RESUMEN

Invasive fungal infections are associated with significant morbidity and mortality, and their management is restricted to a variety of agents from five established classes of antifungal medication. In practice, existing antifungal agents are often constrained by dose-limiting toxicities, drug interactions, and the routes of administration. An increasing prevalence of invasive fungal infections along with rising rates of resistance and the practical limitations of existing agents has created a demand for the development of new antifungals, particularly those with novel mechanisms of action. This article reviews antifungal agents currently in various stages of clinical development. New additions to existing antifungal classes will be discussed, including SUBA-itraconazole, a highly bioavailable azole, and amphotericin B cochleate, an oral amphotericin formulation, as well as rezafungin, a long-acting echinocandin capable of once-weekly administration. Additionally, novel first-in-class agents such as ibrexafungerp, an oral glucan synthase inhibitor with activity against various resistant fungal isolates, and olorofim, a pyrimidine synthesis inhibitor with a broad spectrum of activity and oral formulation, will be reviewed. Various other innovative antifungal agents and classes, including MGCD290, tetrazoles, and fosmanogepix, will also be examined.

RESUMEN

The pharmacokinetics of antipyrine following a single 1-g intravenous dose was determined in 63 healthy women. Subjects were divided into 4 groups as follows: 1) cigarette smokers using low-dose oral contraceptives (n = 15); 2) nonsmokers using low-dose oral contraceptives (n = 12); 3) cigarette smokers not using oral contraceptives (n = 10); and 4) controls, neither cigarette smokers nor oral contraceptive users. Plasma antipyrine concentrations during 24 to 48 hours after dosage were measured by high-performance liquid chromatography. Mean kinetic variables in the nonsmoking, non-oral contraceptive using control group were: volume of distribution, 37.7 L; elimination half-life, 13.2 hours; and clearance, 34.4 mL/min. In cigarette smoking, non-oral contraceptive users versus controls, elimination half-life was reduced (8.0 vs. 13.2 hours, P < 0.05) and clearance increased (56.0 vs. 34.4 mL/min, P < 0.05). In nonsmoker oral contraceptive users, the reverse was true (elimination half-life was significantly increased: 16.6 vs. 13.2 hours, P < 0.05; and clearance was significantly decreased: 24.8 vs. 34.4 mL/min, P < 0.05). In smokers who were using oral contraceptives, values were not significantly different from controls (elimination half-life, 11.2 hours; clearance, 39.5 mL/min). Volume of distribution did not differ among the four groups. Thus the opposing effects on antipyrine clearance of the induction of metabolism by cigarette smoking and the inhibition due to low dose oral contraceptive use in effect negate each other when combined in humans.

Asunto(s)

RESUMEN

BACKGROUND: Exposure to isotretinoin during pregnancy is associated with a high risk of major fetal malformations. OBJECTIVE: Our purpose was to determine the reasons for and outcomes of in utero isotretinoin exposure. METHODS: On the basis of 433 spontaneous reports, we describe the likely reasons these exposures occurred and the outcomes of these pregnancies. In our analysis of the outcomes of pregnancy, we separately consider the pregnancies known to us before their outcomes were determined as prospective cases. RESULTS: Timing of conception in relation to initiation of therapy with isotretinoin was known for 396 women. Of these, 130 patients (33%) were already pregnant when they started isotretinoin. An additional 65 patients (16%) became pregnant in the first 3 weeks of isotretinoin use. Pregnancy outcomes were known on 409 pregnancies. Among these, 222 (54%) ended in elective abortion and 29 (7%) in spontaneous or missed abortion. Of 151 births, 72 (48%) were normal, 71 (47%) had congenital malformations, and 8 (5%) had abnormalities other than malformations. Of 94 prospectively ascertained pregnancies that ended in births, 28% had congenital malformations (95% confidence interval 19% to 37%). Exposure to isotretinoin during any time and for as little as one capsule within the first trimester have been associated with congenital malformations. CONCLUSION: The high proportion of exposures in already or recently pregnant women illustrates the importance of obtaining a negative pregnancy test before the initiation of isotretinoin therapy and of delaying the commencement of isotretinoin therapy until the onset of the next menstrual period. Furthermore, the importance of reliable contraceptive methods should be emphasized to patients when isotretinoin is prescribed. Young women seem to be at an especially high risk of pregnancy exposure to isotretinoin. There is a substantial risk of congenital malformation at all therapeutic doses of isotretinoin, even when the duration of exposure is brief.

