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1.
Eur J Drug Metab Pharmacokinet ; 47(1): 49-56, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34635989

RESUMO

BACKGROUND AND OBJECTIVES: As the prevalence of some gynecological conditions depends on patient characteristics such as race/ethnicity, it is important to study therapies for these conditions in diverse populations. The study described in this article was conducted to investigate the safety, tolerability, and pharmacokinetics of vilaprisan, a selective progesterone receptor modulator, in Japanese women in Japan. It supplements two comparable studies that were conducted in healthy postmenopausal European and Chinese women, respectively. METHODS: In this exploratory randomized, placebo-controlled, double-blind, ascending-dose study, five groups of healthy postmenopausal Japanese women received vilaprisan as immediate-release tablets (1, 5, or 15 mg as a single dose or 1 or 5 mg/day for 28 days) or placebo tablets (single dosing: 8 subjects/dose step, thereof 2 subjects randomized to placebo; multiple dosing: 12 subjects/dose step, thereof 4 subjects randomized to placebo). Blood samples for pharmacokinetic profiles were collected over 14-19 days. Safety assessments were based on adverse event data, vital signs, electrocardiograms, clinical laboratory tests, and transvaginal ultrasound examinations. RESULTS: 48 participants were randomized, treated, and analyzed. Vilaprisan was rapidly absorbed, reaching maximum plasma concentrations (Cmax) between 1 and 3 h post dose. Post maximum, plasma concentrations rapidly declined, indicating pronounced distribution into tissues. The exposure of vilaprisan increased roughly dose-proportionally: The geometric mean (geometric coefficients of variation) areas under the concentration time curves from time zero to infinity (AUC∞) after single administration of 1, 5, or 15 mg vilaprisan were 67 µg·h/l (34%), 249 µg·h/l (15%), and 788 µg·h/l (37%), respectively. The AUC in the dosing interval after multiple administrations (AUC24,md) of 1 mg/day was 76 µg·h/l (59%), and the AUC24,md after 5 mg/day was 311 µg·h/l (20%). Geometric mean Cmax values also increased roughly dose-proportionally: They amounted to 6 µg/l (22%), 16 µg/l (33%), and 52 µg/l (27%) after single administration and to 8 µg/l (28%) and 31 µg/l (22%) after multiple administrations of the above doses. Mild adverse events were observed, similar to those observed in other clinical studies of vilaprisan. CONCLUSIONS: Overall, vilaprisan was safe and well tolerated. The exposure in Japanese women was similar to that observed in European and Chinese women in separate studies. TRIAL REGISTRATION: 15 Nov 2011 (no registration number assigned).


Assuntos
Pós-Menopausa , Congêneres da Progesterona/farmacocinética , Esteroides/farmacocinética , Administração Oral , Idoso , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Congêneres da Progesterona/administração & dosagem , Congêneres da Progesterona/sangue , Receptores de Progesterona/metabolismo , Esteroides/administração & dosagem , Esteroides/sangue
3.
Biochem Biophys Res Commun ; 533(4): 1027-1033, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33012509

RESUMO

Antiretroviral therapy has slowed the HIV/AIDS pandemic and is currently being used as a prophylactic measure for individuals at high risk of infection. However, concerns over adverse effects of long-term use need to be explored. We hypothesize that this may occur, at least in part, through off-target effects via select steroid receptors (SRs) that broadly regulate multiple physiological processes. We investigated the effects of maraviroc (MVC), tenofovir disoproxil fumarate (TDF), and dapivirine (DPV) on progesterone receptor B (PR-B) transcriptional activity. We found that MVC and TDF activate PR-B transcription in the absence of progestogens on a PR-regulated promoter reporter construct and on endogenous PR-regulated genes. MVC and TDF exhibited no direct binding to PR-B; however, increased PR-B phosphorylation was detected with TDF but not MVC. DPV transactivated gilz and ptgs2 in the absence of progestogens and exhibited PR-B binding while showing no effects on phosphorylation, suggesting that it may activate PR-B through a direct mechanism. Our study shows that potential off-target immunomodulatory effects of MVC, TDF and DPV occur in vitro and these are most likely mediated by different mechanisms of PR-B activation.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Maraviroc/efeitos adversos , Pirimidinas/efeitos adversos , Receptores de Progesterona/agonistas , Tenofovir/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Ligação Competitiva , Linhagem Celular , Contraceptivos Hormonais/farmacocinética , Contraceptivos Hormonais/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1 , Humanos , Fatores Imunológicos/efeitos adversos , Técnicas In Vitro , Levanogestrel/farmacocinética , Levanogestrel/farmacologia , Maraviroc/farmacocinética , Fosforilação , Congêneres da Progesterona/farmacocinética , Congêneres da Progesterona/farmacologia , Pirimidinas/farmacocinética , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Tenofovir/farmacocinética , Ativação Transcricional/efeitos dos fármacos
4.
J Vet Pharmacol Ther ; 42(6): 660-664, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31222770

