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PubMed1983

Structure of the isonicotinyl hydrazone of norethindrone.

The contraceptive steroid norethindrone reacts with isoniazid both in vivo and in vitro to give the corresponding hydrazone, which exists as syn and anti (with respect to C-4) isomers. These isomers rapidly interconvert, with the anti form predominating in solution. The identification of the isomers was based on an interpretation of 1H- and 13C-NMR spectroscopic data and corroborated by high-performance liquid chromatographic UV spectrophotometric evidence. 1H- and 13C-NMR spectroscopic data for other derivatives of norethindrone hydrazone are presented and interpreted.

Chemical Phenomena↗
PubMed1979

Accumulation of norethindrone and individual metabolites in human plasma during short- and long-term administration of a contraceptive dosage.

Blood levels of free, sulfate, and glucuronide conjugates of norethindrone (NE) and its ring A reduced metabolites 17alpha-ethynyl-5beta-estrane-3alpha, 17beta-diol and 17alpha-ethynyl-5alpha-estrane-3alpha, 17beta-diol were measured in a female volunteer who received six consecutive daily doses of 2.5 mg. of NE and in four female volunteers undergoing chronic treatment with Orthonovum 2 mg. (2 mg. of NE and 0.1 mg. of mestranol [ME]). The blood levels were quantified by gas chromatograph-mass spectrometry. During treatment for 6 days with 2.5 mg. of NE daily, the 3 hour blood levels of NE and the ring A reduced metabolites increased in a stepwise fashion. During long-term treatment the concentrations of NE, NE sulfate, and the conjugates of the ring A reduced metabolites were seen to build up to a peak at approximately the midpoint of the treatment phase of each cycle, and drop to near baseline during the time when no drug was administered. Individuals varied as to their tendency to accumulate the drug and metabolites, and as to the relative proportion of metabolites formed.

Adult↗
PubMed1979

Pharmacokinetics of norethindrone acetate in women.

The plasma half-life, MCR and plasma metabolite levels at various time intervals have been studied in six women after an intravenous injection of 3H-norethindrone acetate. The disappearance curve due to norethindrone acetate showed an initial rapid disappearance of 3H with an average half-life of 7.5 minutes and a subsequent slow disapperance with a half-life of 51.5 hours. Norethindrone acetate was cleared from the plasma with an average MCR of 495 L/day. Norethindrone acetate is rapidly metabolised after an intravenous injection. Norethindrone, the main metabolite, disappears from the plasma with an average half-life of 34.8 hours. Norethindrone maintains a high level compared with norethindrone acetate at all time intervals up to 24 hours and an equilibrium is reached between the two at 24 to 48 hours.

Acetates↗
PubMed1979

New long-acting injectable microcapsule contraceptive system.

A new long-acting, injectable contraceptive which provides continuous controlled release of the steroid norethisterone (NET) for a precise period of 6 months following a single intramuscular injection is described. The prototype system consists of microcapsules made of the biodegradable polymer d, l-polylactic acid, in which micronized crystals of NET are homogeneously dispersed. NET is slowly released from the microcapsules following intramuscular injection at a rate of 0.90 microgram NET/day/mg of microcapsule by diffusion of the steroid from the polymer matrix. Three different doses of a standard preparation of microcapsules were tested in normally cycling female babbons (4 to 5 baboons/group). Following injection of either 300, 200, or 100 mg of microcapsules containing 75, 50, or 25 mg of NET, blood samples were collected at selected intervals and analyzed for NET, estrogen, and progesterone by radioimmunoassay. All three doses provided continuous NET release for 6 months following injection. The NET serum profiles for the different doses are parallel, and ovulation was inhibited in all baboons for 6 months following treatment.

Animals↗
PubMed1981

Clinical evaluation of injectable biodegradable contraceptive system.

