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PubMed2000

Clinical implications of disturbances of uterine vascular morphology and function.

Menstrual disturbances are one of the most common problems presenting to the gynaecologist. In order for the endometrium to bleed, vessels must break down. Disruption in the regulation of endometrial vascular growth and function has been found in association with spontaneous and sex steroid-induced disturbances of menstrual bleeding. Although circulating oestrogens and progestogens influence the endometrial vessels, this effect appears to be indirect, and regulation is primarily via local factors. Deficient vasoconstriction and haemostasis with excessive fibrinolysis is seen in menorrhagia. Breakthrough bleeding in users of progestogen-only contraceptives is associated with increased superficial vascular fragility and disruptions in the supporting basement membrane. Blood vessels in uterine fibroids are abnormal in distribution and appearance. Adenomyosis is also commonly associated with menstrual disturbance, and alterations in vascular distribution suggest altered angiogenesis. Successful human embryo implantation requires endometrial vascular breakdown. Excessive thrombosis associated with the antiphospholipid syndrome may interfere with this re-modelling and compromise implantation. Arteriovenous malformations are a rare but important cause of excessive or irregular vaginal bleeding. Abundant vessels with abnormal morphology, associated with aberrant angiogenesis can be seen, and embolization of these vessels may be an effective conservative treatment. Improved understanding of the regulation of the uterine vasculature is likely to lead to targeted therapies to prevent unscheduled vascular breakdown and to control menstrual disturbance at an endometrial level.

Arteriovenous Malformations↗
PubMed1993

Marital stability and cancer of the uterine cervix: changing patterns in post-war Britain.

This study investigates the extent to which the distinctive cross-sectional marital status picture of risk for cancer of the uterine cervix (single, married, widowed, divorced in ascending order of risk) has persisted in post-war Britain. Incidence and mortality due to invasive cervical cancer amongst single women now exceeds that of the married, and for both has become much closer to that of the widowed and divorced. A dramatic increase in carcinoma in situ in Scotland, seen particularly in the single since 1982, must partly reflect changes in screening and diagnostic classification, but is also consistent with the later occurrence of the sexual revolution in Scotland. Overall in Britain, the distribution of screening and hysterectomy cannot account for the present day pattern of the disease. Available data on patterns of smoking and oral contraceptive use are broadly consistent with a role for them in determining the current disease pattern associated with marital status but their possible involvement cannot be disentangled from the more likely effect of changing levels of sexual activity increasing the risk of sexually transmitted disease. As marital status becomes a less important social indicator of sexual behaviour, it has also become a much less reliable marker of cervical cancer risk.

Carcinoma↗
PubMedDate not supplied

Africa: support for family planning grows.

African countries, generally regarded as among the world's most cautious on family planning matters, may be the most dramatic growth area for family planning projects over the next few years, according to the Kenya-based Regional Director for Family Planning International Assistance (FPIA), PPFA's own worldwide aid program. In a recent status report to FPIA's New York headquarters, L. Robinson, a U.S. citizen and former Peace Corps volunteer who recently left FPIA to join the staff of the new House Committee on Population, forecasts a near-tripling of FPIA-funded projects in 1978 - from 7 to 19. Most of the potential new projects - in Nigeria, Togo, Liberia, Tanzania, and Sierra Leone - will involve the addition of family planning services to existing maternal and child health delivery systems, with emphasis upon the training of physicians and other medical, counseling, and educational personnel. Other prospective projects include family life education for adolescents in Cameroun and Ghana, and a full-scale rural, mobile services delivery program in Tunisia. Behind these promising prospects is what Mr. Robinson sees as a quiet but deliberate move by several governments - including Sierra Leone, Togo, and Cameroun - towards accepting family planning as an integral component of maternal and child health services. The moves in Cameroun and Togo are especially significant since both are French-speaking, and traditionally "pro-natalist and somewhat hostile to family planning." The pattern of change in these and other countries tends to be somewhat slow and low-keyed, he notes; most governments "prefer not to have explicit official policies and programs, but rather to allow the gradual evolution of private services becoming an integral part of government-administered health and medical facilities." And even in some countries where government policies remain highly restrictive - Ivory Coast, e.g., where laws prohibit family planning except when necessary on medical and health grounds - many druggists stock a variety of contraceptives, all available to individuals and couples upon request. FPIA's current program in Africa, as in other regions, has 2 principal components: distribution of family planning commodities and supplies (more than $500,000 worth of commodities have been distributed in African countries over the past 3 years), and financial and technical support of service and educational projects. Of the current projects, 2 are in Egypt and Kenya, 2 in Ethiopia, and 1 in the Sudan. In one of the most advanced of these - a project in Kenya designed to introduce family life education into the nation's primary and secondary schools - project leaders recently completed and presented to the Ministry of Education a comprehensive package of syllabi, curriculum texts, and teaching guides.

