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The pharmacokinetics of levonorgestrel (LNG) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 27 years) during a treatment period of three months with a tri-step combination oral contraceptive (Triquilar). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.125 mg LNG together with 0.03 mg EE2. There was a washout phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 22 h was observed for LNG. The total clearance was 1.0 ml x min-1 x kg-1 and the volume of distribution was 128 l. During a treatment cycle, LNG levels in the serum accumulated by a factor of about four as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for LNG at the end of treatment cycles one and three: reduced total (0.5 ml x min-1 x kg-1) and free clearance (50 ml x min-1 x kg-1) and a reduced volume of distribution (52 l). A concomitant increase in the SHBG concentrations by a factor of two as compared to pretreatment values was observed during treatment and appeared to be mainly responsible for the changes in the pharmacokinetics of LNG. Marked changes were also seen for the serum protein binding of LNG. After single dose administration, the free fraction of LNG was 1.4% and the fractions bound to SHBG and albumin were 55.0% and 43.6%, respectively. At the end of cycle one, the free fraction was only 1.0% and the fractions bound to SHBG and albumin were 69.4% and 30.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of LNG at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 331.2 and 369.6 pg x ml-1 x h, respectively, which corresponds to an about 11-24% increase as compared to single dose administration, where an AUC(0-4h) value of 298.3 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 41% and 55%, respectively, compared with the corresponding values measured prior to treatment.In Germany, an open, intraindividual comparative study was conducted among 14 women, 18-27 years old, to examine the pharmacokinetics of levonorgestrel (LNG) and ethinyl estradiol (EE2) during a 3-month period of treatment with a tristep oral contraceptive (OC) called Triquilar. The women first received a single oral dose of 0.125 mg LNG and 0.03 mg EE2 followed by a washout period of 1 week. They received Triquilar during 3 cycles (days 1-6, 0.05 mg LNG + 0.03 EE2; days 7-11, 0.075 mg LNG + 0.04 mg EE2; and days 12-21, 0.125 LNG + 0.03 mg EE2). The mean terminal half-life for LNG was 22 hours. Total clearance of LNG was 1 ml x min-1 x kg -1. LNG volume distribution was 128.1. At the end of the treatment cycles 1 and 3, when compared to single dose administration, the total and free LNG clearance was reduced (0.5 ml x min-1 x kg-1 and 50 ml x min-1 x kg-1, respectively). LNG volume distribution was also lower after treatment cycles than after single dose administration (52 l). LNG serum levels during Triquilar treatment accumulated by a factor of 4 when compared to the level of single dose administration. Steady-state LNG levels of around 2-3 ng/ml were achieved on day 16-18 of each treatment cycle. Sex hormone binding globulin (SHBG) levels increased by a factor of 2 when compared to pretreatment levels. This simultaneous increase in SHBG likely accounted for the changes in the pharmacokinetics of LNG. After a single dose, the free fraction of LNG was 1.4% and fractions bound to SHBG and albumin were 55% and 43.6%, respectively. At the end of cycles 1 and 3, no difference in these pharmacokinetic parameters and in the serum protein binding of LNG existed. At the end of cycles 1 and 3, the 0-4 hour area under the curve (AUC) values of EE2 increased from 298.3 to 331.2 and 369.6 pg x ml-1 x h, respectively, a 11% and 24% increase, respectively. When compared to pretreatment levels, total and free testosterone levels fell during treatment cycles 1 and 3 by around 41% and 55%, respectively.

