ABSTRACT
This bioequivalence research aims to evaluate the relative bioavailability and pharmacokinetic characteristics of ethinyl estradiol and drospirenone in the test preparation in comparison to the reference preparation during fasting conditions. A liquid chromatography method with tandem mass spectrometry was used to determine the concentrations of drospirenone and ethinyl estradiol in plasma. The pharmacokinetic parameters that were analyzed were the maximum plasma concentration (Cmax), time to achieve Cmax (tmax), elimination half life, and area under the concentration time curve of plasma (AUC0-t, AUC0-∞ for ethinyl estradiol, and AUC0-72h for drospirenone). Both the AUC and Cmax parameters were determined to be between 80.00% and 125.00% (90% confidence intervals), which is the acceptable range. Based on the study findings, it was concluded that the test formulation, which includes 3 mg of drospirenone and 0.03 mg of ethinyl estradiol, demonstrated bioequivalence when compared to the reference formulation.
Subject(s)
Androstenes , Area Under Curve , Ethinyl Estradiol , Fasting , Tablets , Therapeutic Equivalency , Humans , Ethinyl Estradiol/pharmacokinetics , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/blood , Female , Androstenes/pharmacokinetics , Androstenes/administration & dosage , Adult , Young Adult , Cross-Over Studies , Biological Availability , Healthy Volunteers , Drug Combinations , Tandem Mass Spectrometry/methods , Half-LifeABSTRACT
The patient, an 83-year-old woman, was diagnosed with ER- and PgR-positive left breast cancer(T2N0M0, Stage â ¡A) at the age of 68. At the time, she underwent preoperative chemotherapy followed by Bp+Ax and postoperative radiotherapy to the conserved breast. She also received endocrine therapy as adjuvant therapy. At the age of 73, she underwent radiotherapy for multiple bone metastases and left axillary lymphadenectomy due to left axillary lymph node recurrence. After surgery, she received 4 regimens of endocrine therapy over a period of 5 years and 1 month for bone metastases. At the age of 79, S-1 was administered for pulmonary metastasis which continued for the next 2 years and 8 months. At the age of 81, palbociclib+letrozole were administered for 1 year and 8 months owing to the progression of bone metastases. At the age of 83, she developed liver metastases and was administered ethinyl estradiol, starting at 1.5 mg/day and continued at a reduced dose of 0.5 mg/day for 9 months. The reduction in tumor markers after treatment initiation was rapid, and there were no serious adverse events. Ethinyl estradiol was useful for maintaining QOL in this elderly patient with recurrent breast cancer.
Subject(s)
Breast Neoplasms , Ethinyl Estradiol , Recurrence , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/therapeutic use , Aged, 80 and over , Receptors, Estrogen/analysis , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Receptors, Progesterone/metabolismABSTRACT
Endometriosis is one of the most frequent gynecologic disorders. The pathognomonic symptom of endometriosis is pelvic pain. The recommended pain medications are oral hormonal contraceptives, progestin therapy, danazol, gonadotropin-releasing hormone analogs, nonsteroidal anti-inflammatory drugs, and aromatase inhibitors. In this study, we aimed to compare the efficiency of costing dienogest (DNG) and low-cost oral contraceptives regarding visual analog scores (VAS) score of pelvic pain and also cancer antigen-125 (CA-125), anti-Mullerian hormone (AMH) levels, and size of endometrioma in the patients with endometriosis which is a chronic disease that requires a lifelong management plan. In our study, 18 to 45-year-old patients presented to our institution's gynecology and obstetrician department for various complaints over 2 years, and endometriosis diagnoses were included. Patients were divided into 3 groups (20 patients in each medication group) according to the given medication: cyclic DNG (Visanne) or 0.03 mg ethinylestradiol combined with 2 mg DNG (Dienille) or estradiol valerate combined with 2 mg DNG (Qlarista). We recorded all patients' CA-125/AMH values and VAS scores of pelvic pain. All patients gave informed consent. There was no statistically significant difference between pre-medication and post-medication levels of CA-125, AMH, VAS score, and cyst size in all groups. However, statistically, significant decreases were seen in the cyst size and VAS score, indicating response to therapy in all groups. In conclusion, we think it is more reasonable to use cost-effective oral contraceptive medications, which also cause common side effects, instead of costing DNG since all drugs have the same efficiency and success.