Africa↗
PubMed1999

A pooled analysis of case-control studies of thyroid cancer. III. Oral contraceptives, menopausal replacement therapy and other female hormones.

OBJECTIVE: The relations between oral contraceptives (OC), hormone replacement therapy (HRT) for menopause, and other female hormone use and thyroid cancer risk was analyzed using the original data from 13 studies from North America, Asia and Europe. METHODS: Based on 2,132 cases and 3,301 controls, odds ratios (OR) and the corresponding 95% confidence intervals (CI) were obtained by conditional regression models, conditioning on study and age at diagnosis, and adjusting for age, radiation exposure and parity. RESULTS: Overall, 808 (38%) cases versus 1,290 (39%) controls had ever used OCs, corresponding to an OR of 1.2 (95% CI 1.0 to 1.4). There was no relation with duration of use, age at first use, or use before first birth. The OR was significantly increased for current OC users (OR = 1.5, 95% 1.0 to 2.1), but declined with increasing time since stopping (OR = 1.1 for > 10 years since stopping). The association was stronger for papillary cancers (OR = 1.6 for current users) than for other histologic types. No significant heterogeneity was observed across studies or geographic areas. Eight studies had data on HRT, for a total of 1,305 cases and 2,300 controls: 110 (8%) cases and 205 (9%) controls reported ever using HRT (OR = 0.8; 95% CI 0.6 to 1.1). The ORs were 1.6 (95% to 0.9 to 2.9) for use of fertility drugs, and 1.5 (95% CI 1.1 to 2.1) for lactation suppression treatment. CONCLUSIONS: The studies considered in these analyses include most of the epidemiological data on the role of exogenous hormone use in the etiology of thyroid cancer, and they provide reassuring evidence on the absence of an association of practical relevance. The moderate excess risk in current OC users, if not due to increased surveillance for thyroid masses among OC users, is similar to that described for breast cancer, and would imply a role of female hormones on thyroid cancer promotion. There was no indication of increased thyroid cancer risk 10 or more years after discontinuing OC use.

Adenocarcinoma, Papillary↗
PubMed1991

Anticonvulsants in pregnancy.

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.

Abnormalities, Drug-Induced↗
PubMed1999

Alternative methods in the investigation of adolescents' sexual life.

