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Nitric oxide in human fetal membranes at term gestation: effect on prostaglandin E2 release.

OBJECTIVES: To examine the in vitro release of nitric oxide (NO) by human fetal membranes at term gestation and to investigate whether NO could stimulate prostaglandin E2 (PGE2) release by these tissues. STUDY DESIGN: Explants of fetal membranes (n = 17) were incubated either in the presence of sodium nitroprusside (NP), or L-Arginine (L-Arg), or bacterial lipopolysaccharide (LPS), or in the absence of the above substances (controls). NO and PGE2 concentrations in culture medium were assayed by the Griess reaction and radioimmunoassay, respectively. RESULTS: Fetal membranes spontaneously released NO in culture medium; incubation with NP increased the production of both NO and PGE2. L-Arg and LPS enhanced PGE2 output by tissues but did not influence NO production. CONCLUSIONS: An NO-generating activity might be present in human fetal membranes. NO stimulates PGE2 release by these tissues.

Arginine↗

Instability of (methyl)ergometrine in tropical climates: an overview.

Parenteral ergometrine is widely used for the prevention and treatment of excessive uterine bleeding following birth. Unfortunately, in tropical climates it is often found to contain very little active ingredient: only 32 of 100 field samples from Bangladesh, Gambia, Malawi, Yemen and Zimbabwe contained 90-110% of the amount of active ingredient stated on the label, and 34 contained less than 60%. In this paper the results of nine studies, of which eight were initiated and coordinated by WHO, are reviewed to formulate answers to the following questions: (1) what is the extent of the problem of low potency of ergometrine in tropical climates; (2) is the problem due to instability or low initial quality, or both; (3) which practical measures can assure the quality of injectable ergometrine; and (4) are there any alternative drugs which are more stable? Injectable ergometrine is very unstable under tropical conditions and particularly if stored unrefrigerated and exposed to light, when it may loose up to 20% of its potency per month. However, there are differences between brands. Practical measures to assure the quality of injectable ergometrine therefore include a careful supplier selection and refrigerated storage. Ergometrine injection should always be protected from light until given to the patient. Loss of active ingredient can easily be detected by regular visual checks of the colour of the solution. Any discoloration implies that the solution contains less than 90% of the stated amount of active ingredient, and should not be used. Methylergometrine is no more stable than ergometrine. Parenteral oxytocin is more stable than both ergometrine and methylergometrine injection. Oral and buccal dosage forms are less stable than injections. In view of the better stability in tropical climates, similar cost, fewer side effects and comparative efficacy, parenteral oxytocin, rather than parenteral ergometrine, is the drug of choice in the prevention and treatment of postpartum haemorrhage.

Administration, Oral↗

Second trimester pregnancy termination including fetal death: comparison of five different methods.

OBJECTIVE: To compare the efficacy of methods for second trimester pregnancy termination. METHODS: A prospective randomized study of women undergoing pregnancy termination between 14 and 28 weeks gestation. Three hundred and forty patients with poor cervical condition (Bishop score < or = 4) in whom one of five termination methods were used were assessed: (i) extraamniotic administration of ethacridine lactate (82 patients); (ii) intracervical prostaglandin (PG) E2 gel (100 patients); (iii) intravenous infusion of concentrated oxytocin (36 patients); (iv) vaginal misoprostol (49 patients); and (v) balloon insertion (73 patients). Oxytocin infusion was used in all but concentrated oxytocin group to augment labor, when necessary. Patients in whom effective uterine contractions and cervical dilatation was not obtained within 48 h with the primary termination method were registered as failures. RESULTS: The efficacy of each method were evaluated in terms of abortion within time. Abortion within 48 h were achieved in 98.8% (81/82) of the patients in ethacridine group; 97.3% (35/36) of the patients in concentrated oxytocin group; 90.0% (90/100) of the patients in PGE2 group; 97.2% (71/73) of the patients in balloon group; 77.5% (38/49) of the patients in misoprostol group (P = 0.000, P < 0.01, Wilcoxon (Gehan) statistic). The overall median induction-abortion interval +/- S.D. (in h) in each group were as follows: ethacridine lactate: 15.7 +/- 9.6, PGE2 gel: 20.0 +/- 14.5, concentrated oxytocin: 12.2 +/- 14.4, misoprostol: 24.0 +/- 22.2, balloon: 16.0 +/- 15.4 (one way ANOVA, P = 0.003, P < 0.01). CONCLUSION: In comparison with the five methods, the use of extraamniotic ethacridine, intravenous concentrated oxytocin, and balloon was found to provide more effective treatment than intracervical PGE2 and misoprostol in terms of achievement of abortion within 24 and 48 h.

