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British Medical Journal Mar 1965
Topics: Biopsy; Chemical and Drug Induced Liver Injury; Contraceptive Agents; Contraceptives, Oral; Estradiol Congeners; Estrogens; Ethinyl Estradiol; Female; Hepatitis; Humans; Liver Function Tests; Lynestrenol; Menopause; Mestranol; Norethindrone; Norethynodrel; Progestins; Toxicology
PubMed: 14245215
DOI: 10.1136/bmj.1.5436.723-a -
British Journal of Cancer Apr 2018Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional...
BACKGROUND
Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse and human DGC cells.
METHODS
We derived mouse gastric cancer (GC) cell lines from DGC of the DCKO mice demonstrating enhanced tumourigenic activity in immunodeficient mice and acquired tolerance to cytotoxic anti-cancer agents.
RESULTS
We performed a synthetic lethal screening of 1535 annotated chemical compounds, and identified 27 candidates selectively killing the GC cell lines. The most potent drug mestranol, an oestrogen derivative, and other oestrogen receptor modulators specifically attenuated cell viability of the GC cell lines by inducing apoptosis preceded by DNA damage. Moreover, mestranol could significantly suppress tumour growth of the GC cells subcutaneously transplanted into nude mice, consistent with longer survival time in the female DCKO mice than in the male. Expectedly, human E-cadherin-mutant and -low gastric cancer cells showed higher susceptibility to oestrogen drugs in contrast to E-cadherin-intact ones in vitro and in vivo.
CONCLUSIONS
These findings may lead to the development of novel therapeutic strategies targeting DGC.
Topics: Animals; Antineoplastic Agents; Cdh1 Proteins; Cell Line, Tumor; Disease Models, Animal; Drug Screening Assays, Antitumor; Male; Mice; Mice, Knockout; Mice, Nude; Stomach Neoplasms; Tumor Suppressor Protein p53
PubMed: 29527007
DOI: 10.1038/s41416-018-0008-y -
Fertility and Sterility Apr 1971
Topics: Adolescent; Adult; Blood Glucose; Chlormadinone Acetate; Contraceptives, Oral; Female; Glucose Tolerance Test; Humans; Insulin; Mestranol; Metabolism; Periodicity; Radioimmunoassay; Time Factors
PubMed: 4101969
DOI: No ID Found -
Fertility and Sterility Aug 1978Human subjects, baboons, and beagles were given cyclic regimens of ethynylestradiol or mestranol; after a number of such cycles, concurrent administration of... (Comparative Study)
Comparative Study
Comparative studies of the ethynyl estrogens used in oral contraceptives. VI. Effects with and without progestational agents on carbohydrate metabolism in humans, baboons, and beagles.
Human subjects, baboons, and beagles were given cyclic regimens of ethynylestradiol or mestranol; after a number of such cycles, concurrent administration of norethindrone acetate, dl-norgestrel, or megestrol acetate was introduced for a similar number of cycles. Carbohydrate tolerance was evaluated by oral glucose tolerance testing in the human subjects and by intravenous glucose tolerance testing in the baboons and beagles. In the human subjects, neither mestranol nor ethynylestradiol at daily doses of 50 to 100 microgram/day produced any effect on fasting glucose levels or on glucose tolerance even after six cycles of treatment. The addition of the progestational compounds also had no effect on these two variables. In baboons, ethynylestradiol and mestranol were bioequivalent and produced a dose-related decrease in the glucose disposal rate. All three progestational agents counteracted this effect in a comparable manner. In beagles, on the other hand, estrogens produced an increase in the glucose disposal rate, and the addition of progestational agents produced an initial fall and a subsequent return to pretreatment levels.
Topics: Animals; Blood Glucose; Contraceptives, Oral; Dogs; Dose-Response Relationship, Drug; Estrogens; Ethinyl Estradiol; Fasting; Female; Glucose Tolerance Test; Haplorhini; Humans; Mestranol; Papio; Progestins
PubMed: 98357
DOI: 10.1016/s0015-0282(16)43452-7 -
British Medical Journal Apr 1970Reports of thromboembolism following the use of oral contraceptives received by drug safety committees in the United Kingdom, Sweden, and Denmark have been analysed to...