PURPOSE: To describe two methodological approaches to surveying adolescents' sexual life which were combined within a national survey. METHODS: The questionnaire was designed during a 5-day workshop. Ten adolescents played the roles of imaginary adolescents involved in different situations related to sexual life. The information obtained through the analysis of these role-plays was used to establish the sequence of the questions, their content, and wording. The questionnaire was computerized so that it could be completed by the adolescents using laptop computers. Its arborescent structure, leading each respondent from one module to another, made possible the adjustment of the questions to each respondent's stage of development and type of sexual experience. RESULTS: A total of 4283 teenagers (2075 girls and 2208 boys, and 4 refusals) 16-20 years were included. Only 7.6% did not fill in the whole questionnaire. By the age of 18 years, more than 50% of boys and girls were sexually active. Half of sexually active teenagers have discussed contraception issue before engaging in their first intercourse, but much fewer (14-35%) have discussed issues related to HIV transmission. During their first sexual intercourse, the majority of the respondents used a condom (girls, 63%; boys, 58%) or condom plus oral contraception (girls, 11%; boys, 17%). CONCLUSION: Youth participation and role-play decrease the conceptual biases often associated with professionals' perceptions and bring tools enabling a better exploration of circumstances and negotiations surrounding the sexual encounter. The computerized questionnaire increases confidentiality, attractiveness, easy data collection, and, above all, adjustment of the questions to the respondent's level of experience. These methods could be more systematically used in surveys targeting sensitive issues related to adolescents' health.

Adolescent↗
PubMedDate not supplied

Lateral sinus thrombosis associated with zoster sine herpete.

Herpes zoster results from reactivation of the varicella zoster virus (VZV). Zoster sine herpete (ZSH) is an uncommon manifestation of VZV infection and presents with similar symptoms but without the vesicular rash. We describe an unusual case of lateral sinus thrombosis (LST) that developed during the clinical course of ZSH in the C2 distribution. A 55-year-old woman presented with a 3-day history of left temporal and postauricular pain, nausea, vomiting, and mild photophobia. She denied otalgia, otorrhea, and hearing loss. Examination revealed hyperesthesia in the left C2 nerve root distribution without evidence of herpetic rash. A computed tomography scan showed minimal fluid in the left mastoid cavity (not mastoiditis) and thrombus within the left lateral and sigmoid dural sinus. Magnetic resonance imaging and magnetic resonance angiogram confirmed these findings. Laboratory studies revealed elevated neurotrophic immunoglobulin G levels to VZV. Hypercoagulable studies were normal. She was subsequently treated with Neurontin, acyclovir, and anticoagulation. Her symptoms improved, and she was discharged 3 days later. LST is generally a complication of middle ear infection. Nonseptic LST, however, may result from dehydration, oral contraceptive use, coagulopathy, or thyroid disease. This unusual case raises the suspicion that thrombosis resulted from VZV associated thrombophlebitis in the ipsilateral cerebral venous sinuses along the second cervical nerve root distribution. A high index of suspicion is necessary in such cases so that a different treatment course can be identified and antiviral medication initiated promptly.

Clinical Laboratory Techniques↗
PubMed1992

Female condom launched in UK.

The lone-awaited female condom, Femidom, is to be launched at the end of September by manufacturers Chartex. It is being welcomed by the FPA [Family Planning Association] and other family planning experts as a valuable addition to the existing range of contraceptive methods and as an alternative to the male condom in offering effective protection against sexually transmitted diseases including HIV. A lubricated, loose-fitting polyurethane sheath, Femidom is inserted into the vagina at any time before sex. An inner ring holds the condom in place beyond the pubic bone and an outer ring lies flat against the vulva. In addition to extending choice, it is under direct control of the woman. As FPA Director Doreen Massey puts it: "We have to face the fact that some women who want safer sex can't get their partners to use condoms. for the 1st time with Femidom, you can insist that if he won't use a condom, you'll use yours." In trails of self-selected couples, up to 2/3 of women and their partners found the product acceptable. a study at the Institute of Population Studies in Exeter showed that while some couples had initial misgivings about the condom's size and appearance, especially its visibility when in position, these often declined with repeated use. Researcher Dr. Nicholas Ford pointed out that if the female condom makes a woman feel unattractive, her partner's comments may well influence these feelings. Users' experience of insertion and the condom's comfort also improved with repeated use. While there are no large studies showing ranges of effectiveness, it is likely to be as effective as the male condom (about 85%-98%). In a study of 106 women at the margaret Pyke Center in London, there were 7 unplanned pregnancies: 4 were due to inconsistent use of the method and 3 were method failures. Breakages were rare. 1/3 of participants dropped out in the 1st month. Users should continue with their existing contraceptive method until they are sure that they are using Femidom efficiently, recommended the authors. In October the FPA is launching a new free consumer leaflet on male and female condoms. 1/2 million leaflets will be distributed to UK pharmacies in October and November via the Pharmacy Healthcare Scheme as part of a safer sex campaign. a launch event will include the results of a survey asking pharmacists and consumers what they think of condoms.

