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PubMed1983

Poly(DL-lactide-co-glycolide)/norethisterone microcapsules: an injectable biodegradable contraceptive.

Microcapsules made from a biocompatible, biodegradable polymeric excipient, poly(DL-lactide-co-glycolide) (DL-PLGA) that contained 22 weight percent (wt %) norethisterone (NET), were prepared by a solvent-evaporation microencapsulation process. The effects of changing both the lactide-to-glycolide ratio of the DL-PLGA and the size of the microcapsules on the rate of NET release and the rate of excipient biodegradation were determined in vivo. NET release rates were determined in baboons after injecting the microcapsule formulations intramuscularly. Serum samples obtained at various times following treatment were analyzed for NET, progesterone, and estrogen by radioimmunoassay (RIA). Biodegradation kinetics were determined by injecting NET microcapsules made from radiolabeled DL-PLGA intramuscularly into the hind legs of rats. Residual radioactivity at the injection site was determined at various times after treatment by combustion analysis of the muscle tissue. Changing the ratio of the comonomers to include more glycolide (DL-lactide:glycolide-96:4, 92:8, 87:13, 74:26) increased the rate of NET release and accelerated the biodegradation of the copolymer excipient. Decreasing the size of the microcapsules increased the rate of NET release. On the basis of these studies a NET microcapsule formulation has been identified for clinical testing which releases NET for 3 months and biodegrades completely within 6 months.

Animals↗
PubMed1980

Effects on sex hormone binding globulin of different oral contraceptives containing norethisterone and lynestrenol.

Six combined oral contraceptive drugs containing ethinyloestradiol or mestranol and norethisterone or lynestrenol were studied throughout six 21-day cycles in healthy female volunteers. There was always one menstrual cycle without treatment between every treatment cycle. Plasma levels of norethisterone were determined throughout treatment by use of a specific radioimmunoassay. Sex hormone binding globulin (SHBG) was measured by an ammonium sulphate precipitation method at the beginning and at the end of each treatment cycle. The results indicated an accumulation of norethisterone in plasma when 1 to 3 mg of norethisterone or lynestrenol was given. There was no obvious accumulation during treatment with 0.5 mg norethisterone. SHBG increased during treatment with all combinations studied. However, this increase was most pronounced with the 50 microgram ethinyloestradiol/l mg lynestrenol, 50 microgram mestranol/l mg norethisterone and 35 microgram ethinyloestradiol/0.5 mg norethisterone combinations. There was no statistically significant increase in SHBG with 50 microgram ethinyloestradiol/2.5 mg lynestrenol or 50 microgram ethinyloestradiol/3 mg norethisterone acetate combinations. The results indicated that the induction of SHBG by the synthetic oestrogens was antagonized by the progestogens in a dose-dependent manner. The effect on SHBG by a combind preparation could be one assessment of the oestrogenicity or androgenicity of the preparation.

Adult↗
PubMed1975

Anti-inflammatory steroids, lysosomal stabilization and parachor.

Parachor is an additive constitutive property of a molecule and is related to the molar volume and the surface tension. The parachor of a steroid can be calculated from its constituent atoms and bonds. The parachor of a biologically active molecule is related to the ability of that molecule to permeate hydrophobic regions of cells, especially cellular membranes. An examination of the parachor values of a large number of steroids shows that these values are correlated with a number of different biological activities, from independent sources. The ability of steroids to release lysosomal enzymes from isolated lysosomes in vitro is inversely related to the parachor of the steroid. A similar relationship holds for the release of lysosomal beta-glucoronidase (EC 3.2.1.31) from isolated lysosomes of rat preputial gland following in vivo administration of steroids. The relative anti-inflammatory potencies of steroids by several assay methods are directly proportional to their parachors. The relative ability of corticosteroids to uncouple oxidative phosphorylation and to swell isolated mitochondria in vitro show a direct proportionality with the steroidal parachor. The percutaneous absorptions of steroids show good correlation with parachors, stratum corneum-water partition coefficients and amylcaproate-water partition coefficients; but not with hexadecane-water partition coefficients. The application of parachor as a structure-activity correlation parameter in drug design is likely to yield useful information. The advantages and limitations of the calculated parachor method are discussed.

