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M L Orme - One of the best experts on this subject based on the ideXlab platform.

  • the pharmacokinetics of ethynylestradiol in the presence and absence of gestodene and Desogestrel
    Contraception, 1991
    Co-Authors: M L Orme, D J Back, Stephen A. Ward, S. Green
    Abstract:

    Single doses of ethynylestradiol (30 μg) were given alone and in combination with either gestodene (75 μg) or Desogestrel (150 μg) to 10 healthy female volunteers. The doses of steroids were given both orally and by i.v. infusion over 5–7 minutes. Blood samples were taken at regular intervals over 24 hours. The area under the plasma concentration versus time curve (AUC) for oral EE2 alone was 867 ± 338 pg/ml × h, for oral EE2 in the presence of gestodene it was 795 ± 206 pg/ml × h and for oral EE2 in the presence of Desogestrel it was 614 ± 132 pg/ml × h. With either gestodene or Desogestrel present, the AUC of EE2 was not significantly different from that found when EE2 was given alone. In addition, there was no significant difference between EE2 + gestodene and EE2 + Desogestrel. Comparing the relative oral and iv doses, the bioavailability of EE2 (alone) was 59.0 ± 13% (n = 6), for EE2 plus gestodene it was 62.1 ± 10% and for EE2 in the presence of Desogestrel it was 62.1 ± 4.4%. The clearance of EE2 (alone) was 19.9 ± 5.5 1/h and in the presence of gestodene it was 19.4 ± 9.6 1/h. The clearance of EE2 in the presence of Desogestrel appeared slightly greater at 27.7 ± 8.9 1/h but none of these clearance values were significantly different from each other. The urinary excretion of 6-beta-hydroxy cortisol was similar after all 6 doses of EE2. These data strongly suggest that following single dose administration, neither gestodene nor Desogestrel have any inhibitory effect on the metabolism of EE2 or alter its kinetics to any clinically significant extent.

  • effect of the progestogens gestodene 3 keto Desogestrel levonorgestrel norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes
    The Journal of Steroid Biochemistry and Molecular Biology, 1991
    Co-Authors: D J Back, Stephen A. Ward, R Houlgrave, J Tjia, M L Orme
    Abstract:

    Abstract A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), Desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE 2 ) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or “suicide” inactivation of cytochrome P -450. We have compared the effects of the different progestogens on EE 2 2-hydroxylation (a reaction catalyzed by enzymes from the P -450IIC, P -450IIIA and P -450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE 2 as substrate, GSD, 3-keto Desogestrel (3-KD, the active metabolite of Desogestrel) and LNG produced some concentration-dependent inhibition of EE 2 2-hydroxylation (maximum 32% inhibition at 100 μM 3-keto Desogestrel). K i values determined for GSD and 3-KD were 98.5 ± 12.3 and 93.2 ± 10.3 μ M (mean ± SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 μl) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 μM, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively). In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD > 3-KD > NET > LNG for production of both metabolite M17 and M21. The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.

  • effect of the progestogens gestodene 3 keto Desogestrel levonorgestrel norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes
    The Journal of Steroid Biochemistry and Molecular Biology, 1991
    Co-Authors: D J Back, Stephen A. Ward, R Houlgrave, J Tjia, M L Orme
    Abstract:

    A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), Desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE2) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or "suicide" inactivation of cytochrome P-450. We have compared the effects of the different progestogens on EE2 2-hydroxylation (a reaction catalyzed by enzymes from the P-450IIC, P-450IIIA and P-450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE2 as substrate, GSD, 3-keto Desogestrel (3-KD, the active metabolite of Desogestrel) and LNG produced some concentration-dependent inhibition of EE2 2-hydroxylation (maximum 32% inhibition at 100 microM 3-keto Desogestrel). Ki values determined for GSD and 3-KD were 98.5 +/- 12.3 and 93.2 +/- 10.3 microM (mean +/- SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 microliters) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 microM, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively). In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD greater than 3-KD greater than NET greater than LNG for production of both metabolite M17 and M21. The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.

Laurence Bodineau - One of the best experts on this subject based on the ideXlab platform.