RESUMO

Altrenogest, a synthetic progestogen, is characterized by its estrus synchronization in mares, ewes, sows, and gilts. To investigate the pharmacokinetic profile and evaluate its accumulation in gilts, 18 oral doses of 20 mg altrenogest/gilt/day were given to eight healthy gilts at an interval of 24 hr. Plasma samples were collected, and altrenogest was determined by ultra-high-performance liquid chromatography with mass spectrometry. WinNonlin 6.4 software was used to calculate the pharmacokinetic parameters through noncompartmental model analysis. After the first administration (D 1), the pharmacokinetic parameters, including Tmax , Cmax , and the elimination half-life (T1/2λz ), were similar to those observed after the final administration (D 18). However, the mean residence time at D 1 was significantly lower than D 18. As a whole, the mean steady-state plasma concentration (Css ), degree fluctuation (DF), accumulation factor (Rac ), and area under the plasma concentration-time curve in steady state (AUCss ) were 22.69 ± 6.15 ng/ml, 270.64 ± 42.51%, 1.53 ± 0.23, and 544.63 ± 147.49 ng hr/ml, respectively. These results showed that after 18 consecutive days of oral administration of altrenogest, plasma concentrations of altrenogest had a certain degree of fluctuation, without significant accumulations.


Assuntos
Congêneres da Progesterona/farmacocinética , Suínos/sangue , Acetato de Trembolona/análogos & derivados , Administração Oral , Animais , Área Sob a Curva , Feminino , Meia-Vida , Congêneres da Progesterona/sangue , Acetato de Trembolona/administração & dosagem , Acetato de Trembolona/sangue , Acetato de Trembolona/farmacocinética
5.
Aust Vet J ; 94(7): 248-55, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27349885

RESUMO

OBJECTIVE: To investigate the efficacy and safety of the long-acting altrenogest injection (NV Readyserve® injection) for horses. DESIGN: A single-dose pharmacokinetic (PK) study was conducted. The in vivo efficacy study was a blinded, repeated measures design evaluating behaviour scores. The safety study was a non-blinded, controlled, parallel-group, randomised-block design as per the VICH protocol. METHODS: In the PK study, serial blood samples were obtained for analysis of plasma altrenogest for 150 h following the injection and a non-compartmental PK analysis was performed. For the efficacy study, 12 mares in oestrus were treated; they were monitored daily for 10 days for signs of oestrus during teasing and given a behaviour score that was compared with pretreatment scores. A standard safety study was conducted at 1-, 3- and 5-fold the recommended dosage for 84 days. Physical, haematological and biochemical examinations were performed. RESULTS: Mean plasma altrenogest concentrations were greater than ≈0.5 ng/mL for 148 h following administration. Oestrous behaviour was suppressed in all mares within 24 h of administration. Two mares returned to oestrus by day 6 and the rest on days 7-10. In the safety study there were no significant differences in the physical and haematological examinations, but minor biochemical changes in muscle enzymes. There was a low incidence of injection site reactions following the 3- and 5-fold dose, predominantly for pectoral injections. CONCLUSION: These studies support the efficacy and safety of a single dose of Readyserve® injection for the suppression of the signs of oestrus in mares for 5-7 days.


Assuntos
Estro/efeitos dos fármacos , Cavalos/fisiologia , Congêneres da Progesterona/farmacocinética , Acetato de Trembolona/análogos & derivados , Animais , Feminino , Injeções Intramusculares/veterinária , Progesterona/sangue , Congêneres da Progesterona/efeitos adversos , Congêneres da Progesterona/farmacologia , Acetato de Trembolona/efeitos adversos , Acetato de Trembolona/farmacocinética , Acetato de Trembolona/farmacologia
6.
Contraception ; 93(2): 133-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26365792

RESUMO

OBJECTIVE: Nomegestrol acetate (NOMAC), a selective progestogen, and 17ß-estradiol (E2), which is identical to endogenous oestrogen, are components of a new monophasic combined oral contraceptive--NOMAC/E2. This study aimed to compare pharmacokinetics (PK) of NOMAC in adolescent and adult women following a single dose of NOMAC/E2. STUDY DESIGN: Healthy postmenarcheal adolescent (14-17years) and adult (18-50years) women received a single dose of NOMAC/E2 (2.5mg/1.5mg) in this single-centre, open-label, parallel-group Phase 1 study (EudraCT# 2008-002142-38). Blood samples were obtained for PK analysis, and concentrations of NOMAC, E2 and its metabolite estrone (E1) were determined for up to 129h following dosing to obtain PK data. An independent whole-body physiology-based pharmacokinetic (WB-PBPK) simulation model of NOMAC based on an independent Phase 3 dataset was used to scale NOMAC concentration-time plots to adolescents. RESULTS: Overall, 52 women were screened, of whom 30 (15 adolescents and 15 adults) were enrolled. No statistically significant differences were observed between the adolescent and adult groups for the clinically evaluated NOMAC PK parameters [maximum concentration (Cmax), area under the curve (AUC) and half-life (t1/2)]. The PK of E2 and E1 showed extensive overlap between both age groups. The WB-PBPK model accurately predicted NOMAC AUC and Cmax values in both groups. CONCLUSIONS: No differences were observed in the clinically evaluated PK parameters for NOMAC between adolescent and adult women after a single dose of NOMAC/E2. The WB-PBPK model accurately predicted NOMAC PK data (EudraCT# 2008-002142-38). IMPLICATIONS: PK studies in adolescents are challenging because of ethical considerations. The whole-body physiology-based model described here complements classic noncompartmental and population PK approaches. The utility of this method is its ability to expand to adolescent postmenarcheal girls by using virtual postmenarcheal adolescent population data and applying physiological scaling.


