Premature labor and indomethacin

Women in the 29th – 32nd week of gestation were admitted to hospital following the onset of premature labor contractions. After treatment with bed rest and β-stimulating drugs, those patients with persistent uterine contractions were treated with oral indomethacin (25 mg every 6 hours for 5 days). The effect of indomethacin therapy was monitored by serial external tocometry recordings. This treatment schedule with indomethacin was repeated on several occasions at intervals of 5 to 10 days. Using a standardized technique, uterine contractility was monitored every second or third day throughout the entire treatment period. In this way, the frequency of contractions was evaluated in the presence or absence of indomethacin therapy.Following indomethacin treatment, there was a significant decrease in the frequency of contractions in all cases and a complete arrest of contractions occurred in some women. An increased frequency of contractions was observed during those times that the patient did not receive indomethacin.The plasma concentration of 15-keto-13, 14-dihydro-PGF_2α, the major serum metabolite of PGF_2α, was determined by the gas chromatography — mass spectrometry method before and after indomethacin in a limited number of cases.At the doses given for the duration of therapy used, no untoward effects could be detected in either the mother or the infant. These results indicate that indomethacin is a potent and useful drug in the treatment of premature labor.     

Premature labor and indomethacin

Women in the 29th — 32nd week of gestation were admitted to hospital following the onset of premature labor contractions. After treatment with bed rest and β-stimulating drugs, those patients with persistent uterine contractions were treated with oral indomethacin (25 mg every 6 hours for 5 days). The effect of indomethacin therapy was monitored by serial external tocometry recordings. This treatment schedule with indomethacin was repeated on several occasions at intervals of 5 to 10 days. Using a standardized technique, uterine contractility was monitored every second or third day throughout the entire treatment period. In this way, the frequency of contractions was evaluated in the presence or absence of indomethacin therapy.Following indomethacin treatment, there was a significant decrease in the frequency of contractions in all cases and a complete arrest of contractions occurred in some women. An increased frequency of contractions was observed during those times that the patient did not receive indomethacin.The plasma concentration of 15-keto-13, 14-dihydro-PGF_2α, the major serum metabolite of PGF_2α, was determined by the gas chromatography — mass spectrometry method before and after indomethacin in a limited number of cases.At the doses given for the duration of therapy used, no untoward effects could be detected in either the mother or the infant. These results indicate that indomethacin is a potent and useful drug in the treatment of premature labor.     

Premature labor and indomethacin

Administration of indomethacin to 29 women in the 26th–37th week of gestation with premature labor contractions was followed in 26 by a significant decrease of uterine activity. The effect of therapy was monitored by serial external tocometry recordings and by plasma concentrations of estriol, h.P.L., alpha-fetoprotein, and estriol/creatinine ratio in urine. The labor was monitored by cardiotocography; the newborn infants were examined by the pediatrician. Following oral indomethacin treatment (25 mg every 6 Hours for 5 days) no untoward effects was observed on maternal and fetal wellbeing during pregnancy and labor. Four out 29 newborn infants, all appropriate for gestational age of 36–40 weeks, had one-minute Apgar scores less than 7, cyanosis, tachypnea, hypoxemia and serious oxygen dependency for several days. All the infant survived. These abnormalities may be due to short-term exposure to indomethacin and consequent inhibition of cyclo-oxygenase, impairement of prostaglandin-dependent physiological regulation of vessel tone during fetal life and circulatory disorders at birth.     

Premature labor and indomethacin.

Administration of indomethacin to 29 women in the 26th--37th week of gestation with premature labor contractions was followed in 26 by a significant decrease of uterine activity. The effect of therapy was monitored by serial external tocometry recordings and by plasma concentrations of estriol, h.P.L., alpha-fetoprotein, and estriol/creatinine ratio in urine. The labor was monitored by cardiotocography; the new born infants were examined by the pediatrician. Following oral indomethacin treatment (25 mg every 6 Hours for 5 days) no untoward effects was observed on maternal and fetal wellbeing during pregnancy and labor. Four out 29 newborn infants, all appropriate for gestational age of 36--40 weeks, had one-minute Apgar scores less than 7, cyanosis, tachypnea, hypoxemia and serious oxygen dependency for several days. All the infant survived. These abnormalities may be due to short-term exposure to indomethacin and consequent inhibition of cyclo-oxygenase, impairement of prostaglandin-dependent physiological regulation of vessel tone during fetal life and circulatory disorders at birth.     