A new long-acting injectable contraceptive system was tested in 24 women. The system consists of microspheres made of biodegradable d,l-polylactic acid in which micronized crystals of norethisterone (NET) are homogeneously dispersed. In previous animal studies we showed that NET is slowly released from the microspheres for 6 months, and after the drug is released, the microspheres biodegrade into lactic acid by the process of hydrolysis. The serum levels of NET, estrogen, and progesterone were monitored by radioimmunoassay, and the effects of treatment on ovarian function and menstrual bleeding were evaluated. The doses ranged from 29 to 370 mg of microspheres containing 7.25 to 94.5 mg of NET or 0.134 to 2.30 mg of NET/kg of body weight. The duration of the NET release was 6 months, and the serum NET profiles in women were similar to those previously described in subhuman primates. Following a small burst, there was a gradual decline in the serum levels of NET over 6 months after treatment. The serum levels of NET varied in proportion to the dose. Doses less than 0.267 mg of NET/kg had no discernible effect on either ovarian function or menstrual bleeding. Doses ranging from 0.419 to 2.30 mg had variable effects on ovarian function and menstrual bleeding. Higher doses caused suppression of ovarian function for longer periods of time, increased the interval between episodes of menstrual bleeding, and decreased the quantity of blood loss during each episode. The treatment was well tolerated by all subjects, and, with the exception of spotting and irregular menstrual cycles, there were no adverse side effects. Based on this initial study, it was determined that doses ranging from 1.33 to 3.45 mg of NET/kg are necessary to suppress ovulation for 6 months. Additional studies with the use of higher doses are currently under way.

Adult↗
PubMed1983

Clinical evaluation of an improved injectable microcapsule contraceptive system.

Pharmacokinetics and pharmacodynamics of a long-acting injectable microcapsule, poly(DL-lactide-co-glycolide), delivery system were tested in 10 women. Two doses (75 or 100 mg of norethindrone) were administered by intramuscular injection. Treatment suppressed ovarian function and inhibited ovulation for 3 months in all subjects. Levels of norethindrone in subjects who received the 100 mg dose were proportionately higher than those in subjects who received the 75 mg dose. Subsequent to the injection, there was a rapid rise in the serum levels of norethindrone followed by a gradual decline until 8 to 10 weeks. Between 10 and 20 weeks after treatment, there was a secondary rise and fall in the serum levels of norethindrone. Treatment caused suppression of the endometrium for 3 months, and, except for spotting and irregular menstrual cycles, there were no adverse side effects. Treatment had no significant effect on serum lipids.

Adult↗
PubMed1991

The effect of tetracycline on levels of oral contraceptives.

Despite the widespread use of tetracycline for treatment of dermatologic disorders and sexually transmitted diseases, the pharmacodynamics of oral contraceptive use in the presence of tetracycline has not been studied. Seven normal women ingested an oral contraceptive containing ethinyl estradiol 35 micrograms and norethindrone 1 mg in the follicular phase of the menstrual cycle. On day 0 baseline ethinyl estradiol and norethindrone levels were obtained at 0, 1/2, 3/4, 1, 2, 4, 12, and 24 hours after oral contraceptive administration. On day 1 tetracycline 500 mg was given orally every 6 hours while the oral contraceptive was continued. Tetracycline, ethinyl estradiol, and norethindrone levels were determined at the same time intervals as on day 0. Oral contraceptive and tetracycline were continued for up to 10 days, and additional concentrations of ethinyl estradiol, norethindrone, and tetracycline were determined between days 5 and 10. Four additional normal women ingested tetracycline for 5 to 10 days. Tetracycline levels were determined at the time intervals noted above on day 1 and days 5 to 10. No significant decrease in plasma ethinyl estradiol or norethindrone concentration was seen with either short-term (24 hours) or long-term (5 to 10 days) ingestion of tetracycline. Similarly, levels of tetracycline do not significantly decrease with ingestion of a low-dose oral contraceptive.

Adolescent↗
PubMed1978

A radioimmunoassay for norethindrone (NET): measurement of serum NET concentrations following ingestion of NET-containing oral contraceptive steroids.

