Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Healthy, non-smoking, normotensive, well-motivated young women were assigned at random to one of four different, commercial, low-estrogen, oral contraceptive products. Measurements of biochemical parameters were made on blood specimens collected from fasting subjects twice during the late pretreatment cycle, then again during each late treatment cycle for six months. All women assigned to one product (0.5mg NET + 35 microgram EE) dropped out of the study before the end of the fifth cycle, but discontinuations with the other three products were few. While numbers of subjects are small, the groups are closely matched and most metabolic differences are statistically significant. Products containing EDA and NET were associated with increases in serum total cholesterol and triglycerides, but decreases in HDL-cholesterol. In contrast, the LNG-containing preparation produced significantly less effect on these tests. A similar pattern was seen with a range of blood coagulation and fibrinolytic factors, Minimal alterations were seen with the LNG preparation, while those containing NET or EDA showed marked increases in factors I. VII, VIII, X and plasminogen, associated with a decrease in antithrombin III. It is suggested that differences in the metabolic impact of the various commercially available low-estrogen preparations, combined with effects on intermenstrual bleeding, allow a choice of the progestogen component most suitable for general use.
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PMID:A randomized study of metabolic effects of four low-estrogen oral contraceptives: I. Results after 6 cycles. 679 98

A randomized double-blind study of two combined oral contraceptives and two progestogen-only oral contraceptives was conducted using the same protocol at WHO Collaborating Centres for Clinical Research in Human Reproduction in Bombay and Ljubljana of the 518 women admitted to the trial, 123 received mestranol 50 micrograms + norethisterone 1mg (MES 50 + NET 1); 137 received ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms (EE 30 + LNG 150); 130 received norethisterone 350 micrograms/NET 350); and 128 received levonorgestrel 30 micrograms (LNG 30). At one year, between 52.6 and 61.0 percent of those recruited had discontinued oral contraceptive use for all reasons, and by two years, between 70.5 and 76.5 percent had discontinued the treatment. These rates did not differ between the four treatment groups. However, discontinuation rates for all medical reasons at one and two years, and at two years pregnancy rates and discontinuation rates for bleeding disturbances, were significantly lower in the EE/LNG preparation. The groups receiving the MES/NET, LNG and NET had similar pregnancy rates, discontinuation rates for all medical reasons and all bleeding disturbances. There were two ectopic pregnancies among the 22 pregnancies in the progestogen-only groups. Discontinuation because of headache, dizziness and other central nervous system symptoms were significantly more common in those receiving MES/NET compared to EE/LNG. In contrast, discontinuation for gastro-intestinal disturbances were significantly higher in the EE/LNG combined preparation. Bleeding disturbances in the first few cycles tended to be higher in NET than in the LNG group. The data suggest that greater consideration be given to the benefits and risks of including progestogen-only oral contraceptives in the family planning programmes of some countries.
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PMID:A randomized, double-blind study of two combined and two progestogen-only oral contraceptives. 680 62

A randomized comparative trial of 832 women receiving (NET-EN) norethisterone enanthate and 846 women receiving (DMPA) depot medroxyprogesterone acetate injections at 12 week intervals was conducted in 10 centers. The pregnancy rate with NET-EN was significantly higher than with DMPA. The termination rate for amenorrhea was substantially lower with NET-EN than DMPA, whereas the discontinuation rates for bleeding problems were similar with the 2 drugs. Analysis of bleeding patterns among continuing and discontinuing users suggests that women tolerated frequent bleeding episodes, but found prolonged bleeding or prolonged bleeding-free intervals unacceptable. Bleeding for more than 30 days during an injection interval and complete amenorrhea for a whole injection interval were jointly associated with 43.7% of all terminations among NET-EN users and 64.5% of all terminations among DMPA users. In future efforts to improve the acceptability of long acting injectable contraceptives, more attention should be given to the control of prolonged amenorrhea and prolonged bleeding.
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PMID:Vaginal bleeding disturbances associated with the discontinuation of long-acting injectable contraceptives. From the World Health Organization Special Programme for Research, Development, and Research Training in Human Reproduction; Task Force on Long-acting Systemic Agents for the Regulation of Fertility. 700 25

