Effect of ritodrine hydrochloride infusion on fetal movement with the use of a fetal movement acceleration measurement recorder (FMAM recorder).

AIM: To investigate the effect of ritodrine hydrochloride infusion on fetal movement. METHOD: We gathered 20 pregnant women who received ritodrine hydrochloride infusion as the treated group, and 147 pregnant women who did not as the control group. All women recorded gross fetal movement with the fetal movement acceleration measurement recorder after 28 gestational weeks. The record was divided into epochs of 10 s, and the ratio of movement-positive epochs to all epochs was calculated as the fetal movement index. Furthermore, the mean duration and the mean number per hour of no-fetal movement period, where the fetus did not move for 5 min or more, were calculated as the indexes of no-fetal movement. All indexes were compared between the two groups at 28-31 and 32-35 gestational weeks. RESULTS: The fetal movement indexes (%) were 17.29 ± 7.46 (mean ± SD) in the control group and 13.65 ± 7.13 in the treated group at 28-31 weeks (p = 0.139). At 32-35 weeks, they were 14.55 ± 6.43 and 18.50 ± 5.33, respectively (p = 0.03). Similarly, the no-fetal movement indexes (min, times/h) were 15.03 ± 10.99 and 1.61 ± 0.88, and 18.70 ± 15.80 and 1.75 ± 0.96 (p = 0.824, and 0.673) at 28-31 weeks. At 32-35 weeks, they were 18.13 ± 10.88 and 1.95 ± 0.97, and 9.20 ± 5.51 and 1.14 ± 0.71, respectively (p = 0.003, and 0.003). CONCLUSION: Ritodrine hydrochloride infusion increased the fetal movement and decreased the no-fetal movement period at 32-35 weeks.

In which preterm labor-patients is intravenous maintenance tocolysis effective?

AIM: We evaluated whether maintenance tocolysis (intravenous ritodrine hydrochloride and/or magnesium sulfate) was effective in cases of spontaneous preterm labor with intact membranes. METHODS: One hundred and thirty preterm labor patients who reached 36 weeks of gestation by maintenance tocolysis were selected. Immediate delivery (ID) after ceasing maintenance tocolysis was defined as an 'effective case'. The correlated factors between ID and no immediate delivery (NID) were statistically analyzed. RESULTS: Thirty-six patients delivered < two days after ceasing maintenance tocolysis (27.7%) and were defined as effective cases. Multiple logistic regression analysis revealed that amniotic fluid interleukin-8 at admission (≥ 2.3 ng/mL; odds ratio [OR] 5.6, 95% confidence interval [CI] 2.1-17.6; P < 0.001), pre-pregnancy body mass index (≤ 21.4; OR 5.3, 95% CI 2.0-16.2; P < 0.001) and cerclage (OR 3.6, 95% CI 1.1-11.8; P = 0.028) were independent factors correlated with ID (< 2 days). CONCLUSION: Maintenance tocolysis may be effective in limited cases with mild intra-amniotic inflammation, in lean women and in cerclage cases. Maintenance tocolysis should be ceased in cases without these clinical factors when clinical symptoms disappear.

ATP-sensitive potassium channels modulate in vitro tocolytic effects of ß2-adrenergic receptor agonists on uterine muscle rings in rats in early but not in late pregnancy.