Differences in the effects of vasopressin and oxytocin on rabbit myometrial activity and a possible mediation of prostaglandins

Uterine responses to vasopressin and oxytocin were monitored in non-pregnant and 3- or 6-8-day-pregnant rabbits by recording the intrauterine pressure. Oxytocin stimulated uterine activity in all groups, but the effect of vasopressin was stimulatory in non-pregnant animals, inhibitory in those 3 days post coitum and weakly stimulatory in those later in pregnancy. Inhibition of prostaglandin (PG) synthesis, by the administration of indomethacin, reduced the spontaneous uterine activity as well as the responses to oxytocin and vasopressin in the non-pregnant rabbits, but had little effect in the pregnant animals. During infusion of PGF-2alpha, PGE-1 or PGE-2 in 6-8-day-pregnant rabbits, the stimulatory response to vasopressin, although slight before the infusion, was inhibited whereas the stimulatory response to oxytocin remained virtually unchanged. The results suggest that vasopressin and oxytocin under certain hormonal conditions, are able to activated the uterine contractions by mechanisms in which the involvement of PG is not obligatory.     

Plasma levels of 13,14-dihydro-15-keto prostaglandin F2 alpha, estrogens, and progesterone during stretch-induced labor at term

The uterus of six healthy multiparous women at term was mechanically stretched by a rubber catheter and balloon. Apparent labor was inaugurated in all cases within 5 hours and increased progressively with time. Advanced cervical softening and dilatation were also evident after the stretch treatment. Significant increases in the levels of 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) were observed with the progress of treatment (P less than 0.01). Plasma estrogens and progesterone levels did not change significantly during the treatment (P greater than 0.05). Stretching and/or resulting uterine contractions appear to induce the secretion of prostaglandin F2 alpha (PGF) from the organ, which in turn seems to be involved in both cervical softening, and the onset and progress of labor, under stable conditions of plasma estrogens and progesterone.     

Uterotropic action of indomethacin on the rat uterus

Administration of indomethacin (10 mg/kg body weight, twice daily for 6 days) resulted in a significant (P less than 0.01) increase in the weight, and cross-sectional area of uteri of ovariectomized rats, whereas no such effects were observed following indomethacin administration to normal cycling rats. Prostaglandin F2 alpha (PGF2 alpha) content (ng/uterus) and concentration (ng/g wet weight) in the uterus of indomethacin-treated animals were reduced 40.4% and 60.8%. Simultaneous administration of either estradiol-17 beta (E2), progesterone testosterone with indomethacin to ovariectomized rats failed to reduce the uterine weight increase. On the contrary, concomitant administration of E2 (25 or 100 ng/day) and indomethacin resulted in uterine weight increases which were greater than those associated with indomethacin alone. Uterine E2 content was significantly higher in animals treated with indomethacin plus E2 as compared to those given estradiol alone. Uterine uptake of 2,4,6,7-[3H]E2 following i.v. administration was greater in animals pretreated with indomethacin (5 mg/kg, twice daily) for 3 days than in ovariectomized controls. These results suggest that prostaglandins may be involved in the regulation of uterine growth.     

Preferential reduction of Na+/K+ ATPase alpha3 by 17beta-estradiol influences contraction frequency in rat uteri

