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Calcium alginate-entrapped mycelium of Penicillium raistrickii i 477 was used for the 15 alpha-hydroxylation of 13-ethyl-gon-4-ene-3,17-dione. The system was tested in 10 batches during 40 days of operation, the catalytic activity could be completely regenerated by incubation in a nutrient medium between several batches.
The in vitro and in vivo releases of norgestomet from hydrophilic implants were found to follow a matrix-controlled (Q - t1/2) process. The sorption of drug onto the implants was observed to obey the same mechanism but with a much smaller magnitide of the Q/t1/2 value. The effect of the extent of cross-linking on the magnitude of drug release (Q/t1/2) profiles was analyzed both theoretically and experimentally. The release of norgestomet from hydrophilic implants was found to be an energy-linked process. Two energy terms were calculated; the activation energy for matrix diffusion was 7.71 kcal/mole, and the heat of drug crystal solvation was 25-28.6 kcal/mole.
Protection against the toxicity of parathion (increased LD50) was provided by preadministered ethylestrenol and, to a lesser extent, by norbolethone and spironlactone. Ethylestrenol and norbolethone also offered protection against paraoxon toxicity. With ethylestrenol and spironolactone, the protection against parathion lethality was greater than that against paraoxon lethality.
The roles of cytochrome CYP3A and CYP2B isozymes in the bioactivation and detoxification of the pyrrolizidine alkaloid (PA) senecionine (SN) have been investigated in vitro with sheep and hamster hepatic microsomes. Our results show that the rate of SN activation measured by (+/-)-6, 7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) formation greatly exceeded the rate of SN N-oxide formation (detoxification) in hamsters. In contrast, SN N-oxide, a detoxification product, was the major metabolite in sheep with much lower DHP production. Immunoinhibition studies with anti-sheep CYP3A and CYP2B antibodies show that members of CYP3A subfamily play the major role in the conversion of PA to pyrrolic metabolites in both species (over 90% in sheep; 68% in hamster). These enzymes also contribute 38.8 and 41. 3% of SN N-oxidation in sheep and hamsters, respectively. In contrast, CYP2B isoforms have a limited capacity toward DHP formation in both species (47% in sheep; 32% in hamster), while these enzymes catalyzed only 24.6 and 35.4% SN N-oxidation in sheep and hamster, respectively. Using triacetyloleandomycin (TAO) and gestodene, two highly selective chemical inhibitors of CYP3A isoforms, our data show that 90% of DHP formation was inhibited by either inhibitor in sheep. Gestodene appeared to be more efficient than TAO in the inhibition of DHP production in hamsters. Testosterone 6beta-hydroxylase activity, a functional marker of CYP3A, was significantly inhibited by TAO and gestodene in sheep liver microsomes and by gestodene (100 microM) in hamster liver microsomes. These results suggest that CYP3A isozymes have important roles in bioactivation and detoxification of PA in both species, whereas CYP2B subfamily members are less efficient in biotransformation of PA.
In a controlled clinical trial, the elimination of caffeine was examined in 20 healthy women prior to and during one cycle of treatment with either of two oral contraceptive formulations, one containing 0.075 mg gestodene and 0.03 mg ethinylestradiol and one containing 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol. In addition, caffeine clearance was determined 1 month after the last intake of the oral contraceptives. Compared with pretreatment values, the clearance of caffeine was reduced by about 54% and 55% after one treatment cycle with gestodene- and the levonorgestrel-containing oral contraceptive, respectively. Other pharmacokinetic parameters of caffeine, such as tmax and Cmax, were not affected. Clearance values returned to pretreatment values 1 month after the last administration of the oral contraceptives. There was no difference in the reduction of caffeine clearance between contraceptive formulations. A small, but significant difference in the AUC(0-24 h) values of ethinylestradiol was noted between both preparations. There was no correlation between the AUC(model) values of caffeine and the AUC(0-24 h) values of ethinylestradiol. In the present study, a somewhat more pronounced effect on the elimination of caffeine was observed than in previous investigations, where several contraceptive steroids were administered only for a period of 2 weeks.