Assuntos
Fatores Etários , Anticoncepcionais Orais Combinados/administração & dosagem , Estradiol/administração & dosagem , Megestrol/farmacocinética , Modelos Biológicos , Norpregnadienos/farmacocinética , Congêneres da Progesterona/farmacocinética , Adolescente , Adulto , Estradiol/sangue , Estradiol/farmacocinética , Estrona/sangue , Feminino , Meia-Vida , Humanos , Megestrol/administração & dosagem , Megestrol/sangue , Pessoa de Meia-Idade , Norpregnadienos/administração & dosagem , Norpregnadienos/sangue , Adulto Jovem
7.
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
8.
Endocr Rev ; 34(2): 171-208, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23238854

RESUMO

The safety of progestogens as a class has come under increased scrutiny after the publication of data from the Women's Health Initiative trial, particularly with respect to breast cancer and cardiovascular disease risk, despite the fact that only one progestogen, medroxyprogesterone acetate, was used in this study. Inconsistency in nomenclature has also caused confusion between synthetic progestogens, defined here by the term progestin, and natural progesterone. Although all progestogens by definition have progestational activity, they also have a divergent range of other properties that can translate to very different clinical effects. Endometrial protection is the primary reason for prescribing a progestogen concomitantly with postmenopausal estrogen therapy in women with a uterus, but several progestogens are known to have a range of other potentially beneficial effects, for example on the nervous and cardiovascular systems. Because women remain suspicious of the progestogen component of postmenopausal hormone therapy in the light of the Women's Health Initiative trial, practitioners should not ignore the potential benefits to their patients of some progestogens by considering them to be a single pharmacological class. There is a lack of understanding of the differences between progestins and progesterone and between individual progestins differing in their effects on the cardiovascular and nervous systems, the breast, and bone. This review elucidates the differences between the substantial number of individual progestogens employed in postmenopausal hormone therapy, including both progestins and progesterone. We conclude that these differences in chemical structure, metabolism, pharmacokinetics, affinity, potency, and efficacy via steroid receptors, intracellular action, and biological and clinical effects confirm the absence of a class effect of progestogens.


Assuntos
Terapia de Reposição de Estrogênios/métodos , Congêneres da Progesterona/farmacocinética , Receptores de Esteroides/metabolismo , Terapia de Reposição de Estrogênios/normas , Feminino , Humanos , Pós-Menopausa , Congêneres da Progesterona/uso terapêutico , Relação Estrutura-Atividade
9.
Clin Drug Investig ; 32(6): 413-22, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22540269

RESUMO

BACKGROUND: The etonogestrel (ENG)-releasing implant is a subdermal progestogen-only contraceptive that provides coverage for up to 3 years. This long-acting hormonal contraceptive has been available in Europe since 1998 and in the US since 2006. To date, localization of non-palpable implants at insertion and before removal has been dependent on ultrasound or magnetic resonance imaging by an experienced clinician. To facilitate localization in rare cases of non-palpable implants using widely available equipment without the need for a specialist, a radiopaque ENG implant has been developed that is detectable by two-dimensional x-ray imaging. OBJECTIVE: This study aimed to establish whether the radiopaque ENG implant is bioequivalent in situ compared with the original non-radiopaque ENG implant, and to assess x-ray visibility of the radiopaque ENG implant. METHODS: This was a 3-year, randomized, double-blind, parallel-group study carried out in nine international clinical trial centres. Women aged 18-40 years at the time of screening, with menstrual cycles of a usual length of 24-35 days and a body mass index of between ≥18 and ≤29 kg/m(2) were included. Women were assigned to either the radiopaque or non-radiopaque ENG implant in a 1 : 1 ratio via a block randomization by centre. Bioequivalence testing was performed based on the peak ENG concentration (C(max)), and the area under the curve (AUC) for ENG at 6, 24 and 36 months (AUC(6 mo), AUC(24 mo) and AUC(36 mo)) after insertion. For this purpose, blood sampling for pharmacokinetic determination was performed prior to insertion and for up to 3 years afterwards. Bioequivalence was defined as the 90% confidence interval (CI) of the ratio radiopaque implant/non-radiopaque implant of the geometric means (GMR) within the acceptance range of 0.80-1.25. x-Ray visibility was assessed by two-dimensional x-ray imaging after insertion and before removal of the implant. RESULTS: The pharmacokinetic profiles of ENG indicated that the radiopaque and non-radiopaque implants were bioequivalent with respect to the geometric mean of C(max) (GMR 1.06; 90% CI 0.91, 1.23), AUC(6 mo) (GMR 1.00; 90% CI 0.91, 1.10), AUC(24 mo) (GMR 0.98; 90% CI 0.88, 1.10) and AUC(36 mo) (GMR 1.00; 90% CI 0.89, 1.11). The radiopaque ENG implant was clearly visible in 50 out of 52 women after insertion and in all 52 women before removal, whereas none of the non-radiopaque implants were visible. CONCLUSION: The radiopaque ENG implant is bioequivalent in situ compared with the original non-radiopaque ENG implant and is clearly visible using x-ray imaging. CLINICAL TRIALS REGISTRATION: Registered as ClinicalTrials.gov identifier NCT00620464.


