Distribution and properties of angiotensin-converting enzyme in cerebral microvessels of the rabbit and rat.
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Biomedical subjects
Publications and source records attributed to V Hingorani.
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A comparative pilot study was undertaken in three centers to determine the time of return of ovulation after the injection of the steroidal contraceptive norethisterone oenanthate (NET-OEN). The effect of the compound on the endometrium and some properties of cervical mucus were also assessed. Increases in plasma progesterone levels suggested that ovulation resumed in all six women in Bahia within 60 days of injection of NET-OEN, whereas in Bangkok and New Delhi only two women in each center ovulated within this time. The difference in the time of return of ovulation between women in Bahia (mean time 42 days) and those in Bangkok and New Delhi (92.5 days) was statistically significant. Follicular function returned earlier than luteal function: all six women in Bahia and Bangkok and five of the six in New Delhi showed evidence of follicular activity within 60 days. All endometrial biopsies, obtained at a time of increased progesterone production, were secretory and suggested that administration of the gestagen did not exert a prolonged suppression of endometrial activity. In general, changes in cervical mucus were consistent with variations in plasma steroid levels.
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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.
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A single suppository containing 3.0 mg 15 (S)15-methyl-PGF2 alpha-methyl ester was administered vaginally in women to terminate mid-trimester pregnancy. Plasma levels of the drug (both methyl ester and free acid forms) were measured at different time intervals using deuterated carriers and gas chromatography-mass-spectrometry. 15(S)15-methyl PGF2 alpha (sum of methyl ester + free acid) was found to have a mean value of 1166 pg/ml plasma at 3 hrs after administration of the suppository. The mean levels were subsequently found to be maintained in the range of 1000 pg/ml. Preliminary studies showed that unlike the successfully aborted women, in those who did not abort within 30 hrs with this suppository, the plasma levels of the drug were not maintained for a sufficiently long time. The episodes of side effects, body surface area and the induction-abortion interval in relation to the plasma levels are discussed.
Norethindrone (17beta-hydroxy-19-nor-17alpha-pregn-4-en-20-yn-3-one) and norethindrone acetate (17beta-acetoxy-19-nor-17alpha-pregn-4-en-20-yn-3-one) interfered to a varying degree, by competitive inhibition, with the binding of progesterone and oestradiol to respective cytoplasmic receptors in the human uterus. Progesterone binding to 4S macromolecule was saturable and co-specific for progestins. Competitors like norgestrel (17beta-hydroxy-18-methyl-19-nor-17alpha-pregn-4-en-20-yn-3-one), 19-norprogesterone, medroxyprogesterone acetate (17alpha-acetoxy-6alpha-methylpregn-4-ene-3,20-dione) and compound R(5020) (17,21-dimethyl-19-norpregna-4,9-diene-3,20-dione) possessed higher binding affinities for the progestin receptor. The dissociation constant (K(d)) for the progesterone-receptor interaction was 0.6-1.6nm and the receptor concentration ranged between 6600 and 8200 sites/cell. Norethindrone and norethindrone acetate competed for the progesterone receptor with inhibition constants (K(i)) of 6.8 and 72nm respectively. Gradient displacement and competitive-receptor assays indicated that norethindrone acetate-binding affinity for progestin receptor was approximately one-tenth that of norethindrone and progesterone. The progestins also inhibited oestradiol binding to 4.6S oestrogenic receptor by 8-12%, involving interaction at the oestradiol-binding site with a calculated K(i) value of 0.5-0.8mum. The competitive interaction of progestins with steroid receptors may be of putative importance in explaining the progestin action at the target site.
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A specific radioimmunoassay was developed for the estimation of norethindrone levels in the serum of lactating women. A conjugate of norethindrone-3-BSA was synthesized and antiserum raised against it in rabbits. The antiserum showed high affinity (1.5 x 10(9)M/L) and titer and was specific. The sensitivity of the assay was 125 pg/ml serum. Serum levels of norethindrone were estimated in 25 lactating women, inserted with subdermal implant releasing about 150 ug of norethindrone acetate daily. The norethindrone levels were initially high in the first two months. From there onwards the levels of norethindrone remained constant with an average value of 1.0 ng/ml up to six months. These values were comparable to those obtained in non-lactating women. Thus, lactation does not seem to alter or affect the release of norethindrone acetate from the subdermal implant or its metabolism.
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