A 2-year non-randomized prospective study was carried out in a teaching hospital menopause clinic to assess the effect on the skeleton of tibolone (Livial, Organon) 2.5 mg daily in recently postmenopausal women. One hundred women who were between 6 and 36 months since their last menstrual period and had raised gonadotrophin levels consistent with the menopause were allocated into two groups. One group received 2.5 mg tibolone daily and the other group no medication. Bone densitometry of the spine and femur was performed at 0, 6, 12 and 24 months and biochemical markers of bone metabolism were assessed at these points. Severity of hypo-oestrogenic symptoms was assessed at baseline and at 1 and 2 years. After 2 years there was a significant increase in bone mass as measured by dual energy X-ray absorptiometry (DXA) of 2.5% in the spine, and 3.5% in the neck of femur in the women who took tibolone (n = 46), whereas in the control group (n = 45) bone loss occurred (spine, 2.9%; femur, 3.7%). When these changes were compared they were significantly different for both sites (p < 0.001). In the treatment group the urinary hydroxyproline/creatinine and calcium/creatinine ratios fell from 0.014 (0.002-0.027) to 0.010 (0.000-0.111) (mol/l) (mmol/l) (p < 0.01) and 0.47 (0.08-0.96) to 0.33 (0.09-1.20) (mmol/l) (mmol/l) (p < 0.001) respectively, while the serum osteocalcin and alkaline phosphatase decreased from 1.90 (0.20-4.70) to 1.00 (0.00-3.00) mmol/l (p < 0.01) and 190 (92-301) to 138 (91-283) mmol/l (p < 0.001) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
The serum concentrations of osteocalcin (bone Gla protein) were followed by continuous blood sampling for 24 h in 9 healthy young women before and during treatment with oestrogen/progestogen combinations for oral contraception. There were marked fluctuations during the 24 h sampling period, values ranging from 0.5 to 10.0 ng/ml. Values displayed an apparent circadian rhythm. Daytime values were on average lower than nocturnal concentrations. During treatment with oral contraceptives there was a significant decrease in osteocalcin levels but fluctuations during the 24 h sampling period were still observed. Almost all individual values obtained at 30 min intervals were lower during treatment. For the whole group the mean osteocalcin concentration decreased by 1.4 ng/ml (p less than 0.01) during treatment. In postmenopausal women high serum levels of osteocalcin are supposed to reflect increased bone turnover secondary to enhanced bone resorption. Oestrogens are known to reduce osteocalcin levels and may reduce bone resorption. In healthy young women alternative mechanisms should be considered but the reduced osteocalcin serum levels in this short-term study indicate that oral contraceptive use may influence bone metabolism.
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Carbohydrate metabolism was prospectively evaluated in twenty-one normal women prior to and during their use for three months of a monophasic oral contraceptive containing the progestin gestodene plus ethinyl estradiol. The women had a three-hour oral glucose tolerance test using a 75 gram glucose load, measuring serum glucose and insulin levels. The results demonstrate no significant changes in either of the carbohydrate metabolic indices between the two tests. These data support the safety of this new progestin-containing contraceptive.
Desogestrel is the most selective progestogen used in oral contraceptives (OCs). The clinical characteristics of the monophasic combined OC containing 150 micrograms desogestrel and 30 micrograms EE per tablet (Marvelon) are in accordance with the strong progestogenic and minimal androgenic effects of desogestrel: a very high contraceptive efficacy is combined with minimal and, in the case of lipid metabolism, even potentially positive effects on metabolic parameters. Through increasing the plasma levels of sex hormone binding globulin, and thereby decreasing the plasma levels of free testosterone, the desogestrel-containing OC also has substantial beneficial effects on acne.
A clinical study was performed with a new progestogen, desogestrel, in a 0.15 mg dose associated with 0.03 mg of ethinylestradiol and was administered cyclically during 21 days; 632 cycles were evaluated in 56 women. Side-effects were scarce and generally of a mild nature. Monthly bleeding was normal and present in all cycles. Patients with irregular cycles were normalized to 28/29 days. The intermenstrual bleeding (spotting) was an isolated event in 16 cycles. Mastalgia, the most frequent symptom, disappeared spontaneously in the majority of patients. In only 2 cases was it necessary to stop medication because of side-effects. The contraceptive effect was excellent; no pregnancies occurred. A progestative effect was evident in the cervical mucus and the endometrium. The patients who started treatment with acne improved noticeably. In the mild cases, acne disappeared completely. A discrete improvement in hirsutism was reported. The body-weight variation was not significant. Biochemical studies revealed an increase in HDL-C and a decrease in the ratio LDL-C/HDL-C. Cholesterol and triglycerides did not show variations, which could indicate a lesser cardiovascular risk.