Eleven healthy young women (age range 20-28 years) were given three different oral contraceptives (OCs) in random order, each contraceptive for 3 months. Smoking, eating, drinking and habits of physical activity were similar throughout the study period. The combinations were: ethinyl-estradiol/noretisterone (EE/NET) 35 micrograms/0.5 mg, 35 micrograms/1 mg and 50 micrograms/1 mg. The 35/0.5 and the 50/1 EE/NET combinations led to significant weight increases of 2.4 and 1.7 kg, respectively. All EE/NET combinations produced LDL-TG increases, from a pretreatment value of 0.28 +/- 0.04 (SD) mmol/l to 0.34 +/- 0.07, 0.35 +/- 0.06 and 0.42 +/- 0.13 mmol/l (P less than 0.01 for all). LDL-cholesterol increased from 2.99 +/- 0.63 mmol/l to 3.35 +/- 0.62 (P less than 0.01) after 35/1 treatment and to 3.43 +/- 0.62 mmol/l (P less than 0.001) after 50/1 treatment. These two EE/NET combinations also caused significant reductions of HDL-cholesterol, in both cases from a pretreatment value of 1.75 +/- 0.16 mmol/l to 1.64 +/- 0.24 mmol/l (P less than 0.05). Since all values after EE/NET treatment remained well within normal ranges, these low-dose OCs probably have little effect on the development of atherosclerosis due to serum lipoprotein abnormalities. However, our findings suggest that OCs may interfere with the cholesterol ester/TG exchange between LDL and HDL.
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PMID:Effects of ethinyl-estradiol/noretisterone combinations on serum lipoproteins. 715 2

Ths study examines the effects of SHBGc (sex hormone binding globulin capacity) of 4 oral combination contraceptives containing either norethindrone acetate (NET acet) or levo-norgestrel (Levo-Ng) and ethinyl estradiol (EE2): 1) 6 women used 250 ug levo Ng and 50 ug EE2 for 6 months; 2) 10 women used 150 ug levo-Ng and 30 ug EE2 for 6 months; 3) 5 women used 150 ug levo-Ng and 50 ug EE2 for 3 months; and 4) 9 women were on 1 mg NET acet and 30 ug EE2 for 1 month. Concentration of SHBGc in human plasma varied markedly depending on amount of estrogen and nature of progestational compounds. Levo-Ng reduced the EE2-induced SHBGc depending of the amount of dose. Mean % decrease with 250 ug levo-Ng + 50 ug EE2 was 30.6 + or - 20.9 (P 0.05). A decrease in levo-Ng to 150 ug actually increased the SHBGc. SHBGc remained almost unchanged when dosage of both levo-Ng and EE2 was low (150 ug and 30 ug respectively). NET acet alone did not lower SHBGc but when combined with 30 ug EE2, 1 mg NET acet increased SHBGc. The findings may be useful in the selection of combination therapy for conditions like hirsutism which benefits from increase in SHBGc.
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PMID:Oral contraceptives and sex hormone binding globulin capacity. 718 43

Plasma levels of (NET) norethisterone, (EE) ethinyl estradiol, Ampicillin, or Metronidazole were estimated in 16 women who were taking low-dose (OC) oral contraceptives (containing norethisterone acetate, 1 mg, and ethinyl estradiol, 30 mcg) and in whom concurrently, either Ampicillin (6 women) or Metronidazole therapy (10 women) was given. Neither drug altered the peak or 24-hour plasma levels and area under the curve for NET and EE. Furthermore, OC treatment did not alter the peak levels of either Ampicillin or Metronidazole. (P) Progresterone levels were in the anovulatory range in all Ampicillin-treated cycles. However, in Metronidazole-treated group, 2 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 and only 1 woman showed a P rise of more than 4 ng/ml. The occurrence of 'escape ovulation' as suggested by a P rise of more than 4 ng/ml in 3 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 1 out of 3 women showing a P rise ( 4 ng/ml) during concurrent Metronidazole therapy also showed ovulatory P values in OC-only treated cycles. Furthermore, in the control group, 1 out of 10 women had ovulatory P levels ( 4 ng/ml) in OC-only treated cycles.
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PMID:A study of interaction of low-dose combination oral contraceptive with Ampicillin and Metronidazole. 721 11

Norethisterone oenanthate (NET OEN) was extensively hydrolysed in rabbit, rat and guinea pig plasma (99.9%, 76.1% and 46.0% hydrolysed in 90 min, respectively). In contrast, there was negligible hydrolysis (less than 2.5%) in dog, goat and human plasma. Rabbit liver, kidney, gut wall, stomach, heart and muscle showed marked hydrolytic activity in vitro, but there was little hydrolysis of NET OEN by either human muscle or fat. It is proposed that following intramuscular administration of NET OEN to rabbits, the ester is rapidly hydrolysed at the injection site and in the circulation whereas in humans the liver is the main site of hydrolysis since neither muscle nor plasma cause significant breakdown of the ester. The rabbit is not a good model for predicting the pharmacokinetics of NET OEN in humans.
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PMID:Studies on the enzymatic cleavage of norethisterone oenanthate. 723 40