Abortifacient Agents↗

Neonatal capsaicin attenuates mechanical nociception in the rat.

The contribution of chemosensitive neurons to mechanical nociception and hyperalgesia was studied by evaluating mechanical nociceptive threshold and the effect of three directly-acting hyperalgesic agents (prostaglandin E2, prostaglandin E1 and the A2-adenosine agonist, CGS21680) in rats treated neonatally with capsaicin. Mechanical nociceptive threshold was quantified by the Randall-Selitto paw-withdrawal method. The baseline mechanical paw-withdrawal threshold of the capsaicin-treated rats was 40% higher than that of the untreated rats. In the capsaicin-treated rats mechanical hyperalgesia was not induced by prostaglandin E2, prostaglandin E1 or CGS21680. These results are consistent with the suggestion that mechanical nociception and hyperalgesia induced by inflammatory substances is mediated by action on capsaicin-sensitive nociceptors.

Alprostadil↗

Vascular smooth muscle reactivity to norepinephrine in ovariectomized rats: relationship to vascular PGE2/PGF2 alpha ratio.

1. We have recently demonstrated that, in normal female rats, vascular reactivity (VR) and vascular prostaglandin-E2 (PGE2) and prostacyclin production are influenced by the ovarian cycle. 2. In this study, we investigated the vascular reactivity (VR) of isolated rat thoracic aorta to norepinephrine (NE 10(-12)-10(-6)M) in ovariectomized rats (OVX-rats), 48 hr and 8 days after surgical removal of the ovaries and in normally cycling rats (NR) at the proestrus stage of the estrous cycle, when the level of circulating estrogen was higher. 3. In addition, we determined the vascular synthesis of PGE2 and protaglandin-F2 alpha (PGF2 alpha) in both groups of OVX-rats, and in NR during the proestrous stage. 4. The results showed that VR to NE 10(-12)-10(-10) M was similar between OVX-rats and normal rats. 5. However, aortic rings obtained from both groups of OVX-rats showed a significant increase of the contraction response induced by NE 10(-9)-10(-6) M. 6. Furthermore, the contractile response to NE 10(-7)-10(-6) M was greater in the aortic rings from OVX-rats 8 days after ovariectomy compared to OVX-rats 48 hr (p < 0.001). 7. Vascular PGE2 and PGF2 alpha synthesis (ng/mg protein/hr) was significantly higher in both groups of OVX-rats than NR. But the vascular PGF2 alpha synthesis increased more than PGE2 in these OVX-rats, thus the ratio PGE2/PGF2 alpha was decreased significantly in both groups of OVX-rats (p < 0.01 and p < 0.001 OVX-rats 48 hr and 8 days after surgery, respectively) compared to NR-ratio.

Adrenergic alpha-Agonists↗

Plants of Haiti used as antifertility agents.

Haitian empirical medicine sprang from both European (16th to 19th century) and African (especially voodoo) traditional therapies. The use of medicinal herbs is highly developed. Our purpose was to list the plants held to be antifertility agents in the island. We identified about twenty species more or less currently used by the women as abortifacients or emmenagogues. The chemistry and active components of a few species are well-known. However, for most of them, some were partially studied, and no relation could be established between their chemical composition and their potential activities, and the rest are chemically unknown. We chemically screened extracts of Casearia ilicifolia, Eleutherine bulbosa, Rhoeo spathacea and Stemodia durantifolia, and identified flavonoids, triterpenes and sterols in the leaves of C. ilicifolia, and naphthoquinones, and a new anthraquinone, anthracene-9,10-dione-1,5-diol-4-methoxy-3-methyl-2-carboxylic acid methyl ester, in the bulbs of E, bulbosa. R. spathacea showed a stimulative activity on mouse uterus. Antifertility screening tests of C. ilicifolia and E. bulbosa showed activity in rats, but also probably toxicity.

