmune progesterone dermatitis (APD) is a rare autoimmune dermatosis characterized by recurrent cutaneous and mucosal lesions during the luteal phase of the menstrual cycle that disappear some days after the menses. CASE REPORT: A 34-year-old primipara woman with no significant past medical history and no prior exogenous hormone use, who presented with cyclic skin eruptions starting 1 year after the delivery. The lesions occurred ∼ 6 days before the menses and disappeared in between 1 and 2 days after the menstruation ceased. The patient was diagnosed after a positive response to an intradermal test with progesterone and was successfully treated with combined oral contraceptives. The skin eruptions have not returned since the initiation of this therapy. CONCLUSION: Dermatologists, gynecologists, and obstetricians should be aware of this rare entity. Furthermore, if this condition is suspected, a thorough history taking on the menstrual cycle and results of the intradermal progesterone test are mandatory.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Anticoncepcionais Orais Combinados/administração & dosagem , Dermatite/tratamento farmacológico , Distúrbios Menstruais/tratamento farmacológico , Progesterona/efeitos adversos , Adulto , Androstenos/administração & dosagem , Doenças Autoimunes/diagnóstico , Dermatite/diagnóstico , Etinilestradiol/administração & dosagem , Feminino , Humanos , Distúrbios Menstruais/diagnóstico , Recidiva , Testes Cutâneos , Resultado do Tratamento
6.
Int J Clin Pharmacol Ther ; 57(6): 290-297, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30900980

RESUMO

OBJECTIVES: Folic acid supplementation prevents 50 - 75% of cases of neural tube defects. This study evaluated the folic acid supplementation after oral administration of the ethinyl estradiol 0.02 mg + levonorgestrel 0.10 mg + folic acid 0.4 mg coated tablet as well as its safety and tolerability in healthy female subjects. MATERIALS AND METHODS: 36 healthy female subjects received 1 coated tablet of the test product - ethinyl estradiol 0.02 mg + levonorgestrel 0.10 mg + folic acid 0.4 mg for 21 days and a placebo coated tablet containing folic acid 0.4 mg only on the last 7 days of the cycle, in 3 cycles. Blood samples were collected to quantify folate by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The safety was assessed by recording adverse events, monitoring of vital signs, and the evaluation of laboratory tests and ECG. RESULTS: The mean whole blood level of folic acid at baseline (1st day of 1st cycle) was 42.7 ± 22.2 ng/mL, while on the 28th day of the 3rd cycle it was 47.6 ± 20.1 ng/mL, with a variation of 11.32%. The subjects tolerated the clinical protocol well and reported no clinically significant adverse effects. CONCLUSION: Oral contraceptives may be a good vehicle for folate supplementation in women of reproductive age.


Assuntos
Anticoncepcionais Orais Combinados/administração & dosagem , Suplementos Nutricionais , Etinilestradiol/administração & dosagem , Ácido Fólico/administração & dosagem , Levanogestrel/administração & dosagem , Cromatografia Líquida , Feminino , Ácido Fólico/sangue , Humanos , Espectrometria de Massas em Tandem
7.
Nurs Womens Health ; 23(2): 172-176, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30836070

RESUMO

The U.S. Food and Drug Administration approved a new combination hormonal contraceptive in August 2018. Sold under the brand name Annovera, it is a combination of segesterone acetate and ethinyl estradiol, and it is the first multiuse vaginal contraceptive system that prevents ovulation for up to 13 menstrual cycles in a year. Although there are several combination hormonal contraceptives on the market, this is the first single system that can be repeatedly used for an entire year and does not require placement by a health care provider. This innovation gives women control over when to stop using the contraceptive, should they so desire. Annovera is stored at room temperature when not in use, allowing women living in uncontrolled-temperature climates to use one contraceptive method for an entire year.