Metabolic parameters were studied in 30 patients over 12 treatment cycles in a double-blind randomized comparative trial of the new progestogen gestoden in a triphasic formulation against a fixed dose combination pill containing desogrestrel, in Bandung, Indonesia. The results of this laboratory experience affirm findings in similar previous metabolic studies that: (1) the changes induced by modern low-dose pills are clinically and statistically insignificant; (2) throughout the treatment cycles, the values of the various laboratory tests remain well within the normal range; and (3) the favorable balance between coagulation and fibrinolysis is maintained. Results of lipoprotein, coagulation, fibrinolytic and liver function tests in 27 patients are presented. Gestoden's pharmacologic profile and the worldwide clinical experience with the triphasic gestoden formulation in 4285 women are discussed.
The estrogen component used in virtually all oral contraceptive pills today was synthesized in the laboratories of Schering AG in 1938. The progestogen component varies, but levonorgestrel has become the standard among the lowest-dose pills available. Various attempts to modify the levonorgestrel molecule have resulted in new progestogens like norgestimate and desogestrel without much greater biological activity; therefore, further reduction in dose is unlikely. Gestoden, the newest progestogen from the levonorgestrel class, synthesized in Schering AG's laboratories, is different. Its enhanced biological activity allows for a progestogen content in a fixed combination pill half that in other low-dose pills available today. Furthermore, it has an improved pharmacologic profile with favorable dissociation of the androgenic and progestogenic activities. A unique anti-mineralocorticoid action is seen resembling natural progesterone, a property not presently shared with other synthetic progestogens. Results will be presented from clinical trials with a new monophasic gestoden preparation.
The study was performed in 14 young women. The combination oral contraceptive contained 75 microgram gestodene (GSD) and 20 microgram ethinyl estradiol (EE2) per dosage unit. The volunteers received a single dose on day 21 of a treatment-free precycle (PCd21) and, after a washout period of 7 days, used the preparation in a 21 d/7 d schedule for three months. Daily drug serum level profiles were taken on PCd21 and on days 1 and 21 of treatment cycles 1 and 3. In addition, trough drug serum levels were followed every other day during treatment cycles 1 and 3. Serum levels of GSD, EE2, CBG, SHBG and testosterone (T) were determined by means of specifically developed or commercially available RIAs. Pharmacokinetic evaluation was carried out with TOPFIT and parameters were evaluated for differences with the t-test. Main target variables were Cmax, tmax and AUC for EE2, GSD and unbound GSD on day 21, cycle 3 vs. PCd21. EE2 pharmacokinetics were in agreement with a dose of 20 microgram/unit. Single-dose Cmax of 65 pg/ml and AUC of 612 pg h ml(-1) increased by 40-60% during treatment cycles as a result of accumulation EE2 induced basal SHBG (102nmol/L) and CBG (42 microgram/ml) serum levels to about 220 nmol/L and 87 microgram/ml, respectively, at the end of treatment cycles 1 and 3. Serum T levels dropped to 50% of baseline levels during treatment cycles and free T concentrations were reduced by 60-70%. GSD pharmacokinetics at the end of treatment cycles 1 and 3 were different from single-dose pharmacokinetics. Single-dose Cmax of 3.5 ng/ml and AUC 0-24 h of 22 ng h ml(-1) increased to steady-state levels of 8-8.7 ng/ml and 90-106 ng h ml(-1), respectively. The increase in GSD levels under treatment is the result of two parallel processes, i.e. accumulation and enlargement of the specific binding compartment. This was shown by protein-binding experiments, demonstrating an increase in specific (SHBG) binding from 69% to 80% and a reduction in the free fraction of GSD by 40% during treatment. The results of GSD and EE2 pharmacokinetics obtained in the present study confirm previous results with Femodene, when the reduction in the EE2 dose by 10 microgram/d is taken into account.
