Prostaglandin analogues and their uses.
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Abortion, Induced↗
Biomedical subjects
M Bygdeman
Publications and source records attributed to M Bygdeman.
High and low affinity NGF receptor mRNAs in human foetal spinal cord and ganglia.
The cellular localization of mRNAs encoding the low affinity NGF receptor (here referred to as LANR) and the putative high affinity receptor for NGF, trk, have been studied in the human foetal spinal and sympathetic ganglia, and spinal cord, using in situ hybridization. The receptor mRNAs were highly expressed in the spinal and sympathetic ganglia, with most but not all neurons expressing both LANR and trk mRNA. Spinal nerve rootlets distal to the spinal ganglia expressed LANR but not trk mRNA, confirming the presence of the low affinity receptor in developing Schwann cells. In the spinal cord, LANR mRNA was found throughout the medial and lateral motor columns while, trk mRNA was detected in scattered cells in the dorsal aspect of developing grey matter.
Fetus↗
Antiprogestin drugs: research and clinical use in Sweden.
The Swedish experience indicates that the combination of RU 486 and vaginal or intramuscular administration of different prostaglandin analogues such as Cervagem, Sulprostone, and 15- methyl PGF2 alpha is a highly effective and safe non-surgical method to terminate early pregnancy. The combined treatment may also be used during the second trimester. In mid- and late second trimester abortion this procedure represents a simple, non-invasive, highly effective method. There are several possibilities by which RU 486 can be used as a contraceptive. We have shown that post-ovulatory administration of RU 486 will effectively inhibit implantation. If the preliminary results are confirmed, treatment with RU 486 once a month on day LH+2 may be an attractive alternative to present contraceptive technology.
Abortifacient Agents, Steroidal↗
Contraception with mifepristone.
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Female↗
Function of intraventricular human mesencephalic xenografts in immunosuppressed rats: an electrophysiological and neurochemical analysis.
Solid pieces of human fetal mesencephalic tissue were grafted to the lateral ventricle adjacent to dopamine-depleted striata of rats immunosuppressed with cyclosporin A. Apomorphine-induced rotations were performed before and at monthly intervals after grafting. Reductions in rotations were seen at 2 months post-grafting and these reductions progressively increased. Spontaneously active dopaminergic cells were found within the grafts using extracellular single-unit recording techniques. Recordings of striatal cells ipsilateral to the graft revealed "normal" firing rates compared to those of neurons in the control striatum. In response to the local application of the dopamine antagonist cis-flupenthixol, both the dopaminergic and striatal neurons showed dose-dependent excitations. Potassium-evoked releases of electroactive species ipsilateral to the fetal human graft, measured using high-speed in vivo electrochemistry, revealed response amplitudes that were similar to control striatum when an electrode was placed adjacent to the graft; distal to the graft the responses showed smaller amplitudes but prolonged time courses. Much greater levels of dopamine and serotonin were detected in the grafts, compared to in normal rat substantia nigra, as measured with HPLC coupled to a 16-channel electrochemical array detector. Immunocytochemical studies using antibodies against tyrosine hydroxylase (TH), revealed not only TH-positive cells within the graft, but also a few positive neurons that migrated into the host striatum. Numerous TH-immunoreactive fibers penetrated into striatum and reinnervated its total volume. Taken together, these data suggest that intraventricular graft placement may be a highly efficacious technique for studying fetal brain tissues in terms of maturation, reinnervation, and function.
Analysis of Variance↗
The nerve growth factor receptor gene is expressed in both neuronal and non-neuronal tissues in the human fetus.
In situ hybridization was used to study expression of beta-nerve growth factor receptor (NGF-R) mRNA in the early human fetus. In 8- to 12-week old fetuses, high labelling was found over motoneurons along the entire length of the lateral motor column. High levels of NGF-R mRNA were also seen over most developing nerve cell bodies in both the dorsomedial and ventrolateral part of the dorsal root ganglia. Lower, but clearly specific labelling was detected over a subpopulation of cells in Auerbach's plexus in the intestines. Evidence for a non-neuronal expression of NGF-R mRNA came from labelling over a subpopulation of cells in glomeruli of the kidney in a 12-week old human embryo. Myoblasts in skeletal muscle anlagen were labelled as well as cells along peripheral nerve. The widespread expression of NGF-R mRNA in the human fetus suggests that the NGF-R is important for development of a variety of different tissues of both neuronal and non-neuronal origin.