Animals↗

Preliminary isolated organ studies using an aqueous extract of Clivia miniata leaves.

An infusion of Clivia miniata leaves is a traditional medicine taken by Black South African women to induce or augment labour. A boiling water extract of C. miniata leaves was studied for its pharmacological effects on rat uterus and ileum. The extract caused concentration-dependent contractions in both the uterus and ileum, but at a fraction of the intrinsic activity of acetylcholine. When the organs were pretreated with the extract before the cumulative addition of either oxytocin or acetylcholine, the extract augmented the initial response of the organs to the reference drugs. The frequency of contractions in the spontaneously contracting uterus was increased by the presence of the extract. C. miniata extract, however, inhibited the maximal response of the ileum to acetylcholine in a non-competitive way. It did not affect the maximal response of the uterus to either oxytocin or acetylcholine.

Acetylcholine↗

South African traditional herbal medicines used during pregnancy and childbirth.

Many black South African women use traditional herbal remedies as antenatal medications or to induce or augment labour. Very little is known about the pharmacology and potential toxicity of the plants used in these herbal remedies. The ethnic background and traditional usage of these remedies was researched and a literature survey revealed that 57 different plants were used in herbal remedies during pregnancy and childbirth. Several of these plants are poisonous and details of their toxicity are given.

Black or African American↗

Maternity and medicinal plants in Vanuatu. II. Pharmacological screening of five selected species.

An ethnobotanical survey of reproductive behaviour in Vanuatu and an extensive literature search have resulted in the selection of five plant species (Asplenium nidus, Hemigraphis reptans, Homalanthus nutans, Dysoxylum gaudichaudianum, Pemphis acidula) used for purposes relating to human reproduction in that country. Preliminary screening was carried out to identify possible oestrogenic activity in these species as well as their effects on isolated rat uteri. Dysoxylum gaudichaudianum presented the most interest due to its spasmolytic activity (musculotropic type). Its mode of action has yet to be determined.

Animals↗

Clinical observation of spontaneous anginal attacks and multivessel spasm in variant angina pectoris with normal coronary arteries: evaluation by 24-hour 12-lead electrocardiography with computer analysis.

OBJECTIVES: Using a new, computerized 24-h 12-lead electrocardiographic (ECG) recording and analysis system (the EAGLE system), we sought to evaluate the clinical manifestations of ischemic episodes in patients with variant angina and normal coronary arteries. BACKGROUND: Although the prognosis of variant angina without significant organic stenosis is generally good, the incidence of multivessel spasm, a major prognostic factor, is surprisingly high in provocation tests. METHODS: A total of 122 patients with suspected variant or unstable angina underwent 24-h examination with the EAGLE system and two-channel Holter monitoring. Thirty patients in this group were diagnosed as having variant angina with normal or nearly normal coronary arteries. Twenty-two (73%) of these 30 patients developed anginal attacks with ST segment elevation during monitoring and were enrolled in the study. RESULTS: The 22 patients had a total of 138 episodes of transient ST segment elevation and 13 episodes of ST segment depression. No arrhythmias were observed during ST segment depression, but 26 episodes of ST segment elevation (19%) were associated with arrhythmias: 7 with premature ventricular contractions, 3 with ventricular bigeminy, 3 with complete atrioventricular (AV) block, 1 with complete AV block and couplets of premature ventricular contractions and 12 with marked sinus bradycardia (< 45 beats/min). Ten (45%) of the 22 patients had multivessel spasm. We observed three different patterns of multivessel spasm: 1) spasm at a different site on different occasions (migratory spasm); 2) spasm that sequentially affected two different sites; 3) simultaneous spasm at more than one site. The duration of ST segment elevation was much longer in patients with sequential and simultaneous spasm than in those with single-vessel spasm, and arrhythmias were more frequent during these two types of multivessel spasm. CONCLUSIONS: Although the prognosis of multivessel spasm is believed to be poor, this may not necessarily be so. Anginal attacks due to sequential and simultaneous multivessel spasm seem to be more dangerous than those involving single-vessel spasm or migratory multivessel spasm.