The minimal effective dose of gestodene for inhibition of ovulation was studied in 30 female volunteers. Daily doses of 10 micrograms to 50 micrograms gestodene were given orally for 21 days. A control cycle prior to treatment and a treatment cycle were monitored for LH, FSH, estradiol, progesterone and cervical score. At a daily dose of 40 micrograms of gestodene, 6/7 volunteers exhibited inhibition of ovulation and 1/7 had a cycle with luteal insufficiency. Ovulation was inhibited in all volunteers on 50 micrograms gestodene, suggesting that the minimum dose required to inhibit ovulation was 40 micrograms gestodene. Cervical score was blunted even at 10 micrograms gestodene. Similarly, 20 volunteers were treated with coated tablets containing ethinylestradiol/gestodene at 30/50 micrograms for 6 days, 40/70 micrograms for 5 days and 30/100 micrograms for 10 days. This triphasic gestodene-containing preparation inhibited ovulation in all 20 females. In one cycle in which follicle development was observed only 43 pg estradiol/ml was secreted. Data from this investigation suggest that this triphasic gestodene-containing OC has a high contraceptive efficacy.
The serum concentrations of 3-ketodesogestrel (KDG) and gestodene have been measured in 30 and 31 women respectively who took low dose oral contraceptives containing 30 micrograms ethinylestradiol together with either 150 micrograms desogestrel or 75 micrograms gestodene for 6 months. On days 1, 10 and 21 of the first third and sixth treatment cycles blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4 and 24 h. KDG and gestodene levels were measured by radioimmunoassays and were evaluated for Cmax (peak serum concentration), tmax (time to Cmax), and AUC (area under the curve) to 4 and 24 h. The overall total gestodene concentrations were higher and the accumulation of the steroid throughout a cycle greater than that of KDG. For example, the AUC0-4 of gestodene increased in cycle 1 by a factor of 2.8 (day 10 vs. day 1) and 3.6 (day 21 vs. day 1) compared to 2.3 and 2.6 for KDG. The higher concentration of gestodene reflects a lower volume of distribution than KDG, and is consistent with gestodene binding to sex hormone binding globulin (SHBG) with a higher affinity than KDG. Concentrations of KDG and gestodene were higher on day 1 of cycles 3 and 6 than on day 1 of cycle 1. The serum concentrations of KDG and gestodene during multiple dosing cannot be predicted on the basis of single dose pharmacokinetics.
Fifty-three women were randomly allocated to one of two combined low-dose monophasic oral contraceptives (20 micrograms ethinyl estradiol with 75 micrograms gestodene or 20 micrograms ethinyl estradiol with 150 micrograms desogestrel). The ability of these formulations to inhibit ovulation was compared using hormonal parameters and ovarian ultrasound. The effects on three treated cycles were compared with pre- and post-treatment cycles. No ovulations occurred in either group during therapy. Twenty-one percent of women were observed to show some follicle-like structures accompanied by raised serum estradiol in at least one treatment cycle. No significant differences between the two preparations were demonstrated on residual ovarian function. The secretion of estradiol and progesterone was significantly reduced throughout all three treatment cycles. Mean LH and FSH concentrations were comparable with both treatments. A secondary analysis of cycle control and tolerance was undertaken. Significantly less bleeding was seen in the gestodene group during cycle 2 (p = 0.02). There were no differences between the two treatments with respect to the other cycle control parameters. Approximately half the women recorded intracyclic bleeding during the first treatment cycle. This improved during cycles 2 and 3. Both formulations were tolerated well.
An open prospective clinical trial designed to evaluate the efficacy and safety of the combined hormonal oral contraceptive (OC) containing 75 micrograms gestodene plus 30 micrograms ethinyl estradiol was undertaken in a Mexican population. Sixty-nine healthy women of reproductive age took part in the study for a total of 627 woman-months of observation. The combination of gestodene and ethinyl estradiol proved its effectiveness in preventing pregnancy during the study. Side-effects were minimal and regular endometrial bleeding patterns were observed during one year of continuous use of this OC preparation. The discontinuation rate for medical reasons was 11.6% at one year. Among a sample of 10 women, the gestodene/ethinyl estradiol combination did not induce significant changes in the serum concentration of total cholesterol and LDL cholesterol after 12 months of continuous administration. An increase in serum triglycerides and HDL cholesterol was observed; this effect could be attributed to a lack of androgenic and/or the intrinsic estrogenic behavior of gestodene. It can be concluded that this preparation is highly effective as a combined oral contraceptive; it is well tolerated and might offer some advantages with respect to other oral contraceptive combinations in its short- and medium-term impact on lipid metabolism.