Subject(s)
Endometriosis , Estradiol , Ethinyl Estradiol , Nandrolone , Pain Measurement , Pelvic Pain , Humans , Female , Endometriosis/drug therapy , Endometriosis/complications , Nandrolone/analogs & derivatives , Nandrolone/therapeutic use , Nandrolone/administration & dosage , Adult , Prospective Studies , Pelvic Pain/drug therapy , Pelvic Pain/etiology , Ethinyl Estradiol/therapeutic use , Ethinyl Estradiol/administration & dosage , Estradiol/analogs & derivatives , Estradiol/therapeutic use , Middle Aged , Drug Combinations , CA-125 Antigen/blood , Young Adult , Anti-Mullerian Hormone/blood , AdolescentABSTRACT
PURPOSE: To evaluate the initial impact of a combined oral contraceptive (COC) containing norgestimate (NGM) on female sexuality and on circulating androgen levels in users. MATERIALS AND METHODS: Six months modification in the McCoy Female Sexuality Questionnaire (MFSQ) and testosterone (T) and dehydroepiandrosterone sulphate (DHEAS) serum levels in women starting a monophasic pill containing ethinyl-estradiol (EE) 35 µg and NGM 0.250 mg. RESULTS: The study was completed by 36 subjects. There was a significant increase in MFSQ during treatment (p < 0.0001) (and its domains with the exclusion of vaginal lubrication domain) with concomitant decreases in T (-4.45%, p < 0.0001) and DHEAS (-19.41%, p < 0.0001) serum levels. CONCLUSIONS: Contraception with EE/NGM was associated with a short term non-deteriorating effect on sexuality despite the evident decrease in androgen levels. Female sexuality during COC use is a complex topic and is not only linked with changes in serum androgen levels.
EE/NGM treatment has a short term non-deteriorating effect on sexuality despite the evident decrease in androgen serum levels.
Subject(s)
Contraceptives, Oral, Combined , Ethinyl Estradiol , Testosterone , Humans , Female , Pilot Projects , Ethinyl Estradiol/pharmacology , Ethinyl Estradiol/administration & dosage , Adult , Testosterone/blood , Contraceptives, Oral, Combined/pharmacology , Dehydroepiandrosterone Sulfate/blood , Androgens/blood , Sexuality/drug effects , Nandrolone/analogs & derivatives , Nandrolone/pharmacology , Surveys and Questionnaires , Young Adult , Norgestrel/analogs & derivativesABSTRACT
We compared the efficacy of 4 mg drospirenone (DRSP) progestin-only pills (POPs) versus combined oral contraceptive pills (COCs) containing 0.02 mg of ethinyl estradiol (EE) and 0.075 mg of gestodene (GS) in ovulation inhibition and inducing unfavorable cervical mucus changes using a delayed-starting approach. This randomized controlled trial involved 36 participants aged 18-45 years. The major outcomes included ovulation inhibition assessed using the Hoogland and Skouby score, and cervical mucus permeability, assessed using the modified World Health Organization score. The results demonstrated ovulation inhibition rates of 77.8% for the EE/GS group and 88.9% for the DRSP group. The risk ratio and absolute risk reduction were 0.50 (95% confidence interval [CI]: 0.10, 2.40) and - 0.11 (95% CI: - 0.35, 0.13), respectively, satisfying the 20% non-inferiority margin threshold. The median time to achieve unfavorable cervical mucus changes was comparable between the DRSP (3 days, interquartile range [IQR]: 6 days) and EE/GS (3.5 days, IQR: 4 days) groups. However, the DRSP group had a higher incidence of unscheduled vaginal bleeding (55.56% vs. 11.11%; p = 0.005). DRSP-only pills, initiated on days 7-9 of the menstrual cycle, were non-inferior to EE/GS pills in ovulation inhibition. However, they exhibited delayed unfavorable cervical mucus changes compared to the standard two-day backup recommendation.Clinical trial registration: Thai Clinical Trials Registry (TCTR20220819001) https://www.thaiclinicaltrials.org/show/TCTR20220819001 .
Subject(s)
Androstenes , Contraceptives, Oral, Combined , Ethinyl Estradiol , Ovulation Inhibition , Humans , Female , Adult , Ethinyl Estradiol/administration & dosage , Androstenes/administration & dosage , Androstenes/adverse effects , Young Adult , Adolescent , Contraceptives, Oral, Combined/administration & dosage , Ovulation Inhibition/drug effects , Single-Blind Method , Middle Aged , Norpregnenes/administration & dosage , Norpregnenes/adverse effects , Ovulation/drug effects , Cervix Mucus/drug effectsABSTRACT
Oral contraceptive pills, of all types, are used by approximately 151 million women worldwide; however, a clear understanding of the concentrations of endogenous and exogenous hormones across a 28-day combination monophasic oral contraceptive pill pack is not well described. In our study of 14 female participants taking various combination monophasic oral contraceptive pills, we found significant fluctuations in endogenous and exogenous hormone levels throughout the pill cycle. Our analysis revealed significantly greater levels of ethinyl estradiol on the 20th and 21st days of active pill ingestion, compared with days 1-2 (active) and days 27-28 (inactive pill ingestion). Conversely, estradiol concentrations decreased during active pill consumption, while progestin and progesterone levels remained stable. During the 7 days of inactive pill ingestion, estradiol levels rose sharply and were significantly higher at days 27-28 compared with the mid and late active phase time points, while ethinyl estradiol declined and progestin did not change. These findings challenge the previous assumption that endogenous and exogenous hormones are stable throughout the 28-day pill cycle.NEW & NOTEWORTHY The results from this study have wide-ranging implications for research and treatment in women's health including considerations in research design and interpretation for studies including women taking oral contraceptives, the potential for more precise and personalized methods of dosing to reduce unwanted side effects and adverse events, and the potential treatment of a variety of disorders ranging from musculoskeletal to neurological with exogenous hormones.