  • Desogestrel enhances ventilation in ondine patients: Animal data involving serotoninergic systems
    Neuropharmacology, 2016
    Co-Authors: Fanny Joubert, Thomas Similowski, Christian Straus, Anne-sophie Perrin-terrin, Emilienne Verkaeren, Philippe Cardot, Marie-noëlle Fiamma, Alain Frugière, Isabelle Rivals, Laurence Bodineau
    Abstract:

    Central congenital hypoventilation syndrome (CCHS) is a neurorespiratory disease characterized by life-threatening sleep-related hypoventilation involving an alteration of CO2/H+ chemosensitivity. Incidental findings have suggested that Desogestrel may allow recovery of the ventilatory response to CO2. The effects of Desogestrel on resting ventilation have not been reported. This study was designed to test the hypothesis that Desogestrel strengthens baseline ventilation by analyzing the ventilation of CCHS patients. Rodent models were used in order to determine the mechanisms involved. Ventilation in CCHS patients was measured with a pneumotachometer. In mice, ventilatory neural activity was recorded from ex vivo medullary-spinal cord preparations, ventilation was measured by plethysmography and c-fos expression was studied in medullary respiratory nuclei. Desogestrel increased baseline respiratory frequency of CCHS patients leading to a decrease in their PETCO2. In medullary spinal-cord preparations or in vivo mice, the metabolite of Desogestrel, etonogestrel, induced an increase in respiratory frequency that necessitated the functioning of serotoninergic systems, and modulated GABAA and NMDA ventilatory regulations. c-FOS analysis showed the involvement of medullary respiratory groups of cell including serotoninergic neurons of the raphe pallidus and raphe obscurus nuclei that seem to play a key role. Thus, Desogestrel may improve resting ventilation in CCHS patients by a stimulant effect on baseline respiratory frequency. Our data open up clinical perspectives based on the combination of this progestin with serotoninergic drugs to enhance ventilation in CCHS patients.

  • The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures
    Neuroscience Letters, 2014
    Co-Authors: Camille Loiseau, Diane Osinski, Fanny Joubert, Thomas Similowski, Christian Straus, Laurence Bodineau
    Abstract:

    Abstract Central congenital hypoventilation syndrome is a neuro-respiratory disease characterized by the dysfunction of the CO 2 /H + chemosensitive neurons of the retrotrapezoid nucleus/parafacial respiratory group. A recovery of CO 2 /H + chemosensitivity has been observed in some central congenital hypoventilation syndrome patients coincidental with contraceptive treatment by a potent progestin, Desogestrel (Straus et al., 2010). The mechanisms of this progestin effect remain unknown, although structures of medulla oblongata, midbrain or diencephalon are known to be targets for progesterone. In the present study, on ex vivo preparations of central nervous system of newborn rats, we show that acute exposure to etonogestrel (active metabolite of Desogestrel) enhanced the increased respiratory frequency induced by metabolic acidosis via a mechanism involving supramedullary structures located in pontine, mesencephalic or diencephalic regions.

Hershel Jick - One of the best experts on this subject based on the ideXlab platform.

  • Cerebral venous sinus thrombosis in users of four hormonal contraceptives: levonorgestrel-containing oral contraceptives, norgestimate-containing oral contraceptives, Desogestrel-containing oral contraceptives and the contraceptive patch.
    Contraception, 2006
    Co-Authors: Susan S. Jick, Hershel Jick
    Abstract:

    Abstract Background It has been suggested that the risk for cerebral venous sinus thrombosis (CVST) may be greater among users of the contraceptive patch than among users of oral contraceptives (OCs). Methods From the PharMetrics database, we identified women aged 15–44 years who filled at least one prescription for either the contraceptive patch or Desogestrel-containing, norgestimate-containing or levonorgestrel-containing OCs to assess the risk of CVST. The person-time of current exposure to each study drug, as well as the incidence rates (IRs) and incidence rate ratios (IRRs) of CVST, was calculated. Results We identified over 1 million users of the four study drugs. There were five cases of CVST among current users of Desogestrel, seven cases among current users of norgestimate, two cases among current users of levonorgestrel and none among current users of the contraceptive patch. The IRs per 100,000 woman-years were 2.7 [95% confidence interval (95% CI)=0.9–6.3], 1.6 (95% CI=0.7–3.3), 0.7 (95% CI=0.1–2.4) and 0.0 (95% CI=0.0–4.8), respectively, in users of Desogestrel, norgestimate, levonorgestrel and the contraceptive patch. There were two women who had CVST while not currently taking a hormonal contraceptive (IR=0.4 per 100,000 woman-years; 95% CI=0.1–1.3). The IRRs were 4.0 (95% CI=0.7–42.4) for Desogestrel-containing versus levonorgestrel-containing OCs, and 2.4 (95% CI=0.5–24.0) for norgestimate-containing versus levonorgestrel-containing OCs. The IRR for the patch could not be calculated. Conclusions There is no evidence of an increased risk of CVST in users of the contraceptive patch compared to users of levonorgestrel-containing OCs.

  • Original research article Cerebral venous sinus thrombosis in users of four hormonal contraceptives: levonorgestrel-containing oral contraceptives, norgestimate-containing oral contraceptives, Desogestrel-containing oral contraceptives and the contra
    2006
    Co-Authors: Susan S. Jick, Hershel Jick
    Abstract:

    Background: It has been suggested that the risk for cerebral venous sinus thrombosis (CVST) may be greater among users of the contraceptive patch than among users of oral contraceptives (OCs). Methods: From the PharMetrics database, we identified women aged 15–44 years who filled at least one prescription for either the contraceptive patch or Desogestrel-containing, norgestimate-containing or levonorgestrel-containing OCs to assess the risk of CVST. The person-time of current exposure to each study drug, as well as the incidence rates (IRs) and incidence rate ratios (IRRs) of CVST, was calculated. Results: We identified over 1 million users of the four study drugs. There were five cases of CVSTamong current users of Desogestrel, seven cases among current users of norgestimate, two cases among current users of levonorgestrel and none among current users of the contraceptive patch. The IRs per 100,000 woman-years were 2.7 [95% confidence interval (95% CI)=0.9–6.3], 1.6 (95% CI=0.7–3.3), 0.7 (95% CI=0.1–2.4) and 0.0 (95% CI=0.0–4.8), respectively, in users of Desogestrel, norgestimate, levonorgestrel and the contraceptive patch. There were two women who had CVST while not currently taking a hormonal contraceptive (IR=0.4 per 100,000 woman-years; 95% CI=0.1–1.3). The IRRs were 4.0 (95% CI=0.7–42.4) for Desogestrel-containing versus levonorgestrel-containing OCs, and 2.4 (95% CI=0.5–24.0) for norgestimate-containing versus levonorgestrel-containing OCs. The IRR for the patch could not be calculated. Conclusions: There is no evidence of an increased risk of CVST in users of the contraceptive patch compared to users of levonorgestrelcontaining OCs.

  • risk of idiopathic cardiovascular death and rionfatal venous thromboembolism in women using oral contraceptives with differing progestagen components
    The Lancet, 1995
    Co-Authors: Hershel Jick, Marian Wald Myers, Catherine Vasilakis, Susan S. Jick, Victor Gurewich
    Abstract:

    Abstract Summary Concern about the risks of cardiovascular illness in women using combined oral contraceptives (OC) containing the progestagens Desogestrel and gestodene prompted two studies of data from the UK General Practice Research Database. We compared the risks of certain cardiovascular illnesses in otherwise healthy women exposed to one of three OCs containing In the first study, based on some 470 general practices, there were 15 cases of unexpected idiopathic cardiovascular death among 303 470 women who were current users of one of the study OCs. The estimated incidence rates were 8/184 536 (4·3 per 100 000) woman-years at risk for users of combined OCs containing levonorgestrel, 2/135567 (1·5 per 100 000) for Desogestrel users, and 5/105 201 (4·8 per 100 000) for gestodene users. The relative risk (RR) estimates were 0·4 (95% Cl 0·1-2·1) and 1·4 (Cl 0·5-4·5) for Desogestrel and gestodene, respectively, compared with levonorgestrel. In the second study, derived from some 370 general practices, there were 80 cases of nonfatal venous thromboembolism (VTE) in a cohort of 238 130 otherwise healthy women. The incidence rates of VTE per 100 000 woman-years at risk were 16·1 for levonorgestrel users, 29·3 for Desogestrel, and 28·1 for gestodene. The adjusted RR estimates from the cohort analysis were 1·9 (1·1-3·2) and 1·8 (1·0-3·2) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. In a nested case-control analysis the adjusted matched RR estimates were 2·2 (1·1-4·4) and 2·1 (1·0-4·4) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. The excess risk for nonfatal VTE associated with the new generation of combined OCs containing low-dose oestrogen and the progestagens Desogestrel or gestodene compared with levonorgestrel is estimated to be 16 per 100 000 woman-years.

  • risk of idiopathic cardiovascular death and rionfatal venous thromboembolism in women using oral contraceptives with differing progestagen components
    The Lancet, 1995
    Co-Authors: Hershel Jick, Marian Wald Myers, Catherine Vasilakis, Susan S. Jick, Victor Gurewich
    Abstract:

    Concern about the risks of cardiovascular illness in women using combined oral contraceptives (OC) containing the progestagens Desogestrel and gestodene prompted two studies of data from the UK General Practice Research Database. We compared the risks of certain cardiovascular illnesses in otherwise healthy women exposed to one of three OCs containing < 35 micrograms oestrogen plus levonorgestrel, Desogestrel, or gestodene. In the first study, based on some 470 general practices, there were 15 cases of unexpected idiopathic cardiovascular death among 303,470 women who were current users of one of the study OCs. The estimated incidence rates were 8/184,536 (4.3 per 100,000) woman-years at risk for users of combined OCs containing levonorgestrel, 2/135,567 (1.5 per 100,000) for Desogestrel users, and 5/105,201 (4.8 per 100,000) for gestodene users. The relative risk (RR) estimates were 0.4 (95% CI 0.1-2.1) and 1.4 (CI 0.5-4.5) for Desogestrel and gestodene, respectively, compared with levonorgestrel. In the second study, derived from some 370 general practices, there were 80 cases of nonfatal venous thromboembolism (VTE) in a cohort of 238,130 otherwise healthy women. The incidence rates of VTE per 100,000 woman-years at risk were 16.1 for levonorgestrel users, 29.3 for Desogestrel, and 28.1 for gestodene. The adjusted RR estimates from the cohort analysis were 1.9 (1.1-3.2) and 1.8 (1.0-3.2) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. In a nested case-control analysis the adjusted matched RR estimates were 2.2 (1.1-4.4) and 2.1 (1.0-4.4) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. The excess risk for nonfatal VTE associated with the new generation of combined OCs containing low-dose oestrogen and the progestagens Desogestrel or gestodene compared with levonorgestrel is estimated to be 16 per 100,000 woman-years.

  • risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components
    The Lancet, 1995
    Co-Authors: Hershel Jick, Marian Wald Myers, Catherine Vasilakis, Susan S. Jick, Victor Gurewich
    Abstract:

    Concern about the risks of cardiovascular illness in women using combined oral contraceptives (OC) containing the progestagens Desogestrel and gestodene prompted two studies of data from the UK General Practice Research Database. We compared the risks of certain cardiovascular illnesses in otherwise healthy women exposed to one of three OCs containing < 35 micrograms oestrogen plus levonorgestrel, Desogestrel, or gestodene. In the first study, based on some 470 general practices, there were 15 cases of unexpected idiopathic cardiovascular death among 303,470 women who were current users of one of the study OCs. The estimated incidence rates were 8/184,536 (4.3 per 100,000) woman-years at risk for users of combined OCs containing levonorgestrel, 2/135,567 (1.5 per 100,000) for Desogestrel users, and 5/105,201 (4.8 per 100,000) for gestodene users. The relative risk (RR) estimates were 0.4 (95% CI 0.1-2.1) and 1.4 (CI 0.5-4.5) for Desogestrel and gestodene, respectively, compared with levonorgestrel. In the second study, derived from some 370 general practices, there were 80 cases of nonfatal venous thromboembolism (VTE) in a cohort of 238,130 otherwise healthy women. The incidence rates of VTE per 100,000 woman-years at risk were 16.1 for levonorgestrel users, 29.3 for Desogestrel, and 28.1 for gestodene. The adjusted RR estimates from the cohort analysis were 1.9 (1.1-3.2) and 1.8 (1.0-3.2) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. In a nested case-control analysis the adjusted matched RR estimates were 2.2 (1.1-4.4) and 2.1 (1.0-4.4) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. The excess risk for nonfatal VTE associated with the new generation of combined OCs containing low-dose oestrogen and the progestagens Desogestrel or gestodene compared with levonorgestrel is estimated to be 16 per 100,000 woman-years.