Assuntos
Anticoncepcionais Femininos/uso terapêutico , Desogestrel/uso terapêutico , Implantes de Medicamento , Congêneres da Progesterona/uso terapêutico , Adolescente , Adulto , Área Sob a Curva , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Desogestrel/administração & dosagem , Desogestrel/farmacocinética , Método Duplo-Cego , Humanos , Congêneres da Progesterona/administração & dosagem , Congêneres da Progesterona/farmacocinética , Equivalência Terapêutica , Adulto Jovem
10.
Steroids ; 76(7): 636-52, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21414337

RESUMO

Synthetic progestins are used by millions of women as contraceptives and in hormone replacement therapy (HRT), although their molecular mechanisms of action are not well understood. The importance of investigating these mechanisms, as compared to those of progesterone, has been highlighted by clinical evidence showing that medroxyprogesterone acetate (MPA), a first generation progestin, increases the risk of breast cancer and coronary heart disease in HRT users. A diverse range of later generation progestins with varying structures and pharmacological properties is available for therapeutic use and it is becoming clear that different progestins elicit beneficial and adverse effects to different extents. These differences in biological activity are likely to be due to many factors including variations in dose, metabolism, pharmacokinetics, bioavailability, and regulation of, and/or binding, to serum-binding proteins and steroidogenic enzymes. Since the intracellular effects on gene expression and cell signaling of steroids are mediated via intracellular steroid receptors, differential actions via the progesterone and other steroid receptors and their isoforms, are likely to be the major cause of differential intracellular actions of progestins. Since many progestins bind not only to the progesterone receptor, but also to the glucocorticoid, androgen, mineralocorticoid, and possibly the estrogen receptors, it is plausible that synthetic progestins exert therapeutic actions as well as side-effects via some of these receptors. Here we review the molecular mechanisms of intracellular actions of old (MPA, norethisterone, levonorgestrel, gestodene) vs. new (drospirenone, dienogest, trimegestone) generation progestins, via steroid receptors.


Assuntos
Anticoncepção/métodos , Terapia de Reposição Hormonal/métodos , Congêneres da Progesterona/uso terapêutico , Receptores de Esteroides/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Congêneres da Progesterona/química , Congêneres da Progesterona/farmacocinética , Congêneres da Progesterona/farmacologia
11.
Steroids ; 76(6): 531-9, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21335021

RESUMO

Nomegestrol acetate (NOMAC) is a potent, highly selective progestogen, which is structurally similar to 19-norprogesterone and characterized as a full agonist at the progesterone receptor, with no or minimal binding to other steroid receptors, including the androgen and glucocorticoid receptors. In animal models, NOMAC demonstrated moderate antiandrogenic activity and strong antiestrogenic activity. In clinical studies, the progestogen was associated with effective suppression of gonadotropic activity and ovulation in premenopausal women, and a neutral impact on hemostasis, lipids, and carbohydrate metabolism. In normal and cancerous human breast tissue, NOMAC has shown favorable effects on estrogen metabolism, and in human breast cancer cell lines in vitro, it does not stimulate cell proliferation. The pharmacologic profile of NOMAC suggested that it would be well suited for combination with a physiologic estrogen in a combined oral contraceptive (COC), with the aim of achieving effective contraception with good cycle control and a favorable safety profile. A monophasic COC containing NOMAC 2.5mg and 17ß-estradiol (E2) 1.5mg, administered in a 24/4-day regimen, is currently under clinical investigation. In a phase III study, NOMAC/E2 provided consistent and robust ovulation inhibition, with contraceptive effects that compared favorably with those of drospirenone 3mg/ethinyl estradiol (EE) 30 µg. Investigators for a second phase III study reported less overall impact with NOMAC/E2 on hemostatic, lipid, inflammatory, and carbohydrate metabolism parameters than with levonorgestrel 150 µg/EE 30 µg. These clinical findings are promising; however, full publication of results from the pivotal phase III trials of NOMAC/E2 is pending.