Subject(s)
Contraceptives, Oral, Combined , Estradiol , Ethinyl Estradiol , Menstrual Cycle , Progesterone , Tandem Mass Spectrometry , Humans , Female , Adult , Contraceptives, Oral, Combined/administration & dosage , Tandem Mass Spectrometry/methods , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/blood , Progesterone/blood , Menstrual Cycle/drug effects , Menstrual Cycle/blood , Young Adult , Estradiol/blood , Chromatography, Liquid/methods , Progestins/blood , Progestins/administration & dosage , Contraceptives, Oral, Hormonal/administration & dosageABSTRACT
This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.
Subject(s)
Contraceptives, Oral, Combined , Ethinyl Estradiol , Levonorgestrel , Midazolam , Humans , Midazolam/pharmacokinetics , Midazolam/administration & dosage , Ethinyl Estradiol/pharmacokinetics , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/adverse effects , Female , Adult , Male , Young Adult , Contraceptives, Oral, Combined/administration & dosage , Contraceptives, Oral, Combined/pharmacokinetics , Levonorgestrel/pharmacokinetics , Levonorgestrel/administration & dosage , Levonorgestrel/adverse effects , Drug Interactions , Drug Combinations , Healthy Volunteers , Adolescent , Cytochrome P-450 CYP3A/metabolism , Middle Aged , Area Under Curve , Cytochrome P-450 CYP3A Inducers/administration & dosage , Cytochrome P-450 CYP3A Inducers/pharmacologyABSTRACT
The endothelin A receptor antagonist zibotentan, combined with the sodium-glucose co-transporter-2 inhibitor dapagliflozin, is being investigated for the treatment of chronic kidney disease with high proteinuria. To allow women of childbearing potential access to this treatment, highly effective contraception is required and drug interactions compromising contraception reliability must be avoided. This study investigated the risk of pharmacokinetic (PK) interaction between zibotentan and the contraceptives ethinyl estradiol and levonorgestrel. A single-sequence, within-participant comparison study was conducted in 24 healthy women of non-childbearing potential, comparing the PK of ethinyl estradiol/levonorgestrel alone and with zibotentan. Single oral doses of 0.06 mg ethinyl estradiol/0.3 mg levonorgestrel were administered on Days 1 and 15; zibotentan 10 mg was dosed orally, once-daily through Days 6-19. PK profiles were determined and ethinyl estradiol/levonorgestrel PK was compared between Day 1 and 15 based on geometric least-squares mean ratios of PK parameters, including maximum observed concentration (Cmax) and area under the plasma concentration-time curve from zero to infinity (AUCinf). Co-administration with zibotentan did not affect ethinyl estradiol PK (geometric mean ratio [90% confidence interval] Cmax 1.05 [0.99-1.11], AUCinf 1.00 [0.96-1.05]), while a weak interaction (increased exposure) was observed for levonorgestrel (Cmax 1.12 [1.02-1.23], AUCinf 1.30 [1.21-1.39]), which was regarded as without clinical relevance. Plasma exposure of ethinyl estradiol/levonorgestrel was not reduced by multiple-dose zibotentan. In conclusion, contraception containing ethinyl estradiol/levonorgestrel is regarded possible under zibotentan-containing treatments. This expands choices for women of childbearing potential, supporting diversity in the ZENITH High Proteinuria trial.
