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Biomedical subjects

O Heikinheimo

Publications and source records attributed to O Heikinheimo.

At least 37 records · Page 2Linked to original sources
PubMed1995

Antiovulatory actions of RU 486: the pituitary is not the primary site of action in vivo.

Continuous administration of RU 486 impairs follicular development and inhibits ovulation in women. Yet, the mechanism of ovulation inhibition remains unknown. To characterize the mechanism(s) of ovulation inhibition, we studied six regularly menstruating cynomolgus monkeys for three consecutive (control-rest-treatment) cycles. Monkeys received 1 mg/kg.day RU 486 in between cycle days 2-22. Basal and GnRH-stimulated (1 and 50 micrograms GnRH, iv, 2 h apart) secretion of LH and FSH was assessed using serial blood samples (every 15 min for 12 h) collected on cycle day 10. Serum levels of estradiol (E2), progesterone (P4), RU 486, cortisol, LH, FSH, and PRL were analyzed by RIAs, the bioactivity of LH was assessed using a mouse Leydig cell assay. The mean cycle length was prolonged by RU 486 treatment from 31.8 to 69.8 days (P = 0.008). During RU 486 treatment, patterns of E2 secretion varied considerably; the mean +/- SD E2 level was 204 +/- 139 pmol/L. LH peaks and P4 profiles compatible with luteal function were seen only before resumption of menstruation. However, one monkey had an increase in P4 after the GnRH challenge-induced LH secretion. Basal levels of LH varied between suppressed and apparently normal values, whereas basal FSH seemed little affected by RU 486 treatment. In two monkeys with E2 secretion indicative of normal follicular development, minor peaks of LH, but no rises in serum P4, were seen. The ratio of bioactive/immunoactive LH was reduced in these monkeys during RU 486 treatment compared to that during the washout period of the treatment cycle. Surprisingly, the pituitary responsiveness to acute GnRH challenge was not affected by RU 486 administration. The individual levels of RU 486 were similar during the treatment period (mean, 40 nmol/L). A resumption of ovulatory cycles occurred when RU 486 concentrations were below 2.5 nmol/L. We conclude that in cynomolgus monkeys, inhibition of ovulation by RU 486 occurs mainly at the level of the hypothalamus, with possible additional effects on the granulosa cell function and alterations of LH bioactivity.

Animals↗
PubMed1994

The progestin ST 1435--rapid metabolism in man.

Parenterally administered ST 1435 (Nestorone) is highly potent for contraception, and ovulation can be inhibited with very low serum levels of ST 1435. Orally administered ST 1435 is ineffective in various laboratory animals, presumably due to extensive first-pass metabolism. Thus, ST 1435 has been proposed for lactational contraception, to be metabolized by the suckling infant. We have studied the metabolism of ST 1435 in female volunteers following oral (10 mg), intravenous (iv) (0.1 mg) and transdermal (4.5-9.0 mg) routes of ST 1435 administration. Preliminary studies using rats were performed to develop the methodology of high performance-liquid chromatography (HPLC) fractionation and ST 1435-RIA detection. Rat portal serum revealed 4 distinct peaks of immunoreactive material with the retention times (Rt's) of 7.5, 10, 14.5 and 17.5 min (ST 1435 = 10 min). In systemic serum, only the peak with the Rt of 7.5 min could be detected. Therefore, orally administered ST 1435 is very effectively metabolized by the rat liver; this also explains the previously observed lack of biological effects of oral ST 1435. Following oral administration of ST 1435 to two women, the Rt of the major peak was 10 min. The magnitude of the ST 1435 peak decreased rapidly, and at 24h following ingestion, no ST 1435 could be detected by this method. The t1/2 of ST 1435 was approximately 1-2h. In addition, two minor peaks with Rt's of 4.5 and 16 min could be detected with the ST 1435 RIA at 1-4h following oral ingestion. Competitive receptor binding assays using the human uterine progesterone receptors (hPR) revealed that the ST 1435 fraction exhibits strong binding affinity towards the hPR; thus, in the human, a small fraction of biologically active ST 1435 seems to escape from the first-pass metabolism following oral intake. Following iv and transdermal administration of ST 1435, the only detectable peak with ST 1435-RIA was that of ST 1435. Similar magnitude of the ST 1435 peaks following oral administration of 10 mg and iv administration of 0.1 mg indicated that the bioavailability of ST 1435 is low. These data seem to confirm the suspicion that orally administered ST 1435 is also rapidly metabolized in the human, therefore encouraging further evaluation of ST 1435 during lactation. However, the rapid metabolism seen after oral intake can be successfully circumvented by sustained parenteral administration of ST 1435.