The pharmacokinetics of cyproterone acetate (CPA) and ethinylestradiol (EE2) were determined in 15 healthy women (age 19 to 34 years), following single dose administration of a combination oral contraceptive, containing 2.0 mg CPA together with 0.035 mg EE2 (Diane-35R). After a wash-out period of one week, the same preparation was administered during a treatment period of three months. After single dose administration, maximum concentrations of CPA in the serum were 15.2 +/- 6.6 ng/ml. Post maximum drug levels declined biphasically with half-lives of 0.8 +/- 0.4 h and 54.0 +/- 26.0 h, respectively. The apparent clearance was calculated to be 3.6 +/- 0.9 ml x min-1 x kg-1 and the volume of distribution (Vz) was 986 +/- 4371. The free fraction of CPA was 3.5 +/- 1.9% and the fractions bound to heat labile proteins and albumin were 4.6 +/- 2.2% and 92.0 +/- 3.5%, respectively. Trough levels of CPA in the serum increased during a treatment cycle, reaching a steady-state around day 16. An about two-fold accumulation of CPA was observed, which was less than expected theoretically. SHBG concentrations in the serum increased by a factor of three during a cycle, without having any effect on the protein binding of CPA. At the end of treatment cycle three, the terminal half-life of CPA had increased to a mean value of 78.6 +/- 16.0 h and the volume of distribution to a value of 1304 +/- 427 1. The apparent clearance showed a small, although significant decrease to a value of 3.0 +/- 0.4 ml x min-1 x kg-1. The observed changes Vz and t 1/2 during the treatment period were attributed to the distribution of CPA into a deep compartment and the slow release of the drug from this compartment. The AUC(0-4h) values of EE2 following single dose administration of the combination oral contraceptive were found to be 187.5 +/- 79.7 pg x ml-1 x h. On the last day of cycles one and three, the AUC(0-4h) values were 311.2 +/- 109.3 and 304.8 +/- 121.5 pg x ml-1 x h, respectively, which corresponds to an about 60% increase as compared to single dose administration. Total and free testosterone concentrations decreased during treatment cycles one and three by about 39% and 62%, respectively, compared with the corresponding values measured prior to treatment.In Germany, 15 healthy young women received a single dose of an oral contraceptive (OC) (Diane-35R) with 2 mg cyproterone acetate (CPA) and .035 mg ethinyl estradiol (EE2) and, after a 2 week wash-out period, they received the same OC over a treatment period of 3 cycles. A drug-free interval separated each of the 3 cycles. The researchers aimed to examine the pharmacokinetics of CPA and EE2 of this OC. After 1 oral dose, CPA was rapidly absorbed and CPA serum levels rose as high as 15.2 ng/ml. 24 hours after the single dose, the free fraction of serum CPA was 3.5%. The fractions bound to albumin and heat labile proteins were 92% and 4.6%, respectively. The terminal half-life of CPA was higher at the end of treatment cycle 3 than after a single dose (78.6 hours vs. 54 hours). The apparent mean volume of distribution also increased from 986 to 1304. The apparent total clearance fell somewhat from 3.6 to 3 ml x min-1 x kg-1. Mean serum CPA trough levels rose during treatment and stabilized on day 16 of cycles 1 and 3. Accumulated CPA in the serum during treatment cycle 1 was more than 2 times higher than that expected based on data obtained after single dose administration. Serum concentration of sex hormone binding globulin increased by a factor of 3.3 during a treatment cycle due to concomitant administration of EE2. This increase did not affect the protein binding capacity of CPA. Distribution of CPA into a deep compartment (e.g., fatty tissue and skin) and the slow release of CPA from this compartment accounted for the increases in volume of distribution and the terminal half-life. The area under the curve of EE2 was about 60% higher on the last days of cycles 1 and 3 than it was after single dose administration (311.2 and 304.8, respectively vs. 187.5). When compared to baseline values, free and total testosterone levels fell during treatment cycles 1 and 3 by around 62% and 39%, respectively.