Subject(s)
Contraceptives, Oral, Combined , Drug Interactions , Ethinyl Estradiol , Levonorgestrel , Humans , Female , Ethinyl Estradiol/pharmacokinetics , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/adverse effects , Levonorgestrel/pharmacokinetics , Levonorgestrel/administration & dosage , Levonorgestrel/adverse effects , Adult , Young Adult , Contraceptives, Oral, Combined/pharmacokinetics , Contraceptives, Oral, Combined/administration & dosage , Drug Combinations , Endothelin A Receptor Antagonists/pharmacokinetics , Endothelin A Receptor Antagonists/administration & dosage , Area Under CurveABSTRACT
Glecaprevir/pibrentasvir (GLE/PIB) is an approved guideline-recommended chronic hepatitis C virus infection treatment. GLE/PIB coadministration with ethinyl oestradiol (EE) is not recommended in current labels owing to a Phase 1 study observing Grade ≥2 alanine aminotransferase (ALT) elevation in 2 out of 12 healthy women cotreated for 11 days with GLE/PIB and oral contraceptive (OC) containing 35 µg/250 µg EE/norgestimate. No Grade ≥2 elevation was observed with low-dose (20 µg) EE (n = 14). This Phase 1 study examined safety/tolerability of GLE/PIB coadministered with an OC containing low-dose EE using a larger sample size and longer treatment duration. Healthy premenopausal women were treated with EE/levonorgestrel alone (20/100 µg, Cycles 1-2), followed by coadministration with GLE/PIB (300/120 mg; Cycles 3-4). A safety criterion of special interest was a confirmed Grade ≥2 ALT elevation (>3× upper normal limit). Adverse events (AEs) and study drugs concentrations were examined. Of 85 enrolled women, 72 initiated combined GLE/PIB + EE/levonorgestrel treatment, 66 completed the study and 19 discontinued prematurely (non-safety reason, n = 16; AE [deemed unelated to GLE/PIB], n = 3). No participant met the safety criterion of special interest of confirmed Grade ≥2 ALT elevation. No serious/Grade ≥3 AEs were reported. Study drug concentrations were within the expected ranges. GLE/PIB in combination with an OC containing low-dose EE was generally well tolerated with no confirmed Grade ≥2 ALT elevation and no evidence of drug-induced liver injury. No pattern to the reported AEs and no new safety issues were identified. This was a Phase 1 study of healthy volunteers, not a registered clinical trial.
Subject(s)
Antiviral Agents , Benzimidazoles , Ethinyl Estradiol , Healthy Volunteers , Premenopause , Pyrrolidines , Quinoxalines , Sulfonamides , Humans , Female , Adult , Benzimidazoles/adverse effects , Benzimidazoles/administration & dosage , Quinoxalines/adverse effects , Quinoxalines/administration & dosage , Ethinyl Estradiol/adverse effects , Ethinyl Estradiol/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Young Adult , Pyrrolidines/adverse effects , Pyrrolidines/administration & dosage , Middle Aged , Contraceptives, Oral/adverse effects , Contraceptives, Oral/administration & dosage , Alanine Transaminase/blood , Aminoisobutyric Acids , Leucine/analogs & derivatives , Leucine/adverse effects , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug CombinationsABSTRACT
AIMS: The current work describes the development of mechanistic vaginal absorption and metabolism model within Simcyp Simulator to predict systemic concentrations following vaginal application of ring and gel formulations. METHODS: Vaginal and cervix physiology parameters were incorporated in the model development. The study highlights the model assumptions including simulation results comparing systemic concentrations of 5 different compounds, namely, dapivirine, tenofovir, lidocaine, ethinylestradiol and etonogestrel, administered as vaginal ring or gel. Due to lack of data, the vaginal absorption parameters were calculated based on assumptions or optimized. The model uses release rate/in vitro release profiles with formulation characteristics to predict drug mass transfer across vaginal tissue into the systemic circulation. RESULTS: For lidocaine and tenofovir vaginal gel, the predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits. The average fold error (AFE) and absolute AFE indicating bias and precision of predictions range from 0.62 to 1.61. For dapivirine, the pharmacokinetic parameters are under and overpredicted in some studies due to lack of formulation composition details and relevance of release rate used in ring model. The predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits for etonogestrel and ethinylestradiol vaginal ring (AFEs and absolute AFEs from 0.84 to 1.83). CONCLUSION: The current study provides first of its kind physiologically based pharmacokinetic framework integrating physiology, population and formulation data to carry out in silico mechanistic vaginal absorption studies, with the potential for virtual bioequivalence assessment in the future.