Reports of thromboembolism following the use of oral contraceptives received by drug safety committees in the United Kingdom, Sweden, and Denmark have been analysed to investigate possible differences in the risks associated with the various preparations. For this purpose the numbers of reports of thromboembolism attributed to each product were compared with the distribution that would have been expected from market research estimates of sales, assuming that all products carried the same risk.A positive correlation was found between the dose of oestrogen and the risk of pulmonary embolism, deep vein thrombosis, cerebral thrombosis, and coronary thrombosis in the United Kingdom. A similar association was found for venous thrombosis and pulmonary embolism in Sweden and Denmark. No significant differences could be detected between sequential and combined preparations containing the same doses of oestrogen, nor between the two oestrogens, ethinyloestradiol and mestranol.Certain discrepancies in the data suggest that the dose of oestrogen may not be the only factor related to the risk of thromboembolism; thus there was a significant deficit of reports associated with the combination of mestranol 100 mug. with norethynodrel 2.5 mg. and a significant excess of reports associated with the combination of ethinyloestradiol 50 mug. with megestrol acetate 4 mg. An excess of reports also occurred with other combined preparations containing megestrol acetate.The data obtained in earlier epidemiological studies were re-examined and, though no trend was obvious in any one of them, the combined results showed an excess of cases of thromboembolism at the highest dose of oestrogen.The finding of a positive correlation between the dose of oestrogen and the risk of coronary thrombosis is of special interest since previous studies have failed to provide clear evidence of a relationship between oral contraceptives and this condition.
Topics: Contraceptives, Oral; Coronary Disease; Denmark; Estrogens; Ethinyl Estradiol; Female; Humans; Intracranial Embolism and Thrombosis; Megestrol; Mestranol; Norethynodrel; Progestins; Pulmonary Embolism; Sweden; Thromboembolism; Thrombophlebitis; United Kingdom
PubMed: 5443406
DOI: 10.1136/bmj.2.5703.203 -
Fertility and Sterility Apr 1971
Topics: Adolescent; Adult; Age Factors; Birth Weight; Blood Glucose; Body Weight; Chlormadinone Acetate; Contraceptives, Oral; Female; Glucose Tolerance Test; Humans; Insulin; Mestranol; Metabolism; Periodicity; Radioimmunoassay; Time Factors
PubMed: 4101970
DOI: No ID Found -
Clinical and Diagnostic Laboratory... Jul 2001Splenic-macrophage Fcgamma receptors (FcgammaRs) participate in the pathophysiologies of immune-complex diseases and in host defense against infection. Modulation of...
Splenic-macrophage Fcgamma receptors (FcgammaRs) participate in the pathophysiologies of immune-complex diseases and in host defense against infection. Modulation of macrophage FcgammaR expression is an immuno-therapeutic target. Glucocorticoids, sex steroids, and dopaminergic drugs modulate macrophage FcgammaR expression. Previous data indicate that estradiol increases macrophage FcgammaR expression. Nevertheless, the effects of clinically used estrogens upon macrophage FcgammaR expression are unknown. We assessed the effects of treatment with commonly used estrogens on the expression of macrophage FcgammaRs using a guinea pig experimental model. Six estrogens have been studied: ethynylestradiol (Et), mestranol (M), chlortianisene (Ct), promestriene, 17-epiestriol, and 17beta-estradiol. Following in vivo treatment of guinea pigs, we determined the clearance of immunoglobulin G (IgG)-sensitized erythrocytes in vivo, the binding of IgG-sensitized erythrocytes by isolated splenic macrophages, and splenic-macrophage FcgammaR cell surface expression. Estrogens enhance the clearance of IgG-sensitized erythrocytes by increasing splenic-macrophage FcgammaR expression. Et, M, and Ct were more effective than the other estrogens. Flow cytometry and fluorescence microscopy with monoclonal antibodies demonstrated that estrogens increase the cell surface expression of FcgammaR1 and -2 more than that of FcgammaR2. These data indicate that treatment with commonly used estrogens enhances the clearance of IgG-sensitized cells by improving splenic-macrophage FcgammaR expression.
Topics: Animals; Erythrocytes; Estrogens; Guinea Pigs; Macrophages; Male; Receptors, IgG; Spleen
PubMed: 11427431
DOI: 10.1128/CDLI.8.4.806-810.2001 -
Molecules (Basel, Switzerland) Feb 2019Microwave-assisted syntheses of novel ring d-condensed 2-pyrazolines in the estrone series were efficiently carried out from steroidal ,-enones and hydrazine...