Assuntos
Anticoncepção/instrumentação , Dispositivos Anticoncepcionais Femininos/normas , Anticoncepção/efeitos adversos , Anticoncepção/métodos , Dispositivos Anticoncepcionais Femininos/efeitos adversos , Dispositivos Anticoncepcionais Femininos/tendências , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/complicações , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Etinilestradiol/administração & dosagem , Etinilestradiol/efeitos adversos , Etinilestradiol/uso terapêutico , Humanos
8.
Eur J Gastroenterol Hepatol ; 31(3): 312-315, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30676471

RESUMO

OBJECTIVE: This study aims to assess the efficacy of hormone therapy in patients with severe gastrointestinal bleeding due to multiple angiodysplastic lesions. PATIENTS AND METHODS: Between May 2010 and July 2017, we included 12 consecutive patients with anaemia or recurrent bleeding due to angiodysplasia who had been started on hormone therapy. The therapy given was a combination of levonorgestrel (between 0.10 and 0.25 mg) and ethinylestradiol (between 0.02 and 0.05 mg). We determined the mean number of transfusions required in the 6 months before and after the start of the treatment, as well as the mean haemoglobin levels, number of admissions for anaemia due to gastrointestinal bleeding and length of hospital stay in these periods. RESULTS: The mean age of patients included was 77.83 years old and 75% were male. The follow-up period after treatment initiation was 6 months. Of the 12 patients included, only one stopped the treatment owing to it not being effective. Overall, 83.3% of the patients reported subjective improvement. Furthermore, we found significant differences comparing before and after starting treatment regarding the mean number of transfusions (7±4.8 vs. 3.4±4.6; P=0.005), the mean haemoglobin levels (9.5±1.2 vs. 10.8±2.6; P=0.034) and the mean number of admissions (1.6±1.6 vs. 0.2±0.4; P=0.024). On the contrary, differences between pretreatment and post-treatment length of hospital stay were not significant. CONCLUSION: Hormone therapy is a potentially useful therapeutic tool in patients with refractory bleeding and anaemia due to angiodysplasia.


Assuntos
Anemia/tratamento farmacológico , Angiodisplasia/tratamento farmacológico , Etinilestradiol/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Hemorragia Gastrointestinal/tratamento farmacológico , Levanogestrel/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Anemia/diagnóstico , Anemia/etiologia , Angiodisplasia/complicações , Angiodisplasia/diagnóstico , Transfusão de Sangue , Combinação de Medicamentos , Etinilestradiol/efeitos adversos , Feminino , Fármacos Gastrointestinais/efeitos adversos , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Hemoglobinas/metabolismo , Humanos , Tempo de Internação , Levanogestrel/efeitos adversos , Masculino , Admissão do Paciente , Recidiva , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
9.
Eur J Clin Pharmacol ; 75(1): 41-49, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30191262

RESUMO

PURPOSE: Laquinimod is an orally dosed immuno-modulator currently under development for Huntington's disease (HD). Preclinical findings suggest potential teratogenicity of laquinimod, thus the reproductive ability of females with HD treated with laquinimod needs to be closely managed. Because combined oral contraceptives (COC) are often used in this context, the pharmacokinetics of COC containing ethinylestradiol (EE) and levonorgestrel (LNG) in combination with laquinimod (0.6 mg/day) was evaluated. METHODS: In this randomized, phase-1 single-center, double-blind, placebo-controlled, 2-way crossover drug-drug interaction (DDI) study in 48 healthy premenopausal women, COC were administered in a 28-day regimen of 21 days followed by 7 pill-free days for 4 cycles and laquinimod or placebo was administered for 28 days in cycle 1 and cycle 3 starting 7 days prior to COC administration. Blood samples for pharmacokinetic profiling of laquinimod, EE and LNG were collected on day 21 and day 22 of Cycles 1 and 3 pre-dose and multiple times post-dose. RESULTS: The ratio of geometric means and 90% confidence intervals for AUC0-24 and Cmax of EE and LNG with and without laquinimod were all within the bioequivalence range (80 to 125%). Laquinimod pharmacokinetics was consistent with those observed in previous studies. The adverse event profile was in line with the current knowledge on the safety profile of both drugs, with headache as the most frequently reported treatment-related adverse event. CONCLUSION: The combination of COC and laquinimod treatment was found to be safe, tolerable, and devoid of any noticeable pharmacokinetic interaction.