Subject(s)
Computer Simulation , Contraceptive Devices, Female , Models, Biological , Tenofovir , Vagina , Vaginal Absorption , Vaginal Creams, Foams, and Jellies , Female , Humans , Vaginal Creams, Foams, and Jellies/administration & dosage , Vaginal Creams, Foams, and Jellies/pharmacokinetics , Tenofovir/pharmacokinetics , Tenofovir/administration & dosage , Vagina/metabolism , Vagina/drug effects , Administration, Intravaginal , Ethinyl Estradiol/pharmacokinetics , Ethinyl Estradiol/administration & dosage , Desogestrel/administration & dosage , Desogestrel/pharmacokinetics , Pyrimidines/pharmacokinetics , Pyrimidines/administration & dosage , Adult , Area Under Curve , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/administration & dosageABSTRACT
Estradiol and progesterone potentiate and attenuate reward processes, respectively. Despite these well-characterized effects, there is minimal research on the effects of synthetic estrogens (e.g., ethinyl estradiol, or EE) and progestins (e.g., levonorgestrel, or LEVO) contained in clinically-utilized hormonal contraceptives. The present study characterized the separate effects of repeated exposure to EE or LEVO on responding maintained by a reinforcing visual stimulus. Forty ovary-intact female Sprague-Dawley rats received either sesame oil vehicle (n = 16), 0.18 µg/day EE (n = 16), or 0.6 µg/day LEVO (n = 8) subcutaneous injections 30-min before daily one-hour sessions. Rats' responding was maintained by a 30-sec visual stimulus on a Variable Ratio-3 schedule of reinforcement. The day after rats' last session, we determined rats estrous cycle phase via vaginal cytology before sacrifice and subsequently weighing each rat's uterus to further verify the contraceptive hormone manipulation. The visual stimulus functioned as a reinforcer, but neither EE nor LEVO enhanced visual stimulus maintained responding. Estrous cytology was consistent with normal cycling in vehicle rats and halting of normal cycling in EE and LEVO rats. EE increased uterine weights consistent with typical uterotrophic effects observed with estrogens, further confirming the physiological impacts of our EE and LEVO doses. In conclusion, a physiologically effective dose of neither EE nor LEVO did not alter the reinforcing efficacy of a visual stimulus reinforcer. Future research should characterize the effects of hormonal contraceptives on responding maintained by other reinforcer types to determine the generality of the present findings.
Subject(s)
Ethinyl Estradiol , Levonorgestrel , Rats, Sprague-Dawley , Animals , Female , Ethinyl Estradiol/pharmacology , Ethinyl Estradiol/administration & dosage , Levonorgestrel/pharmacology , Levonorgestrel/administration & dosage , Rats , Reinforcement, Psychology , Photic Stimulation/methods , Ovary/drug effects , Estrous Cycle/drug effectsABSTRACT
PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.
Subject(s)
Bupropion , Cytochrome P-450 CYP2B6 , Cytochrome P-450 CYP2C8 , Cytochrome P-450 CYP3A , Drug Interactions , Midazolam , Staurosporine , Humans , Area Under Curve , Bupropion/pharmacokinetics , Bupropion/administration & dosage , Contraceptives, Oral/administration & dosage , Contraceptives, Oral/pharmacology , Contraceptives, Oral/pharmacokinetics , Cytochrome P-450 CYP2B6/metabolism , Cytochrome P-450 CYP2B6/genetics , Cytochrome P-450 CYP2C8/metabolism , Cytochrome P-450 CYP3A/metabolism , Drug Combinations , Ethinyl Estradiol/pharmacokinetics , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/pharmacology , Healthy Volunteers , Levonorgestrel/pharmacokinetics , Levonorgestrel/administration & dosage , Levonorgestrel/pharmacology , Midazolam/pharmacokinetics , Midazolam/administration & dosage , Pioglitazone/pharmacology , Pioglitazone/administration & dosage , Pioglitazone/pharmacokinetics , Staurosporine/analogs & derivatives , Staurosporine/pharmacology , Staurosporine/pharmacokinetics , Staurosporine/administration & dosage , Male , Female , Adolescent , Young Adult , Adult , Middle AgedABSTRACT
BACKGROUND/AIM: Ra-223 is a therapeutic agent for bone metastatic castration-resistant prostate cancer (mCRPC). We examined the efficacy of a treatment method using Ra-223 together with ethinylestradiol (EE). PATIENTS AND METHODS: Patients who received Ra-223 three or more times were included and two groups (with or without EE) were compared retrospectively. RESULTS: Eighteen patients were treated with Ra-223 and EE concomitantly (EstRadium therapy) and 13 patients were treated with Ra-223 alone or Ra-223 and agents other than EE (non-EstRadium therapy). The number of patients with decreased serum prostate-specific antigen level was significantly higher in the EstRadium therapy group than in the non-EstRadium therapy group (p=0.029). CONCLUSION: The combination of Ra-223 and EE, compared to Ra-223 alone, is an effective treatment option for bone mCRPC patients, in terms of PSA response.