Administration, Cutaneous↗
PubMed1994

Hepatic metabolism and distribution of mifepristone and its metabolites in rats.

The hepatic metabolism of mifepristone was studied in female Wistar rats following oral administration of 10 mg/kg. The extraction of mifepristone by the rat liver was effective, eliminating 80% of the mifepristone. During the absorption phase, the portal serum concentrations of mifepristone were over 10-fold higher than those measured in systemic serum. The serum concentrations of the monodemethylated, didemethylated and hydroxylated metabolites of mifepristone were lower in systemic serum, indicating that the metabolites were also effectively excreted by the rat liver. The distribution of mifepristone and its demethylated metabolites between serum, brain, muscle and adipose tissue was studied in lean and obese Zucker rats following repeated oral administration of 10 mg/kg. The individual serum concentrations of mifepristone varied considerably, from 24-482 ng/ml; the mean (+/- SE) serum concentrations for lean and obese rats were 167 (+/- 86) and 211 (+/- 62) ng/ml respectively. Mifepristone could be measured in brain in each animal, its concentrations being 28% of those measured in serum. Muscle tissue and serum contained approximately similar concentrations of mifepristone. Adipose tissue effectively concentrated mifepristone, and its concentrations were 40-fold higher in fat than in serum. The difference in the concentrations of mifepristone between the lean and obese animals was statistically significant only in brain tissue (P < 0.05). The serum concentrations and brain, muscle and adipose tissue concentrations of mifepristone were significantly correlated (P < 0.05). The distribution of the demethylated metabolites was roughly similar to that of mifepristone. However, their concentrations were significantly higher (P < 0.02) in the obese animals in each tissue type investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

Effect of mifepristone on inhibition of ovulation and induction of luteolysis.

Mifepristone administration to women in the mid- or late follicular phase delays the luteinizing hormone (LH) surge and prolongs the follicular phase. Since the resumption of follicular growth commences following mifepristone cessation, the drug must be given either continuously or at repeated intervals in order to block ovulation. Using various regimens with or without exogenous progestins, ovulation was inhibited in the majority of subjects. However, this was not consistent and in several instances, LH surges and a rise in plasma progesterone were suggestive of ovulation and corpus luteum function. Therefore, mifepristone cannot be used as a contraceptive which will reliably inhibit ovulation. With low-dose mifepristone administration, alterations in endometrial morphology were characterized by a delay in maturation despite the presence of ovulation. This suggests that the endometrium displays a greater sensitivity to mifepristone than does the pituitary, a finding that may have important contraceptive implications. Late luteal-phase mifepristone administration to women who were not sexually active did not alter their menstrual rhythm, bleeding patterns or steroid and gonadotrophin concentrations. However, when used in unprotected women in the late luteal phase, mifepristone did not uniformly terminate all pregnancies. On the other hand, when used within 72 h of intercourse, mifepristone was as effective a post-coital agent as the standard high-dose oestrogen-progestin combination.

Abortion, Induced↗
PubMed1993

Pharmacokinetics and bioavailability of ST 1435 administered by different routes.

The ovulation inhibiting potency of the synthetic progestin ST 1435 (Nestorone) is high after parenteral administration and practically nil after oral administration. The purpose of this study was to determine the pharmacokinetic parameters of ST 1435 after single oral or intravenous administration or after long-term treatment with subdermal implants in women. After administration, as a single i.v. bolus, the plasma disappearance rate of immunoreactive ST 1435 had two components with half-lives (mean +/- SE) of 3.5 +/- 0.5 and 83 +/- 14 min, respectively. The volume of distribution was 4.7 +/- 1.3 L/Kg and the metabolic clearance rate was 55 +/- 6 L/Kg/d. After oral administration, the bioavailability was about 10% of the dose. After chronic subdermal administration, the plasmatic clearance was slower than following the acute doses. These results show that ST 1435 has shorter half-lives and a faster clearance rate than progestins which bind SHBG. The large volume of distribution indicates accumulation in the extravascular space and was expected in view of the high affinity of ST 1435 for progesterone receptors. The slower plasma elimination rate after chronic administration was attributed to the re-entry of a larger mass of drug from the extravascular space, and/or accumulation of immunoreactive metabolites with slower clearance than the parent steroid.