One beta1 and two alpha (alpha1 and alpha3) isoforms of Na+/K+-ATPase exist in rat uteri. Previous immunocytochemistry studies have suggested that the alpha3 isoform may be involved in calcium regulation indirectly. Estrogens are known to both modulate Na+/K+-ATPase activities in non-uterine tissues and suppress spontaneous uterine contractions in rats. Thus the purpose of this study was to examine the correlation between estrogens-modulated uterine contraction and the expression of Na+/K+-ATPase alpha3 isoform in rats. After 1-, 2-, and 4- day treatments with 17beta-estradiol (E2, 5 microg/ml/kg, s.c., daily), the diameter of uterine horn was measured. The contraction force of uterine strips was measured by standard muscle bath apparatus. The protein abundance and enzyme activity of Na+/K+-ATPase in rat uteri were measured by Western blot analysis and ATPase assay, respectively. One day of E2 decreased both contraction frequency and alpha3-protein expression without the change in uterine diameter, enzyme activity or other isoforms. Two days of E2 reduced contraction frequency, the enzyme activity, as well as alpha3- and beta1- protein abundance but increased alpha1-protein and uterine diameter. Four days of E2 elicited similar effects as two days of E2, but did not affect alpha1-protein abundance. In conclusion, E2 elicits differential effects on isoform expression. After 1-day treatment with 17beta-estradiol, the decrease in the expression of alpha3 and beta1 without a change in Na+/K+-ATPase activity suggests that some isoform other than beta1 exist in rat uteri. The positive correlation between the reduction of alpha3-and the decrease of contraction frequency suggests the involvement of alpha3 isoform in uterine oscillation.     

早产病因及发病机制的研究现状

早产在妇产科临床上比较常见,其作为围生医学当中的一类重要而复杂的妊娠并发症,对早产儿的预后具有较大危害,严重时可能直接导致早产儿死亡。通常而言,早产患者的临床表现主要是子宫收缩,初期表现为不规律的宫缩,并伴有少量的阴道出血亦或是血性分泌物,进而发展成规律性的宫缩,此过程中宫颈管先发生消退,而后扩张。早产儿的体重大多数低于2500 g,且头围小于33 cm,部分胎儿的器官功能及适应能力与足月儿相比明显较差,常需给予特殊的处理。因此,及时梳理导致早产的原因并分析其发病机制,有利于早期掌握防治早产的基础要点。本文就此展开综述,以期为改善母婴妊娠结局提供理论支持。     

Vaginal treatment with a prostaglandin F2 alpha derivative (alfaprostol) for inducing labor in pregnancy at term

The effectiveness and acceptability of Alfaprostol (an analog of PGF2 alpha) in inducing labor were assessed in 20 pregnant women at term. All subjects had no spontaneous uterine activity before treatment and the mean (M +/- SE) Bishop score was 2.45 +/- 0.21. The drug was administered by vaginal route at the dose of 10 mg every 3 hours. Regular uterine contractions appeared in all patients and delivery occurred in 85% of the patients after a mean time of 9h50min +/- 0h55min following the start of treatment. The mean dose of Alfaprostol utilized to achieve delivery was 29.4 +/- 2.0 mg. No major side effects were noted in the mothers and their fetuses at any time during treatment. Two patients exhibited vomiting. The Apgar score of all newborns at birth was 8 or more. These results suggest the usefulness of Alfaprostol to induce labor in pregnant women at term, as it has oxytocic activity without adverse effects on either the mother or the fetus.     

Uterine motility in the reptile Anolis carolinensis: interactive effects of tension, prostaglandins, calcium, and vasotocin

Uteri of Anolis carolinensis exhibited spontaneous rhythmic contractions in vitro. Addition of arginine vasotocin (AVT) caused an immediate, strong, tonic contraction followed by rhythmic contractions with the same frequency as spontaneous contractions but of a greater amplitude. At low tension (1.5 g) the AVT-induced tonic contraction was blocked by low dose of indomethacin, suggesting that it is influenced by calcium rather than prostaglandins (PGs). An increase in tension (from 1.5 to 15 g) reduced the duration of the AVT-induced tonic contraction; this stretch-induced decrease was also blocked by indomethacin. Stretch also decreased the duration of the rhythmic contractions, but this stretch effect was not inhibited by indomethacin. The rest interval between rhythmic contractions was decreased by PGF2alpha and PGE2, and indomethacin or stretch blocked these PG effects. Indomethacin, AVT, or stretch alone did not affect PGF2alpha secretion from AVT-treated uteri. Stretch also reduced PGF2alpha secretion from AVT-treated uteri, an effect inhibited by indomethacin.     