Subject(s)
Bone Neoplasms/therapy , Chemoradiotherapy/methods , Ethinyl Estradiol/administration & dosage , Prostatic Neoplasms, Castration-Resistant/therapy , Radium/administration & dosage , Aged , Aged, 80 and over , Bone Neoplasms/blood , Bone Neoplasms/mortality , Bone Neoplasms/secondary , Case-Control Studies , Humans , Japan/epidemiology , Kallikreins/blood , Male , Middle Aged , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/mortality , Prostatic Neoplasms, Castration-Resistant/pathology , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
Combined oral contraceptive pills are the most commonly used hormonal contraceptives for the prevention of unintended pregnancies in United States. They consist of a progestin (e.g., levonorgestrel (LNG)) and an estrogen component, typically ethinyl estradiol (EE). In addition to adherence issues, drug-drug interactions (DDIs) and obesity (women with body mass index (BMI) ≥ 30 kg/m2 ) are prime suspects for decreased LNG efficacy. Therefore, we developed an integrated physiologically-based pharmacokinetic modeling and model-based meta-analysis approach to determine LNG's efficacy threshold concentrations and to evaluate the impact of DDIs and obesity on the efficacy of LNG-containing hormonal contraceptives (HCs). Based on this approach, co-administration of strong CYP3A4 inducers and LNG-containing HCs (LNG150: LNG 150 µg + EE 30 µg and LNG100: LNG 100 µg + EE 20 µg) resulted in a predicted clinically relevant decrease of LNG plasma exposure (women with BMI < 25 kg/m2 : 50-65%; obese women: 70-75%). Following administration of LNG150 or LNG100 in the presence of a CYP3A4 inducer, there was an increase in mean Pearl Index of 1.2-1.30 and 1.80-2.10, respectively, in women with BMI < 25 kg/m2 (incidence rate ratios (IRRs): 1.7-2.2), whereas it ranged from 1.6-1.80 and 2.40-2.85 in obese women (IRR: 2.2-3.0), respectively. Our results suggest that the use of backup or alternate methods of contraception is not necessarily required for oral LNG + EE formulations except within circumstances of both obesity and strong CYP3A4 inducer concomitance following administration of LNG100.
Subject(s)
Contraceptive Agents, Hormonal/administration & dosage , Contraceptives, Oral, Combined/administration & dosage , Contraceptives, Oral, Synthetic/administration & dosage , Ethinyl Estradiol/administration & dosage , Levonorgestrel/administration & dosage , Models, Biological , Body Mass Index , Contraceptive Agents, Hormonal/adverse effects , Contraceptive Agents, Hormonal/pharmacokinetics , Contraceptives, Oral, Combined/adverse effects , Contraceptives, Oral, Combined/pharmacokinetics , Contraceptives, Oral, Synthetic/adverse effects , Contraceptives, Oral, Synthetic/pharmacokinetics , Cytochrome P-450 CYP3A Inducers/adverse effects , Dose-Response Relationship, Drug , Drug Combinations , Drug Interactions , Ethinyl Estradiol/adverse effects , Ethinyl Estradiol/pharmacokinetics , Female , Humans , Levonorgestrel/adverse effects , Levonorgestrel/pharmacokinetics , Obesity/physiopathology , Pregnancy , Pregnancy, Unplanned , Risk Assessment , Risk FactorsABSTRACT
OBJECTIVE: Polycystic ovary syndrome (PCOS) is an endocrinological and metabolic disorder widely diffused and diagnosed in women of reproductive age. The pathology exhibits alteration of the reproductive functions, including conditions as hyperandrogenism, menstrual cycle irregularity, type 2 diabetes. These conditions are visible in the patients through phenotypical manifestations as hirsutism, acne, and obesity. Even if the syndrome is characterized by common features among both adult and adolescent women, the diagnostic criteria are different for the two age categories and to date still controversial. We investigated different treatments in PCOS adolescents with non-severe metabolic conditions, to evaluate which could be the appropriate therapeutical approach for these patients. PATIENTS AND METHODS: We enrolled lean teenagers with PCOS, and we divided the patients in two age ranges: 13-16 years old and 17-19 years old. They were treated for 3 months either with oral contraceptive pills (OCP) drospirenone/ethinylestradiol (group A), myo-Inositol (myo-Ins) (group B), or OCP plus myo-Ins (group C). Data were analyzed with a descriptive statistics summarizing quantitative variables including median, 25th and 75th percentiles. RESULTS: We pointed out that the group of 13-16 years old lean teenagers treated with myo-Ins exhibit a significant decrease of weight and body mass index (BMI), and an effective improvement the metabolic and hormonal parameters achieved with a non-pharmacological treatment. In the older teenagers aged 17-19 years, data highlights that myo-Ins treatment in combination with OCP prevents the increases of weight and BMI, improves the metabolic profile of the patients, and strongly ameliorates the hormonal parameters analyzed. CONCLUSIONS: The results indicate a different scenario in the two age ranges considered and interestingly suggest an important role of myo-Ins in the PCOS context. A therapy based on this natural compound alone or in combination with OCP seems effective to improve both metabolic and hormonal parameters of PCOS adolescents and thus could represent a novel and valid option to consider for the treatment of this syndrome.