Behavior↗
PubMed1969

Biologically active cortisol in plasma of oestrogen-treated and normal subjects.

Biologically active (non-protein-bound) cortisol levels in the plasma of 13 women taking oral contraceptives and of 67 normal subjects were compared, using a new method-steady-state gel filtration. Both total and unbound cortisol levels in the 67 normal subjects showed a skew distribution, which was roughly log-normal.Unbound cortisol levels in 11 of the oestrogen-treated women were in the normal range, but the median value was significantly increased in this group. Total plasma cortisol levels in the oestrogen-treated group were, as expected, increased threefold, and all were outside the normal range.

Adolescent↗
PubMed1981

The use of condoms by VD clinic patients. A survey.

The use of the condom, as a prophylactic agent against the transmission of venereal disease, is considered an effective method of disease prevention. The importance of initiating free condom distribution programs needs, however, to be demonstrated. The purpose of this study was to estimate and determine if VD clinic patients use condoms and would accept free condoms as disease prevention devices. The reasons why venereal disease patients use or do not use condoms were also established. The findings indicated a generally favorable attitude about condom usage, although a greater number of patients viewed the condom primarily as a contraceptive device. The major objection to the use of the condom was that it "lowered satisfaction." The majority of patients, however, stated that they would use free condoms if they were made available from a VD clinic. Both the survey and the condom distribution program exemplify the need for educational programs to encourage public awareness about the use of condoms as a preventive against sexually transmitted diseases.

Adolescent↗
PubMed1995

Compliance and oral contraceptives: a review.

Compliance difficulties are more common among oral contraceptive (OC) users than generally appreciated by clinicians, in part because unintended pregnancy is a relatively infrequent consequence and in part because more common manifestations such as spotting and bleeding may not be recognized as resulting from poor compliance. While improving compliance is a shared responsibility of patients, clinicians, and manufacturers, the clinician is the focal point for these efforts. Counseling must be individualized, which requires knowledge of factors that predict compliance and an understanding of the patient's decision-making process as it relates to medications. Most OC compliance research has focused on adolescents, where predictors of poor compliance include multiple sex partners, low evaluation of personal health, degree of concern about pregnancy, and previous abortion. Good compliance has been linked with patient satisfaction with the clinician, the absence of certain side effects, establishing a regular daily routine to take OCs, and reading information distributed with OC packaging.

Contraceptives, Oral↗
PubMed2006

Cancer screening and risk-reducing behaviors of women seeking genetic cancer risk assessment for breast and ovarian cancers.

PURPOSE/OBJECTIVES: To examine breast and ovarian cancer screening and risk-reducing behaviors of women seeking genetic cancer risk assessment (GCRA). DESIGN: Descriptive, cross-sectional. SETTING: An insurance-based clinic that serves high-risk patients in a southern California cancer center. SAMPLE: 134 women with breast or ovarian cancer (affected group) and 80 women with a family history of breast or ovarian cancer (unaffected group). The mean age of the sample was 48 years (range = 21-86), 79% were Caucasian, 66% were married, 60% were college educated, and 78% had children. Most affected women had early-stage disease. Unaffected women had a family history of breast (86%) or ovarian (14%) cancer. METHODS: Mailed surveys assessed pre-GCRA health behaviors and health and family histories. MAIN RESEARCH VARIABLES: Breast cancer screening (mammograms, clinical breast examination [CBE], breast self-examination), ovarian cancer screening (CA-125, pelvic ultrasound), and breast and ovarian cancer risk-reducing strategies (tamoxifen, bilateral mastectomy, oral contraceptive pills, bilateral salpingo-oophorectomy). FINDINGS: Twenty-one percent of the women who should have been having a mammogram had not had an annual examination as recommended, and 30% of affected women had not had annual CBEs. Few women took tamoxifen or oral contraceptive pills or had a bilateral salpingo-oophorectomy or bilateral mastectomy for cancer risk reduction. Twelve percent likely had unnecessary ovarian cancer screening. About 35% used other means, including herbs and homeopathy, for cancer prevention. CONCLUSIONS: Nearly a third of the affected women had not had appropriate breast cancer screening. About 12% used unsubstantiated, potentially harmful cancer "prevention" measures (e.g., herbs). IMPLICATIONS FOR NURSING: Nurses should assess clients' personal and family breast and ovarian cancer histories and promote cancer screening and risk-reducing behaviors that are appropriate for age and risk level.