Administration, Oral↗
PubMed1993

The divergent effect of RU 486 on adrenal function in the dog is related to differences in its pharmacokinetics.

This study has evaluated the relationship between the antiglucocorticoid effect of RU 486 and its pharmacokinetics in seven female mongrel dogs (weight 21-30 kg), all of which had appropriate responses to insulin-induced hypoglycemia and metyrapone. They were given RU 486 (50 mg.kg-1.d-1) for ten days. Three dogs (responders) demonstrated increased secretion of ACTH and cortisol which reached a maximum at the termination of RU 486 administration and returned to baseline by days 22 and 18, respectively. The remaining four dogs (non-responders) showed only transient non-sustained increases in ACTH and cortisol. Serum concentrations of RU 486 and its monodemethylated and di-demethylated (but not its hydroxylated) metabolites were significantly higher in the responder dogs. The ratios of the hydroxylated metabolite to RU 486 and its demethylated derivatives were higher in the non-responders, whereas the ratio of the di-demethylated to monodemethylated compound was higher in the responders. Since variations in the hydroxylation and reductive catabolism of steroids have been well documented in different strains of a species, it is possible that the differences in levels of RU 486 and its metabolites in the two groups are accounted for by variations in RU 486 metabolism. In the responder group the metabolism of RU 486 is directed to demethylation, and in the non-responder group to hydroxylation. Thus, differences in pharmacokinetics of RU 486 in the two groups of dogs may explain the variable biological response to this antiglucocorticoid.

Administration, Oral↗
PubMed1993

Dose-response relationships of RU 486.

Clinical experience has indicated that the effects of RU 486 can be divided into dose-dependent and dose-independent effects. Examples of the dose-dependent effects include the antiglucocorticoid effects of RU 486, whereas pregnancy termination or dilatation of the cervix can be considered dose-independent with the various regimens tested so far. Following oral intake in man, the serum levels of RU 486 are in the micromolar range, and the half-life is approximately 30 hours. The concentrations of RU 486 in myometrial tissue are approximately one-third of those measured in serum. However, due to saturation of alpha 1-acid glycoprotein (AAG), the serum binding protein for RU 486, the serum levels remain similar within the dose range of 100-800 mg of RU 486. The unbound RU 486 is metabolized by two-step demethylation or by hydroxylation. The demethylated and hydroxylated metabolites of RU 486 retain considerable affinities of 9-21% towards the human progesterone receptor, and 45-61% towards the human glucocorticoid receptor (RU 486 = 100%), suggesting a biological role for the metabolites. Rat serum lacks a specific binding protein for RU 486. Even though the levels of RU 486 in rat adipose tissue are 40 times as high as those seen in serum, the concentrations of RU 486 in rat brain are only 28% of the serum levels. This indicates that diffusion of RU 486 into the central nervous system is restricted by the blood-brain barrier. Hence, the dose-dependency of certain centrally mediated effects of RU 486 might be explained by the limited diffusion of RU 486 into hypothalamic/hypophyseal sites, which seem to be reached only after ingestion of high doses of RU 486. However, the peripheral effects of RU 486, such as termination of pregnancy, are mediated via steroid receptors in target tissues. This suggests that similar biological effects can be attained at considerably lower doses than the ones currently in use.

Abortion, Induced↗
PubMed1993

Response to intermittent RU486 in women.

OBJECTIVE: To determine the effects of intermittent administration of the antiprogestin RU486 on ovarian function. DESIGN: Three different regimens of RU486 were tested. PARTICIPANTS: Nine healthy regularly menstruating volunteers protected by an intrauterine device or surgical sterilization. INTERVENTIONS: Two groups of three women each received 10 mg or 50 mg RU486 at weekly intervals for 5 weeks. Another three women received 50 mg RU486 for 3 consecutive days at 10-day intervals for 80 days. MAIN OUTCOME MEASURES: Serum E2, P and RU486 levels. Ovarian ultrasound (US) and serum LH and FSH in select subjects. RESULTS: The predominant effect was partial inhibition of E2 secretion and suppressed P levels. During a total aggregate of 16 treatment months, there were seven episodes of elevated P levels; however, US did not always indicate the occurrence of normal ovulation. CONCLUSION: Intermittent RU486 administration can interfere with normal follicular development and function, but its clinical application may require a more effective dose and/or timing of administration.