Assuntos
Anticoncepcionais Orais Sintéticos/farmacologia , Megestrol/farmacologia , Norpregnadienos/farmacologia , Congêneres da Progesterona/farmacologia , Anticoncepcionais Orais Sintéticos/efeitos adversos , Anticoncepcionais Orais Sintéticos/farmacocinética , Endométrio/anatomia & histologia , Endométrio/efeitos dos fármacos , Endométrio/fisiologia , Estrogênios/metabolismo , Feminino , Humanos , Megestrol/efeitos adversos , Megestrol/farmacocinética , Norpregnadienos/efeitos adversos , Norpregnadienos/farmacocinética , Ovulação/efeitos dos fármacos , Congêneres da Progesterona/efeitos adversos , Congêneres da Progesterona/farmacocinética , Receptores de Esteroides/metabolismo , Tromboembolia Venosa/induzido quimicamente
12.
Drugs ; 70(5): 541-59, 2010 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-20329803

RESUMO

This review summarizes the pharmacology, safety and clinical efficacy of nomegestrol acetate, based on the available published literature, and assesses the pharmacological characteristics that underlie a role in different gynaecological disorders and hormone replacement therapy (HRT), and a potential role in combination estrogen/progestogen oral contraception. Nomegestrol acetate is a potent, orally active progestogen with a favourable tolerability profile and neutral metabolic characteristics. Unlike the majority of older progestogens, which were 19-nortestosterone derivatives synthesized primarily for their antigonadotropic activity as a component of hormonal contraception in combination with an estrogen, nomegestrol acetate is a 19-norprogesterone derivative designed to bind specifically to the progesterone receptor, and is relatively lacking in affinity for other steroid receptors. Nomegestrol acetate exerts strong antiestrogenic effects at the level of the endometrium and has potent antigonadotropic activity, but without any residual androgenic or glucocorticoid properties. At a dosage of 1.25 mg/day, nomegestrol acetate inhibits ovulation while permitting follicle growth, whereas at dosages of 2.5 or 5 mg/day, both ovulation and follicle development are suppressed. The antigonadotropic action of nomegestrol acetate is mediated, like other progestins, at the hypothalamic and pituitary level. Moreover, nomegestrol acetate has partial antiandrogenic activity. Absorption of nomegestrol acetate is rapid after oral administration, reaching a peak serum concentration within 4 hours, with a terminal half-life of approximately 50 hours. Nomegestrol acetate has been used successfully for the treatment of some gynaecological disorders (menstrual disturbances, dysmenorrhoea, premenstrual syndrome) and as a component of HRT in combination with estradiol for the relief of menopausal symptoms; it has been approved in Europe as monotherapy for the treatment of the menopausal syndrome, uterine diseases and menorrhagia, and in combination with an estrogen for the treatment of menopausal symptoms. In vitro data suggest that nomegestrol acetate preserves the beneficial haemostatic effects of estrogen; furthermore, nomegestrol acetate has a neutral or beneficial effect on lipid profiles, and does not adversely affect glucose metabolism or bodyweight. Nomegestrol acetate has shown a lack of profilerative activity in normal and cancerous breast tissue, and does not have a deleterious effect on bone remodelling. These potent antigonadotropic properties, and other beneficial metabolic and pharmacological characteristics, suggest that nomegestrol acetate can be an effective progestogen for use in combination with an estrogen in oral estrogen/progestogen contraceptive treatment and in HRT, while it also provides some non-contraceptive benefits for women's health.


Assuntos
Anticoncepcionais Orais Hormonais/uso terapêutico , Terapia de Reposição Hormonal/métodos , Megestrol/uso terapêutico , Norpregnadienos/uso terapêutico , Congêneres da Progesterona/uso terapêutico , Animais , Remodelação Óssea/efeitos dos fármacos , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/prevenção & controle , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Anticoncepcionais Orais Hormonais/efeitos adversos , Anticoncepcionais Orais Hormonais/farmacocinética , Hiperplasia Endometrial/induzido quimicamente , Hiperplasia Endometrial/prevenção & controle , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Megestrol/efeitos adversos , Megestrol/farmacocinética , Norpregnadienos/efeitos adversos , Norpregnadienos/farmacocinética , Congêneres da Progesterona/efeitos adversos , Congêneres da Progesterona/farmacocinética , Medição de Risco , Fatores de Risco , Tromboembolia/induzido quimicamente , Resultado do Tratamento
13.
Expert Opin Pharmacother ; 8(7): 989-99, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17472544

RESUMO

Drospirenone is a novel progestin available in combined oral contraceptives and menopausal hormonal therapy. Similar to its parent compound spirolactone, an analog of spironolactone, drospirenone has antimineralocorticoid and antiandrogenic activity. Combined with ethinyl estradiol in oral contraceptive formulations, drospirenone-containing contraceptives have similar efficacy and safety profiles to other low-dose oral contraceptives, but seem to offer improved tolerability with regard to weight gain, mood changes, acne and treatment of a severe form of premenstrual syndrome called premenstrual dysphoric disorder. Combined with estradiol as a continuous hormone therapy regimen, the compound was shown to reduce vasomotor symptoms, maintain bone mass, have a beneficial effect on body weight and, more importantly, was shown to lower blood pressure in postmenopausal women.