Androgens↗
PubMed1992

Existence of multiple peaks in plasma ethinyl estradiol and norethindrone after oral administration of a contraceptive pill.

Previous measurements of plasma ethinyl estradiol (EE2) and norethindrone (NE) over 24 h after oral administration of a contraceptive pill have demonstrated a single steroid peak occurring 1-2 h after pill ingestion, with a gradual decline over the next 22 h. In the present study plasma concentrations of EE2 and NE were measured 0, 0.5, 0.75, 1, 2, 4, 12, and 24 h after oral ingestion of a contraceptive pill containing 35 micrograms EE2 and 1 mg NE at 0, 3, 6, and 9 months of use in 58 normal healthy women. Contrary to previous reports, analysis of the 464 steroid curves (58 subjects x 4 time periods x 2 steroids) revealed the presence of multiple hormone peaks. Two peaks of EE2 were identified in 44.8% of women during the first pill cycle and in 75.9%, 55.2%, and 67.2% of women after 3, 6, and 9 months of pill use. Two hormone peaks of NE were observed in 29.3% of women during the first cycle and in 36.2%, 50%, and 44.8% at 3, 6, and 9 months, respectively. Existence of these multiple peaks at the frequency observed has not previously been reported. Further quantification of the frequency and magnitude of these peaks could be helpful in explaining differences in biological responses associated with pill use.

Adult↗
PubMed1975

[The experimental studies on the estrogenic activities of 17alpha-ethynyl-17beta-hydroxy-19-norandrost-4-en-3-one (ENT) (author's transl)].

Today, ENT is a popular synthetic progesteron for clinical use, and is well known to have some estrogenic activity. Estradiol-17beta (E2) or 17alpha-ethynyl estradiol (EE2) binding to the specific protein in the nuclear fraction of hypothalamus were examined by 3H-E2 exchange assay reported by Anderson. The possible mode of the estrogenic actions of ENT are as follows: 1) Conversion of ENT to EE2. 2) Estrogenic of ENT per se without changing the chemical structure. 3) Conversion of ENT to other estrogenic compounds except for EE2. In this experiment, 3H-ENT or 3H-testosterone (3H-T) was incubated with human placental microsomes and NADPH generating system for 1 hr at 37 degrees C, 3H-delta4AD, 3H-T and 3H-ENT were incubated also with homogenates of rat hypothalamus under the same conditions. Isolation and purification of the metabolites were performed by using phenolic separation and paper chromatography. Identification of EE2, a metabolite of ENT, was established by measuring the radiochemical homogenity with the authentic standard on paper chromatography. In another experiment where alkali was not used during the extraction procedure to avoid making artificial products, the conversion rate of ENT to EE2 was measured. This experimental data indicated that ENT was converted to 1beta-OH-ENT and to EE2 by human placental microsomes. The former compound was easily converted to EE2 in the presence of NaOH or by incubation with bile. In the incubation with hypothalamic preparation neither aromatization nor 1beta-hydroxylation of delta4AD, T and ENT were detected. In the exchange assays of E2 receptor, the animals were killed 1 hr after the administration of 25 mug of various steroids. The hypothalamic nuclear fraction was incubated with various 3H-steroids for 30 min at 37 degrees C. After washing this nuclear pellet, the radioactivity was counted. Administration of E2 in vivo resulted in the increase of the amount of 3H-EE2 bound to the nuclear fraction in vitro. But only a small increase of binding was observed in the similar experiment with 3H-ENT. 3H-EE2 was exchanged more abundantly after ENT administration than after EE2 injection. From the above results, it was concluded that the estrogenic effect of ENT is attributed to the EE2 converted in vivo. In addition, a possibility was proposed that ENT or its metabolites other than EE2 could regulate some step in the mechanism of estrogen action.