Assuntos
Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/farmacocinética , Fatores Imunológicos/farmacologia , Levanogestrel/farmacocinética , Quinolonas/farmacologia , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Combinação de Medicamentos , Interações Medicamentosas , Etinilestradiol/administração & dosagem , Etinilestradiol/efeitos adversos , Feminino , Cefaleia/induzido quimicamente , Cefaleia/epidemiologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Levanogestrel/administração & dosagem , Levanogestrel/efeitos adversos , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Equivalência Terapêutica , Adulto Jovem
10.
Br J Sports Med ; 53(4): 229-236, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30301734

RESUMO

OBJECTIVE: Normal-weight oligo-amenorrhoeic athletes (OAA) are at risk for low bone mineral density (BMD). Data are lacking regarding the impact of oestrogen administration on bone outcomes in OAA. Our objective was to determine the effects of transdermal versus oral oestrogen administration on bone in OAA engaged in weight-bearing activity. METHODS: 121 patients with OAA aged 14-25 years were randomised to receive: (1) a 17ß-estradiol transdermal patch continuously with cyclic oral micronised progesterone (PATCH), (2) a combined ethinyl estradiol and desogestrel pill (PILL) or (3) no oestrogen/progesterone (NONE). All participants received calcium and vitamin D supplementation. Areal BMD was assessed at the lumbar spine, femoral neck, total hip and total body less head using dual-energy X-ray absorptiometry at baseline, 6 and 12 months. Intention-to-treat (ITT) and completers analyses were performed. RESULTS: Randomised groups did not differ for age, body mass index or BMD Z-scores at baseline. For ITT analysis, spine and femoral neck BMD Z-scores significantly increased in the PATCH versus PILL (p=0.011 and p=0.021, respectively) and NONE (p=0.021 and p=0.033, respectively) groups, and hip BMD Z-scores significantly increased in the PATCH versus PILL group (p=0.018). Similar findings were noted in completers analysis. CONCLUSION: Transdermal estradiol over 12 months improves BMD in young OAA, particularly compared with an ethinyl estradiol-containing contraceptive pill/oral contraceptives. TRIAL REGISTRATION NUMBER: NCT00946192; Pre-results.


Assuntos
Amenorreia/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Terapia de Reposição de Estrogênios , Absorciometria de Fóton , Administração Oral , Adolescente , Adulto , Amenorreia/fisiopatologia , Atletas , Desogestrel/administração & dosagem , Estradiol/administração & dosagem , Etinilestradiol/administração & dosagem , Feminino , Humanos , Adesivo Transdérmico , Adulto Jovem
11.
Environ Toxicol Chem ; 38(3): 533-547, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30569562

RESUMO

Fish (embryo) toxicity test guidelines are mostly based on aquatic exposures. However, in some cases, other exposure routes can be more practical and relevant. Micro-injection into the yolk of fish embryos could offer a particular advantage for administering hydrophobic compounds, such as many endocrine disruptors. Single-dose micro-injection was compared with continuous aquatic exposure in terms of compound accumulation and biological responses. 17α-Ethinyl estradiol (EE2) was used as a model compound. First, the optimal solvent and droplet size were optimized, and needle variation was assessed. Next, biological endpoints were evaluated. The accumulated internal dose of EE2 decreased over time in both exposure scenarios. Estrogen receptor activation was concentration/injected dose dependent, increased daily, and was related to esr2b transcription. Transcription of vitellogenin 1 (vtg1) and brain aromatase (cyp19a1b) was induced in both scenarios, but the cyp19a1b transcription pattern differed between routes. Injection caused an increase in cyp19a1b transcripts from 48 hours post fertilization (hpf) onward, whereas after aquatic exposure the main increase occurred between 96 and 120 hpf. Some malformations only occurred after injection, whereas others were present for both scenarios. We conclude that responses can differ between exposure routes and therefore micro-injection is not a direct substitute for, but can be complementary to aquatic exposure. Nevertheless, vtg1and cyp19a1b transcription and estrogen receptor activation are suitable biomarkers for endocrine disruptor screening in both scenarios. Environ Toxicol Chem 2019;38:533-547. © 2018 SETAC.