Serum ethinyl estradiol (EE2), sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) concentrations were studied in healthy young women randomly allocated to one of two low-dose combination oral contraceptives containing 30 micrograms EE2 and either 75 micrograms gestodene (F) or 150 micrograms desogestrel (M) per unit. There was either no (formerly non-pill users) or one (pill users) wash-out cycle before the study started with a pill-free pretreatment cycle in which the hormone status and basal SHBG and CBG levels were measured. Treatment was for three months. During treatment cycles 1 and 3, there were three test days each. Seven serum samples were obtained up to four hours and one sample 24 hours after intake of the first, tenth and the last (21st) pill. Additional samples were taken prior to morning ingestion of pills 5 and 15. For each individual and each test day, a representative serum pool has been constructed for SHBG and CBG analysis. EE2 concentrations were analyzed in all individual samples by means of a specific and sensitive RIA using anti-EE2-6 beta-CMO-BSA antiserum. Area under the curves (AUC) up to 4 and 24 hours, Cmax and tmax were evaluated and compared between the two treatment groups (n = 40 for F, n = 43 for M). SHBG and CBG concentrations were measured using commercially available immunoassay kits. Groups were large enough to detect a difference in group means of 75% of one standard deviation (alpha = 0.05, 1-beta = 0.9) of target variables, which is equivalent to 28 pg EE2/ml for Cmax, 69 pg.h.ml-1 for AUCEE2 0-4h, 257 pg.h.ml-1 for AUCEE2 0-24h, 39 nmol/l SHBG and 13.4 micrograms CBG/ml. Results clearly demonstrate that there were no differences between the two treatment groups in any of the target variables at any of the six test days distributed over a three-month period. Mean SHBG and CBG pretreatment levels of about 70 nmol/l and 37 micrograms/ml, respectively, increased to about 210 nmol/l and 88 micrograms/ml during the first treatment cycle and to about 230 nmol/l and 93 micrograms/ml during the third treatment cycle. Whereas the time of maximum EE2 serum levels did not differ significantly between test days, Cmax, AUCEE2 0-4h and AUCEE2 0-24h values increased by 30-35% or 40-50%, respectively, when test days 10 and 21 were compared to test day 1. Similar results were found for the third treatment cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Die Ernahrung stellt ein wichtiges therapeutisches Prinzip bei der Behandlung aller Diabetiker dar. Die Diabeteskost orientiert sich an den allgemeinen Ernahrungsempfehlungen fur Gesunde. Der Anteil der jeweiligen Nahrwerte sollte nach anerkannten Empfehlungen 10–15% Protein betragen, maximal 30–35% Fett, mindestens 50–60% Kohlenhydrate, wobei der Anteil der niedermolekularen Kohlenhydrate wiederum maximal 10% betragen sollte (Biesalski u. Grimm 1999; Ziegler et al. 1997).

The pharmacokinetics of gestodene (GEST) and ethinylestradiol (EE2) were determined in 14 healthy women (age 18 to 32 years) during a treatment period of three months with a new tri-step combination oral contraceptive (Milvane). Prior to this treatment period, the same women received a single administration of a coated tablet containing 0.1 mg GEST together with 0.03 mg EE2. There was a wash-out phase of one week between both treatments. Following single dose administration, a mean terminal half-life of 18 h was observed for GEST. The total clearance was 0.9 ml x min-1 x kg-1 and the volume of distribution was 84 l. During a treatment cycle, GEST levels in the serum accumulated by a factor of 8 as compared to single dose administration. Steady-state drug levels were reached during the second half of each cycle. As compared to single dose administration, the following changes were observed for GEST at the end of treatment cycles one and three: prolonged terminal half-life (20 to 22 h), reduced total (0.16 ml x min-1 x kg-1) and free clearance (ca. 27 ml x min-1 x kg-1), reduced volume of distribution (ca. 18 l). A concomitant EE2-induced increase in the SHBG concentrations by a factor of three as compared to pretreatment values was observed during a treatment cycle and appeared to be mainly responsible for the changes in the pharmacokinetics of GEST. Marked changes were also seen for the serum protein binding of GEST. After single dose administration, the free fraction of GEST was 1.3% and the fractions bound to SHBG and albumin were 69.4% and 29.3%, respectively. At the end of cycle one, the free fraction was only 0.6% and the fractions bound to SHBG and albumin were 81.4% and 18.0%, respectively. There was no difference in corresponding pharmacokinetic parameters and in the serum protein binding of GEST at the end of cycles one and three. On the last day of treatment cycles one and three, the AUC(0-4h) values of EE2 were 299.2 and 278.1 pg x ml-1 x h, respectively, which corresponds to an about 30% increase as compared to single dose administration, where an AUC(0-4h) value of 216.1 pg x ml-1 x h was found. Total and free testosterone concentrations