Asunto(s)

RESUMEN

Artemether is an oil-soluble methyl ether of artemesinin (qinghaosu). It has been studied extensively in China, where it has been shown to be rapidly effective in severe falciparum malaria. Nearly all the patients studied previously were adults. We have investigated the efficacy of artemether in children with moderate or severe falciparum malaria. In the preliminary study of moderately severe malaria, 30 Gambian children were randomised in pairs to receive either intramuscular artemether (4 mg/kg loading dose followed by 2 mg/kg daily) or intramuscular chloroquine ('Nivaquine') 3.5 mg base/kg every 6 h. Both drugs were well tolerated and rapidly effective. The times to parasite clearance were significantly shorter in the artemether recipients (mean 36.7 [SD 11.3] vs 48.4 [16.8] h, p less than 0.05). 43 children with severe malaria were then randomised to receive intramuscular treatment with the same regimens of artemether (n = 21) or chloroquine (n = 22) as used in the preliminary study. 8 children (19%) died. There were no significant differences between the two groups in the clinical, haematological, biochemical, or parasitological measures of therapeutic response in survivors and there was no evidence of local or systemic toxicity. Despite similar parasite counts on admission, clearance times overall were longer in severe malaria than in moderate malaria. Artemether is a well tolerated and rapidly effective parenteral treatment for severe malaria in children, and would be especially valuable in areas with chloroquine-resistant P falciparum.

Asunto(s)

RESUMEN

The population pharmacokinetics of imipramine (IMI) and its active metabolite desipramine (DMI) have been evaluated using 177 IMI and DMI serum levels from 49 enuretic children (6-13 y) on IMI treatment. Standard two stage (STS) and maximum likelihood (ML) methods were used to estimate fixed and random effect parameters of IMI. Simultaneous estimation of the drug and metabolite parameters was carried out by the STS method. The mean value of the elimination constant of the drug and metabolite were 0.0425 h-1 and 0.0359, h-1 respectively. Significantly higher variability was found in the pharmacokinetic parameters of the metabolite. According to these estimated pharmacokinetic parameters, the recommended dose for enuretic children should be 1.7 mg.kg-1.day-1. The population pharmacokinetic parameters obtained in the study permit dosage individualisation using a bayesian algorithm.

PIP: Researchers used population pharmacokinetic parameters and data on the concentration effect relationship from 49 6-13 year old children suffering from enuresis who attended an outpatient psychiatric clinic at University Clinical Hospital in Salamanca, Spain to design rational dosing guidelines of the antidepressant imipramine (IMI) for individual patients. They evaluated 177 IMI serum levels and IMI's active metabolite desipramine (DMI) serum levels. The researchers used standard 2-stage (STS) and maximum likelihood methods to conduct the population pharmacokinetic analysis of IMI. They used STS to simultaneously estimate IMI and DMI parameters. The average value of IMI's elimination constant stood at 0.0425 h-1 and that of DMI's elimination constant stood at 0.0359 h-1. The researchers observed more variability in pharmacokinetic parameters of DMI than those of IMI. Based on estimated pharmacokinetic parameters, a dose of 1.7 mg kg-1 day-1 IMI is needed in children to reach the total serum level of 80 ng/ml which was higher than the dose generally administered in clinical practice (1 mg kg-1 day-1). The researchers demonstrated that applying the population pharmacokinetic parameters to Bayesian fitting methods allows clinicians to individualize IMI dose in children.

Asunto(s)

RESUMEN

The influence of chemotherapy agents, doxorubicin (adriamycin), cyclophosphamide, procarbazine, and dexamethasone on the activity of sialyltransferase in human semen has been examined. Aliquots of 25 mcL semen were incubated for 2 hours with the above substances at concentrations ranging from 10 to 800 mcg/incubation mixture. The measurement of sialyltransferase activity was based on the incorporation of radioactive sialic acid from CMP (14) C sialic acid) into asialofetuin. Doxorubicin and cyclophosphamide, at the maximal concentration of 800 mcg/incubation mixture exhibited an inhibiting effect on sialyltransferase activity which accounted for 15.7 +or- 16% and 12.2 +or- 16%, respectively. The rate of inhibition following incubation with maximal doses of dexamethasone (400 mcg) was 25.3 +or- 13%, respectively. The rate of inhibition following incubation with maximal doses of dexamethasone (400 mcg) was 25.3 +or- 12%. Inhibition caused by procarbazine did not exceed 5%. Inhibition of sialyltransferase in human semen by the materials examined in this study can diminish the transfer of sialic acid, thus interfering with normal glycoprotein's and glycolipid's syntheses in semen and possibly also in other fluids and tissues.