Assuntos
Disruptores Endócrinos/administração & dosagem , Testes de Toxicidade/métodos , Poluentes Químicos da Água/administração & dosagem , Animais , Aromatase/genética , Aromatase/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Etinilestradiol/administração & dosagem , Etinilestradiol/toxicidade , Masculino , Microinjeções/métodos , Receptores Estrogênicos/metabolismo , Vitelogeninas/genética , Vitelogeninas/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
13.
Expert Rev Clin Pharmacol ; 11(11): 1085-1098, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30325245

RESUMO

INTRODUCTION: Following a historical overview, the ovulation-inhibiting effect of various orally administered estrogen-progestin combinations (combined oral contraceptives [COCs]) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Inhibition of ovulation with progestins alone; estrogens alone; various progestins in combination with ethinyl estradiol; various progestins in combination with natural estrogens (estradiol, estradiol valerate, and estetrol). Expert commentary: The original idea to achieve ovulation blockage through the administration of steroid hormones involved the use a progestogen (both progesterone and its synthetic homologous). The ability of a progestin to inhibit ovulation depends on the type of compound and on its dosage and a difference of more than 20-fold in activity exists between compounds utilized today in COCs. Initially, the estrogenic component was present only because it contaminated the first progestin utilized. It was soon found that an estrogen is necessary for proper cycle control. It was also found that the estrogen acts synergistically in inhibiting ovulation. For almost half a century, most COCs contained ethinyl estradiol. Today, also natural estrogens are being employed. Inhibition of ovulation was complete with all early high dose preparations. Decreasing dosage allowed some ovarian activity to occur, occasionally leading to a mature follicle. Even in this situation, defective corpus luteum formation assured contraceptive protection.


Assuntos
Anticoncepcionais Orais Combinados/administração & dosagem , Estrogênios/administração & dosagem , Progestinas/administração & dosagem , Animais , Anticoncepcionais Orais Combinados/farmacologia , Relação Dose-Resposta a Droga , Estrogênios/farmacologia , Etinilestradiol/administração & dosagem , Etinilestradiol/farmacologia , Feminino , Humanos , Ovulação/efeitos dos fármacos , Progesterona/administração & dosagem , Progesterona/farmacologia , Progestinas/farmacologia
14.
AAPS PharmSciTech ; 19(8): 3850-3858, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30280353

RESUMO

Chlormadinone acetate (CMA) is a derivative of the naturally secreted hormone progesterone and exhibits reliable contraceptive and non-contraceptive benefits. Although the marketed product of CMA as oral tablets under the trade name Belara® has been highly successful, there is still room for further improvements in oral bioavailability and a reduction in the clinical dose to decrease related adverse effects. In the current study, a CMA-based self-microemulsifying drug delivery system (SMEDDS) was developed using 32% ethyl oleate as an oil phase, 40% Tween-80 as a surfactant, and 12% Transcutol P combined with 16% PEG400 as a cosurfactant, resulting in spherical droplets with a z-average particle size of 38.92 nm and an average zeta potential of - 3.18 mv. The in vitro release rate of CMA from CMA-SMEDDS in different media (distilled water, HCl solution at pH 1.2, phosphate buffers at pH 4.5 and pH 6.8) was significantly faster than that from Belara® in the first 15 min. A pharmacokinetic study in rats showed that the Cmax and AUC of CMA-SMEDDS were significantly higher (P < 0.01) than those of Belara®, with a 1.98-fold increase in oral bioavailability. In comparison with Belara®, the developed CMA-SMEDDS showed promising release profiles both in vitro and in vivo, which could potentially be useful in enhancing oral bioavailability and reducing the clinical dose of CMA.


Assuntos
Acetato de Clormadinona/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Emulsificantes/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Acetato de Clormadinona/química , Acetato de Clormadinona/metabolismo , Relação Dose-Resposta a Droga , Emulsificantes/química , Emulsificantes/metabolismo , Etinilestradiol/administração & dosagem , Etinilestradiol/química , Etinilestradiol/metabolismo , Feminino , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Tensoativos/administração & dosagem , Tensoativos/química , Tensoativos/metabolismo
15.
Eur J Contracept Reprod Health Care ; 23(4): 245-254, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30203681

