RESUMO
OBJECTIVES: This work evaluated chronic treatment with 17ß-oestradiol (E2) and 17ß-aminoestrogen pentolame (AEP) on prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), and fibrinogen concentration (FIB). Male (M) and ovariectomized (Ovx) Wistar rats were used to explore gender differences in the pharmacological response. MATERIALS AND METHODS: Rats (n=12-18) were treated every third day during three months with E2 (1, 10, 100 µg/kg), AEP (1, 10, 100, 500 µg/kg) or vehicle (propylenglycol 1 ml/ kg). PT, aPTT, TT, and FIB were measured using standardized techniques. RESULTS: Chronic treatment with E2 in male rats increased PT (4-7%; P<0.05), decreased aPTT (9%; 100 µg/kg; P<0.05) and decreased TT (5% at 100 µg/Kg; P<0.05). Chronic treatment with E2 in ovariectomized female rats decreased PT (3-4%; P<0.05), did not induce significant changes on aPTT and decreased TT in a dose dependent manner (12-27%; P<0.05). Chronic treatment with AEP in male rats did not alter PT, increased aPTT in a dose dependent manner (5-16%; P<0.05), and decreased TT (5%; 500 µg/Kg; P<0.05) while in female ovariectomized rats it decreased PT (5-9%; P<0.05), increased aPTT (8-13%; P<0.05) and decreased TT (6-13%; P<0.05). E2 and AEP decreased FIB in M and Ovx animals. Decreases in FIB by E2 were more pronounced in male (15-18% P<0.05) than in ovariectomized rats (10-14% P<0.05). E2 showed more potency than AEP, lowering FIB at 1 and 10 µg/kg doses. Both estrogens decreased FIB in ovariectomized animals (E2, 10-14%, P<0.05; AEP, 9% P<0.05) and were reverted by increasing dosage. CONCLUSIONS: Gender influenced response to chronic treatment with E2 and AEP on hemostatic parameters. PT and aPTT were the most affected parameters, demonstrating non-equivalence in the pharmacological response of M and Ovx rats.
Assuntos
Amino Álcoois/farmacologia , Congêneres do Estradiol/farmacologia , Estradiol/farmacologia , Estrenos/farmacologia , Estrogênios/farmacologia , Hemostasia/efeitos dos fármacos , Animais , Testes de Coagulação Sanguínea , Feminino , Masculino , Ovariectomia , Ratos , Ratos Wistar , Caracteres SexuaisRESUMO
BACKGROUND: Buame [17ß-(butylamino)-1,3,5(10)-estratrien-3-ol] possesses anticoagulant and antiplatelet activities that are potentially antithrombotic. Since its estrogenicity is unknown, it was evaluated by established methods. METHODS: Buame (10, 100, 500, and 1,000 µg/kg), 17ß-estradiol (E(2)) (100 µg/kg), or propylene glycol (10 ml/kg) were subcutaneously (sc) administered for three days to immature Wistar female rats (21 days old). The relative uterotrophic effect to E(2) was 78 (E(2) = 100) with a relative uterotrophic potency of 1.48 (E(2) = 100). Adult ovariectomized Wistar rats received an sc injection at 8:00 h (reversed cycle) of: 7.5 µg of E(2) (≈ 30 µg/kg), buame (≈ 750, 1,500, 3,000 µg/kg), or corn oil (≈ 1.2 ml/kg). After 24 h, progesterone (4-5 mg/kg) was administered. Sexual receptivity was assessed 5 to 7 h later, and the lordosis quotient (LQ; number lordosis/number mounts x 100) was evaluated. RESULTS: Buame induced lordosis (LQmax 85 ± 9; ED50 952 ± 19 µg/kg) and E(2) LQmax 56 ± 8; ED50 10 ± 2 µg/kg; the relative LQ-potency was 0.51 (E(2) = 100). Buame competed with [(3)H]E(2) for the estrogen receptor (Buame RBA= 0.15 and Ki = 5.9 x 10(-7) M; E(2) RBA= 100;Ki = 6.6 x 10(-9) M). Buame increased MCF-7 cells proliferation, from 10(-11) to 10(-)9 M, its proliferative effect was 1.73-1.79 (E(2) = 3.0-3.9); its relative proliferative effect to E(2) was 33-40% (E(2) = 100%) and relative potency 10.4-10.7 (E(2) = 100). Tamoxifen and fulvestrant (ICI 182,780) inhibited buame's proliferation indicating mediation through estrogen receptors in this response. CONCLUSION: Buame is therefore an estrogen partial agonist with a weak estrogenic activity.