Fetus↗
Uterine contractility and interaction between prostaglandins and antiprogestins. Clinical implications.
It is generally believed that progesterone and PGF2 alpha are of major importance in the regulation of uterine contractility. The results summarized herein indicate that progesterone withdrawal is essential for the changes in uterine contractility normally observed during the secretory phase of the menstrual cycle and that the inactivity of the early pregnant uterus is progesterone dependent. Treatment with the antiprogestin RU486 will convert the inactive early pregnant uterus to an active organ and will increase the sensitivity of the myometrium to prostaglandin. These latter effects of antiprogestin have resulted in the development of highly effective, nonsurgical procedures to terminate early pregnancy based on a combined treatment with RU486 and different PG analogues administered orally, vaginally, or intramuscularly. RU486 also has a softening effect on the cervix as demonstrated in late first trimester of pregnancy. This effect may be useful as pretreatment to vacuum aspiration in late first and early second trimester abortion performed by vacuum aspiration or dilatation and curettage. In prostaglandin-induced second trimester abortions, pretreatment with RU486 will significantly reduce the induction-to-abortion interval and the dose of prostaglandin needed.
Abortion, Induced↗
Vacuum aspiration for termination of early second trimester pregnancy after treatment with vaginal prostaglandin.
Vaginal and intramuscular administration of prostaglandin analogues are routinely used for dilatation of the cervical canal prior to vacuum aspiration in first trimester abortion. Whether the same procedure is also useful during the first weeks of the second trimester has been much less investigated. In the present study, 127 women in the 13th and 14th week of pregnancy were pretreated with 3 mg 9-deoxo-16,16-dimethyl-9-methylene PGE2 administered vaginally 12 hours before surgery. At surgery the cervical canal was dilated to 9.8 mm +/- 2.5 mm (mean +/- SD) and the evacuation of the uterus was uneventful. In 21% of the patients vaginal bleeding occurred prior to the operation. The mean blood loss at surgery was 49 ml and exceeded 100 ml in only 6 patients. Gastrointestinal side effects were rare but analgesic injections were demanded by 29% of the patients during the pretreatment period. No subsequent curettage was performed during the follow-up period but 2 patients (1.6%) were readmitted because of post-abortion endometritis. It can be concluded that after pretreatment with PG, vacuum aspiration can be safely performed during the first weeks of the second trimester.
16,16-Dimethylprostaglandin E2↗
The use of antiprogestin (RU 486) for termination of second trimester pregnancy.
Pretreatment with laminaria tent is often used in prostaglandin-induced second-trimester abortion to increase efficacy and shorten induction-to-abortion time. In the present study, two alternatives to soften the cervix and dilate the cervical canal, the antiprogestin RU 486 and intra-cervical application of PGE2, were studied. The study included 71 women requesting legal abortion in the 15th to 23rd week of pregnancy who were treated with repeated vaginal applications of 9-methylene PGE2 in a hydrophilic gel (5 mg every 4th hour) following pretreatment with 200 mg of RU 486 and/or intracervical administration of 0.5 mg of PGE2 gel. The mean interval from start of vaginal prostaglandin treatment to abortion was 13.2 h after intracervical PG-treatment, 10.0 h after antiprogestin and 6.6 h after the combined pretreatment. Patients who received pretreatment with RU 486 alone or in combination with intracervical PGE2 experienced the lowest frequency of episodes of vomiting. Of these two pretreatment alternatives, RU 486 alone has the advantage of a shorter hospital stay. It can be concluded that vaginal administration of 9-methylene PGE2 after pretreatment with RU 486 was a highly effective, safe and rapid procedure for termination of mid-trimester pregnancy, was well tolerated by the patients and was associated with few side effects.
16,16-Dimethylprostaglandin E2↗
The role of prostaglandins and ovarian hormones in the regulation of human uterine contractility.
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Dinoprostone↗
Platelet-derived growth factor is detected in human blastocyst culture medium but not in human follicular fluid--a preliminary report.
The content of PDGF in human blastocyst culture medium (n = 8), serum (n = 12), and FF (n = 17) from natural IVF cycles was determined by an RIA specific for PDGF B-chain. The blastocysts were cultured under serum-free conditions throughout development. The findings show that PDGF B-chain is released into the culture medium of human blastocysts and that serum is positive, whereas FF is negative for PDGF.