Microwave-assisted syntheses of novel ring d-condensed 2-pyrazolines in the estrone series were efficiently carried out from steroidal ,-enones and hydrazine derivatives. The ring-closure reaction of 16-benzylidene estrone 3-methyl ether with hydrazine in acetic acid resulted in a 2:1 diastereomeric mixture of two 16,17- fused pyrazolines, which is contrary to the former literature data for both stereoselectivity and product structure. However, the cyclization reactions of a mestranol-derived unsaturated ketone with different arylhydrazines in acidic ethanol furnished the heterocyclic products in good to excellent yields independently of the substituents present on the aromatic ring of the reagents applied. The MW conditions also permitted the ring-closure reaction with -nitrophenylhydrazine which is unfavorable under conventional heating. Moreover, the transformations led to the heterocyclic compounds stereoselectively with a 16,17- ring junction without being susceptible to spontaneous and promoted oxidation to pyrazoles.
Topics: Cyclization; Estrone; Microwaves; Models, Molecular; Molecular Structure; Pyrazoles; Stereoisomerism
PubMed: 30720767
DOI: 10.3390/molecules24030569 -
Epilepsia Apr 2003To study the pharmacokinetics of a combination oral contraceptive (OC) containing norethindrone and ethinyl estradiol during OC monotherapy, concomitant OC and... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects.
PURPOSE
To study the pharmacokinetics of a combination oral contraceptive (OC) containing norethindrone and ethinyl estradiol during OC monotherapy, concomitant OC and topiramate (TPM) therapy, and concomitant OC and carbamazepine (CBZ) therapy in order to comparatively evaluate the pharmacokinetic interaction, which may cause contraceptive failure.
METHODS
This randomized, open-label, five-group study included two 28-day cycles. Five groups of female subjects received oral doses of ORTHO-NOVUM 1/35 alone (cycle 1) and then concomitant with TPM or CBZ (cycle 2). The treatment groups were group 1, TPM, 50 mg/day; group 2, TPM, 100 mg/day; group 3, TPM, 200 mg/day; group 4, TPM, 200 mg/day (obese women); and group 5, CBZ, 600 mg/day. Group 4 comprised obese women whose body mass index (BMI) was between 30 and 35 kg/m(2). The BMI of the remaining four groups was < or =27 kg/m2.
RESULTS
Coadministration of TPM at daily doses of 50, 100, and 200 mg (nonobese) and 200 mg (obese) nonsignificantly (p > 0.05) changed the mean area under the curve (AUC) of ethinyl estradiol by -12%, +5%, -11%, and -9%, respectively, compared with OC monotherapy. A similar nonsignificant difference was observed with the plasma levels and AUC values of norethindrone (p > 0.05). CBZ (600 mg/day) significantly (p < 0.05) decreased the AUC values of norethindrone and ethinyl estradiol by 58% and 42%, respectively, and increased their respective oral clearance by 69% and 127% (p < 0.05). Because CBZ induces CYP 3A-mediated and glucuronide conjugation metabolic pathways, the significant increase in the oral clearance of ethinyl estradiol and norethindrone was anticipated.
CONCLUSIONS
TPM, at daily doses of 50-200 mg, does not interact with an OC containing norethindrone and ethinyl estradiol. The lack of the TPM-OC interaction is notable when it is compared with the CBZ-OC interaction.
Topics: Administration, Oral; Adult; Anticonvulsants; Area Under Curve; Body Mass Index; Carbamazepine; Contraceptives, Oral, Combined; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Drug Interactions; Enzyme Induction; Ethinyl Estradiol; Female; Fructose; Humans; Mestranol; Metabolic Clearance Rate; Norethindrone; Obesity; Topiramate
PubMed: 12681003
DOI: 10.1046/j.1528-1157.2003.55602.x -
Fertility and Sterility Jun 1974
Review
Topics: Anencephaly; Cell Differentiation; Contraceptives, Oral; Embryonic and Fetal Development; Ethinyl Estradiol; Female; Gonadotropins, Pituitary; Histocytochemistry; Humans; Hypopituitarism; Lynestrenol; Maternal-Fetal Exchange; Mestranol; Norethindrone; Ovary; Pituitary Gland; Pregnancy; Trophoblasts
PubMed: 4599101
DOI: 10.1016/s0015-0282(16)40458-9