Aged↗

Osteoclasts are not the major source of interleukin-6 in mouse parietal bones.

Interleukin-6 (IL-6) is produced by bone cells and has been shown to stimulate the proliferation of osteoclast progenitors. Which cells in bone produce IL-6 is controversial. This article tests the hypothesis that tartrate-resistant acid phosphatase-positive osteoclasts (TRAP + OC) in neonatal mouse parietal bones are the major source of IL-6. Bones were preincubated with indomethacin to decrease the number of TRAP + OC and the amount of IL-6 produced. Incubation with parathyroid hormone or prostaglandin E2 increased the number of TRAP + OC and the amount of IL-6 produced. Calcitonin and 17 beta-estradiol inhibited this increase in TRAP + OC but had no effect on IL-6 production. 1,25-dihydroxy-vitamin D3 also stimulated an increase in TRAP + OC number but did not cause increased IL-6 production. Both the endocranial and ectocranial membranes of these bones produced large amounts of IL-6. TRAP activity in extracts of endocranial membranes was 14-fold that of the ectocranial membrane and, histochemically, some TRAP + cells could be detected here. However, the ectocranial membranes produced more IL-6 than the endocranial membranes. We conclude that TRAP + OC are not a major source of IL-6 in this system.

Acid Phosphatase↗

A randomized trial that compared intravaginal misoprostol and dinoprostone vaginal insert in pregnancies at high risk of fetal distress.

OBJECTIVE: The purpose of this study was to compare the safety and efficacy of misoprostol and dinoprostone in pregnancies at high risk of fetal distress. STUDY DESIGN: Medical indications for the induction of labor with postdate pregnancy or intrauterine growth restriction were randomized. A sequential design that was based on the triangular test was used. RESULTS: At the fourth interim analysis, which included 140 patients, the trial was stopped because no significant difference was found in neonatal safety between misoprostol and dinoprostone, which was assessed on arterial cord pH <7.20 (14.3% vs 10.0%, respectively; P=.60). Neonatal tolerance was similar in the 2 groups, with no difference in the cesarean delivery rate for fetal distress or in the incidence of meconium-stained amniotic fluid. Time to vaginal delivery was shortened by misoprostol (P=.03). CONCLUSION: Misoprostol and dinoprostone are equally safe for the induction of labor in pregnancies that are at high risk of fetal distress; however, misoprostol allowed the earlier induction of labor than did dinoprostone.

Administration, Intravaginal↗

Labor induction in women with an unfavorable Bishop score: randomized controlled trial of intrauterine Foley catheter with concurrent oxytocin infusion versus Foley catheter with extra-amniotic saline infusion with concurrent oxytocin infusion.

OBJECTIVES: This study was undertaken to determine whether the addition of extra-amniotic saline infusion improves the efficacy of the Foley catheter in women undergoing cervical ripening and induction of labor with an unfavorable cervical examination. STUDY DESIGN: One hundred consenting women with a Bishop score less than 5 with singleton gestation, intact membranes, vertex presentation, who required induction of labor were randomly assigned to 2 groups: Foley alone (Foley, n=49) or to the Foley catheter with extra-amniotic saline infusion (EASI, 30 mL of NS per hour infused through the distal port of the Foley, n=51). All women received concurrent dilute oxytocin infusion per protocol. The primary analysis was intent to treat. Nonparametric tests were used as indicated. RESULTS: At randomization, the groups were well balanced for potential confounders including: parity, gestational age, prior cesarean delivery, preeclampsia, mean dilation, effacement, and Bishop score. There were no differences between the groups for time to delivery (Foley 17.7 +/- 10.5 hours vs EASI 17.4 +/- 11.7 hours, P=.9), the proportion of women delivered before 24 hours (Foley 41/49 [84%] vs EASI 39/51 [77%], P=.37) or cesarean rates (Foley 9/49 [17.7%] vs EASI 9/51 [18.4%], P=.92). There were also no differences in complications, including chorioamnionitis, endometritis, and neonatal morbidity. CONCLUSION: EASI does not increase the efficacy of cervical ripening and induction of labor with a Foley catheter and concurrent oxytocin infusion.