Assuntos
Androstenos/uso terapêutico , Anticoncepcionais Orais Combinados/uso terapêutico , Congêneres da Progesterona/uso terapêutico , Acne Vulgar/tratamento farmacológico , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Androgênios/farmacocinética , Antagonistas de Androgênios/uso terapêutico , Androstenos/efeitos adversos , Androstenos/farmacocinética , Animais , Ensaios Clínicos como Assunto , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Combinados/farmacocinética , Combinação de Medicamentos , Terapia de Reposição de Estrogênios , Etinilestradiol/uso terapêutico , Feminino , Humanos , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Síndrome Pré-Menstrual/tratamento farmacológico , Congêneres da Progesterona/efeitos adversos , Congêneres da Progesterona/farmacocinética
14.
J Vet Pharmacol Ther ; 30(1): 86-90, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17217407

RESUMO

The Federation Equestre Internationale has permitted the use of altrenogest in mares for the control of oestrus. However, altrenogest is also suspicious to misuse in competition horses for its potential anabolic effects and suppression of typical male behaviour, and thus is a controlled drug. To investigate the pharmacokinetics of altrenogest in horses we conducted an elimination study. Five oral doses of 44 mug/kg altrenogest were administered to 10 horses at a dose interval of 24 h. Following administration blood and urine samples were collected at appropriate intervals. Altrenogest concentrations were measured by liquid chromatography-tandem mass spectrometry. The plasma levels of altrenogest reached maximal concentrations of 23-75 ng/mL. Baseline values were achieved within 3 days after the final administration. Urine peak concentrations of total altrenogest ranged from 823 to 3895 ng/mL. Twelve days after the final administration concentrations were below the limit of detection (ca 2 ng/mL).


Assuntos
Cavalos/metabolismo , Congêneres da Progesterona/farmacocinética , Acetato de Trembolona/análogos & derivados , Administração Oral , Animais , Cromatografia Líquida/veterinária , Dopagem Esportivo/prevenção & controle , Masculino , Espectrometria de Massas/veterinária , Congêneres da Progesterona/administração & dosagem , Congêneres da Progesterona/sangue , Congêneres da Progesterona/urina , Reprodutibilidade dos Testes , Detecção do Abuso de Substâncias/veterinária , Acetato de Trembolona/administração & dosagem , Acetato de Trembolona/sangue , Acetato de Trembolona/farmacocinética , Acetato de Trembolona/urina
15.
Fertil Steril ; 85(1): 57-62, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16412731

RESUMO

OBJECTIVE: To compare uterine tissue concentrations of ethinyl estradiol (EE) and etonogestrel (ENG) after one cycle of use of a contraceptive vaginal ring (NuvaRing; NV Organon, Oss, The Netherlands) or a combined oral contraceptive (COC). DESIGN: Randomized, open-label, pharmacokinetic study. SETTING: Obstetrics and gynecology unit. PATIENT(S): Eight premenopausal women about to undergo hysterectomy but otherwise healthy. INTERVENTION(S): One cycle (17-21 days) of NuvaRing or COC treatment that ended with surgical hysterectomy. MAIN OUTCOME MEASURE(S): Tissue concentrations of EE and ENG in uterine tissue samples taken from the upper myometrium and mid-myometrium, the cervical region, and the endometrium. RESULT(S): In both groups, concentrations of EE and ENG were similar in uterine tissue taken from the upper myometrium and mid-myometrium and the cervical region. However, compared with the COC group, concentrations of both hormones were markedly lower in tissue samples from the endometrium of women who had been treated with NuvaRing. CONCLUSION(S): Vaginal administration of hormones with NuvaRing did not produce elevated uterine concentrations of EE and ENG, compared with an oral contraceptive.


Assuntos
Dispositivos Anticoncepcionais Femininos , Anticoncepcionais Orais Combinados/farmacocinética , Desogestrel/farmacocinética , Estrogênios/farmacocinética , Etinilestradiol/farmacocinética , Administração Intravaginal , Adulto , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/sangue , Desogestrel/administração & dosagem , Desogestrel/sangue , Estrogênios/administração & dosagem , Estrogênios/sangue , Etinilestradiol/administração & dosagem , Etinilestradiol/sangue , Feminino , Humanos , Histerectomia , Pessoa de Meia-Idade , Congêneres da Progesterona/administração & dosagem , Congêneres da Progesterona/sangue , Congêneres da Progesterona/farmacocinética , Distribuição Tecidual , Útero/cirurgia
16.
Drugs ; 63(5): 463-92, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12600226

RESUMO

Chlormadinone acetate, cyproterone acetate and dienogest are potent, orally active progestogens, which have antiandrogenic instead of partial androgenic activity. They act mainly by blocking androgen receptors in target organs, but also reduce the activity of skin 5alpha-reductase, the enzyme responsible for converting testosterone to the more potent androgen, 5alpha-dihydrotestosterone, in sebaceous glands and hair follicles. Chlormadinone acetate and cyproterone acetate also suppress gonadotropin secretion, thereby reducing ovarian and adrenal androgen production. Combined oral contraceptives (COCs) containing antiandrogenic progestogens provide highly effective contraception (gross and adjusted Pearl indices: 0-0.7 and 0-0.3, respectively) with excellent cycle control. Furthermore, COCs containing 2mg of chlormadinone acetate or cyproterone acetate plus 30 or 35 microg of ethinylestradiol produced improvement or resolution of seborrhoea in 80% of users, acne in 59-70%, hirsutism in 36% and androgen-related alopecia in up to 86%. These COCs are generally well tolerated, the main adverse effects being nonspecific or as expected for a COC (headache, breast tenderness and nausea). They have no clinically relevant effects on metabolic or liver functions or on bodyweight. Effects on mood and libido are uncommon (<3.5% and <6% of women, respectively). COCs containing antiandrogenic progestogens are likely to be particularly valuable in women with pre-existing androgen-related disorders who require contraception. They also increase the choice of products available for women with normal skin and hair who are concerned about the possibility of developing seborrhoea or acne with other COCs.