Administration, Oral↗
PubMed1992

Contraception with subdermal implants releasing the progestin ST-1435: a dose-finding study.

A new modified subdermal implant releasing the potent progestin ST-1435 was studied in eleven fertile-aged women. These implants have been developed for contraception and they have a life-time of two years. Three implant lengths of 4, 6 and 8 cm were tested to find the optimal steroid dose for inhibition of ovulation. Serum samples were collected twice per week during a six-week period every six months. The concentrations of serum ST-1435, estradiol and progesterone were determined by RIA. Ovulation was inhibited by all ST-1435 doses tested. The concentration of serum progesterone was below 6 nmol/l in all samples tested showing the absence of luteinization. The concentration of serum ST-1435 increased with increasing ST-1435 dose. Serum estradiol concentrations were quite variable, showing wide range and occasional high peak values typical of progestin treatment; the mean value of serum estradiol concentrations measured did not differ with different ST-1435 doses. The results of steroid determinations led to the conclusion that a single 4 cm subdermal implant is optimal for contraception. With this dosage level, ovulation is inhibited and side effects are minimized. Bleeding control was variable. No hormonal side effects due to the progestin ST-1435 were reported. This method, using a single 4 cm subcutaneous implant releasing the progestin ST-1435 with a life-time of two years, represents a promising alternative for inhibition of ovulation and contraception.

Adult↗
PubMed1992

The glucocorticoid antagonist mifepristone reveals abnormal regulation of the adrenocortical system in obese Zucker rats.

The effects of the potent glucocorticoid type-II receptor (GR) antagonist, mifepristone, on corticosterone secretion and on expression of preprocorticotrophin-releasing factor (preproCRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and of pro-opiomelanocortin (POMC) mRNA in the pituitary gland were investigated in lean and obese Zucker rats. Treatment with mifepristone for 4 days (10 mg/kg orally twice daily) significantly (P less than 0.05) stimulated corticosterone secretion in lean but not in obese rats. In lean rats the enhanced corticosterone secretion was associated with non-significant increments in the expression of preproCRF mRNA in the PVN and of POMC mRNA in the pituitary gland, while mifepristone significantly (P less than 0.05) reduced the expression of preproCRF mRNA in the PVN of obese Zucker rats. It is concluded that antagonism of GR by mifepristone results in persistent activation of the adrenocortical axis in lean Zucker rats due to blockade of feedback inhibition by circulating corticosterone. In obese animals the abnormal response to mifepristone suggests that the neuroendocrine control of the HPA axis is altered in genetically determined obesity.

Animals↗
PubMed1991

Transdermal absorption of the progestin ST-1435: therapeutic serum steroid concentrations and high excretion of the steroid in saliva.

The synthetic progestin ST-1435 was administered transdermally to six healthy women during the late luteal phase. The steroid was applied to the periumbilical area in a commercial gel ("Progestogel"), also containing progesterone. Single doses of 2.3, 4.5 and 9.0 mg of ST-1435 were given in three experiments and repeated doses of 2.3 mg of ST-1435 for five days were given in another three experiments. Samples of serum and saliva were collected and the concentrations of ST-1435 and progesterone were determined by radioimmunoassays. Transdermal absorption of the synthetic progestin ST-1435 was shown to result in serum steroid concentrations high enough for therapeutic purposes. The concentration of ST-1435 in serum was still high 24 hours after application, reflecting sustained release of the steroid from the skin. In the five-day experiments, relatively constant serum levels were achieved in different individuals, and a single dose per day seems sufficient. High excretion of ST-1435 in saliva was found two hours after gel application. However, the concentrations of serum and salivary ST-1435 were not directly correlated in different individuals. Transdermal application of ST-1435 might offer a good alternative for systemic progestin treatment.

Administration, Cutaneous↗
PubMed1990

A contraceptive vaginal ring releasing ethinyl estradiol and the progestin ST-1435: bleeding control, serum steroid concentrations, serum lipids and serum chemistry.