Subject(s)
Androstenes/administration & dosage , Contraceptives, Oral/administration & dosage , Ethinyl Estradiol/administration & dosage , Inositol/administration & dosage , Polycystic Ovary Syndrome/drug therapy , Adolescent , Age Factors , Body Mass Index , Female , Follow-Up Studies , Humans , Polycystic Ovary Syndrome/physiopathology , Thinness , Young AdultABSTRACT
This study evaluated such as exposure to ethinylestradiol during the prenatal (18th-22nd day) and pubertal (42nd-49th day) periods acts on the male ventral prostate and female prostate of 12-month old gerbils. We performed the analysis to serum hormone levels for estradiol and testosterone. The prostates were submitted to morphometric and immunohistochemical analyses. Exposure to ethinylestradiol during these developmental periods decreased the testosterone serum levels in males and increased the estradiol serum levels in females. Morphologically, prostate intraepithelial neoplasia and disorders in the arrangement of the fibrous components were observed in the prostate glands of both sexes of gerbil exposed to ethinylestradiol during development periods. In the male prostate, the ethinylestradiol promoted decreased in the frequency of positive epithelial cell for androgen receptor (AR) and increased the frequency of positive stromal cell for estrogen receptor α. However, in the female prostate, this synthetic estrogen caused AR upregulation and increased cell proliferation. This study shows that the exposure to ethinylestradiol during development phases alters the morphology and the hormonal signaling in the male and female prostates of old gerbils, confirming the action of ethinylestradiol as endocrine disruptor.
Subject(s)
Epithelial Cells/cytology , Ethinyl Estradiol/pharmacology , Prenatal Exposure Delayed Effects/pathology , Prostate/anatomy & histology , Animals , Animals, Newborn , Cell Proliferation , Epithelial Cells/drug effects , Estrogens/pharmacology , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/toxicity , Female , Gerbillinae , Male , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Prostate/drug effectsABSTRACT
Lemborexant is a dual orexin receptor antagonist approved in multiple countries including the United States, Canada, and Japan for the treatment of insomnia in adults. As women of childbearing potential may be prescribed insomnia drugs, a drug-drug interaction study was conducted. This single-center, open-label, fixed-sequence study examined potential drug-drug interactions between lemborexant and an oral contraceptive (OC) in healthy females (18-44 years, n = 20). The purpose of this study was to determine the effect of lemborexant 10 mg (at steady state) on the pharmacokinetics of a single dose of OC (0.03 mg ethinyl estradiol and 1.5 mg norethindrone acetate), assess the effect of a single dose of OC on lemborexant pharmacokinetics, and evaluate safety and tolerability of lemborexant and OC coadministration. Ethinyl estradiol maximum plasma drug concentration was not altered by lemborexant coadministration; area under the curve from zero time to the last quantifiable concentration was slightly increased, by 13%. No clinically relevant effects on norethindrone acetate pharmacokinetics were observed. Coadministration of OC with lemborexant had no clinically relevant effect on the steady-state pharmacokinetics of lemborexant. Adverse events were consistent with the known safety profile. These results support the conclusion that lemborexant and OC can be coadministered without dose adjustment.