Assuntos
Antagonistas de Androgênios/farmacologia , Nandrolona/análogos & derivados , Congêneres da Progesterona/farmacologia , Progestinas/farmacologia , Inibidores de 5-alfa Redutase , Acne Vulgar/tratamento farmacológico , Alopecia/tratamento farmacológico , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Androgênios/farmacocinética , Animais , Acetato de Clormadinona/efeitos adversos , Acetato de Clormadinona/farmacocinética , Acetato de Clormadinona/farmacologia , Ensaios Clínicos como Assunto , Anticoncepcionais Orais Sintéticos/efeitos adversos , Anticoncepcionais Orais Sintéticos/farmacocinética , Anticoncepcionais Orais Sintéticos/farmacologia , Acetato de Ciproterona/efeitos adversos , Acetato de Ciproterona/farmacocinética , Acetato de Ciproterona/farmacologia , Dermatite Seborreica/tratamento farmacológico , Feminino , Hirsutismo/tratamento farmacológico , Humanos , Nandrolona/farmacocinética , Nandrolona/farmacologia , Congêneres da Progesterona/efeitos adversos , Congêneres da Progesterona/farmacocinética , Progestinas/efeitos adversos , Progestinas/farmacocinética , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/fisiologia
17.
J Clin Pharmacol ; 43(1): 52-8, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12520628

RESUMO

As part of the development of a combination product containing norethindrone acetate and low-dose ethinyl estradiol for continuous hormone replacement therapy in postmenopausal women, a study was conducted to determine the effect of a high-fat meal on the bioavailability of norethindrone and ethinyl estradiol from tablets containing 1 mg norethindrone acetate/10 micrograms ethinyl estradiol. Eighteen healthy postmenopausal women participated in an open-label, single-dose, randomized, three-way crossover study in which 2 x 1/10 norethindrone acetate/ethinyl estradiol tablets were administered fasting and with a high-fat breakfast, and the same dose was administered in solution. Following each treatment, serial blood samples were collected for 48 hours, and plasma ethinyl estradiol and norethindrone concentrations were determined by a validated gas chromatography/mass spectrometry (GC/MS) method. Individual plasma ethinyl estradiol and norethindrone pharmacokinetic parameters were calculated by noncompartmental methods for each treatment and analyzed by ANOVA to obtain differences between least squares treatment mean values and associated 90% confidence intervals. Rates of ethinyl estradiol and norethindrone availability from tablets administered with food were slower than availability rates from tablets administered while fasting. Systemic exposure to ethinyl estradiol was unaffected by administration of tablets with food, whereas exposure to norethindrone increased by 27%. Because administration of norethindrone acetate/ethinyl estradiol 1/10 tablets with a high-fat meal did not decrease systemic exposure to norethindrone and ethinyl estradiol, this formulation can be taken without regard to meals.


Assuntos
Congêneres do Estradiol/farmacocinética , Etinilestradiol/farmacocinética , Interações Alimento-Droga , Noretindrona/farmacocinética , Congêneres da Progesterona/farmacocinética , Idoso , Disponibilidade Biológica , Estudos Cross-Over , Terapia de Reposição de Estrogênios , Feminino , Humanos , Pessoa de Meia-Idade , Comprimidos
18.
Contraception ; 66(5): 357-64, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12443967

RESUMO

We have investigated the pharmacokinetics and effects on the male reproductive axis of a novel preparation of testosterone decanoate (TD) with a progestogen implant. Twenty healthy Chinese men were administered TD (400 mg intramuscular 4 weekly) with two subcutaneous (SC) etonogestrel implants. Trough testosterone concentrations rose with repeated administration. Peak concentrations 1 week after the fourth injection were 31 +/- 2 nmol/liter. Both LH and FSH were rapidly suppressed and continued to fall during treatment. Spermatogenesis was also suppressed, to

Assuntos
Anticoncepcionais Masculinos/farmacocinética , Desogestrel , Congêneres da Progesterona/farmacocinética , Espermatogênese/efeitos dos fármacos , Testosterona/análogos & derivados , Testosterona/farmacocinética , Compostos de Vinila/farmacocinética , Adulto , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Anticoncepcionais Masculinos/administração & dosagem , Anticoncepcionais Masculinos/farmacologia , Esquema de Medicação , Implantes de Medicamento , Hematócrito , Humanos , Injeções , Masculino , Congêneres da Progesterona/administração & dosagem , Congêneres da Progesterona/farmacologia , Contagem de Espermatozoides , Testosterona/administração & dosagem , Testosterona/sangue , Testosterona/farmacologia , Compostos de Vinila/administração & dosagem , Compostos de Vinila/farmacologia
19.
Steroids ; 67(13-14): 1045-55, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12441190