RESUMO

PURPOSE: To identify at least one contraceptive vaginal ring that effectively inhibits ovulation and demonstrates cycle control that is non-inferior to NuvaRing® (Merck Sharp & Dohme B.V., The Netherlands) in terms of an unscheduled bleeding incidence, with a non-inferiority margin of 10%. METHODS: This was a randomised, active controlled, parallel group, multicentre, partially blinded trial in healthy women 18-35 years of age. Subjects received one of six contraceptive vaginal rings with an average daily release rate of 300 µg 17ß-estradiol (E2) and various rates of either etonogestrel (ENG; 75, 100, or 125 µg/day) or nomegestrol acetate (NOMAC; 500, 700, or 900 µg/day), or the active control NuvaRing® (ENG/ethinylestradiol 120/15 µg), for three 28-day cycles. RESULTS: Ovulation inhibition was observed in all groups as confirmed by absence of progesterone concentrations compatible with ovulation (>16 nmol/L) and absence of ultrasound evidence of ovulation. All investigational rings provided good cycle control, with the ENG-E2 125/300 µg/day group being associated with the best cycle control based on the numerically lowest incidence of unscheduled bleeding and absence of scheduled bleeding. Non-inferiority to NuvaRing® with respect to the incidence of unscheduled bleeding could not be concluded for any of the investigational ring groups. The safety profile was consistent with the known safety profile of combined estrogen/progestin contraceptives and similar across all groups. CONCLUSIONS: Contraceptive rings releasing 300 µg E2 and 75-125 µg/day of ENG or 500-900 µg/day of NOMAC provided adequate ovulation inhibition and cycle control and are generally well-tolerated. While non-inferiority to NuvaRing® was not met, among the investigational rings, the ENG-E2 125/300 ring provided the best cycle control.


Assuntos
Desogestrel/análogos & derivados , Estradiol , Etinilestradiol , Ciclo Menstrual/efeitos dos fármacos , Inibição da Ovulação/efeitos dos fármacos , Adulto , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Dispositivos Anticoncepcionais Femininos , Desogestrel/administração & dosagem , Desogestrel/efeitos adversos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Estrogênios Conjugados (USP)/administração & dosagem , Estrogênios Conjugados (USP)/efeitos adversos , Etinilestradiol/administração & dosagem , Etinilestradiol/efeitos adversos , Feminino , Humanos
16.
Am J Physiol Heart Circ Physiol ; 315(4): H925-H933, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29906227

RESUMO

Hypertension, obesity, and endothelial function predict cardiovascular disease in women, and these factors are interrelated. We hypothesized that hypertension and obesity are associated with endothelial dysfunction in young women and that short-term ethinyl estradiol exposure mitigates this dysfunction. We examined flow-mediated dilation (FMD) responses before and during 7 days of oral ethinyl estradiol (30 µg/day) in 19 women (25 ± 5, 18-35 yr). We divided our sample into two groups based on two criteria: blood pressure and obesity. Women were divided into normal blood pressure (NBP; mean arterial pressure range: 78-91 mmHg, n = 7) and high blood pressure (HBP; mean arterial pressure range: 95-113 mmHg, n = 9) groups. We also stratified our subjects by body composition (lean: 18-31%, n = 8; obese: 38-59%, n = 9). We evaluated brachial FMD after two distinct shear stress stimuli: occlusion alone and occlusion with ischemic handgrip exercise. Obesity was unrelated to both FMD responses. Before ethinyl estradiol administration, the HBP group had blunted ischemic exercise responses relative to the NBP group (8.0 ± 3.5 vs. 12.3 ± 3.2%, respectively, P = 0.05). However, during ethinyl estradiol administration, ischemic exercise responses increased in the HBP group (12.8 ± 6.1%, P = 0.04) but decreased in the NBP group (5.6 ± 2.4%, P = 0.01). Standard FMD did not reveal differences between groups. In summary, 1) moderate HBP predicted endothelial impairment, 2) ethinyl estradiol administration had divergent effects on FMD in women with NBP versus HBP, and 3) enhanced FMD (ischemic handgrip exercise) revealed differences in endothelial function, whereas standard FMD (occlusion alone) did not. NEW & NOTEWORTHY We are the first to show that mild hypertension is a stronger predictor of endothelial dysfunction than obesity in healthy women without overt cardiovascular dysfunction. Importantly, the standard 5-min flow-mediated vasodilation stimulus did not detect endothelial dysfunction in our healthy population; only an enhanced ischemic handgrip exercise shear stress stimulus detected endothelial impairment. Estradiol administration increased flow-mediated dilation in women with high blood pressure, so it may be a therapeutic intervention to improve endothelial function.


Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Arterial/efeitos dos fármacos , Artéria Braquial/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Etinilestradiol/administração & dosagem , Hipertensão/tratamento farmacológico , Obesidade/tratamento farmacológico , Vasodilatadores/administração & dosagem , Adiposidade , Administração Oral , Adolescente , Adulto , Anti-Hipertensivos/efeitos adversos , Artéria Braquial/fisiopatologia , Esquema de Medicação , Endotélio Vascular/fisiopatologia , Etinilestradiol/efeitos adversos , Teste de Esforço , Feminino , Força da Mão , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Isquemia/fisiopatologia , Obesidade/diagnóstico , Obesidade/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/efeitos adversos , Adulto Jovem
17.
Taiwan J Obstet Gynecol ; 57(3): 411-416, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29880175

RESUMO

OBJECTIVE: This study was designed to evaluate the effects of 3 mg drospirenone/30 µg ethinyl estradiol (OC) alone or combined with 1700 mg metformin on metabolic risk factors. MATERIALS AND METHODS: In this randomized, prospective, controlled study, 87 non-obese (18-30 BMI) women of reproductive age (18-39) with polycystic ovary syndrome (PCOS) were assigned to control (n = 17), OC (n = 21), combination (n = 20) and metformin (n = 29) therapy groups. RESULTS: Adiponectin levels changed -28.27%, -20.37% and 35.78% after OC, combination and metformin therapies, respectively. High sensitive C-reactive protein levels (hsCRP) changed with OC, combination and metformin therapies by 102.32%, 3.2% and -7.14%, respectively. Plasminogen activator inhibitor-1 levels decreased 41.34% in the metformin group. Apolipoprotein-B levels changed in a manner similar to changes in hsCRP levels. The homeostatic model insulin resistance index changed significantly between the groups following treatment (p = 0.001). CONCLUSION: Six cycles of treatments with OC alone may cause metabolic variables to deteriorate in non-obese women with PCOS. The addition of metformin to OC may ameliorate some aspects of this effect.


Assuntos
Apolipoproteínas B/efeitos dos fármacos , Glicemia/metabolismo , Proteína C-Reativa/efeitos dos fármacos , Resistência à Insulina , Fragmentos de Peptídeos/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Androstenos/administração & dosagem , Apolipoproteínas B/metabolismo , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Quimioterapia Combinada , Etinilestradiol/administração & dosagem , Feminino , Homocisteína/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Síndrome Metabólica/prevenção & controle , Metformina/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Fragmentos de Peptídeos/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Síndrome do Ovário Policístico/complicações , Substâncias para o Controle da Reprodução/administração & dosagem , Fatores de Risco , Adulto Jovem
18.
Clin Pharmacol Ther ; 104(6): 1229-1239, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29637542

RESUMO

Current formulations of combined oral contraceptives (COC) containing ethinylestradiol (EE) have ≤35 µg due to increased risks of cardiovascular diseases (CVD) with higher doses of EE. Low-dose formulations however, have resulted in increased incidences of breakthrough bleeding and contraceptive failure, particularly when coadministered with inducers of cytochrome P450 enzymes (CYP). The developed physiologically based pharmacokinetic model quantitatively predicted the effect of CYP3A4 inhibition and induction on the pharmacokinetics of EE. The predicted Cmax and AUC ratios when coadministered with voriconazole, fluconazole, rifampicin, and carbamazepine were within 1.25 of the observed data. Based on published clinical data, an AUCss value of 1,000 pg/ml.h was selected as the threshold for breakthrough bleeding. Prospective application of the model in simulations of different doses of EE (20 µg, 35 µg, and 50 µg) identified percentages of the population at risk of breakthrough bleeding alone and with varying degrees of CYP modulation.


Assuntos
Simulação por Computador , Anticoncepcionais Orais Hormonais/farmacocinética , Etinilestradiol/farmacocinética , Ciclo Menstrual/efeitos dos fármacos , Modelos Biológicos , Biotransformação , Doenças Cardiovasculares/induzido quimicamente , Eficácia de Contraceptivos , Anticoncepcionais Orais Hormonais/administração & dosagem , Anticoncepcionais Orais Hormonais/efeitos adversos , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Etinilestradiol/administração & dosagem , Etinilestradiol/efeitos adversos , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Medição de Risco , Fatores de Risco
19.
Climacteric ; 21(3): 276-279, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29488818