Asunto(s)

RESUMEN

OBJECTIVE: To review the potential problems and their management associated with the use of anticonvulsant drugs during pregnancy. DATA SOURCES: Studies published between 1968 and 1990 assessing the effect of pregnancy on the pharmacokinetics of anticonvulsant drugs, the teratogenicity of anticonvulsants, breast feeding and anticonvulsants and use of the oral contraceptive pill in patients taking anticonvulsant medication, were reviewed. RESULTS OF DATA SYNTHESIS: In general, plasma levels fall during pregnancy and rise during the puerperium. A number of factors including possible reduced absorption, increased volume of distribution, reduced protein binding, increased clearance and noncompliance, contribute to this fall in plasma concentration. All anticonvulsants are potentially teratogenic. The incidence of fetal malformations is higher in patients treated with multiple anticonvulsant drugs and on higher dosages with higher plasma levels. Anticonvulsants are excreted in low concentrations in breast milk. All anticonvulsants except valproic acid have been associated with failure of the oral contraceptive pill. This is due to liver enzyme induction of these drugs. CONCLUSION: As plasma levels of anticonvulsants fall during pregnancy, concentrations should be monitored regularly. Due to the fall in protein binding, marginally low total plasma levels of highly protein bound drugs may not reflect reduced unbound levels, and hence an increase in dosage may not be required. In order to reduce teratogenicity, one should aim to use a single anticonvulsant drug and the lowest dosage able to achieve seizure control. In general, breast feeding is not contraindicated.

PIP: The objective of this study was to review the potential problems and their management associated with the use of anticonvulsants in pregnancy. Studies published between 1968-90 assessing the effect of pregnancy on the pharmacokinetics of anticonvulsant drugs, the teratogenicity of anticonvulsants, breastfeeding, and anticonvulsants and the use of oral contraceptives (OCs) in patients taking anticonvulsant medication were reviewed. In general, plasma levels fall during pregnancy and rise during the puerperium. A number of factors including possible reduced absorption, increased volume of distribution, reduced protein binding, increased clearance, and noncompliance all contribute to this fall in plasma concentration. All such drugs are potentially teratogenic. The incidence of fetal malformations is higher in those patients treated with multiple anticonvulsant drugs and on higher dosages with higher plasma levels. Anticonvulsants are excreted i low concentrations in breastmilk. All except valproic acid have been associated with the failure of OCs, this due to liver enzyme induction of these drugs. As plasma levels of anticonvulsants fall during pregnancy, concentrations should be monitored regularly. Due to the fall in protein binding, marginally low total plasma levels of highly protein bound drugs may not reflect reduced unbound levels, and thus an increase in dosage may not be required. In order to reduce teratogenicity, one should aim to use a single anticonvulsant drug and the lowest dosage able to receive seizure control. In general, breastfeeding is not contraindicated.

Asunto(s)

RESUMEN

PIP: This updated literature review on heterosteroids and drug research has information on chemical structure, pharmacology, and effects. It first discusses the anti-inflammatory heterosteroids, such as mometasone furoate and cortivazol. It also covers heterosteroidal antimineralocorticoids and anabolic hetero derivatives. The review discusses at length the 19-norsteroid, mifepristone (RU-486), which exhibits antiprogestational activity and is being used for fertility control in women. It also has antiglucocorticoid activity and shows promise as a treatment of diseases characterized by muscle atrophy. In vitro studies indicate that mifepristone inhibits growth of breast cancer cell lines and of endometrial cancer cell lines. It has already exhibited growth inhibitory effects in some breast cancer patients. Discussions of mifepristone's pharmacokinetics and structural modifications of mifepristone follow. Danazol is an antigonadotropin and is used to treat endometriosis, benign breast disease, precocious puberty, hereditary angioneurotic edema, menorrhagia, some types of infertility, and gynecomastia. Danazol effects considerable changes in lipid metabolism. Other hormonal, antihormonal, and/or antifertility heterosteroids and/or aspects include androgen antagonists (e.g., cyproterone acetate), estrogen activity, antiestrogens, STS-557, and oximinosteroids. Heterosteroidal inhibitors of steroid hormone biosynthesis discussed are aromatase inhibitors, 5 alpha-reductase inhibitors, and 3 beta-hydroxysteroid dehydrogenase inhibitors (trilostane, epostane, and azastene). Heterosteroids affect the cardiovascular system, including the cardiac glycosides, antiarrhythmic agents, and antilipemic agents. Some heterosteroids affect central nervous system activity (e.g., RU-5135 causes convulsions in rodents). Pancuronium analogues and chandonium and analogues are neuromuscular blocking azasteroids. In addition to danazol and RU-486, several other antineoplastic heterosteroids exist (e.g., estramustine phosphate sodium, a prostate cancer drug).^ieng