The characteristics and transfer of human uterine progestin receptors from cytosol to nucleus were studied in a cell-free system using [3H]progesterone ([3H]P), [3H]norethindrone ([3H]NET), and [3H]norethindrone acetate ([3H]NETA) as progestin receptor tags. Nuclear receptor binding was observed only in the presence of uterine cytosol. Various prior treatments of uterine cytosol, including warming to 20 C, increasing the salt concentration to 150 mM KCl, or dilution of the cytosol protein concentration to 3 mg/ml, increased the affinity of the receptor for the cell nucleus and thus, facilitated more translocation. However, there was no detectable difference in the receptor sedimentation value after activation. The binding of salt-extractable (400 mM KCl) nuclear sites to [3H]P, [3H]NET, and [3H]NETA was characterized by distinct commonality in their physiochemical properties, as indexed by their coelution during gel chromatography (mol wt, 72,000), their similar sedimentation rates (4.2S), and their similar isoelectric profiles (isoelectric pH 5.3--5.6). The concentrations of specific binding sites were similar for the different 3H-labeled progestins used. However, in general, the number of binding sites was higher (3780--4480 molecules/cell) in proliferative phase tissues and significantly lower (1790--1920 molecules/cell) in secretory phase tissues. Furthermore, nuclear binding was progestin specific and of high affinity (Kd of NET, similar to or approximately 0.7--0.8 nM; Kd of P, similar to or approximately 0.9--1.2 nM; Kd of NETA, similar to or approximately 6.7--7.1 nM). Despite the similarities in the molecular properties, the nuclear bindings of NET and NETA could be distinguished from that of P by their lower dissociation rates (t 1/2 of NET, similar to or approximately 6.3 h; t 1/2 of NETA, similar to or approximately 5.5 h; t 1/2 of P, similar to or approximately 1.2 h). Moreover, NET and NETA, unlike P, did not bind to corticosteroid-binding globulin. These observations indicate that the various progestins mediate their action via a common receptor, which translocates from cytosol to nucleus. Further, because of the distinct advantages, NET could be conveniently used as a receptor tag to evaluate the progestin receptor.
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PMID:Nuclear progestin receptors in human uterus. 725 58

The pharmacokinetics of a dose of 200 mg NET-OEN were studied after intramuscular injection into nine subjects. Blood levels of NET and NET-OEN increased rapidly, reaching peaks in most subjects within seven days. At all times after injection, serum levels of NET exceeded those of NET-OEN. The half-life of absorption varied from 5.4 to 22.3 days and the half-life of elimination varied from 7.5 to 22.5 days; there was a significant correlation (R = 0.78) between these two half-lives. There were significant correlations between the absorption half-lives and the peak values of NET and NET-OEN, the time to reach peak values and the time for which NET was detectable in serum. In all subjects NET was detectable in the circulation for a longer time after injection (mean value 74 days) than NET-OEN (mean value 43 days). The time for which the two steroids were detectable in the circulation showed a significant correlation with the elimination half-lives but there was no correlation with the peak values attained, the time taken to reach peak values and bioavailability. There was a two-fold variation between the subjects in the bioavailability of NET, less than 5% of the bioavailable NET was released after day 60.
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PMID:Pharmacokinetics of norethisterone oenanthate in humans. 727 65

The effect of Norethisterone-oenanthate (NET-OEN), a long acting injectable contraceptive on cervical spinnbarkeit and protein content were studied in adult female virgin rats. A single injection of NET-OEN (1 mg/rat) and sacrificed after 3 vaginal cycles produced a highly significant reduction (P less than 0.001) in the spinnbarkeit and a non-significant increase in the protein content of the cervical mucus. But two successive injections of NET-OEN (1 mg/rat each) produced a highly significant decrease (P less than 0.001) in the spinnbarkeit as well as a significant increase (P less than 0.01) in the protein content. The increased protein content of cervical mucus corroborates the hypothesis that NET-OEN exerts its contraceptive effect primarily through effect on cervical mucus.
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PMID:Effect of norethisterone oenanthate-a long acting injectable contraceptive on cervical mucus changes in adult female virgin rats. 734 5


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