Oxytocin enhances the basal release of uterine prostaglandin F2 alpha, but not that of PGE1, or of PGE2, and changes the metabolism of exogenous arachidonate, favouring the formation of prostaglandin F2 alpha and 5-HETE. Relationships with its uterotonic action and modulation by estradiol

We attempted to explore possible mechanism(s) subserving the influence of oxytocin on uterine motility by studying the action of the hormone on: 1) the contractile activity of isolated rat uteri in the presence or absence of indomethacin; 2) the synthesis and release of prostaglandins (PGs) into the solution incubating the uterine tissue as well as the metabolism of labelled arachidonic acid; 3) the uptake of 45Ca2+ by uterine strips. The experiments were bone with uterine preparations isolated from spayed rats treated or not with 17-beta-estradiol. The values of isometric developed tension (IDT) and of frequency of contractions (FC) induced by oxytocin in uterine strips isolated from spayed and spayed-estrogenized rats, were not modified by indomethacin at 10(-6) M. On the other hand, uterine strips from untreated spayed rats, release into the incubating medium approximately equal amounts of PGE1, PGE2 and PGF2 alpha. The in vitro presence of oxytocin (50 mU/ml) increased significantly (p 0.05) the output of PGF 2 alpha without changing the release of PGE1 or PGE2. Uteri from spayed rats injected prior to sacrifice with 17-beta-estradiol released significantly less PGE1 and PGE2 (p less than 0.005) than preparations from non-injected animals, whereas the output of PGF2 alpha in the suspending solution remained unchanged. Following estrogenization the addition of oxytocin to preparations obtained from spayed-estrogenized rats also increased the output of uterine PGF2 alpha (p less than 0.001) without changing that of PGs E1 or E2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myometrial activity around estrus in sows: spontaneous activity and effects of estrogens,cloprostenol, seminal plasma and clenbuterol

A new, nonsurgical, open-end catheter technique was used to study spontaneous uterine activity around estrus in sows, and the effects of estrogens, seminal plasma, cloprostenol, and clenbuterol on uterine activity. In the first experiment, uterine activity was studied in 14 multiparous, cyclic sows, during one or more estrous cycles, from day -4 to day 4 of the cycle (day 0: first day of standing estrus). From a few days before estrus until estrus, the percentage of sows showing any uterine contractions increased from 55 to 100%, and frequency and mean amplitude of uterine contractions for these sows increased from 15 to 22/h, and from 20 to 40 mmHg on average. After estrus, uterine activity decreased. There were large differences between sows in uterine activity, which were consistent over the days of the cycle. In the second experiment, 11.5 microg of estrogens in 100 ml saline (n = 17), 100 ml seminal plasma (n = 5), 1 mg cloprostenol in 100 ml saline (n = 10), 0.30 mg clenbuterol in 100 ml saline (n = 11), or 100 ml saline (n = 5) was infused IU, after recording spontaneous activity. Infusion with saline or seminal plasma did not affect uterine activity. Estrogens increased frequency of contractions. Cloprostenol increased both frequency and amplitude of contractions. Clenbuterol reduced both frequency and amplitude of contractions. In conclusion, this study shows that spontaneous uterine activity in sows is increased around estrus, and it supports the role of estrogens in boar seminal plasma in affecting uterine activity around mating. Further, this study has yielded possible tools to study the relation between uterine activity and sperm transport.     

Effects of gentamicin sulfate on the contractility of myometrium isolated from non-pregnant cows

