[Induction of uterine hemorrhage using 17-alpha-ethynyl-4-estrene-3-beta, 17-beta-diol diacetate (ethynodiol diacetate)].
Explore the source record for details and available documents.
Amenorrhea↗
SEARCH · PubMed Health
Results for “ETHYNODIOL DIACETATE”
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Colorimetric determination of mestranol in combination with ethynodiol diacetate.
Mestranol in combination with ethynodiol diacetate, an oral contraceptive formulation, is isolated from the sample on a partition chromatographic column prior to colorimetric determination. The color reaction which is specific for estrogens is formed by shaking an aliquot of the heptane eluate of mestranol with a 30% methanol-sulfuric acid solution. A collaborative study of the method gave results of 99.8% of added mestranol for the simulated mix and 100.7% of labelled mestranol for the commercial tablet. The method has been adopted as official first aciton.
Chemical Phenomena↗
Estimation of impurity profiles of drugs and related materials: part XXI. HPLC/UV/MS study of the impurity profile of ethynodiol diacetate.
The impurity profile of ethynodiol diacetate was investigated using the HPLC/UV/MS method. Using the slightly modified HPLC method of USP 24 two impurities, earlier isolated by preparative HPLC and investigated by NMR spectroscopy were separated and characterised. The mass spectra amended by the diode-array UV spectra supported the earlier found structures (E and Z isomers of 17alpha-ethinyl-estr-4-ene-3beta,17-diol-3-acetate-17-(3'-acetoxy-2'-butenoate). Another, hitherto not described impurity, 17alpha-ethinyl-estr-4-ene-3beta,17-diol-3-acetate-17-(3-oxo-butanoate) has also been separated and characterised by means of its mass spectrum, NMR and UV spectra.
Chromatography, High Pressure Liquid↗
[Analysis of steroids. Part 40. Isolation and identification of unusual impurities in ethynodiol diacetate].
In the course of the estimation of the impurity profile of ethynodiol diacetate, in addition to common impurities such as norethisterone acetate, ethynodiol-3-acetate and alpha-ethynodiol diacetate, two unknown impurities were detected by analytical reversed phase HPLC (C-18 silica and 80% aq. methanol as the eluent) and isolated by normal phase preparative HPLC (silica and 98:2 mixture of hexane and 2-propanol as the eluent). The 1H- and 13C-NMR spectra of the isolated impurities revealed that their structures could be characterized as the E and Z isomers of an analogue of EDDA containing "trimerised acetyl" group at the 17-hydroxy group (structures 4 and 4a). These structures were in good agreement with the extended UV spectra of the impurities and the mass spectra with the m/z 438 peak which can be derived from 4 and 4a by the loss of ketene.
Chromatography, High Pressure Liquid↗
Norethisterone concentration in breast milk and infant and maternal plasma during ethynodiol diacetate administration.
Twelve women with established lactation of 4-8 weeks duration were given a low-dose progestogen-only contraceptive, ethynodiol diacetate 0.5 mg (Femulen) daily. On the seventh and eight day of the study, prior to the mother's taking the pill, a blood sample was taken from her and from the infant. Further blood samples were collected from the mother 4 and 12 hours later. Breast milk samples were collected at every feed on day 7 and day 8. Ethynodiol diacetate is rapidly metabolised in humans, changing into the metabolite norethisterone which is found in both blood and milk. Hence, norethisterone concentrations were estimated. On day 7 and day 8, four hours after ingestion of the pill, the median norethisterone maternal plasma concentration was 1.60 ng/ml and it fell to a median level of 0.30 ng/ml prior to the next dose of the pill. At this time the median infant concentration was 0.10 ng/ml but the maximum observed level was 0.50 ng/ml. In the breast milk the norethisterone concentration appears to peak at around 4-8 hours following the ingestion of the pill. The maximum observed concentration in breast milk was 0.84 ng/ml. The amount of norethisterone ingested by the infant averaged 0.02% (6.65 micrograms) of the dose of ethynodiol diacetate ingested by the mother. The maximum observed on any one day was 0.07% (27.52 micrograms). The above results indicate that the amount of progestogen ingested by the infant from its mother's milk is small and is unlikely to pose a risk to the infant.