Adult↗
PubMed1990

Protein binding of the contraceptive steroids gestodene, 3-keto-desogestrel and ethinylestradiol in human serum.

The protein binding of ethinylestradiol (EE2), gestodene (GEST) and 3-keto-desogestrel (KDG) has been determined by ultrafiltration in the serum of women who had either taken a gestodene (n = 37) or desogestrel (n = 28) containing oral contraceptive for a time period of at least 3 months. GEST and KDG were analyzed in individual serum pools whereas EE2 was repeatedly measured in two serum pools, each one representing one treatment group. The respective free fractions of the three steroids were 0.6 +/- 0.1% (GEST), 2.5 +/- 0.2% (KDG), 1.7 +/- 0.6% (EE2, in the gestodene-group) and 1.5 +/- 0.2% (EE2, in the desogestrel-group). EE2 was exclusively bound to albumin, whereas GEST and KDG were also bound to sex-hormone-binding globulin (SHBG). The distribution of the two progestins over the serum binding proteins was determined after heat-treatment of serum samples. For GEST, the contribution of albumin and SHBG was 24.1 +/- 9.1 and 75.3 +/- 9.1%, respectively and for KDG it was 65.9 +/- 11.9 and 31.6 +/- 12.0%, respectively. SHBG and corticosteroid-binding globulin (CBG) concentrations were measured in the serum samples obtained from both treatment groups. In the gestodene-group 180 +/- 61 nmol/l (SHBG) and 89 +/- 13 mg/l (CBG) were measured, the corresponding values in the desogestrel-group were 226 +/- 64 nmol/l (SHBG) and 93 +/- 14 mg/l (CBG). SHBG concentrations were correlated with the total concentration of GEST and its free fraction and a positive (r = 0.395) and negative (r = -0.491) correlation respectively was found. Only a weak negative correlation (r = -0.291) was found for SHBG and the free fraction of KDG in the serum. These data demonstrate that the three contraceptive steroids EE2, GEST and KDG were all bound extensively to serum proteins, however, with pronounced differences concerning their distribution over the various binding proteins.

Blood Proteins↗
PubMed1991

Urinary glucuronide excretion of fenofibric and clofibric acid glucuronides in man. Is it polymorphic?

The possible polymorphism of the glucuronidation reaction in man has been investigated using two hypolipidaemic compounds, fenofibrate and clofibrate, as the test probes. The formation of fenofibryl and clofibryl glucuronides was identified by their susceptibility to hydrolyses by beta-glucuronidase. The urinary excretion of the glucuronides was measured in 72 healthy volunteers after a single dose of fenofibrate, and in 104 subjects given a single dose of clofibric acid. Fenofibrate was excreted at a lower rate than clofibrate, since 13.94% and 26.55% of the doses of fenofibrate and clofibrate respectively, were recovered in urine in 8 h. Correlation analysis indicated that sex and body mass index significantly influenced the formation of fenofibryl glucuronide, whereas age and oral contraceptives affected the excretion of clofibryl acid glucuronide. The 8-hour urinary excretion patterns of clofibryl glucuronide and of clofibric acid presented a Gaussian distribution, whereas those of fenofibryl glucuronide and fenofibric acid showed 2 populations. When the metabolic ratio free fenofibric acid/glucuronide was considered, 84.7% of subjects presented the ratio 0.147, and 15.3% had the 3-fold higher ratio of 0.421. The study has shown, in the human population studied, that the glucuronidation of fenofibric acid but not that of clofibric acid may present a polymorphism.