Assuntos
Estradiol/farmacologia , Estrogênios/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Óleo de Milho/farmacologia , Estradiol/análogos & derivados , Congêneres do Estradiol/farmacologia , Feminino , Fulvestranto , Humanos , Lordose/tratamento farmacológico , Lordose/metabolismo , Células MCF-7 , Progesterona/administração & dosagem , Propilenoglicol/farmacologia , Ratos , Ratos Wistar , Receptores de Estrogênio/metabolismo , Comportamento Sexual Animal/efeitos dos fármacos , Tamoxifeno/farmacologiaRESUMO
Compounds with estrogenic effects that also inhibit platelet aggregation might be useful in reducing thrombotic events associated with estrogenic therapy. In this study, two aminoestrogens, Buame [N-(3-hydroxy-1,3,5(10)-estratrien-17ß-yl)-butylamine] and Diebud [N,N'-bis-(3-hydroxy-1,3,5(10)-estratrien-17ß-yl)-1,4-butanediamine], were synthesized and characterized using common analytical methods and spectrophotometric analyses. The location and orientation of these molecules on the estrogenic receptor α (ERα) were also evaluated. Platelet inhibitory effects were elucidated ADP-induced platelet aggregation and ADP- and collagen-induced ATP release. Molecular docking demonstrated that Buame can reach and bind to the ERα in the ligand binding domain (LBD) similar to 17ß-estradiol (co-crystallized ligand). On the other hand, Diebud binds only to the surface of ERα due to its high molecular volume compared to 17ß-estradiol and Buame.
Assuntos
Congêneres do Estradiol/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Adulto , Sítios de Ligação , Colágeno/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Congêneres do Estradiol/química , Congêneres do Estradiol/metabolismo , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Humanos , Lipossomos/química , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Estrutura Molecular , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Adulto JovemRESUMO
17beta-aminoestrogens (AEs) produce anticoagulant effects in rats contrastingwith 17beta-estradiol (E2) procoagulant effects, their estrogenic effects are similar to E2, decreasing serum luteinizing hormone (LH), increasing uterine weight (Uw), activate transcription through the ERalpha and ERbeta receptors and pentolame induces progesterone (P) receptors in the anterior pituitary of ovariectomized (Ovx) rats similarly to E2, suggesting possible effects on female rats' sexual behavior. This work evaluated the AEs prolame, butolame, pentolame compared to E2 and estradiol benzoate (EB) as facilitators on the rat lordotic behavior. Dose-response curves were performed in rats by single subcutaneous (s.c.) injection (timezero) of: E2 (approximately 0.3, 3, 30, 60, 300 microg/kg); EB (approximately 0.4, 4, 40, 80, 400 microg/kg); prolame, butolame, pentolame (approximately 40, 400, 2000 or 4000 mg/kg), vehicle (corn oil; 300 microL/day; approximately 1.2 mL/kg) as control; 24 h after, P (1 mg/rat in 100 microL of corn oil; approximately 4 to 5 mg/kg) was administered, and 5 to 7 h later LQ was evaluated (number of lordosis displays/number of mounts x 100). E2, EB and AEs followed by P administration, induced lordosis in a dose-dependent manner. Prolame induced an LQEmax of 92, butolame85, EB 81, pentolame 44 and E2 43. The most potent was EB (LQED50 of 4.1 +/- 0.5 microg/kg); then E2 10 microg +/- 2.2/kg; prolame 268 +/- 19 microg/kg; butolame 402 +/- 21 microg/kg, and pentolame 1037 +/- 28 microg/kg. The AEs LQ potency decreases as length substitution on the amine group in C-17 increases. AEs LQDE50 values correlate with previous Uw DE50, LH ID50 and binding studies indicates mediation of the response by estrogen receptors. AEs facilitate sexual behavior of Ovx rats as partial estrogenic agonists.