Gentamicin sulfate, an aminoglycoside antibiotic known to cause depression of neuromuscular function, is a drug of choice in intrauterine antibiotic treatment of bovine chronical or subclinical uterine infections but its effects on the contractility of the cow uterus have not been studied. The aim of this study was to characterize, in vitro, the effect of gentamicin sulfate on spontaneous as well as prostaglandin F2alpha (PGF2alpha) and oxytocin-induced contractility of the non-pregnant cow uterus. Myometrial strips were isolated from non-pregnant cows in follicular phase and suspended in a jacketed organ bath filled with Krebs solution at 37 degrees C (pH 7.4) continuously bubbled with 95% oxygen and 5% carbon dioxide and isometric contractions were recorded using isometric force displacement transducer. After manifestation of the spontaneous contractions during equilibration period the test substances PGF2alpha (1 microM), oxytocin (2.5 mIU/ml bath fluid) and gentamicin sulfate (150-600 microm) were added to the bath. The effects of gentamicin sulfate on amplitude (g) and frequency of spontaneous and the agonist-induced contractions were evaluated by 20 min intervals. Data were statistically analyzed using the Student's t-test and Wilcoxon signed-rank test where appropriate. P <0.05 was considered to be significant. Gentamicin sulfate inhibited spontaneous, as well as oxytocin or PGF2alpha-induced contractions in a dose-dependent manner. Although both the frequency and amplitude of contractions were significantly inhibited by gentamicin sulfate, the effect on the frequency of the spontaneous and agonist-induced contractions were more prominent than on the amplitude. The result from this in vitro study indicated that gentamicin sulfate inhibits spontaneous as well as oxytocin and PGF2alpha-induced contractions of myometrium isolated from non-pregnant cows. This may be of importance considering the potentially negative effect of gentamicin sulfate on uterine involution in cows with puerperal endometritis, resulting in impairment of fertility performance.     

Inhibition of epoxy-eicosanoid degradation improves the tocolytic effects of indomethacin in the uterus from pregnant women

The incidence of preterm birth is an increasing problem. Indomethacin, a non-specific cyclooxygenase inhibitor, has been largely used as tocolytic in the treatment of preterm labor. The aim of the present study was to assess a putative synergistic tocolytic effect between the inhibition of the production of prostanoids and stabilization of epoxides fatty acids, particularly arachidonate on spontaneous uterine contractile activity. The experimental work was performed on uterine biopsies from consenting women undergoing elective cesarean delivery at term. Isometric tension measurements were performed on fresh human myometrial strips. Contractile activities have been monitored upon individual and combined treatments of indomethacin, DDMS, an inhibitor of hydroxy-eicosanoids production and AUDA, an inhibitor of epoxy-eicosanoids degradation. Interestingly, a significant and consistent synergic effect was observed when indomethacin and AUDA were simultaneously added, raising the possibility of a combined clinical use of cyclooxygenase and sEH inhibitors in attempt to treat preterm labor.     

Evidence for the involvement of prostaglandins throughout the decidual cell reaction in the rat

Previous studies in which prostaglandin (PG) production was inhibited for a limited time by the s.c. administration of indomethacin have suggested that PGs are involved in the initiation of decidualization as well as the growth and differentiation of decidual cells. To reduce PG production during decidualization, in the present study indomethacin was infused from Alzet osmotic minipumps into the uterine lumen of ovariectomized rats with uteri sensitized for decidualization. To determine the effect of route of indomethacin administration on decidualization, rats received a single s.c. injection of indomethacin or its vehicle, and unilateral intrauterine infusion of indomethacin or its vehicle, in a factorial experiment. The inhibitory effects on decidualization, as assessed 5 days later by uterine weights, were greatest when both treatments were combined. Prostaglandins E and F concentrations 24 and 48 h after the insertion of the pumps were lower in the indomethacin-infused horns, suggesting that the indomethacin reduced uterine PG production. By contrast, subcutaneously administered indomethacin reduced uterine PG concentrations at 24 h but not at 48 h. Prostaglandin E2 and PGF2 alpha alone or combined, infused with indomethacin into the uterine lumen of rats treated subcutaneously with indomethacin, overrode the inhibitory effects of indomethacin. The dose-response relationships between these PGs and decidualization did not differ. These data suggest that PGs are required during the growth and differentiation of decidual cells from endometrial stromal cells.     