Blastocyst↗
[Assisted fertilization in involuntary sterility. A consensus panel: we have considered the facts presented by the experts].
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Female↗
Opiate addiction in adult offspring through possible imprinting after obstetric treatment.
OBJECTIVE: To test the hypothesis that opiate addiction in adults might stem partly from an imprinting process during birth when certain drugs are given to the mother. DESIGN: Retrospective study by logistic regression of opiate addicts with siblings as controls. SETTING: Stockholm, Sweden. SUBJECTS: 200 Opiate addicts born in Stockholm during 1945-66, comprising 41 identified during interviews of probands for an earlier study; 75 patients whose death from opiate addiction had been confirmed during 1978-88; and 84 accepted for the methadone programme. 262 Siblings (controls) born in Stockholm during the same period, 24 of whom were excluded for drug addiction or being brought up outside the family. Birth records were unavailable for eight, leaving 230 siblings and 139 corresponding probands. MAIN OUTCOME MEASURES: Administration of opiates, barbiturates, and nitrous oxide (for greater than 1 h) to mothers of all subjects during labour within 10 hours before birth as a risk factor for adult opiate addiction. RESULTS: In subjects who had subsequently become addicts a significant proportion of mothers had received opiates or barbiturates, or both, compared with unmatched siblings (25% v 16%, chi 2 = 5.83, df = 1, p = 0.02), and these mothers had received nitrous oxide for longer and more often. After controlling for hospital of birth, order of birth, duration of labour, presentation other than vertex, surgical intervention, asphyxia, meconium stained amniotic fluid, and birth weight the relative risk for offspring subsequently becoming an adult opiate addict increased with the number of administrations of any of the three drugs. When the addicts were matched with their own siblings the estimated relative risk was 4.7 (95% confidence interval 1.8 to 12.4, p for trend = 0.002) for three administrations compared with when no drug was given. CONCLUSIONS: The results are compatible with the imprinting hypothesis. Therefore, for obstetric pain relief methods are preferable that do not permit substantial passage of drugs through the placenta.
Analgesia, Obstetrical↗
Regulation of non-pregnant human uterine contractility. Effect of antihormones.
Uterine contractility was recorded on cycle day LH+6 to LH+8 in a control and treatment cycle in 14 healthy non-pregnant volunteers. In the treatment cycle the subjects received either 50 mg of the antiprogestin RU 486 daily for three days or 40 mg of the anti-estrogen tamoxifen daily for two days. The treatment started on day LH+2. During the recording, 2 to 5 micrograms PGF2 alpha was administered into the uterine cavity. The plasma levels of progesterone and estrogen were the same in both the control and treatment cycles. RU 486 caused a significant increase in uterine contractility expressed in Montevideo Units (MU) and a decrease in uterine tonus in comparison with corresponding data obtained in the control cycle. Following treatment with tamoxifen, uterine contractility was lower but the difference was not significant. PGF2 alpha invariably caused a stimulation of uterine contractility. However, treatment with the antihormones did not influence the response. The result of the present study indicates that the change in uterine contractility occurring in the latter part of the menstrual cycle and during menstruation is due to progesterone withdrawal.
Adult↗
Oral administration of RU 486 and 9-methylene PGE2 for termination of early pregnancy.
It has been shown that the antiprogestin RU 486 increases the sensitivity of the early pregnant human uterus to the stimulatory action of prostaglandin E analogues administered vaginally or intramuscularly. To examine if RU 486 also increases uterine sensitivity to a PGE analogue given orally, two investigative approaches were used in the present study: 1) direct registration of uterine contractions before and after administration of 9-methylene PGE2 in untreated and RU-486-treated early pregnant women; and 2) an efficacy trial involving treatment of pregnant women (amenorrhea of 49 days or less) with 25 mg RU 486 twice daily for three or four days followed by 2.5, 5.0 or 10 mg 9-methylene PGE2, or 600 mg RU486 followed by 10 mg 9-methylene PGE2 administered on day 3 and 4. The results showed that oral 9-methylene PGE2 had a clear stimulatory effect on uterine contractility which was further increased by pretreatment with RU 486. Following 2.5, 5.0 or 10.0 mg 9-methylene PGE2, the frequency of complete abortion was the same, or approximately 80%. The success rate is higher than that generally reported for RU 486 treatment alone. If 600 mg RU 486 was complemented with 10 mg 9-methylene PGE2 administered on both days 3 and 4, the frequency of complete abortion increased to 95%. Side effects were of a mild nature and generally occurred following administration of 9-methylene PGE2. The results of the present study indicate that a combined treatment based on oral administration of both the antiprogestin and the prostaglandin analogue can be developed into a highly effective and simple method to terminate early pregnancy.