A sensitive and reliable radioimmunoassay (RIA) for the measurement of norethindrone (NET) in serum has been established employing anti-11 alpha-hydroxynorethindrone 11-hemisuccinyl-bovine serum albumin serum in conjunction with norethindrone-3-(0-carboxymethyl) oximino-[125I]-iodohistamine. Of a number of ring A reduced NET metabolites, only 17 beta-hydroxy-17 alpha-ethinyl-5 beta-estran-3-one (43%) and 17 alpha-ethinyl-5 alpha-estrane-3 beta, 17 beta-diol (15.7%) cross-reacted appreciably in this RIA. Ethinyl estradiol (EE2) and mestranol (MEE2) exhibited cross-reactions of only 1.1 and 0.4%, respectively. Serum NET levels were measured in four groups of 3 women, each ingesting either 1 mg NET plus 0.05 mg MEE2 (Norinyl 1 + 50 or Ortho Novum 1/50), 0.5 mg NET plus 0.035 mg EE2 (Brevicon) or only 0.35 mg NET (Micronor) daily for 5 consecutive days. Peak serum NET levels were observed within 1/2 to 4 hours after oral intake and fell precipitously thereafter. After reaching a maximum, serum NET concentrations declined in a manner consistent with at least two disposition phases. The average half-life for the first disposition phase was 2.3, 3.4, 3.9 and 4.4 hours in subjects ingesting Norinyl 1 + 50, Ortho Novum 1/50, Brevicon and Micronor, respectively. Peak and 3-hour post-ingestion serum NET concentrations were dose-related but showed considerable subject-to-subject variations. Following discontinuation of tablet intake, serum NET levels remained detectable (greater than 0.05 ng/ml) for at least 5 days in all 3 women who had taken Ortho Novum 1/50, but in none of the other 9 volunteers. These results suggest that different preparations of identical doses and combinations of oral contraceptive steroids may yield different serum NET profiles. However, due to considerable subject-to-subject variations, larger numbers of subjects are required for a conclusive investigation.

Adult↗
PubMed1979

Subdermal norethindrone pellets -- a method for contraception?

The mode of action of compressed pellets containing 85 per cent norethindrone (NET) and 15 per cent cholesterol was studied. Four pellets were inserted subcutaneously, in each of five healthy volunteers and left in place for 200--229 days. The NET content of the pellets varied between 23.9 mg and 25.6 mg; and the cholesterol content between 4.2 mg and 4.5 mg. Plasma levels of NET, estradiol and progesterone were determined by radioimmunoassays. Plasma levels of NET varied mostly between 1--2 ng/ml the first month after insertion. After two months plasma levels of NET ranged between 0.5 ng/ml and 1 ng/ml in all volunteers and there was a gradual decrease of the plasma NET levels throughout treatment. Pronounced day-to-day variations in plasma NET levels were recorded. The release rates of NET was calculated to be between 187 micrograms/day and 243 micrograms/day among the five volunteers. Ovulations occurred in four out of five subjects during treatment. This study indicates that the release of gestagen from four NET pellets was only initially high enough to completely inhibit ovulation and that to accomplish full contraceptive efficacy, a higher dose, i.e. more pellets, would have to be inserted.

Adult↗
PubMed1979

Pharmacokinetics of norethindrone in Indian Women.

Pharmacokinetics of norethindrone (NET) was evaluated in eleven women belonging to a low socio-economic group and in five womem belonging to the high socio-economic group after the administration of an oral dose of 0.35 mg NET minipill on an empty stomach. Blood samples were collected at different intervals of time over a period of 24 hours. Plasma NET was estimated by radioimmunoassay. In all women, peak levels of NET occurred within 1-2 hours and a semi-log plot of plasma NET levels showed a biexponential decline. The half-life of plasma NET clearance was relatively shorter in women of low socio-economic group with poor nutritional status as indicated by anthropometric indices, as compared to that in well nourished women of high socio-economic group. There was a significant positive correlation between weight/(height) 2x 100 index on the one hand and t1/2 (beta) on the other in all the women studied, thereby suggesting a role for nutritional status in the metabolic handling of NET.

Absorption↗
PubMed1980

Release of 19-nor-testosterone type of contraceptive steroids through different drug delivery systems into serum and breast milk of lactating women.