RESUMO

OBJECTIVE: To report a case series of in vitro fertilization patients with premature ovarian insufficiency, who were treated with oral contraceptives to reduce follicle stimulating hormone levels. METHOD: This was a consecutive case series in a tertiary teaching hospital in China. Twenty-two women with refractory and idiopathic premature ovarian insufficiency were administered a drospirenone/ethinylestradiol oral contraceptive orally. The main outcome measures were the number of oocytes retrieved and the number of embryos frozen. RESULTS: There were total 106 oral contraceptive treatment cycles and 53 oocyte retrieval cycles in 20 patients (91%, 20/22; 2.4 cycles per woman, 53/22). The total number of oocytes retrieved was 48 in 17 patients (77%, 17/22; 2.2 oocytes per woman, 48/22), and the total number of embryos frozen was 33 in 16 patients (73%, 16/22; 1.5 embryos per woman, 33/22). CONCLUSION: Oral contraception may be an effective method to induce ovulation for some patients with premature ovarian insufficiency.


Assuntos
Androstenos/administração & dosagem , Anticoncepcionais Orais/administração & dosagem , Etinilestradiol/administração & dosagem , Fertilização In Vitro , Indução da Ovulação/métodos , Insuficiência Ovariana Primária/tratamento farmacológico , Adulto , China , Feminino , Hospitais de Ensino , Humanos , Infertilidade Feminina/tratamento farmacológico , Menopausa Precoce , Recuperação de Oócitos , Insuficiência Ovariana Primária/complicações , Estudos Retrospectivos
20.
Fertil Steril ; 109(4): 720-727, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29525688

RESUMO

OBJECTIVE: To evaluate the prevalence of adverse pregnancy outcomes in healthy Chinese women and to investigate whether these outcomes could be decreased in patients with polycystic ovary syndrome (PCOS) by ethinylestradiol/cyproterone acetate (EE/CPA) pretreatment. DESIGN: Retrospective study. SETTING: Medical university. PATIENT(S): Six thousand healthy women (group A) were selected from 24,566 pregnant women by randomized sampling. Four hundred forty-eight patients with PCOS without EE/CPA pretreatment were assigned to group B, and 222 patients with PCOS with 3 months of pretreatment to group C. All patients with PCOS had biochemical and/or clinical hyperandrogenism and conceived within 3 monthly ovulation inductions using clomiphene. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), premature delivery (PD), and neonatal birth weight. RESULT(S): The prevalence of GDM, PIH, and PD was higher in group B than in groups A and C (A vs. B vs. C: GDM, 21.2% vs. 35.0% vs. 22.5%; PIH, 6.5% vs. 14.1% vs. 7.7%; PD, 5.4% vs. 8.6% vs. 6.8%). No significant difference was found in neonatal birth weight. After adjusting for age, pregestational body mass index, education level, and employment status, PCOS without pretreatment increased the risk of GDM (adjusted odds ratio [aOR] = 1.666; 95% confidence interval [CI], 1.340-2.072), PIH (aOR = 1.487; 95% CI, 1.093-2.023), and PD (aOR = 1.522; 95% CI 1.051-2.205), compared with healthy women. No increased risk was found in group C. CONCLUSION(S): In our highly selected study population, patients with PCOS are more likely to develop GDM, PIH, and PD. Pretreatment with EE/CPA was associated with a lower risk of GDM, PIH, and PD.


Assuntos
Antagonistas de Androgênios/efeitos adversos , Clomifeno/administração & dosagem , Acetato de Ciproterona/efeitos adversos , Etinilestradiol/efeitos adversos , Fármacos para a Fertilidade Feminina/administração & dosagem , Infertilidade Feminina/terapia , Síndrome do Ovário Policístico/tratamento farmacológico , Complicações na Gravidez/induzido quimicamente , Adulto , Antagonistas de Androgênios/administração & dosagem , Peso ao Nascer , China/epidemiologia , Clomifeno/efeitos adversos , Acetato de Ciproterona/administração & dosagem , Diabetes Gestacional/induzido quimicamente , Diabetes Gestacional/epidemiologia , Combinação de Medicamentos , Etinilestradiol/administração & dosagem , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Humanos , Hipertensão Induzida pela Gravidez/induzido quimicamente , Hipertensão Induzida pela Gravidez/epidemiologia , Recém-Nascido , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/epidemiologia , Infertilidade Feminina/fisiopatologia , Indução da Ovulação/efeitos adversos , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/fisiopatologia , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/epidemiologia , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/epidemiologia , Prevalência , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Tempo para Engravidar , Resultado do Tratamento , Adulto Jovem
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