Biotransformation↗
Saliva level of ethynylestradiol in presence of ethynodiol diacetate after oral administration.
In the presence of ethynodiol diacetate the ethynylestradiol concentration in serum and saliva after oral administration was measured by a rapid radioimmunoassay method developed by the authors. By means of the saliva/serum quotient, and from the concentration of ethynylestradiol in the saliva samples, it was possible to infer the ethynylestradiol content of the serum. Attention is called to the relation between the quotient and time, which should be taken into account when values are calculated. 2, 4 and 12 h after oral administration, the saliva/serum quotients for an ethynylestradiol dose of 0.05 mg were 0.27, 0.76 and 0.40, respectively.
Ethinyl Estradiol↗
Serum and placenta levels of ethynylestradiol in presence of ethynodiol diacetate after oral administration.
The ethynylestradiol concentration--in the presence of ethynodiol diacetate--in serum after oral administration was measured by a rapid radioimmunoassay method developed by the authors. It was found that the peak level was reached 1 h after administration, and even after 12 h a significant amount of free ethynylestradiol was present in the serum. The transfer of ethynylestradiol into the placenta was also studied in subjects who were 10-12 weeks pregnant. Placenta/serum quotients were calculated for the ethynylestradiol, and were found to increase in parallel with the dose of the drug administered, proving that an ethynylestradiol enrichment of the placenta occurred as early as 10-12 weeks of pregnancy.
Administration, Oral↗
Influence of Ethynodiol Diacetate on the Formation of A-Homo-3Oxa-5?-Pregnane-4,20-Dione in Female Rats.
OBJECTIVE: To give more insight in the progesterone metabolism in rat after the treatment with the progestin ethynodiol diacetate. METHODS: Urinary excretion of the metabolites of subcutaneously administred (4-14C)-progesterone was studied in female rats. After an acid hydrolysis and extraction of urine the metabolites were analysed by thin layer chromatography and by gas chromatography-mass spectrometry. RESULTS: The most of radioactivity was excreted during the first 24 h, and total of 8.36 % has been recovered within four days. The excreted metabolites in urine were found as glucuronides and free steroids (80.72 %), and 19.28 % were determined as sulphates. Among detected metabolites, 5alpha-pregnane-3,20-dione, 3alpha-hydroxy-5alpha-pregnan-20-one and A-homo-3-oxa-5alpha-pregnane-4,20-dione were determined in the urinary extracts. The last one has not yet been identified before in rat urine. CONCLUSIONS: Consecutive injections of progestin ethynodiol diacetate (6 mg/kg b.w. daily) to adult female rats during 10 days (short-term treatment), or during 70 days (long-term treatment), starting on the 21st day of life, caused significant differences in the amounts of excreted 3alpha-hydroxy-5alpha-pregnan-20-one and A-homo-3-oxa-5alpha-pregnane-4,20-dione. Significant increase in the weights of pituitary, liver and kidneys were noted in rats treated with ethynodiol diacetate. The short-term treatment caused an increase, while after the long-term treatment a decrease of the ovarian weight was observed.
Journal Article↗
Metabolism of ethynodiol diacetate in the rhesus monkey before and after administration of rifampicin.