decreased during treatment cycles one and three by about 36% and 60%, respectively, compared with the corresponding values measured prior to treatment. The fraction of unbound testosterone thus decreased from 0.5% to 0.3% during treatment.In Germany, researchers examined blood samples from 14 healthy young women, who first took a single oral dose of 0.1 mg gestodene and .03 mg ethinyl estradiol, then Milvane, a new tri-step combination oral contraceptive, for 3 months, to learn in detail the pharmacokinetics of gestodene. A 1-week wash-out phase occurred between the 2 treatments. The mean terminal half-life for gestodene after receiving the single dose was 18 hours. It volume of distribution stood at 84. Total clearance was 0.9 ml x min-1 x kg-1. Gestodene serum levels accumulated by a factor of 8 when compared to levels after single-dose administration. Drug levels reached a steady-state by the second part of each treatment cycle. At the end of treatment cycles 1 and 3, in comparison with single-dose administration, gestodene had a prolonged terminal half-life (20-22 h), reduced total and free clearance (0.16 ml x min-1 x kg-1 and ca. 27 ml x min-1 x kg-1, respectively), and reduced volume of distribution (ca. 18 1). When comparing single-dose administration and 3-month treatment levels, ethinyl estradiol increased sex hormone binding globulin (SHBG) levels by a factor of 3, apparently causing the changes in the pharmacokinetics of gestodene. Further, the free fraction of gestodene fell from 1.3 to 6%, and the fractions bound to SHBG increased from 69.4 to 81.4% while the fractions bound to albumin fell from 29.3 to 18%. The ethinyl estradiol values of the area under the curve stood at 299.2 pg x ml-1 x h at 0 hours of the last day of treatment cycle 1 and 3. At 4 hours, it was 278.1 pg x ml-1 s h. Between pretreatment and treatment cycles 1 and 3, total and free testosterone levels fell by almost 36% and 60%, respectively, resulting in a decrease of the fraction of unbound testosterone from 0.5 to .03% during treatment. These findings showed that pharmacokinetic parameters did not differ between cycles 1 and 3, indicating that equilibrium had been already reached after one cycle and that prolonged treatment should not result in any other changes.

The serum concentrations of 3-keto-desogestrel have been measured in 43 women who took a low-dose oral contraceptive containing 30 micrograms ethinyl estradiol (CAS 57-63-6) together with 150 micrograms desogestrel (CAS 54024-22-5) for a period of 3 months. Basic pharmacokinetic parameters, like Cmax, tmax and AUC, as well as the serum protein binding of 3-keto-desogestrel were determined on days 1, 10 and 21 of the first and the third treatment cycle, respectively. During cycle one, Cmax, AUC(0-4h) and AUC(0-24h) values on day 1 were 1.9 +/- 0.7 ng/ml, 3.9 +/- 1.3 ng.ml-1.h and 12.4 +/- 5.7 ng.ml-1.h, respectively. These values increased to 4.7 +/- 2.0 ng/ml, 12.1 +/- 5.6 ng.ml-1.h and 47.3 +/- 26.0 ng.ml-1.h on day 21. Within cycle 3, a similar, although less steep increase was observed for these parameters and there was practically no difference in the values of corresponding parameters on day 21 of both cycles. Throughout treatment, there was a redistribution of 3-keto-desogestrel with respect to the binding proteins albumin and sex hormone binding globulin (SHBG). During cycle 1, the free fraction decreased from 1.8% on day 1 to 1.1% on day 21, and the SHBG-bound fraction increased at the same time from 40% to 62%, mainly at the expense of the albumin-bound fraction. During cycle 3, there were only minor changes as compared to cycle one. The observed changes in the serum protein binding were related to an increase in SHBG levels during the treatment period.In Germany, health workers drew serum samples from 43 healthy young women who used a low dose oral contraceptive with 30 mcg ethinyl estradiol and 150 mcg desogestrel for 3 treatment cycles to measure 3-Keto-desogestrel (KDG) levels and determine serum protein binding proteins. The mean maximum KDG level on test day 1 was 1.9 ng/ml during the first treatment cycle. The area under the curve zero to 4 hours after pill intake was 3.9 ng ml-1 and, zero to 24 hours after intake, it was 12.4 ng ml-1. These figures rose to 4.7 ng/ml, 12.1 ng ml-1, and 47.3 ng ml-1, respectively on day 21. During the third treatment cycle, the increase was somewhat lower than it was during the first cycle. Further, the figures of the corresponding parameters on day 21 of both cycles, 1 and 3 barely changed. Between day 1 and 21, the free fraction of KDG fell from 1.8% to 1.1% while the sex hormone binding globulin (SHBG) bound fraction of KDG rose from 40% to 62%. This increase was largely at the expense of the albumin bound fraction (decrease from 32.2-26.1%). Just slight changes occurred during cycle 3. Women with lower body weights had significantly higher KDG serum levels than those with higher body weights (p .05). The results on serum protein binding of KDG can help researchers interpret overall pharmacokinetic changes.