Asunto(s)

RESUMEN

Interferences between drugs and oral contraceptives are considered to alter pharmacokinetics and thus the efficacy of steroidal hormones. It should be noted, however, that steroids can also modify the metabolism and pharmacodynamic effects of various substances. To the present knowledge, phase I (i.e., oxidation, demethylation) and phase II reactions (conjugation) are concerned. Drugs sharing those enzymatic systems with oral contraceptives experience either an increase in bioavailability by inhibition of oxidative metabolism or undergo accelerated elimination by induced conjugation. Such interaction may be of practical interest in subjects who take oral contraceptives and are simultaneously treated with antidepressants, antihypertensives, insulin, synthetic glucocorticoids, theophylline, and caffeine.

PIP: The effects of oral contraceptives (OCs) on drug therapy are related mainly to the inhibition of microsomal oxidation as well as the induction of enzymes involved in conjugation reactions. Since many drugs share these catabolic pathways, their pharmacodynamics will be affected by OCs. Notable interactions include an increased bioavailability of analgesics, tranquilizers, and tricyclic antidepressants. OCs increase the risk for hypertension, and pharmacokinetic interactions are to be expected when OCs are administered with antihypertensive drugs. Likewise, OCs affect lipid metabolism and thus modify the effects of atherogenic drugs; however, the different forms of hyperlipidemia show a heterogeneous response to OCs. Another particular concern is that the gestagen components of OCs may cause peripheral insulin resistance and may require dose adaption with antidiabetic treatments. Two common nonprescription drugs, theophylline and caffeine, show decreased clearance rates due to OCs. All share a common oxidation pathway involving cytochrome P-450 and P-448. However, cigarette smoking stimulates these enzymes, and the decreased clearance of theophylline and caffeine is usually not observed in smokers. The reports of effects of OCs and alcohol taken together are mixed, and no clinically relevant conclusions can be drawn. Most vitamin and mineral levels are influenced by OCs, but this is a concern only under conditions of deprived diet, when normal dietary adjustments are impossible. An important caveat of the many documented effects of OCs on the pharmacodynamics of other drugs is that, in most instances, these effects will be counterbalanced with kinetic changes and result in no clinical manifestation. Nevertheless, clinicians must be aware of possible adverse reactions, particularly in predisposed patients.

Asunto(s)

RESUMEN

Serum lithium levels were analyzed in six healthy, normal women during the midfollicular, midluteal, and premenstrual phases of their menstrual cycles after they had received 300 mg of lithium carbonate orally. An identical protocol was followed for seven women with artificial cycles induced by oral contraceptive steroids. Analysis of variance for repeated measures over time showed no significant differences between groups or between cycle phases. Therefore, hormonal effects of ovarian or contraceptive steroids per se do not appear to alter serum lithium concentrations. Other factors may account for changing lithium requirements during the menstrual cycle in some patients with affective illness.