D J Back - One of the best experts on this subject based on the ideXlab platform.

  • the pharmacokinetics of ethynylestradiol in the presence and absence of gestodene and Desogestrel
    Contraception, 1991
    Co-Authors: M L Orme, D J Back, Stephen A. Ward, S. Green
    Abstract:

    Single doses of ethynylestradiol (30 μg) were given alone and in combination with either gestodene (75 μg) or Desogestrel (150 μg) to 10 healthy female volunteers. The doses of steroids were given both orally and by i.v. infusion over 5–7 minutes. Blood samples were taken at regular intervals over 24 hours. The area under the plasma concentration versus time curve (AUC) for oral EE2 alone was 867 ± 338 pg/ml × h, for oral EE2 in the presence of gestodene it was 795 ± 206 pg/ml × h and for oral EE2 in the presence of Desogestrel it was 614 ± 132 pg/ml × h. With either gestodene or Desogestrel present, the AUC of EE2 was not significantly different from that found when EE2 was given alone. In addition, there was no significant difference between EE2 + gestodene and EE2 + Desogestrel. Comparing the relative oral and iv doses, the bioavailability of EE2 (alone) was 59.0 ± 13% (n = 6), for EE2 plus gestodene it was 62.1 ± 10% and for EE2 in the presence of Desogestrel it was 62.1 ± 4.4%. The clearance of EE2 (alone) was 19.9 ± 5.5 1/h and in the presence of gestodene it was 19.4 ± 9.6 1/h. The clearance of EE2 in the presence of Desogestrel appeared slightly greater at 27.7 ± 8.9 1/h but none of these clearance values were significantly different from each other. The urinary excretion of 6-beta-hydroxy cortisol was similar after all 6 doses of EE2. These data strongly suggest that following single dose administration, neither gestodene nor Desogestrel have any inhibitory effect on the metabolism of EE2 or alter its kinetics to any clinically significant extent.

  • effect of the progestogens gestodene 3 keto Desogestrel levonorgestrel norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes
    The Journal of Steroid Biochemistry and Molecular Biology, 1991
    Co-Authors: D J Back, Stephen A. Ward, R Houlgrave, J Tjia, M L Orme
    Abstract:

    Abstract A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), Desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE 2 ) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or “suicide” inactivation of cytochrome P -450. We have compared the effects of the different progestogens on EE 2 2-hydroxylation (a reaction catalyzed by enzymes from the P -450IIC, P -450IIIA and P -450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE 2 as substrate, GSD, 3-keto Desogestrel (3-KD, the active metabolite of Desogestrel) and LNG produced some concentration-dependent inhibition of EE 2 2-hydroxylation (maximum 32% inhibition at 100 μM 3-keto Desogestrel). K i values determined for GSD and 3-KD were 98.5 ± 12.3 and 93.2 ± 10.3 μ M (mean ± SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 μl) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 μM, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively). In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD > 3-KD > NET > LNG for production of both metabolite M17 and M21. The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.