Androstenedione↗
PubMed1981

[Pharmacokinetics of norethindrone and lynestrenol studied by HPLC (author's transl)].

The concentration of norethindrone in plasma samples from subjects receiving norethindrone (norethisterone) and lynestrenol orally was measured by high pressure liquid chromatography (HPLC). Norethindrone is a synthetic gestagen widely used in contraceptive formulations, and lynestrenol is also a synthetic gestagen which is metabolized to norethindrone in humans. But the evaluation of plasma norethindrone levels in subjects receiving lynestrenol has not yet been reported. After the administration of norethindrone, the peak level of norethindrone in the plasma was obtained within 2h, and the peak concentration in the plasma was about 3.5 ng/ml/mg norethindrone. During a period of 2-6hs after the administration of norethindrone, the half life of norethindrone in the plasma was approximately 1.8h, and during the period of 6-24hs, half life was variable. On the other hand, after the administration of lynestrenol, the peak level of norethindrone in the plasma was obtained within 4h, and the peak concentration of norethindrone was about 1.9 ng/ml/mg lynestrenol. During a period of 4-12hs, the half life of norethindrone was about 2.5h. The peak of the norethindrone level after the administration of lynestrenol was lower and appeared later than that after the administration of the same dose of norethindrone. Norethindrone in plasma in subjects receiving lynestrenol could be measured for a longer period than in those receiving the same dose of norethindrone. These results suggest that lynestrenol is stored in fat tissue and is slowly metabolized to norethindrone.

Administration, Oral↗
PubMed1982

Pharmacokinetics of norethindrone acetate in women after the insertion of a single subdermal implant releasing norethindrone acetate.

The metabolic clearance rate (MCR) of norethindrone acetate (NETA) and norethindrone (NET) levels in plasma were studied after an iv injection of [3H]NETA in three women before and at 1 week, 1, 2 and 6 months following the insertion of a single silastic subdermal implant releasing microquantities of NETA. No significant change in the MCR of NETA was observed at 1 week (459 +/- 72 1/day), 1 month (489 +/- 113 1/day) and 2 months (522 +/- 144 1/day) compared with that of control (525 +/- 108 1/day). However, MCR of NETA showed significant increase in women exposed to continuous presence of NETA for a period of 6 months (608 +/- 121 1/day; P less than 0.025). NETA was rapidly and extensively metabolized into NET. At 1 week, 1, 2 and 6 months of study, NET was observed to be present in higher amounts compared with NETA. The production rate (PR) of progesterone decreased significantly at 2 and 6 months of NETA implant insertion compared with the PR before the insertion of implant.

Adult↗
PubMed1983

Norethindrone in serum after use of an oral contraceptive containing norethindrone acetate.

The availability of norethindrone (NET) in serum was studied in 8 women after daily administration of a combination oral contraceptive pill (MinovlarR) containing 1 mg norethindrone acetate (NETA) and 50 micrograms ethinyl estradiol (EE2) from day 5 to day 25 of the menstrual cycle. The pill was taken daily at 9:30 a.m. after a light breakfast and blood samples were collected at 3 hr on alternate days and at 24 hr on other days after ingestion of the pill. On day 12 or day 15 of the first treatment cycle, serial blood samples were also collected at 1/2, 1, 2, 4, 6, 8 and 24 hr after taking the pill. Serum NET levels were estimated by the radioimmunoassay (RIA) technique. The plot of serum NET concentration versus time (0-24 hr) profile showed a rapid absorption of steroid and a peak NET concentration (18.3 +/- 4.8 ng/ml) reached at 2 hr after ingestion of the pill. By linear regression analysis of data (y = 0.27 + 0.12x; r = 0.95), it was observed that the serum NET level was initially about 1 ng/ml. Thereafter, it increased by 0.12 ng/ml per day up to 3.5 ng/ml by the end of 21 days' treatment with oral pills. The serum NET concentration decay slope fitted a two-compartment open model with an initial rapid decay (half-life of 1.2 +/- 0.1 hr) followed by a slower beta-phase with a half-life of 8.5 +/- 1.5 hr. The study revealed that there was an accumulation of norethindrone in plasma during the treatment period and this suggests the possibility of exploring a reduction in the dose of this preparation so as to achieve the optimum NET concentration for contraception, and thereby avoiding unwanted steroid accumulation in the plasma of women.