Asunto(s)

RESUMEN

Fluconazole, a water-soluble bis-triazole antifungal agent that effectively penetrates the cerebrospinal fluid, is a highly selective inhibitor of the fungal cytochrome P450 system. In single-dose studies, coadministration of cimetidine and fluconazole (100 mg) resulted in an insignificant decrease in the absorption of fluconazole. The coadministration of rifampin and fluconazole (200 mg) decreased both the half-life and the area under the plasma concentration-time curve (AUC) of fluconazole. In multiple-dose studies, fluconazole (50 mg) did not significantly alter the pharmacokinetics of the two steroid components of an oral contraceptive. Coadministration of tolbutamide with fluconazole (100 mg) increased both the maximal plasma concentration and the AUC of tolbutamide without changing levels of blood glucose. The coadministration of cyclosporin A with a low dose of fluconazole (100 mg) was not associated with significant changes in the minimal and the maximal plasma concentrations of cyclosporin A. While higher doses of fluconazole (200 mg) did not affect endogenous steroids, coadministration resulted in changes in the pharmacodynamics of warfarin and the pharmacokinetics of phenytoin and cyclosporin A.

Asunto(s)

RESUMEN

The single dose pharmacokinetics of diflunisal were studied in 4 groups of 6 young volunteers: control men, control women, women taking low estrogen oral contraceptive steroids (OCS), and women smokers (10-20 cigarettes day). The plasma clearance of diflunisal was significantly higher in men (0.169 ml.min-1.kg-1) and in women on OCS (0.165 ml.min-1.kg-1) as compared to control women (0.108 ml.min-1.kg-1). Partial metabolic clearances of diflunisal by the three conjugative pathways (phenolic and acyl glucuronide formation, sulphate conjugation) were all increased in men and women OCS users as compared to control women. Statistically significant increases, however, were only observed for the partial metabolic clearance of diflunisal by phenolic glucuronidation between men and women (2.91 vs. 1.85 ml.min-1 respectively), and for the partial clearance by acyl glucuronidation between OCS users and control women (4.81 vs. 3.01 ml.min-1 respectively). Smoking resulted in a moderate increase (35%) in plasma diflunisal clearance. However, a significant reduction in total urinary recovery of diflunisal and its glucuronide and sulphate conjugates was found in smokers (70.5% in smokers as compared to 84.2-87.2% in the 3 other study groups). Consequently, smoking may have induced hydroxylation, a minor oxidative metabolic pathway of diflunisal recently discovered in man.

Asunto(s)

RESUMEN

The clinical duration of vecuronium was measured in two groups of postpartum patients undergoing elective tubal ligation. Ten patients received no premedication and ten others ranitidine 150 mg orally the morning of surgery. The mean duration of action of vecuronium was 57.2 +/- 9.9 min in the unmedicated patients and 54.0 +/- 12.9 min in the ranitidine treated patients. These values were significantly greater than the mean value for nonpregnant control patients (35.3 +/- 8.4 min) but indistinguishable from the mean value for cimetidine pretreated patients (63.0 +/- 17.6 min) reported previously. The combined results of the previous and present studies provide convincing evidence that the clinical duration of vecuronium-induced neuromuscular blockade is significantly longer in the postpartum patient and independent of cimetidine or ranitidine pretreatment.

Asunto(s)

RESUMEN

Thirteen women chronically using low-dose estrogen-containing oral contraceptives (50 micrograms or less of ethinyl estradiol or its equivalent for a minimum of 3 months) and 12 age-matched drug-free control women received a single 25 mg oral dose of doxylamine succinate in the fasting state. Ten women taking oral contraceptives and ten controls received a single 50 mg oral dose of diphenhydramine hydrochloride. Multiple plasma samples drawn during 30 hours following the dose of doxylamine, and 12 hours after diphenhydramine dosage, were analyzed by gas chromatography using nitrogen-phosphorus detection. Mean pharmacokinetic variables for doxylamine in control and oral contraceptive groups were: peak plasma concentration, 103 vs 100 ng/ml; time of peak, 2.40 vs 1.87 hours after dosage, elimination half-life, 10.1 vs 10.2 hours; and total clearance, 3.70 vs 3.88 ml/min/kg. Mean pharmacokinetic variables for diphenhydramine in control and oral contraceptive groups were: peak plasma concentration, 63.7 vs 73.8 ng/ml; time of peak, 2.7 vs 2.2 hours after dosage; elimination half-life, 6.0 vs 5.1 hours; and total clearance, 21.8 vs 25.5 ml/min/kg. None of these differences were statistically significant. Thus, low-dose estrogen-containing oral contraceptives do not significantly influence the pharmacokinetics of the antihistamines doxylamine or diphenhydramine.