  • effect of the progestogens gestodene 3 keto Desogestrel levonorgestrel norethisterone and norgestimate on the oxidation of ethinyloestradiol and other substrates by human liver microsomes
    The Journal of Steroid Biochemistry and Molecular Biology, 1991
    Co-Authors: D J Back, Stephen A. Ward, R Houlgrave, J Tjia, M L Orme
    Abstract:

    A number of different progestogens, levonorgestrel (LNG), norethisterone (NET), gestodene (GSD), Desogestrel (DG) and norgestimate (NORG) are used in combination with the oestrogen ethinyloestradiol (EE2) in oral contraceptive steroid preparations. All the progestogens are acetylenic steroids and previous studies have indicated the potential of acetylenic steroids to cause mechanism-based or "suicide" inactivation of cytochrome P-450. We have compared the effects of the different progestogens on EE2 2-hydroxylation (a reaction catalyzed by enzymes from the P-450IIC, P-450IIIA and P-450IIE gene families) and also the oxidative metabolism of other drug substrates (cyclosporin, diazepam, tolbutamide) by human liver microsomes. On coincubation with EE2 as substrate, GSD, 3-keto Desogestrel (3-KD, the active metabolite of Desogestrel) and LNG produced some concentration-dependent inhibition of EE2 2-hydroxylation (maximum 32% inhibition at 100 microM 3-keto Desogestrel). Ki values determined for GSD and 3-KD were 98.5 +/- 12.3 and 93.2 +/- 10.3 microM (mean +/- SD; n = 4), respectively. Preincubation of progestogens in a small volume (50 microliters) incubation for 30 min in the presence of an NADPH-generating system enhanced the inhibitory potential of all the steroids (at 100 microM, inhibition was for GSD 39%, 3-KD 46%, LNG 46%, NET 51% and NORG 43%). Inhibitory effects were therefore comparable and also similar to the macrolide antibiotic troleandomycin. The most marked inhibition seen was of diazepam N-demethylation and hydroxylation by GSD (71 and 57%, respectively) and 3-KD (62 and 50%, respectively). In preincubation studies involving cyclosporin as the substrate, the order of inhibitory potency was GSD greater than 3-KD greater than NET greater than LNG for production of both metabolite M17 and M21. The results of the study indicate that all the progestogens in common use have the propensity to inhibit a number of oxidative pathways but there is little evidence for one progestogen being more markedly inhibitory than others.

Susan S. Jick - One of the best experts on this subject based on the ideXlab platform.

  • Cerebral venous sinus thrombosis in users of four hormonal contraceptives: levonorgestrel-containing oral contraceptives, norgestimate-containing oral contraceptives, Desogestrel-containing oral contraceptives and the contraceptive patch.
    Contraception, 2006
    Co-Authors: Susan S. Jick, Hershel Jick
    Abstract:

    Abstract Background It has been suggested that the risk for cerebral venous sinus thrombosis (CVST) may be greater among users of the contraceptive patch than among users of oral contraceptives (OCs). Methods From the PharMetrics database, we identified women aged 15–44 years who filled at least one prescription for either the contraceptive patch or Desogestrel-containing, norgestimate-containing or levonorgestrel-containing OCs to assess the risk of CVST. The person-time of current exposure to each study drug, as well as the incidence rates (IRs) and incidence rate ratios (IRRs) of CVST, was calculated. Results We identified over 1 million users of the four study drugs. There were five cases of CVST among current users of Desogestrel, seven cases among current users of norgestimate, two cases among current users of levonorgestrel and none among current users of the contraceptive patch. The IRs per 100,000 woman-years were 2.7 [95% confidence interval (95% CI)=0.9–6.3], 1.6 (95% CI=0.7–3.3), 0.7 (95% CI=0.1–2.4) and 0.0 (95% CI=0.0–4.8), respectively, in users of Desogestrel, norgestimate, levonorgestrel and the contraceptive patch. There were two women who had CVST while not currently taking a hormonal contraceptive (IR=0.4 per 100,000 woman-years; 95% CI=0.1–1.3). The IRRs were 4.0 (95% CI=0.7–42.4) for Desogestrel-containing versus levonorgestrel-containing OCs, and 2.4 (95% CI=0.5–24.0) for norgestimate-containing versus levonorgestrel-containing OCs. The IRR for the patch could not be calculated. Conclusions There is no evidence of an increased risk of CVST in users of the contraceptive patch compared to users of levonorgestrel-containing OCs.