1. On administration of a single oral dose of [4-(14)C]ethynodiol diacetate (0.15 mg/kg) to rhesus monkey, plasma concn. of total 14C peaked after about 4 h. About 60% of the plasma radioactivity was present as glucuronide conjugates and no unchanged drug was detected. 2. Some 67 +/- 6% (mean +/- S.D.) of the dose of 14C was excreted in 4 days, 50 +/- 6% in urine and 18 +/- 2% in faeces. Most of the urinary excretion occurred within 24 h of dosage. 3. Glucuronide conjugates accounted for 60% of the urinary 14C, and 46% of the faecal 14C was free steroids. 4. Norethisterone and its tetrahydro metabolites were identified in the free, glucuronide and sulphate fractions of plasma and urine. Keto-4,5-dihydronorethisterones and trihydroxy metabolites were identified in the conjugated fractions of urine, and a complex mixture of polar metabolites was detected in faeces. 5. Rifampicin treatment (7.5 mg/kg/day, orally) for 8 days decreased the half-life of total 14C in plasma following a single oral dose of 4-[14C]ethynodiol diacetate (0.15 mg/kg) from 44 +/- to 24 +/- 2 h. 6. Faecal elimination of total 14C was significantly increased to 29 +/- 5% of the dose following rifampicin treatment, but urinary excretion was unchanged. 7. Rifampicin treatment increased the amount of polar metabolites and decreased the amount of norethisterone in the free and conjugated fractions of plasma and urine. The amounts of sulphate and non-hydrolysed conjugates in faeces were increased after rifampicin treatment.
Animals↗
Metabolic fate of ethynodiol diacetate in the baboon.
The enterohepatic circulation and metabolism of ethynodiol diacetate (3beta,17beta-diacetoxy-17alpha-ethynyl-estr-4-ene) in baboons were studied following the intravenous injection of this contraceptive steroid labeled with 14C (4-position) and with 3H (in either the 3- or 17-acetoxy moieties). Bile and urine from four baboons with biliary fistulas and urine from four intact baboons were collected for 7 hours. On the average, 40% and 44% of the injected dose were excreted in the bile and urine, respectively. Only 48% was recovered in the urine of intact baboons. Analysis of these excretion rates indicates an insignificant enterohepatic circulation of this compound. The steroid was excreted mostly (over 80%) as a glucosiduronate in urine and bile. Very little excretion of the 3-acetoxy compound was detected in the urine or bile at any time interval. 17-Monoacetoxy compounds, however, were detected both in urine and bile, suggesting a difference in the rate of in vivo hydrolysis of the 17beta- vs. the 3beta-acetate.
Animals↗
Incidence of ovarian cyst formation in women taking ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms.
A total of 7,759 women were treated with ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms (EDA 1 mg with EE 35 micrograms) in a field study involving 983 obstetrician-gynecologists evaluating the incidence of ovarian cyst formation. Six thousand three hundred eighty-two patients were evaluable; 1,377 could not be evaluated because of failure to meet inclusion criteria or inconsistent or incomplete data collection. Cysts were detected in 80 patients at the time of the final visit. Follow-up questionnaires were received on 61% of patients and confirmed the presence of 12 newly formed ovarian cysts in patients taking EDA 1 mg with EE 35 micrograms. Only three women required an operation for ovarian cysts; two women had functional ovarian cysts (one follicular and one luteal), and one had a neoplastic cyst (cystadenoma). Thus, the incidence of ovarian cyst formation requiring surgical intervention was 0.05% in women taking EDA 1 mg with EE 35 micrograms.
Adult↗
Effect of ethynodiol diacetate and combination--type oral contraceptive compounds on carbohydrate metabolism. I. Six month intravenous glucose tolerance study.
In order to evaluate long-term effects of different types of oral contraceptive compounds, blood glucose and plasma insulin levels were measured during an intravenous glucose tolerance test in 2 groups of normal, nondiabetic patients: 36 women using a progesterone-alone oral contraceptive, ethynodiol diacetate, and 36 women using a combination-type drug, containing norethynodrel and mestranol. Each patient was tested before and after 6 months of treatment. There were no significant differences from pre-treatment glucose and insulin values in the first group of women (on ethynodiol diacetate). In the second group (on norethynodrel and mestranol), there was a significant elevation of mean blood glucose levels at 15, 30 and 120 min of the glucose tolerance test. Nevertheless, a significant elevation of plasma insulin was seen only at 60 min of the test. Patients participating in this study will continue this treatment, and monitoring of carbohydrate metabolism is contemplated over a period of several years.