Adult↗
PubMed1983

Dural sinus and cerebral venous thrombosis.

Eighty patients with 'primary' dural sinus and cerebral venous thrombosis were seen over a period of 16 years. There was an equal distribution amongst the sexes and the largest number of patients presented in the third decade. The commonest predisposing factors were puerperium, pregnancy, synthetic steroid contraceptives and anaemia. Seventy patients presented in an acute fashion with headache, focal or generalized seizures and focal neurological deficits. Ten patients presented in a subacute to chronic manner, with features to suggest an intracerebral space-occupying lesion. The investigation of choice was angiography. Thirty-five patients were treated conservatively with anticonvulsants, low molecular weight dextran and anti-oedema measures. Anti-coagulants were not used for fear of haemorrhage in the associated red infarcts. Antibiotics were not needed as infection played no part in the pathogenesis. Thirty-four patients needed an operation which took the form of a decompressive craniotomy and dural closure with the aid of a pericranial graft. The conservatively treated group appeared to fare better only because it included patients with a milder ictus. Forty patients improved, three remained unchanged and 37 expired. Autopsy in the 35 of the 37 patients showed cortical vein and sinus thrombosis and oedema with a haemorrhagic infarct. Long term follow-up showed good recovery of neurological function, but epilepsy was a troublesome sequel and needs regular anti-epileptic drug treatment.

Adolescent↗
PubMed1993

Pharmacokinetics of cyproterone acetate and ethinylestradiol in 15 women who received a combination oral contraceptive during three treatment cycles.

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.

Adult↗
PubMed2000

Influence of an aziridine precursor on the in vitro binding parameters of rat and ovine corticosteroid-binding globulin (CBG).

Aziridines are highly reactive alkylating compounds used in cancer treatment. Salsola tuberculatiformis Botsch., which causes prolonged gestation in sheep and contraception in rats, contains a very labile hydroxy-phenylaziridine or its precursor. A less labile analogue, 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride (Compound I), was synthesized and has been shown to be contraceptive in rats and to be stabilized by corticosteroid-binding globulin (CBG). The current study compared the binding parameters of rat and ovine CBG and evaluated the effect of the aziridine precursor, Compound I, on these parameters. Kd and Bmax values of 0.646 and 578 nM for corticosterone binding to rat CBG and 0.577 and 19.8 nM for cortisol binding to sheep CBG, respectively, were measured. In competitive binding studies with rat plasma, Ki values of 3.48 nM, 0.856 nM, 22.2 nM, 722 microM, and > 1,000,000 microM for cortisol, corticosterone, progesterone, Compound I, and synephrine (Compound II), respectively, were found, while in sheep plasma the values were 0.409 nM, 1.78 nM, 5.28 nM, 594 microM, and > 1,000,000 microM, respectively. Concentrations of Compound I equivalent to an effective pharmacological dose resulted in a significant (P < 0.01) decrease in CBG bound corticosterone and a significant (P < 0.01) increase in free corticosterone in rat plasma. In sheep, a similar effect was observed with cortisol. Progesterone binding, however, did not appear to be affected significantly by Compound I in either rat or sheep plasma. Compound I was found to be a competitive inhibitor of glucocorticoid binding to CBG. These results suggest that binding of Compound I to CBG with concomitant displacement of endogenous glucocorticoids, but not progesterone, may be part of the mechanism of action of these phenylaziridine compounds.

Acetates↗