Four women used vaginal rings releasing the synthetic progestin ST-1435 and ethinyl estradiol for at least three 21-day cycles with a 7-day treatment-free period between intervals of use. Patterns of bleeding were evaluated and serum concentrations of ST-1435, estradiol, progesterone and ethinyl estradiol were measured by radioimmunoassay. Total serum cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and serum chemistry were determined before ring use and during the first and third treatment cycles. The women experienced no difficulties in using the vaginal ring and all continued to use the ring after the first three cycles. Bleeding control was good and hormonal side effects were minimal. Serum steroid concentrations were: ST-1435, 289 +/- 117 pmol/l (mean +/- SD); ethinyl estradiol, 172 +/- 108 pmol/l; and estradiol, 184 +/- 107 pmol/l. Concentrations of serum progesterone were low, indicating complete suppression of ovulation during treatment. Total serum cholesterol increased slightly during use of ring. However, this increase could be accounted for by an increase in serum HDL-cholesterol. Liver function tests were in the normal range during ring use and values of serum chemistry showed no significant changes. This contraceptive vaginal ring presents a good method of contraception, showing good bleeding control and no harmful metabolic effects.

Adult↗
PubMed1990

Pharmacokinetics of the antiprogesterone RU 486: no correlation to clinical performance of RU 486.

The pharmacokinetics and metabolism of RU 486 were characterized in 17 women who received a single dose of 600 mg of RU 486 for termination of an early unwanted pregnancy. Based on the clinical outcome and serum chorionic gonadotropin values, the subjects were divided into two groups: those who aborted completely (i.e. responders: N = 13) and those who did not respond to RU 486 treatment (i.e. non-responders: N = 4). The serum levels of RU 486, the monodemethylated, didemethylated and hydroxylated metabolites of RU 486 were measured by HPLC preceded by column chromatography. There were no significant differences in the serum levels of RU 486 or its metabolites between the two groups. The serum concentrations of alpha 1-acid glycoprotein, the binding protein for RU 486, were quantitated by immunoturbidimetry. The alpha 1-acid glycoprotein concentrations were similar in responders and non-responders. The metabolism of RU 486 was also studied by fractionating extracts of serum pools of responders and non-responders on thin-layer chromatography, and subsequent RIA analysis of the eluates of the sliced thin-layer chromatography. Spots with similar distribution and percentages of cross-reactivity were found in both groups on the chromatography; the results were also similar to those from a serum pool to which synthetic RU 486 and its three metabolites had been added. Hence it is concluded that failure to abort in response to RU 486 therapy is not associated with altered pharmacokinetics or metabolism of RU 486.

Abortion, Induced↗
PubMed1990

Antiprogesterone RU 486--a drug for non-surgical abortion.

RU 486 is the first steroidal antiprogesterone in clinical use. It acts by binding to progesterone receptor, thus blocking the effects of progesterone at the uterine level, and provoking endometrial necrosis and shedding. RU 486 can, therefore, be used to interrupt early human pregnancy. In pregnancies of up to 7-8 weeks duration, the rate of complete abortions with RU 486 has ranged from 50% to 90%. The success rate can, however, be augmented up to 95%-100% by combining RU 486 with a low dose prostaglandin. RU 486 induced abortion has been well tolerated by women and highly acceptable to them. The bleeding starts 2-3 days after RU 486 administration lasting for 12-14 days. Possible clinical uses of RU 486 include induction of menstruation, late post-coital contraception, induction of labour after intrauterine fetal death, preoperative cervical ripening and treatment of progesterone receptor positive mammary tumours. When administered in the follicular phase of the cycle, RU 486 inhibits follicular development. In addition, the antiglucocorticoid properties of RU 486 have been used in symptomatic treatment of hypercortisolemia of Cushings disease. The pharmacokinetics of RU 486 are characterised by high micromolar serum concentrations, long half-life of 26-48 hours and substantial metabolism after oral administration. Although effective and well tolerated, RU 486 has aroused great moral controversy, which is currently hampering further testing and distribution of the drug. So far RU 486 has been accepted for termination of pregnancy in France and in the Peoples Republic of China, to be used with prostaglandins and under strict medical surveillance.

Female↗