  • Original research article Cerebral venous sinus thrombosis in users of four hormonal contraceptives: levonorgestrel-containing oral contraceptives, norgestimate-containing oral contraceptives, Desogestrel-containing oral contraceptives and the contra
    2006
    Co-Authors: Susan S. Jick, Hershel Jick
    Abstract:

    Background: It has been suggested that the risk for cerebral venous sinus thrombosis (CVST) may be greater among users of the contraceptive patch than among users of oral contraceptives (OCs). Methods: From the PharMetrics database, we identified women aged 15–44 years who filled at least one prescription for either the contraceptive patch or Desogestrel-containing, norgestimate-containing or levonorgestrel-containing OCs to assess the risk of CVST. The person-time of current exposure to each study drug, as well as the incidence rates (IRs) and incidence rate ratios (IRRs) of CVST, was calculated. Results: We identified over 1 million users of the four study drugs. There were five cases of CVSTamong current users of Desogestrel, seven cases among current users of norgestimate, two cases among current users of levonorgestrel and none among current users of the contraceptive patch. The IRs per 100,000 woman-years were 2.7 [95% confidence interval (95% CI)=0.9–6.3], 1.6 (95% CI=0.7–3.3), 0.7 (95% CI=0.1–2.4) and 0.0 (95% CI=0.0–4.8), respectively, in users of Desogestrel, norgestimate, levonorgestrel and the contraceptive patch. There were two women who had CVST while not currently taking a hormonal contraceptive (IR=0.4 per 100,000 woman-years; 95% CI=0.1–1.3). The IRRs were 4.0 (95% CI=0.7–42.4) for Desogestrel-containing versus levonorgestrel-containing OCs, and 2.4 (95% CI=0.5–24.0) for norgestimate-containing versus levonorgestrel-containing OCs. The IRR for the patch could not be calculated. Conclusions: There is no evidence of an increased risk of CVST in users of the contraceptive patch compared to users of levonorgestrelcontaining OCs.

  • risk of idiopathic cardiovascular death and rionfatal venous thromboembolism in women using oral contraceptives with differing progestagen components
    The Lancet, 1995
    Co-Authors: Hershel Jick, Marian Wald Myers, Catherine Vasilakis, Susan S. Jick, Victor Gurewich
    Abstract:

    Abstract Summary Concern about the risks of cardiovascular illness in women using combined oral contraceptives (OC) containing the progestagens Desogestrel and gestodene prompted two studies of data from the UK General Practice Research Database. We compared the risks of certain cardiovascular illnesses in otherwise healthy women exposed to one of three OCs containing In the first study, based on some 470 general practices, there were 15 cases of unexpected idiopathic cardiovascular death among 303 470 women who were current users of one of the study OCs. The estimated incidence rates were 8/184 536 (4·3 per 100 000) woman-years at risk for users of combined OCs containing levonorgestrel, 2/135567 (1·5 per 100 000) for Desogestrel users, and 5/105 201 (4·8 per 100 000) for gestodene users. The relative risk (RR) estimates were 0·4 (95% Cl 0·1-2·1) and 1·4 (Cl 0·5-4·5) for Desogestrel and gestodene, respectively, compared with levonorgestrel. In the second study, derived from some 370 general practices, there were 80 cases of nonfatal venous thromboembolism (VTE) in a cohort of 238 130 otherwise healthy women. The incidence rates of VTE per 100 000 woman-years at risk were 16·1 for levonorgestrel users, 29·3 for Desogestrel, and 28·1 for gestodene. The adjusted RR estimates from the cohort analysis were 1·9 (1·1-3·2) and 1·8 (1·0-3·2) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. In a nested case-control analysis the adjusted matched RR estimates were 2·2 (1·1-4·4) and 2·1 (1·0-4·4) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. The excess risk for nonfatal VTE associated with the new generation of combined OCs containing low-dose oestrogen and the progestagens Desogestrel or gestodene compared with levonorgestrel is estimated to be 16 per 100 000 woman-years.