The release of contraceptive steroids through different drug delivery systems into serum and breast milk was investigated in a group of lactating women. Four women in each group were taking either a low dosage progestogen compound like norethisterone (NET) 350 micrograms or d-norgestrel (d-Ng) 50 micrograms alone or low dosage combination pills containing NET 1 mg or d-Ng 150 micrograms with 30 micrograms ethinyl estradiol (EE2) or a biodegradable implant containing 25 mg NET or d-Ng. Peak levels in plasma and milk were seen in oral contraceptive users around 2 hours. Of the two low dosage progestogen compounds, d-Ng was below the detection limit in milk within 4 hours whereas NET was still detectable at the 24-hour interval. In contrast to this, because of the larger quantity of steroids in the combination pills, the NET/d-Ng levels in serum as well as in milk were high throughout the 24-hour period. With the subdermal route because of the sustained low release of the drug from the biodegradable implants, the levels in milk were below the detection limit within a day with d-Ng and within a week with NET.

Drug Implants↗
PubMed1980

The effect of injectable norethisterone oenanthate on ovarian hormones in Thai women.

The ovarian hormones, progesterone and estradiol, as well as norethisterone concentrations were studied in 15 subjects receiving a single intramuscular injection of norethisterone oenanthate. Three treatment groups were studied. The 5 subjects of group A had no additional treatment, the 5 subjects of group B received ethynylestradiol and the 5 subjects of group C received combined ethynylestradiol and norgestrel orally. Additional treatment was for 5 consecutive days 6 weeks after the injection. Blood samples were obtained weekly for 12 weeks post-treatment. All subjects showed a similar pattern of norethisterone concentrations with a range of 3.5-19.5 ng/ml 1 week after injection, declining to levels of less than 0.02 ng/ml at the end of treatment period. Progesterone concentrations of greater than 4 ng/ml indicated that ovulation had occurred in 2 subjects of group A, 5 subjects of group B and 2 subjects of group C during the study period. Serum estradiol concentrations reached pre-ovulatory levels (greater than 200 pg/ml) in 4,3 and 2 subjects of group A,B and C, respectively, during the treatment period. With the other subjects, serum estradiol showed lesser increases. Among the 15 Thai women in the study, the median time of ovulation was 11 weeks, with the earliest occurring at 6 weeks. Three women receiving NET-OEN and no other treatment had ovulated by 6 weeks. Thai women in this study appear to be more resistant to the antiovulatory effect of NET-OEN as compared to women in other published studies.

Adult↗
PubMed1980

A study of interaction of low-dose combination oral contraceptive with Ampicillin and Metronidazole.

Plasma levels of norethisterone (NET), ethinyl estradiol (EE), Ampicillin or Metronidazole were estimated in 16 women, who were taking low-dose oral combination contraceptive pills (containing norethisterone acetate 1 mg and ethinyl estradiol 30 microgram) and in whom concurrently, either Ampicillin (6 women) or Metronidazole therapy (10 women) was given. Neither Ampicillin nor Metronidazole therapy altered the 'peak' or 24-hour plasma levels and area under the curve, for NET and EE. Furthermore, oral contraceptive treatment did not alter the 'peak' levels of Ampicillin or Metronidazole. Progesterone (P) levels were in the anovulatory range in all Ampicillin treated cycles. However, in Metronidazole treated group, two out of 10 women showed a P rise of more than 4 ng/ml. The study was expanded to include another group of 15 women treated with Metronidazole, where only one women showed a P rise of more than 4 ng/ml. The occurrence of 'escape ovulation' as suggested by P rise of more than 4 ng/ml in three out of 25 Metronidazole treated women is either a chance incidence due to a different pharmacological response in them, or most probably due to the default in the regular intake of pills in these women. This is supported by the observation that one out of three women showing a P rise (greater than 4 ng/ml( during concurrent Metronidazole therapy, also showed ovulatory P values in oral contraceptive-only treated cycles. Furthermore, in the control group also, one out of 10 women had ovulatory P levels (greater than 4 ng/ml) in oral contraceptive-only treated cycles.

Adult↗