Asunto(s)

RESUMEN

The effects of age, gender and low-dose (50 mcg or less) oral contraceptive steroids (OCS) on the pharmacokinetics of midazolam were evaluated following a single 7.5 mg intramuscular dose to five groups (8/group) of healthy volunteers consisting of young males, young females, elderly males, elderly females, and young female users of oral contraceptives. Blood samples were collected at specified times over a 24-hour period, and plasma concentrations of midazolam and its 1-hydroxymethyl metabolite were determined by a GC-EC assay. Midazolam was rapidly absorbed following intramuscular administration to the different groups. Comparison of young men vs elderly men, young women vs elderly women, young men vs young women, elderly men vs elderly women, and young women OCS-users vs young women non-OCS users indicated no substantial differences in the pharmacokinetic profile of midazolam between groups except for the comparison between the young and elderly men groups. The rate of elimination of midazolam was significantly slower in the elderly males compared to the young men. The pharmacokinetic profile of 1-hydroxymethyl midazolam paralleled that of the parent compound. This is to be expected since this metabolite exhibits formation rate-limited kinetics. Except for one subject who reported hives and itching, considered to be remotely related to test drug, no other adverse experiences or laboratory abnormalities were reported.

Asunto(s)

RESUMEN

Seventeen healthy women aged 24-45 years with regular menstrual periods, proven fertility and not using steroidal contraceptives or IUD were recruited for the study. The volunteers were followed during one control, one treatment and one follow-up cycle. Daily morning urine samples were obtained during the control and the treatment cycle. The samples were analysed with regard to pregnanediol glucuronide (P2-G), oestrone glucuronide (E1-G), oestradiol (E2), progesterone (P4), LH and creatinine. During the entire 3-month study the subjects kept a record of uterine bleeding and side effects. The subjects received 50 mg RU486 daily either on cycle days 7-10 (n = 7) or on cycle days 20-23 (n = 10). An endometrial biopsy was taken on cycle day 10 in the first group and on cycle days 21-28 in the second group of patients. Treatment during the proliferative phase caused significant prolongation of the cycle length due to a delay of the oestrogen and LH surge. However, once the oestrogen concentration started to increase, the remaining part of the cycle was normal. The length of the follow-up cycle was similar to that of the control cycle. The morphology of the endometrium did not differ from control samples taken from untreated women at the same time of the cycle. All ovulating women (n = 9) treated in the mid-luteal phase started to bleed on the 3rd to 4th day of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: 17 healthy women ages 24-45 years with regular menstrual periods, proven fertility, and no use of steroid contraceptives or IUD were recruited for this study. Volunteers were followed during 1 control, 1 treatment, and 1 follow-up cycle. Daily morning urine samples were obtained during the control and treatment cycles. The samples were analyzed for pregnanediol glucuronide (P2-G), estrone glucuronide (E1-G), estradiol (E2), progesterone (P4), LH, and creatinine. Over the 3-month study, the subjects kept a record of uterine bleeding and side effects. The subjects received 50 mg RU 486 daily either on cycle days 7-10 (n=7) or on cycle days 20-23 (n=10). An endometrial biopsy was taken on cycle day 10 in the 1st group and on cycle days 21-28 in the 2nd group of patients. Treatment during the proliferative phase caused significant prolongation of the cycle due to a delay in the estrogen and LH surges. Once the estrogen concentration was on the increase, the remainder of the cycle was normal. The length of the follow-up cycle was similar to that of the control and the morphology of the endometrium did not differ from control samples taken from untreated women at the same time of cycle. All ovulating women (n=9) treated during the midluteal phase began to bleed on the 3rd-4th days of treatment; in 4 of these women, bleeding was scanty and was followed by menstrual-like bleeding at the expected time. The remaining 5 volunteers had heavier bleeding and did not have new bleeding until a month later. The secretory phase lasted 16.5 +or- 1.3 days in women with 2 bleeding episodes and 11.8 +or- 1.9 days in women with 1 bleeding episode (p 0.05). The hormonal parameters were similar in both groups until the start of treatment. In those with 1 bleeding episode, treatment was associated with a reduction in progesterone concentration, while for those with 2, progesterone concentration remained elevated until the 2nd episode. Light microscopic examination of the endometrium revealed unique changes in the endometrial morphology. Results indicate that Ru 486 acts mainly on the endometrium but a direct or indirect effect on the corpus luteum cannot be discounted. The age of the corpus luteum may be of importance for its susceptibility to RU 486 treatment.