Adult↗
PubMed1984

Pharmacodynamics of a contraceptive vaginal ring releasing norethindrone and estradiol: ovarian function, bleeding control and lipoprotein patterns.

A new contraceptive vaginal ring (CVR), releasing approximately 700 micrograms of norethindrone (NET) and approximately 140 micrograms of estradiol (E2) daily, was studied in eleven women for a total of 61 21-day cycles. Ovarian function, as judged by plasma progesterone (P) and E2 levels, and plasma NET levels were studied by weekly blood samples in 30 cycles. The lipoprotein pattern was studied before, after two and six months of treatment and one month after completed treatment. The CVR gave rise to stable plasma NET levels which however varied considerably between individuals. Signs of luteal activity/ovulation were encountered in 4/30 cycles, all in subjects with the lowest NET plasma levels. E2 levels above 250 pmol/l, indicating follicular activity, were encountered in 22/30 cycles. Breakthrough bleeding and spotting appeared in 40/61 cycles and in 12 per cent of the treatment days. Bleeding control was significantly better in the same subjects when using a CVR releasing levo-Norgestrel and E2. Serum and HDL cholesterol concentrations decreased significantly by 10-12 per cent during treatment. The ratios between apolipoproteins A-I and A-II on one hand and HDL cholesterol on the other increased significantly and the ratio apolipoprotein A-I:A-II decreased significantly, indicating a change in the lipoprotein composition. These changes are qualitatively similar but quantitatively not as pronounced as with the more extensively studied 1-Ng/E2 CVR. The difference in clinical performance and in the effects on the lipoprotein pattern between the presently studied CVR and the 1-Ng/E2 CVR is most likely the result of not using equipment doses of gestagen in the CVRs.

Adult↗
PubMed1975

Microbiological hydroxylation of norethisterone.

Hydroxylation of norethisterone by a large number of fungi has been investigated. 1alpha-Hydroxy-, 6beta-hydroxy-, 10beta-hydroxy-, 10beta,11beta-dihydroxy-15alpha-and 15beta-hydroxy-derivatives were formed from norethisterone. The microbiological dehydrogenation of 10beta-hydroxy-norethisterone resulting in 10beta,17beta-dihydroxy-17-ethynyl-1,4-estradien-3-one was also observed. The structure of transformation products was established by chemical and spectroscopical methods.

Chemical Phenomena↗
PubMedDate not supplied

Radioimmunoassay of norethindrone (17 alpha-ethynyl-17 beta-hydroxy-4-estren-3-one) and ethynyl-estradiol (17 alpha-ethynyl-1,3,5, (10)-estratien-3, 17 beta-diol). Application to human plasma determination of norethindrone after oral administration of this steroid.

The experiment conditions for the evaluation of Norethindrone (17 alpha-Ethynyl-17 beta-hydroxy-4-estren-3-one, NET) and Ethynyl-estradiol (17 alpha-ethynyl-1, 3, 5 (10) estratrien-3, 17 beta-diol, EE) by radioimmunoassay are described. A minimal quantity of 25 pg of these two steroids could be evaluated using different reduced metabolites of NET, very little cross reaction is observed with 200 pg of these metabolites. No effect was observed with estradiol for the EE-antiserum. The NET-antiserum was used to evaluate this steroid and ethynodiol diacetate after oral administration to female volunteers. Maximal values in the plasma (2-3% of the administered dose) was found between 1-3 h after administration and at 24 h a concentration of 0.1-0.3% still remained in the plasma.

Administration, Oral↗