RESUMO

We describe the development of a serum chlormadinone acetate (CMA) time-resolved fluoroimmunoassay (TR-FIA). We prepared haptens (3-CMO-chlormadinone acetate and 6-chloropregna-4,6-dien-17,20-diol-3-one-20-hemisuccinate), biotinylated tracers (3(biotinylaminopropylamido) 3-CMO-chlormadinone acetate and 3-(6-chloropregna-4,6-dien-17,20-diol-3-one-20-hemisuccinylamino)1-biotinylaminopropane), and immunogens necessary for eliciting two antibodies (anti-chlormadinone acetate 3-CMO/BSA and anti-chlormadinone 20-hemisuccinate/BSA). The specificity of the assay was rigorously studied to eliminate possible interference by polar metabolites of CMA, particularly 17 alpha-acetoxy-6-chloro-3beta-hydroxypregna-4,6-diene-20-one (3beta-hydroxy metabolite), employing an easy-to-use ethylene glycol chromatographic step prior to immunoassay, so as to separate the polar metabolites, in particular the 3beta-hydroxy-CMA metabolite, from the intact CMA. The choice of the anti-CMA antibody was guided by the high assay sensitivity obtained with the anti-CMA 3-CMO/BSA antibody. The detection limit was 51pg/ml. Interassay reproducibility CVs were between 2.6 and 4.5%. This TR-FIA thus appeared to be a sensitive, specific, precise, and consequently well-suited method for measurement of serum CMA during a pharmacokinetic study in women.


Assuntos
Acetato de Clormadinona/sangue , Fluorimunoensaio/métodos , Menopausa/sangue , Acetato de Clormadinona/administração & dosagem , Acetato de Clormadinona/imunologia , Acetato de Clormadinona/farmacocinética , Anticoncepcionais Orais Sintéticos/administração & dosagem , Anticoncepcionais Orais Sintéticos/sangue , Anticoncepcionais Orais Sintéticos/farmacocinética , Terapia de Reposição de Estrogênios , Feminino , Fluorimunoensaio/normas , Humanos , Soros Imunes/imunologia , Menopausa/efeitos dos fármacos , Estrutura Molecular , Congêneres da Progesterona/administração & dosagem , Congêneres da Progesterona/sangue , Congêneres da Progesterona/farmacocinética , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
Eur J Contracept Reprod Health Care ; 7(2): 79-90, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12201326

RESUMO

This study investigated the pharmacokinetics of a dose-reduced oral contraceptive containing 20 microg ethinylestradiol (EE) + 100 microg levonorgestrel (LNG) in 18 young, healthy females. Serum levels of EE and LNG were determined after single and repeated daily oral administration over three treatment cycles, each consisting of 21 treatment days followed by a 7-day treatment-free period. Additionally, the time courses of sex hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and total and free testosterone serum levels were analyzed. Both active ingredients were rapidly absorbed and maximum concentrations in serum were reached between, on average, 1 and 2 h after single and multiple administrations, respectively. Concentrations of EE increased during repeated daily administration. An approximate two-fold accumulation was calculated based on the comparison of EE area under the curve (AUC) (0-24 h) values determined after the first and the last tablet administration within a treatment cycle. LNG serum concentrations also increased during repeated daily administration, reaching steady-state levels after about 11 days. Based on the comparison of AUC (0-24 h) values determined after the first and the last tablet administration, LNG accumulated approximately by a factor of 3 within a treatment cycle. Steady-state pharmacokinetics of LNG were similar at the end of the first and the third treatment cycles, indicating no further accumulation of LNG beyond a treatment cycle under long-term use of this combined oral contraceptive. The clearance and volume of distribution of LNG decreased and the terminal half-life increased after repeated daily administration, compared with single administration. These effects have also been reported for other LNG/EE combinations. SHBG serum concentrations increased during repeated daily intake by, on average, 1.5-1.6-fold, and for CBG, an average increase of 1.4-1.8-fold was found. Although free testosterone concentrations declined during repeated daily administration by about 40%, total testosterone remained relatively unchanged at a low level. In conclusion, the pharmacokinetics of EE and LNG determined in the present study were in good agreement with those previously reported for 30 microg EE + 150 microg LNG, taking the 33% dose reduction into account.


Assuntos
Anticoncepcionais Orais Sintéticos/farmacocinética , Etinilestradiol/farmacocinética , Levanogestrel/farmacocinética , Congêneres da Progesterona/farmacocinética , Adulto , Área Sob a Curva , Anticoncepcionais Orais Sintéticos/administração & dosagem , Relação Dose-Resposta a Droga , Etinilestradiol/administração & dosagem , Feminino , Meia-Vida , Humanos , Levanogestrel/administração & dosagem , Fígado/metabolismo , Congêneres da Progesterona/administração & dosagem , Albumina Sérica/metabolismo , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Fatores de Tempo
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