Role of prostaglandins in development of porcine blastocysts

Rapid elongation of porcine blastocysts between Days 11 to 12 of pregnancy coincides with an increase in uterine luminal content of prostaglandins. The present study evaluated the effect of two prostaglandin synthesis inhibitors (indomethacin and flunixin meglumine) on elongation of porcine blastocysts from spherical to filamentous forms between Day 11 to 12 of pregnancy. Gilts were hemi-hysterectomized on Day 11 of pregnancy. The excised uterine horn was flushed with 0.9% saline and diameter of blastocysts recovered were measured. Immediately following surgery, pregnant gilts were assigned to receive either: 1) vehicle every 4 h, 2) flunixin meglumine (banamine) every 4 h, or 3) indomethacin every 12 h. The remaining uterine horn was removed and flushed after the time of blastocyst elongation estimated for each gilt on basis of blastocyst development in the first horn. Uterine flushings were analyzed for total calcium, protein, acid phosphatase activity, estrone, estradiol-17 beta and prostaglandin F. Pretreatment blastocyst diameter was similar for all groups and ranged from 1 mm to 20 mm. Treatment of gilts with either banamine or indomethacin effectively inhibited (P less than 0.001) the increase in uterine luminal content of PGF. Total calcium, estrone and estradiol-17 beta were not influenced by treatment. Total uterine luminal protein and acid phosphatase activity were reduced (P less than 0.05) in banamine treated gilts compared to those receiving vehicle or indomethacin treatments. Although total PGF recovered in uterine flushings was reduced during the period of blastocyst elongation, treatment with PGF synthetase inhibitors failed to block rapid elongation of blastocysts from the spherical to filamentous forms.     

Contractility of rat testicular seminiferous tubules in vitro: prostaglandin f 1 alpha and indomethacin-1,2.

The frequency of spontaneous in vitro contractions of seminiferous tubules of the rat appeared to be increased in a dose-dependent manner by prostaglandin F1alpha. PGF1alpha treatment increased the tonus of the smooth muscle cells in the wall of the tubules as indicated by a reduction in the diameter of the tubules. When the tubules were rinsed successively with fresh Tyrode's solution, the contractile frequency was diminished. Returning the original bathing medium to the tubules restored their contractile frequency, as did treatment of the rinsed tubules with PGF1alpha (10(-7) M). Preinjecting ther rats with indomethacin tended to reduce the contractile frequency of the extirpated tubules. Treating the tubules with a solution of indomethacin for 90 min. in vitro was more effective than pretreatment in vivo in reducing contractile frequency, but a combination of these two procedures produced the greatest inhibition. PGF1alpha restored the contractile frequency of the indomethacin-treated tubules. Our results indicate that PGs modulate the in vitro contractility of the tubules.     

Altered fetal pituitary-adrenal function in the ovine fetus treated with RU486 and meloxicam, an inhibitor of prostaglandin synthase-II

Term and preterm labor are associated with increased fetal hypothalamic-pituitary-adrenal (HPA) activation and synthesis of prostaglandins (PGs) generated through the increased expression of prostaglandin H synthase-II (PGHS-II) in the placenta. Inhibition of PGHS-II has been advocated as a means of producing uterine tocolysis, but the effects of such treatment on fetal endocrine functions have not been thoroughly examined. Because PGE(2) is known to activate the fetal HPA axis, we hypothesized that administration of meloxicam, a PGHS-II inhibitor, to sheep in induced labor would suppress fetal HPA function. Chronically catheterized pregnant ewes were treated with RU486, a progesterone receptor antagonist, to produce active labor, and then treated with either high-maintenance-dose meloxicam, graded-maintenance-dose meloxicam, or a saline infusion. Maternal uterine contraction frequency increased 24 h after the RU486 injection and the animals were in active labor by 48 +/- 4 h. RU486 injection led to increased concentrations of PGE(2), ACTH, and cortisol in the fetal circulation, and increased concentrations of 13,14 dihydro 15-ketoprostaglandin F(2 alpha) (PGFM) in the maternal circulation. Uterine activity was inhibited within 12 h of beginning meloxicam infusion at both infusion regimes. During meloxicam infusion there were significant decreases in fetal plasma PGE(2), ACTH, and cortisol concentrations, and PGFM concentrations in maternal plasma. In control animals, frequency of uterine contractions, maternal plasma PGFM, fetal plasma PGE(2), ACTH, and cortisol concentrations increased after RU486 administration, and continued to rise during saline infusion until delivery occurred. We conclude that RU486-provoked labor in sheep is associated with activation of fetal HPA function, and that this is attenuated during meloxicam treatment to a level considered compatible with pregnancy maintenance.