Administration, Intravaginal↗

A comparison of orally administered misoprostol to intravenous oxytocin for labor induction in women with favorable cervical examinations.

OBJECTIVE: The purpose of this study was to compare orally administered misoprostol with intravenous oxytocin infusion for labor induction in women with favorable cervical examinations (defined as a Bishop score of 6 or more). STUDY DESIGN: One hundred ninety-eight women with indications for labor induction and favorable cervical examinations were assigned randomly to receive oral misoprostol or oxytocin induction. Misoprostol, 100 mg, was administered every 4 hours up to 6 doses, or intravenous oxytocin was administered by standardized protocol. RESULTS: One hundred ten (55.6%) women received misoprostol; 88 (44.4%) received intravenous oxytocin. There was no statistically significant difference in the average interval from start of induction to vaginal delivery, being longer in the misoprostol group (789.4 +/- 510.2 minutes) than in the oxytocin group (654.0 +/- 338.2 minutes, P=.19, log-transformed data). Two women had tachysystole develop in each treatment group. More women in the misoprostol group experienced hyperstimulation (7/110, 6.4%) than in the oxytocin group (0/88, P=.02, Fisher exact test). Nine (8.1%) misoprostol-treated women and 8 (9.1%) oxytocin-treated women underwent cesarean deliveries (P=.82). There was a presumed uterine rupture in a misoprostol-treated multipara women. There were no statistically significant differences in neonatal outcomes between the groups. CONCLUSION: Oral misoprostol offers no benefit over intravenous oxytocin for labor induction in women with favorable cervical examinations. It is associated with a higher likelihood of uterine hyperstimulation and may increase the risk of uterine rupture.

Administration, Oral↗

Labor induction with dinoprostone or oxytocine and postpartum disseminated intravascular coagulation: a hospital-based case-control study.

OBJECTIVE: This study was undertaken to test the hypothesis of an association between pharmacologic agents used for labor induction, in particular dinoprostone, and postpartum disseminated intravascular coagulation (DIC). STUDY DESIGN: A retrospective hospital-based case-control study. Adjusted odds ratios (AOR) were calculated by a conditional logistic regression. RESULTS: Forty valid cases of postpartum DIC were compared against 197 matched controls. Labor was induced in 17% of controls, and 56% of cases (AOR = 7.2; 95% CI: 2.1-24.6). The association was observed for both dinoprostone (AOR = 6.7; 95% CI: 1.7-26.5) and oxytocin (AOR = 8.4; 95% CI: 1.4-50.9). Other risk factors identified were as follows: a maternal age older than 34 years (AOR = 9.5; 95% CI: 2.4-37.7), complications during pregnancy (AOR = 5.5; 95% CI: 1.3-22.8), and a gestational age of over 40 weeks (AOR = 3.5; 95% CI: 1.1-11.1). Such factors were shown to also have an interaction with the induction of labor. Oxytocin augmentation showed a negative association (AOR = 0.1; 95% CI: 0.02-0.4). The absolute risk attributable to induction was estimated in 5 per 10,000 deliveries. CONCLUSION: The pharmacologic induction of labor is associated with an increased risk of postpartum DIC, regardless the substance used. Although the absolute risk seems to be quite low, the obstetricians should not neglect it, in particular for the special risk groups identified.

Adolescent↗

Physical and biomechanical characteristics of rat cervical ripening are not consistent with increased collagenase activity.