The serum concentrations of gestodene (CAS 60282-87-3) as well as the binding of this progestin to serum proteins were studied in 40 women who took a low-dose oral contraceptive (Femovan, Femodene) containing 30 micrograms ethinyl estradiol (CAS 57-63-6) and 75 micrograms gestodene for 3 months. On days 1, 10, and 21 of the first and the third treatment cycle, respectively, 7 blood samples were drawn before and up to 4 h after pill intake; additional samples were taken prior to morning ingestion of pill on days 2, 5, 11, 15 and 22 of these cycles. Gestodene levels were measured by means of a specific radioimmunoassay and were evaluated for Cmax, tmax, and AUC up to 4 and 24 h. Independent of the test day and the treatment cycle studied, mean maximum gestodene serum levels were found about 0.8 to 0.9 h after pill intake. During the first treatment cycle, mean values of Cmax, AUC(0-4h), and AUC(0-24h) amounted to 4.3 ng.ml-1, 9.3 ng.ml-1.h, and 27.3 ng.ml-1.h on test day 1; these values increased by 250-400% and by 300-500%, respectively, when days 10 and 21 were compared to day 1. On day 1 of the third treatment cycle, these pharmacokinetic parameters were higher by almost a factor of two as compared to the corresponding data obtained on the beginning of the first cycle whereas the increase of these values between day 1 and the subsequent test days (200-300%) was slightly lower in cycle 3 as compared to cycle 1.(ABSTRACT TRUNCATED AT 250 WORDS)In Germany, health workers drew serum samples from 40 healthy young women who used a low dose oral contraceptive (OC) (Femovan, Femodene) with 30 mcg ethinyl estradiol and 75 mcg gestodene for 3 treatment cycles to measure gestodene levels, the free fraction of gestodene, and its distribution over the binding proteins in serum pools from all women. Mean maximum gestodene levels occurred .8 to .9 hours after taking the pill. The mean maximum gestodene level on test day 1 was 4.3 ng ml-1 during the first treatment cycle. This figure increased significantly to 7.4 ng ml-1 during the third cycle. Both day 1 levels were significantly lower than the levels obtained on day 10 (10.4 and 13.1 ng ml-1, respectively) and day 21 (12.1 and 13.4 ng ml-1, respectively). The area under the curve zero to 4 hours after pill intake was 9.3 ng ml-1. These figures rose 250-400% and 300-500%, respectively, on days 10 and 21. During the third treatment cycle, figures for days 10 and 21 were somewhat lower than those during the first cycle. 78% of total gestodene was bound to sex hormone binding globulin (SHBG) and 21% was bound to albumin on day 1 of the first treatment cycle. Just 1% of gestodene continued to be free. ON day 21, the fraction of gestodene bound to SHBG rose to 87%, that bound to albumin was 13%, and 0.5% remained free. Gestodene was not redistributed over its binding proteins during the third treatment cycle. These results indicated that pharmacokinetic accumulation and the increase in serum SHBG concentration and binding capacity for gestodene allows researchers to understand changes in gestodene levels during longterm treatment with a low dose OC containing gestodene.

Jung-Hoffmann und Kuhl (1989) berichteten kurzlich uber den an einem kleinen Probandenkollektiv erhobenen Befund vergleichsweise hoherer Serumkonzentrationen des Athinylostradiols (EE2) nach Einnahme von Femovan ((F) 30 μg EE2,75 μg Gestoden; n = 11) als nach Einnahme von Marvelon ((M) 30 μg EE2, 150 μg Desogestrel; n = 11). Die trotz gleicher EE2-Dosis beobachteten unterschiedlichen EE2-Serumkonzentrationen wurden mit einer von der jeweiligen Gestagenkomponente abhangigen, unterschiedlichen Metabolisierung und Elimination des EE2 erklart. Eine andere Arbeitsgruppe (Humpel et al., 1990; Kuhnz et al., 1990) beschrieb dagegen identische EE2-Serumkonzentrationen unter der Behandlung mit beiden Kontrazeptiva.