Subject(s)
Ethinyl Estradiol/administration & dosage , Norethindrone/administration & dosage , Pyridines/administration & dosage , Pyrimidines/administration & dosage , Adolescent , Adult , Area Under Curve , Contraceptives, Oral, Combined/administration & dosage , Contraceptives, Oral, Combined/pharmacokinetics , Contraceptives, Oral, Combined/pharmacology , Drug Interactions , Ethinyl Estradiol/pharmacokinetics , Ethinyl Estradiol/pharmacology , Female , Humans , Norethindrone/pharmacokinetics , Norethindrone/pharmacology , Orexin Receptor Antagonists/administration & dosage , Orexin Receptor Antagonists/pharmacokinetics , Orexin Receptor Antagonists/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Young AdultABSTRACT
BACKGROUND: This study aims to assess the therapeutic effects of a well-known component (puerarin) obtained from a Chinese herb root in patients with polycystic ovary syndrome (PCOS). METHODS: Women with premature ovarian failure (POF) were assigned to the obese group (body mass index [BMI] ≥24âkg/m2 and waist hip ratio [WHR] >0.85) or non-obese group (group 3, nâ=â21). Obese patients were further randomly assigned to the obese treatment group (group 1, nâ=â15) and obese control group (group 1, nâ=â15). All patients received standard treatment (Diane-35, 1âtablet/d, orally, plus metformin, 1.5âg/d, orally). In addition to the standard modality, patients in group 1 and group 3 also orally received 150âmg/d of puerarin tablets for 3 months. Venous blood was drawn before and after treatment. Then, the metabolic and antioxidant biomarkers were measured. The normality of distribution of the data was tested using the Kolmogorov-Smirnov method. The baseline characteristics were analyzed using one-factor analysis of variance (ANOVA), and post-hoc was performed using the least significance difference (LSD)-t test. RESULTS: Significantly improved blood levels of sex hormone binding globulin (SHBG) and superoxide dismutase (SOD) were observed in patients who received the additional treatment of puerarin, regardless of their lean or obese status, while these were not observed in patients who did not receive puerarin. Furthermore, obese patients with PCOS had significantly lower systolic blood pressure, total cholesterol, and testosterone blood levels, when compared with before treatment. CONCLUSION: The addition of puerarin to the present treatment protocol can be considered for the management of metabolic disorders and hyperandrogenism in PCOS patients.
Subject(s)
Isoflavones/administration & dosage , Obesity/drug therapy , Polycystic Ovary Syndrome/drug therapy , Primary Ovarian Insufficiency/drug therapy , Administration, Oral , Adolescent , Adult , China , Cholesterol/blood , Cyproterone Acetate/administration & dosage , Drug Administration Schedule , Drug Combinations , Drug Therapy, Combination/methods , Ethinyl Estradiol/administration & dosage , Female , Humans , Metformin/administration & dosage , Obesity/blood , Obesity/complications , Obesity/metabolism , Polycystic Ovary Syndrome/blood , Polycystic Ovary Syndrome/complications , Polycystic Ovary Syndrome/metabolism , Primary Ovarian Insufficiency/blood , Primary Ovarian Insufficiency/etiology , Primary Ovarian Insufficiency/metabolism , Sex Hormone-Binding Globulin/analysis , Superoxide Dismutase/blood , Tablets , Testosterone/blood , Treatment Outcome , Young AdultABSTRACT
PROBLEM: Changes in sex hormones during the menstrual cycle and contraceptive vaginal ring (CVR) use influence immunity within the female genital tract, but the magnitude of these effects and their anatomical location are unclear. METHOD OF STUDY: In a prospective study, 29 women were assessed at three-time points: follicular phase, luteal phase, and one month after initiation of the ethinyl estradiol/etonogestrel CVR (NuvaRing®, Merck). We performed microarrays on endocervical cytobrushes and measured immune mediators in cervicovaginal fluid, adjusting for bacterial vaginosis and the presence of blood. We compared these results to public gene expression data from the fallopian tubes, endometrium, endo- and ectocervix, and vagina. RESULTS: Immune-related gene expression in the endocervix and immune mediators in cervicovaginal fluid increased during CVR use versus both menstrual phases, and in the follicular versus luteal phase. The antimicrobial protein granulysin was high during CVR use, intermediate in the follicular phase, and nearly absent from the luteal phase. Re-analysis of public gene expression data confirmed increased immune-related gene expression in the endocervix during the follicular phase. However, in the fallopian tube, endometrium, and vagina, the follicular phase showed immunosuppression. CONCLUSIONS: Immune-related genes in the cervicovaginal tract were highest during CVR use, intermediate in the follicular phase, and lowest in the luteal phase. Granulysin is a potential biomarker of menstrual phase: Frequently detected in follicular samples, but rare in luteal. Lastly, immunological differences between the follicular and luteal phases vary throughout the female genital tract.
Subject(s)
Antigens, Differentiation, T-Lymphocyte/immunology , Contraceptive Agents, Female/administration & dosage , Contraceptive Devices, Female , Desogestrel/administration & dosage , Ethinyl Estradiol/administration & dosage , Immunity, Mucosal/drug effects , Menstrual Cycle , Adult , Female , Humans , Menstrual Cycle/drug effects , Menstrual Cycle/immunology , Middle AgedABSTRACT
Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses' Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65-0.91]; >10 years of use, 0.43 [0.32-0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (> 5 years) of ethinyl estradiol (0.52 [0.41-0.67]) and second-generation progestins (0.43 [0.30-0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50-0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49-0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (< vs. ≥ median; ever use vs. never OC use), with the exception of high estrogen and low progestin dose. OCs were associated with lower endometrial cancer risk, independent of time since last use. Use of ethinyl estradiol and second-generation progestins were more strongly inversely associated with risk compared with older formulations.