  • risk of idiopathic cardiovascular death and rionfatal venous thromboembolism in women using oral contraceptives with differing progestagen components
    The Lancet, 1995
    Co-Authors: Hershel Jick, Marian Wald Myers, Catherine Vasilakis, Susan S. Jick, Victor Gurewich
    Abstract:

    Concern about the risks of cardiovascular illness in women using combined oral contraceptives (OC) containing the progestagens Desogestrel and gestodene prompted two studies of data from the UK General Practice Research Database. We compared the risks of certain cardiovascular illnesses in otherwise healthy women exposed to one of three OCs containing < 35 micrograms oestrogen plus levonorgestrel, Desogestrel, or gestodene. In the first study, based on some 470 general practices, there were 15 cases of unexpected idiopathic cardiovascular death among 303,470 women who were current users of one of the study OCs. The estimated incidence rates were 8/184,536 (4.3 per 100,000) woman-years at risk for users of combined OCs containing levonorgestrel, 2/135,567 (1.5 per 100,000) for Desogestrel users, and 5/105,201 (4.8 per 100,000) for gestodene users. The relative risk (RR) estimates were 0.4 (95% CI 0.1-2.1) and 1.4 (CI 0.5-4.5) for Desogestrel and gestodene, respectively, compared with levonorgestrel. In the second study, derived from some 370 general practices, there were 80 cases of nonfatal venous thromboembolism (VTE) in a cohort of 238,130 otherwise healthy women. The incidence rates of VTE per 100,000 woman-years at risk were 16.1 for levonorgestrel users, 29.3 for Desogestrel, and 28.1 for gestodene. The adjusted RR estimates from the cohort analysis were 1.9 (1.1-3.2) and 1.8 (1.0-3.2) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. In a nested case-control analysis the adjusted matched RR estimates were 2.2 (1.1-4.4) and 2.1 (1.0-4.4) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. The excess risk for nonfatal VTE associated with the new generation of combined OCs containing low-dose oestrogen and the progestagens Desogestrel or gestodene compared with levonorgestrel is estimated to be 16 per 100,000 woman-years.

  • risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components
    The Lancet, 1995
    Co-Authors: Hershel Jick, Marian Wald Myers, Catherine Vasilakis, Susan S. Jick, Victor Gurewich
    Abstract:

    Concern about the risks of cardiovascular illness in women using combined oral contraceptives (OC) containing the progestagens Desogestrel and gestodene prompted two studies of data from the UK General Practice Research Database. We compared the risks of certain cardiovascular illnesses in otherwise healthy women exposed to one of three OCs containing < 35 micrograms oestrogen plus levonorgestrel, Desogestrel, or gestodene. In the first study, based on some 470 general practices, there were 15 cases of unexpected idiopathic cardiovascular death among 303,470 women who were current users of one of the study OCs. The estimated incidence rates were 8/184,536 (4.3 per 100,000) woman-years at risk for users of combined OCs containing levonorgestrel, 2/135,567 (1.5 per 100,000) for Desogestrel users, and 5/105,201 (4.8 per 100,000) for gestodene users. The relative risk (RR) estimates were 0.4 (95% CI 0.1-2.1) and 1.4 (CI 0.5-4.5) for Desogestrel and gestodene, respectively, compared with levonorgestrel. In the second study, derived from some 370 general practices, there were 80 cases of nonfatal venous thromboembolism (VTE) in a cohort of 238,130 otherwise healthy women. The incidence rates of VTE per 100,000 woman-years at risk were 16.1 for levonorgestrel users, 29.3 for Desogestrel, and 28.1 for gestodene. The adjusted RR estimates from the cohort analysis were 1.9 (1.1-3.2) and 1.8 (1.0-3.2) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. In a nested case-control analysis the adjusted matched RR estimates were 2.2 (1.1-4.4) and 2.1 (1.0-4.4) for Desogestrel and gestodene users, respectively, compared with users of levonorgestrel. The excess risk for nonfatal VTE associated with the new generation of combined OCs containing low-dose oestrogen and the progestagens Desogestrel or gestodene compared with levonorgestrel is estimated to be 16 per 100,000 woman-years.