The myometrium of the rabbit contains a 17-β-hydroxysteroid: NAD(P) oxidoreductase, whose specific activity depends on the functional state of the uterus. In pregnancy one observes a 25-fold increase and after parenteral administration of oestradiol or stilboestrol an approximately 50-fold increase compared to the normal adult rabbit. The enzyme was purified from myometrium about 100-fold by precipitation twice with ammonium sulfate and by gel filtration. The enzyme was assayed by incubation with [16-14C]oestradiol-17β, determining oestron as the reaction product. Specific activity was expressed as n-moles oestron/60 min/mg protein. The molecular weight of the 17-β-hydroxysteroid: NAD(P) oxidoreductase can be estimated from gel filtration studies in the range from 10,000 to 50,000. The enzyme requires NAD+ or NADP+ as cofactor, NADP+ giving a 20% lower activity than an equimolar amount of NAD+. The optimal pH for the enzymatic oxidation of oestradiol to oestron is 9.4, and for the reduction of oestron to oestradiol 6.4. The Michaelis-Menten constant for oestradiol is 7.6 × 10−6 M. The oxidation of testosterone is at least 100 times slower than that of oestradiol. In phosphate-free buffer solutions, the addition of phosphate gives an increase of the enzyme activity. p-Chlormercuribenzoic acid (10−4M) and o-iodosobenzoic acid (10−4M) inhibit the activity of 17-β-hydroxysteroid: NAD(P)oxidoreductase of the myometrium by 97% and 26% respectively.

Zu den wenigen Vitaminen, deren biochemische Funktion bisher ungeklart war, gehort das Biotin. Es wurde nun gefunden, das das Enzym β-Methyl-crotonyl-CoA-Carboxylase Biotin enthalt und das dieses mit der Wirkgruppe des Enzyms identisch ist. Durch Austauschversuche mit radioaktiv markierten Verbindungen konnte nachgewiesen werden, das bei der Carboxylierung intermediar aktives CO2 in Form einer CO2 ∼ Biotin-Enzym-Verbindung entsteht. Am CO2∼Biotin als Modell lies sich zeigen, das das CO2 mit der Biotin-Molekel an einem der beiden N-Atome zu einer allophansaure-artigen Struktur verknupft ist, was schlieslich durch Synthese des Dimethyl-esters der CO2∼ Biotin-Verbindung bewiesen werden konnte.

Es wird uber die Erfahrungen mit der Anwendung von Cefoxitin bei Harnwegsinfekten berichtet, wie sie haufig nach gynakologischen Operationen, wie abdominalen oder vaginalen Hysterektomien, Kolporrhaphien, Sectio caesarea, auftreten. Im Anschlus an die meist zehn Tage dauernde Therapie mit Cefoxitin waren die Patientinnen, mit zwei Ausnahmen, als geheilt anzusehen. Die lokale und die allgemeine Vertraglichkeit konnten als gut bezeichnet werden. Als bisher einzige Nebenwirkung trat eine Diarrhoe auf, welche nach einer mehr als zehn Tage dauernden Therapie bemerkt wurde. Im zweiten Abschnitt wird uber die Behandlung einer Pyometra mit lokalen Spulungen mit Cefoxitin berichtet. Die durchEscherichia coli hervorgerufene Pyometra, welche zunachst nur als eitrige Zervizitis imponierte, war die Ursache fur wiederholte pathologische Abstriche gewesen. Nach mehrmaliger Spulung mit je 2 g Cefoxitin war der Kontroll-Abstrich steril und der zytologische Abstrich einwandfrei. Eine gleichzeitig durchgefuhrte systemische Therapie mit Cefoxitin scheint dabei von untergeordneter Bedeutung gewesen zu sein.