16,16-Dimethylprostaglandin E2↗
Induced cervical ripening with mifepristone (RU 486) and bioconversion of arachidonic acid in human pregnant uterine cervix in the first trimester. A double-blind, randomized, biomechanical and biochemical study.
The effect of mifepristone on the uterine cervix was studied in 55 nulliparae at 7 to 10 weeks gestation, wishing to undergo a vacuum aspiration. The patients were randomly assigned to three groups which received preoperative drug or placebo treatment starting 36 or 48 hours before surgery. Cervical biopsies from 12 of the subjects were used in a double-blind test to study the bioconversion of 14C-labeled arachidonic acid. By using an objective method to study the cervical resistance to dilatation, it was shown that the cervix was significantly less (p less than 0.05) resistant to dilatation after pretreatment with mifepristone compared to placebo. The longer treatment was significantly (p less than 0.05) more effective than the shorter. No significant difference of the 14C-arachidonic acid bioconversion was demonstrated.
Adolescent↗
Behavioral and electrophysiological correlates of human mesencephalic dopaminergic xenograft function in the rat striatum.
While human fetal xenografts placed into immunocompromised animal hosts have been shown to survive and grow, their ability to function and influence the host tissue has not been fully examined. Therefore, we implanted grafts of human fetal mesencephalic tissue intracranially into rats with unilateral 6-hydroxydopamine lesions of their nigrostriatal dopaminergic innervation and tested the rats behaviorally for reductions in apomorphine-induced rotations. The purpose of this study was to test the ability of these grafts to provide a functional reinnervation by comparing the behavioral changes with the morphology and presence of electrophysiologically active dopaminergic neurons within the graft and with firing rates of host striatal neurons. Adult Sprague-Dawley rats that had been unilaterally lesioned and that showed a stable two peak pattern of apomorphine-induced rotations received grafts of human fetal mesencephalic tissue placed directly into the lesioned striatum. These rats were then further tested each month for five months for reductions in their turning behavior. At 5 to 6 months postgrafting, electrophysiological recordings were made of cells within the graft and within the host striatum. The rats were then examined immunohistochemically to evaluate graft survival and extent of reinnervation of the host tissue. The rats receiving mesencephalic dopaminergic grafts demonstrated a 79% reduction in their apomorphine-induced rotations. Electrophysiological recordings revealed spontaneously active dopaminergic neurons within the graft as well as host striatal cell firing rates consistent with those of dopamine-innervated cells. Furthermore, immunohistochemical studies confirmed graft survival and revealed marked fiber outgrowth from the graft into and throughout the striatum. Taken together these findings provide evidence that grafts of human fetal mesencephalic tissue are able to produce behavioral improvements in lesioned animals which are associated with the presence of dopaminergic neurons within the graft and are consistent with normal host striatal cell activity levels.
Animals↗
Uterine contractility during pregnancy and the effect of abortifacient drugs.
There are a number of compounds in clinical use for termination of pregnancy. Treatment with all of them will result in increased uterine contractility. PGF2 alpha and PGE2 as well as different prostaglandin analogues all have a direct stimulatory effect on the myometrium, while other compounds such as hypertonic saline and Rivanol seem to act mainly through a stimulation of the endogenous production of PGF2 alpha. Treatment with antiprogestins which compete with progesterone at the receptor level or which inhibit progesterone biosynthesis results in an increased uterine contractility probably through a release from progesterone inhibition. If the withdrawal of progesterone also induces an increased endogenous prostaglandin production is unclear. The medical method to induce abortion which best resembles the physiological events during a spontaneous abortion is probably treatment with antiprogestins (receptor blockers or progesterone biosynthesis inhibitors) followed by prostaglandin.
Abortifacient Agents↗