Assuntos
Congêneres do Estradiol/farmacologia , Estradiol/fisiologia , Estrenos/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Amino Álcoois/farmacologia , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Postura , Progesterona/fisiologia , Ratos , Ratos Wistar , Comportamento Sexual Animal/fisiologia , Estatísticas não ParamétricasAssuntos
Disruptores Endócrinos/efeitos adversos , Exposição Ambiental , Estrogênios/efeitos adversos , Praguicidas/efeitos adversos , Anormalidades Induzidas por Medicamentos/etiologia , Adulto , Animais , Neoplasias da Mama/induzido quimicamente , DDT/efeitos adversos , DDT/farmacologia , Disruptores Endócrinos/farmacologia , Poluentes Ambientais/efeitos adversos , Poluentes Ambientais/farmacologia , Congêneres do Estradiol/efeitos adversos , Congêneres do Estradiol/farmacologia , Estrogênios/farmacologia , Estrogênios não Esteroides/efeitos adversos , Estrogênios não Esteroides/farmacologia , Feminino , Humanos , Recém-Nascido , Infertilidade Masculina/induzido quimicamente , Masculino , Praguicidas/farmacologia , Fitoestrógenos/efeitos adversos , Fitoestrógenos/análise , Fitoestrógenos/farmacologia , Gravidez , Espanha , Toxicologia/organização & administração , Universidades/organização & administraçãoRESUMO
Estrogens have been associated with thromboembolic events. Our group has described the anticoagulant effect of 17 beta-aminoestrogens in rodents, potentially new alternative estrogenic agents without thrombogenic risk. This work compares the contrasting effects of estradiol and the 17 beta-aminoestrogens (prolame, butolame, and pentolame) on blood clotting time. Ovariectomized CD1 mice received a single injection of 17beta-aminoestrogens, estradiol (20 to 80 mg/kg), or vehicle. Estradiol decreased blood clotting time from -10% to -25% (48 h; P<0.01) and 17 beta-aminoestrogens increased it, differing in latency (approximately 12 h; +48%, P<0.01) and duration (approximately 72 h +58%, P<0.01). In male Wistar rats, similar effects (pentolame +45%; estradiol -31%; P<0.01) were observed 48 h after five consecutive daily injections of 1000 microg/animal/day. The maximum procoagulant effect of estradiol was obtained after 72 h with 10 microg/animal/day (-45%; P<0.01). 17 Beta-aminoestrogens always produced opposite effects to those of estradiol on blood coagulation.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Congêneres do Estradiol/farmacologia , Estradiol/farmacologia , Amino Álcoois/farmacologia , Animais , Relação Dose-Resposta a Droga , Estradiol/administração & dosagem , Congêneres do Estradiol/administração & dosagem , Estrenos/administração & dosagem , Estrenos/farmacologia , Feminino , Masculino , Camundongos , Ovariectomia , Ratos , Ratos WistarRESUMO
Administration of exogenous estrogens has been associated with an increase of thromboembolic events. The 17 beta-aminoestrogens produce anticoagulant effects contrasting with the procoagulant effects of the natural occurring estradiol in rodents. This work compares the estrogenic effects induced by 17 beta-aminoestrogens prolame, butolame, pentolame, and estradiol in vivo models. Dose-response curves were performed using immature CD1 mice and Wistar rats. The animals were injected with estradiol or 17 beta-aminoestrogens (0.01 to 1000 microg/kg), or vehicle. The uterine wet and dry weights were determined. The 17 beta-aminoestrogens increased uterine weight in a dose-dependent manner. The uterotrophic effect produced by estradiol induced lower ED50 (6.5 and 4 microg/kg) and higher E(max) values (+523-350%) in mice as compared with those from the rat, indicating more susceptibility of the mice model. The 17 beta-aminoestrogens are partial estrogenic agonists with a relative uterotrophic effect of estradiol (100%) from 9-86%. Only the ED50 values of 17 beta-aminoestrogens in CD1 mice showed a direct correlation to the length of the amine group substitution in C-17 since their efficacy and potency were in the order: prolame>butolame>pentolame.