Asunto(s)

RESUMEN

The serum concentrations of 3-keto-desogestrel (KDG) have been determined radioimmunologically in 11 female volunteers on Day 1, 10, and 21 of the 1st, 3rd, 6th, and 12th cycle of treatment with 30 micrograms ethinylestradiol and 150 micrograms desogestrel during the first 4 hours and 24 hours after intake. On the first day of each cycle the KDG levels were low, but increased thereafter until Day 21. Highest serum concentrations were measured on Day 21 of the 3rd and 6th cycle with peak levels between 1.5 and 6.2 ng/ml. Contrary to this, the KDG levels were significantly reduced during the 12th treatment cycle. The serum concentrations of SHBG rose significantly between Day 1 and Day 21 of each cycle reaching values which were 3-fold of those at the beginning of treatment. During the pill-free intervals, SHBG levels decreased but remained elevated as compared to controls. There was a significant correlation between the SHBG levels and the area under the KDG-concentration-versus-time curves (AUC) indicating a pronounced influence of the serum steroid-binding protein upon the pharmacokinetics of KDG. There were great interindividual differences in the KDG levels. The serum levels of the individual woman remain, however, in a relatively constant range throughout the treatment period of 12 months, possibly due to genetic factors.

Asunto(s)

RESUMEN

The pharmacokinetic characteristics of RU486 and its acute effects on anterior pituitary hormone secretion after oral administration were examined in six normal women. Serum RU486 concentrations were determined by a radioimmunoassay. The absorption of RU486 was rapid with peak serum levels reached approximately 90 minutes after a single oral dose (4 mg/kg). The disappearance of RU486 and its metabolites conformed to a noncompartmental model with a mean apparent half-life of 53.7 +/- 6.9 hours. The mean apparent volume of distribution and clearance rate were 1.47 +/- 0.25 l/kg and 1.04 +/- 0.09 1/hour, respectively. In comparison with a control group of normal women (n = 9), there were significant elevations in transverse mean cortisol levels in the RU486 group (P less than 0.01). However, mean adrenocorticotropic hormone (ACTH) levels and the diurnal pattern of ACTH and cortisol secretion were not changed. RU486 induced a mild prolactin (PRL) elevation (P less than 0.01), whereas thyroid-stimulating hormone (TSH) and luteinizing hormone (LH) levels were not altered. In view of the relatively slow clearance rate for RU486 and its metabolites, our findings suggest that the pharmacologic action of RU486 is prolonged after a single oral dose.

Asunto(s)

RESUMEN

The elimination of caffeine from the plasma and the excretion of the major metabolites of metamizol (AnalginR) in the urine was studied in 25 women on long-term oral steroid contraceptives. Both tests allowed to draw conclusions about metabolic liver function. A steroid-induced delay of the elimination of caffeine in clinically healthy women with/without serologic elevation of aminotransferase activities was demonstrated. --We regard this as the consequence of an inhibition of the cytochrome P-450-dependent poly-functional oxidases of the P-450MC type, which was produced by oral contraceptives. The differences in the elimination of metamizol were not significant.

PIP: The elimination of caffeine from the plasma and the excretion of the major metabolites of metamizol (Analgin) in the urine was studied in 25 women on longterm oral contraceptives (OCs). Both tests allowed for conclusions about metabolic liver function. A steroid-induced delay of the elimination of caffeine in clinically healthy women with and without serologic elevation of aminotransferase activities was demonstrated. The author's regard this as the consequence of an inhibition of the cytochrome p-450-dependent polyfunctioned oxidases of the P-450 MC type, which was produced by OCs. The differences in the elimination of metamizol were not significant. (author's)

Asunto(s)

RESUMEN

Seven healthy women chronically (greater than 6 months) treated with oral contraceptives and 7 age- and weight-matched female controls were studied. Each subject was given 20 mg fluocortolone orally and the plasma concentrations of total and unbound fluocortolone in multiple samples obtained during the following 24 h were determined by HPLC and equilibrium dialysis. In the subjects on oral contraceptives there was no significant change in total clearance, unbound clearance or volume of distribution at steady-state of total and unbound fluocortolone, but there was a significant increase in hydrocortisone concentration compared to the control subjects. It appears that the elimination of the synthetic corticoid fluocortolone was not impaired by chronic administration of contraceptive steroids.

Asunto(s)