Adult↗
Bioavailability and pharmacokinetics of norethisterone in women after oral doses of ethynodiol diacetate.
Measurement by radioimmunoassay of plasma norethisterone (NE) has been used to compare the bioavailability of tablets containing ethynodiol diacetate (EDA) with that of a standard oral solution of this progestogen in 12 normal women. The tablets investigated were from three batches which showed different in vitro dissolution rates. There were no significant differences in the bioavailability of the tablet formulations, which were essentially bioequivalent to the solution. Peak blood levels of NE were reached within 4h of EDA administration in solution or tablets. After the peak, NE plasma levels declined in two phases, with a mean terminal elimination half lives of 4 to 6.9h. The pharmacokinetics of NE after EDA administration showed some similarity to those observed by other workers after oral doses of NE itself.
Adult↗
Efficacy and safety of ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms, with an emphasis on contraceptive efficacy. A phase IV trial.
A phase IV trial evaluated the efficacy and safety of a monophasic oral contraceptive formulation, ethynodiol diacetate, 1 mg, plus ethinyl estradiol, 35 micrograms (EDA 1 mg with EE 35 micrograms) (Demulen 1/35). Nine hundred eighty-three community-based obstetrician-gynecologists treated a total of 7,759 patients with EDA 1 mg with EE 35 micrograms for one to eight months. Clinical evaluation forms on 6,382 patients were amenable to analysis for safety (including breakthrough bleeding, ovarian cyst formation and complexion changes); 5,412 patients were evaluable for efficacy (prevention of pregnancy), with a total of 21,440 cycles recorded. The study results were interpreted in terms of the impact on clinical management of oral contraceptive users and the methods, strengths and weaknesses of phase IV trials, particularly as they relate to confirmation of the results reported here.
Adolescent↗
Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.
Femulen, a progestogen only oral contraceptive (ethynodiol diacetate 0.5mg), was evaluated for its contraceptive efficacy and safety in 425 women aged between 16 and 47 years. This was a multicentre open study carried out in General Practice and Family Planning clinics. Five pregnancies were reported, three of which were a result of patient failure. The net pregnancy rate at one year for method failure was 0.5%. No ectopic pregnancy was reported. The median length of the menstrual period was between four and five days and the average length of the non-bleeding interval remained between 24 and 25 days throughout the study. Blood pressure on the whole remained within normal limits. However, there was a small decrease in both systolic and diastolic blood pressure which did not reach significant levels. Body weight was unaltered and no abnormality was found in cervical smears. Femulen was shown to be an effective and acceptable contraceptive in women of varying ages.
Adolescent↗
Quantitative analysis of ethynodiol diacetate and ethinyl estradiol/mestranol in oral contraceptive tablets by high-performance liquid chromatography.
A procedure is described for the assay of ethynodiol diacetate and ethinyl estradiol/mestranol by HPLC using two UV detectors at 210 and 280 nm. The system was acetonitrile 38% (v/v) in water as mobile phase on a 250 x 3.2-mm i.d. RP-2 column, with butylated hydroxytoluene as the internal standard. There was greater than 99% recovery from synthetic preparations and the coefficient of variation was greater than 2.0% for formulations.
Chromatography, High Pressure Liquid↗
Controlled drug release from polymeric delivery devices. III: In vitro-in vivo correlation for intravaginal release of ethynodiol diacetate from silicone devices in rabbits.
Forty female rabbits were implanted with silicone vaginal devices containing ethynodiol diacetate for up to 8 weeks. As predicted from in vitro studies, a Q - t1/2 (matrix-controlled) release profile was observed in vivo. The in vivo drug release profile was compared with in vitro data measured at three hydrodynamic conditions, and the diffusional resistance across the vaginal wall was estimated. Drug released from silicone devices yielded a prolonged plasma level when compared with data following intravaginal or intravenous administration of a solution dose. The rate constant for elimination was unchanged. The plasma concentration of the drug was related to the intravaginal drug release profile both theoretically and experimentally and was above the concentration required to inhibit fertilization.
Animals↗