Assuntos
Congêneres do Estradiol/farmacologia , Útero/efeitos dos fármacos , Amino Álcoois/administração & dosagem , Amino Álcoois/farmacologia , Animais , Relação Dose-Resposta a Droga , Estradiol/administração & dosagem , Estradiol/farmacologia , Congêneres do Estradiol/administração & dosagem , Estrenos/administração & dosagem , Estrenos/farmacologia , Feminino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Útero/anatomia & histologiaRESUMO
OBJECTIVE: Blood coagulation and fibrinolytic variables were evaluated in 46 Brazilian women treated with either of two monophasic oral contraceptives (OC), containing 30 or 20 microg of ethinyl estradiol, and 75 microg of gestodene. METHODS: The effects on procoagulants, anticoagulants, pro-fibrinolytics and antifibrinolytics and fibrin turnover were evaluated after treatment for six consecutive cycles, the impact of reduction of ethinyl estradiol dosage on these effects being assessed. RESULTS: The OC containing 30 microg of ethinyl estradiol significantly increased the activities of factors VIII and X, whereas the one containing 20 microg of ethinyl estradiol caused no changes in clotting factors. Neither treatment altered fibrinogen levels or factor VII, IX or XII activity. There were no changes in antithrombin levels, but treatment with 30 microg ethinyl estradiol increased protein C levels and treatment with 20 microg decreased total protein S levels. Concerning the fibrinolytic parameters, both OCs increased plasminogen activity, whereas no changes in PAI-1, t-PA, alpha-2-antiplasmin or fibrin degradation products were observed. The reduction in ethinyl estradiol dosage from 30 microg to 20 microg eliminated the effects on factors VIII and X. CONCLUSIONS: The results show that the OC studied did not cause sufficient changes to indicate that there may be a correlation between these laboratory alterations and clinical results. The lack of reports concerning the hemostatic effects of OCs on Brazilian women hinders comparison of the present data with those obtained for other ethnic groups, at different geographical locations, and emphasizes the importance of such a study for future epidemiological investigation of the prothrombotic effects of OCs in Brazilian women.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Anticoncepcionais Orais Combinados/farmacologia , Etinilestradiol/farmacologia , Norpregnenos/farmacologia , Adulto , Fatores de Coagulação Sanguínea/metabolismo , Brasil , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/efeitos adversos , Relação Dose-Resposta a Droga , Congêneres do Estradiol/farmacologia , Etinilestradiol/administração & dosagem , Etinilestradiol/efeitos adversos , Feminino , Fibrinólise/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Norpregnenos/administração & dosagem , Norpregnenos/efeitos adversos , Congêneres da Progesterona/farmacologia , Estatísticas não ParamétricasRESUMO
The effect of silymarin (SIL) on 17alpha-ethynylestradiol (EE)-induced cholestasis was evaluated in rats. EE (5 mg/kg, subcutaneously, daily, for 5 days) decreased both the bile-salt-dependent and the bile-salt-independent fractions of the bile flow. The decrease in the former was associated to a reduction in the bile salt pool size (-58%), and this effect was completely prevented by SIL. This compound also counteracted the inhibitory effect induced by EE on HCO(3)(-) but not glutathione output, 2 major determinants of the bile-salt-independent bile flow. EE decreased the secretory rate maximum (SRM) of tauroursodeoxycholate, (-71%) and bromosulfophthalein (BSP; -60%), as well as the expression of the BSP canalicular carrier, mrp2; SIL failed to increase mrp2 expression, and had only a marginal beneficial effect on both tauroursodeoxycholate and BSP SRM values. However, the two-compartment model-based kinetic constant for BSP canalicular transfer was significantly improved by SIL (+262%). SIL decreased rather than increased CYP3A4, the cytochrome P450 isoenzyme involved in the oxidative metabolism of EE, and had no inhibitory effect on the UDP-glucuronosyltrasferase isoforms involved in the formation of its 17beta-glucuronidated, more cholestatic metabolite. Pretreatment of isolated rat hepatocyte couplets with silibinin, the major, active component of SIL, counteracted the estradiol 17beta-glucuronide-induced decrease in the percentage of couplets secreting apically the fluorescent bile acid analogue, cholyl-lysyl-fluorescein. These results show that SIL protects against EE-induced cholestasis by normalizing mainly the decrease in the bile salt pool size and HCO(3)(-) output, and probably by counteracting the cholestatic effect of its cholestatic, glucuronidated metabolite.
Assuntos
Colestase/induzido quimicamente , Colestase/prevenção & controle , Congêneres do Estradiol , Etinilestradiol , Proteínas de Membrana Transportadoras , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Silimarina/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Fosfatase Alcalina/sangue , Animais , Bile/efeitos dos fármacos , Bile/fisiologia , Ácidos e Sais Biliares/antagonistas & inibidores , Ácidos e Sais Biliares/metabolismo , Membrana Celular/efeitos dos fármacos , Elasticidade , Congêneres do Estradiol/farmacologia , Etinilestradiol/farmacologia , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Proteína 2 Associada à Farmacorresistência Múltipla , Ratos , Ratos WistarRESUMO
Objetivo: Son escasos los estudios que han evaluado los efectos metabólicos de los estrógenos conjugados sintéticos. Como en Chile este tipo de estrógeno son los más usados, decidimos evaluar la respuesta ósea y de los lípidos a estos fármacos. Material y método: 61 pacientes tratadas con estrógenos conjugados sintéticos durante un año; aquellas pacientes que tenían útero y menos de 60 años de edad se le indicó medroxiprogesterona asociada en forma secuencial, a las mayores, se les indicó en forma combinada continua. La masa ósea se evaluó con un equipo de ultrasonografía ósea. DBI-Sonic (Igea, Italia), cuyo bajo coeficiente de variación (0,4 por ciento) permite monitorizar la respuesta terapéutica al año.Los lípidos plasmaticos, se midieron con métodos enzimáticos. Se realizó ultrasonografía ósea y se midió los lípidos plasmáticos al inicio y al final del seguimiento. Resultados: La masa ósea no sufrió la pérdida esperada durante el año de tratamiento. Evaluado con AD-SOS (amplitude-dependent speed of sound), se observa que esta se mantuvo constante: basal: 2014+- 62 m/seg, al año: 2015+- 60m/seg. Tampoco hubo deterioro de microarquitectura ósea como la muestra la UBPS; 39,7 +- 23,7 Y 40,5 +- 20,2 respectivamente (ns). En cuanto a los lípidos, se observaron los beneficios característicos de los estrógenos orales.El colesterol total bajo de 222+- 31 mg/dl a 211+- 28 (p<0,06); el HDL, de 49,5+- 7,9 subió a 55,9+-7,1 (p<0.001); LDL, DE 134+-33 PASÓ A 125+-26(NS). Los triglicéridos bajaron de 188+-85 a 153+-52(p<0,004); mejoría atribuible a la dieta que se indica de rutina de estas pacientes. Conclusiones :los estrógenos conjugados sintéticos evitan la pérdida de masa ósea y mejoran el perfil lipídico