OBJECTIVE: The cervix progressively softens during pregnancy to allow stretch without rupture in labor. Cervical softening is the product of complex modifications that include increased proteoglycan-to-collagen ratio, increased hyaluronic acid and water content, and breakdown of collagen by matrix metalloproteases. The relative contribution of collagen breakdown to cervical ripening is unclear. We sought to identify, discriminate, and quantify the physical characteristics of rat cervix during pregnancy, labor, and both before and after exposure to either prostaglandin (PGE(2)) or the collagenolytic enzyme matrix metalloprotease-1 (MMP-1). STUDY DESIGN: Cervices were collected from nonpregnant rats in diestrus (n=4) and pregnant rats on d10 (n=4), d16 (n=11), d20 (n=5), and d22 (term) nonlabor (NL: n=4) and d22 in term labor (TL: n=7). Cervices were also collected from a separate group in preterm labor induced by RU486 (PTL: n=10). The effect of PGE(2) on cervical characteristics was determined after intravaginal placement of PGE(2) gel (0.5 mg PGE(2): n=3) or placebo metylcellulose gel (CRL(PG) n=6) for 20 hours before euthanasia on d16. The effect of collagen was determined by incubating in vitro cervices from untreated d16 rats with (MMP-1: n=3) and without (CRL(MMP): n=7) activated collagenase before tensile testing. Tensile properties were quantitated by using Shimadzu EZ-test instrumentation (Shimadzu North America, Columbia, Md) with a stretching regimen that mimicked labor contractions while recording the force opposed by the tissue. Parameters such as the slope (a measure of stiffness), yield point (YP; moment the tissue changes its proprieties from elastic to plastic), and break point (BP; a measure of tissue strength) were recorded and analyzed. The plateau was defined as the phase after YP but before BP. RESULTS: Compared with d16, cervical extensibility increased significantly by d20 (slope d16: 0.41 +/- 0.03 N/mm vs d20: 0.19 +/- 0.05 N/mm, P < .01), and during both PTL (slope: 0.17 +/- 0.03 N/mm) and TL (slope: 0.11 +/- 0.02 N/mm). This increase was mimicked by PGE(2) (slope PGE(2): 0.24 +/- 0.03 vs CRL(PG): 0.40 +/- 0.05 N/mm, P=.04), but not by collagenase (slope MMP-1: 0.35 +/- 0.02 vs CRL(MMP): 0.38 +/- 0.05 N/mm, P>.05). YP was significantly reduced as pregnancy advanced, whereas BP increased, suggesting both increased plasticity (compliance) and strength. However, the plateau length increased 3-fold both by d20 and after PGE(2). In contrast, the addition of MMP-1 reduced the plateau. BP occurred significantly earlier in collagenase-treated tissues, but later in PTL-, TL-, and PGE(2)-treated cervices. CONCLUSION: The changes in physical properties of the rat cervix during physiologic ripening are similar to those induced by PGE(2) and RU486, and consist of increased extensibility, compliance, and strength. These changes cannot be attributed to increased collagenase activity, which would decrease tissue compliance and strength.

Animals↗

Misoprostol versus methylergometrine: pharmacokinetics in human milk.

OBJECTIVE: The purpose of this study to compare breast milk pharmacokinetics between misoprostol 200 mug and methylergometrine 250 mug after single oral dosing in women who require postpartum uterotonic therapy. STUDY DESIGN: Open prospective randomized phase I study measuring misoprostol and methylergometrine on postpartum days 3 to 6 in milk 0.5, 1, 2, 3, 4, and 5 hours postdose, and in maternal serum at 0.5 and 1 hours (misoprostol) and 1 and 2 hours (methylergometrine) in 10 lactating women per group. RESULTS: Milk misoprostol levels rose and declined rapidly, which gave a milk elimination half-life of less than one half that of methylergometrine (mean +/- SE, 1.1 +/- 0.3 hours [median, 0.6 hours] vs 2.33 +/- 0.3 hours [median, 1.9 hours]; P = .003). Milk/plasma ratios for misoprostol were one third of those for methylergometrine at 1 hour ( P < .0001) and 2 hours ( P < .0015). CONCLUSION: Misoprostol warrants further investigation as an alternative to postpartum methylergometrine because it enters and leaves breast milk at twice the rate, with one third of the milk/plasma ratio, which significantly lowers infant exposure and facilitates a timed dosing regimen.

Administration, Oral↗