AIM: To investigate whether ATP-sensitive potassium (K(ATP)) channels modulate the tocolytic effect of ß2-adrenergic receptor (ß2-AR) agonists (ritodrine and salmeterol) in early-pregnant (day 6) and late-pregnant (day 22) rat uterus in vitro, in order to examine the relation between the K(ATP) channel sulphonylurea-binding regulatory subunit (SUR) expression and pharmacological reactivity of ß2-AR agonists. METHODS: The tocolytic effects of ritodrine and salmeterol (10(-10)-10(-5) M) on spontaneous rhythmic contractions were investigated cumulatively, alone, or in the presence of the K(ATP) channel blocker glibenclamide (10(-6) M) and the K(ATP) channel opener pinacidil (10(-9)-10(-7) M) after 5-min preincubation. RESULTS: ß2-AR agonist induced myometrial relaxation was inhibited by glibenclamide and enhanced by pinacidil on day 6, when SUR1 expression levels were high. Neither glibenclamide nor pinacidil mediated tocolytic effect was measured on day 22. CONCLUSION: Low expression of the K(ATP) channels at the end of gestation may facilitate enhanced excitability and contractility in the rat myometrium. The combination of a betamimetic and a K(ATP) channel opener will therefore not be of therapeutic relevance in the treatment of preterm delivery.

Sperm transport and retention at the fertilization site is orchestrated by a chemical guidance and oviduct movement.

In mammals, only a few spermatozoa arrive at the fertilization site. During the last step in the journey to the egg, apart from their self-propulsion, spermatozoa may be assisted by oviduct movement and/or a guidance mechanism. The proportion of rabbit spermatozoa that arrive at the fertilization site was determined under in vivo conditions, in which either the ovulation products (secreting chemoattractants) and/or the oviduct movement (causing the displacement of the oviductal fluid) was inhibited. When only one of these components was inhibited, sperm transport to the fertilization site was partially reduced. However, when both the ovulation products and the oviduct movement were inhibited, almost no spermatozoa arrived at the fertilization site. The results suggest that spermatozoa are transported to and retained at the fertilization site by the combined action of a chemical guidance and the oviduct movement. A working model is proposed to explain how these two mechanisms may operate to transport spermatozoa to the fertilization site, probably as an evolutionary adaptation to maximize the chance of fertilizing an egg.

The effects of benzoylecgonine, oxytocin, ritodrine and atosiban on the contractility of myometrium. An experimental study.

PURPOSE: To investigate the response of pregnant and non pregnant rat myometrium to benzoylecgonine, a cocaine metabolite, and oxytocin and to investigate the efficiency of ritodrine and atosiban to overcome the effects of benzoylecgonine and oxytocin. METHODS: Isolation of rat myometrial tissue and recording of contractile activity with isotonic muscle transducer. RESULTS: Benzoylecgonine and oxytocin increase myometrial contractility, while atosiban and ritodrine induce myometrial relaxation. Atosiban was able to revoke the action of oxytocin but not the action of benzoylecgonine. Ritodrine was able to induce muscle relaxation in both oxytocin and benzoylecgonine administration. CONCLUSION: Cocaine metabolites seem to act on the myometrium through different pathways compared with oxytocin. After comparing two widely used tocolytic agents: atosiban and ritodrine, it is indicated that only ritodrine, a beta2 adrenergic receptor agonist, can inhibit the action of cocaine metabolites. This finding indicates that the actions of cocaine on adrenergic mechanisms are responsible to a large part for its effects on myometrium contractility. The use of beta2 adrenergic receptor agonists seems to be preferable for the treatment of myometrial contractions induced by cocaine consumption.

The protective effects of ritodrine against hypoxia/reoxygenation-induced injury in endometrial stromal cells.

Endometriosis (EMS) is often observed in women of childbearing age and significantly impacts patients' quality of life. Ritodrine is a ß2 receptor agonist applied for relaxing the uterine smooth muscle. Its inhibitory effects on inflammation have recently been noted. The present study explored the protective impact of Ritodrine on hypoxia/reoxygenation (H/R)- induced injury in endometrial stromal cells (ESCs). Human ESCs (HESCs) were treated with Ritodrine (0.1, 0.5 µM) for 24 h, followed by exposure to H/R for 6 h. Ritodrine ameliorated H/R-induced higher reactive oxygen species (ROS), declined glutathione (GSH) concentration and increased production of tumor necrosis factor-α (TNF-α), interleukin- 6 (IL-6), and monocyte chemotactic protein 1 (MCP-1) in HESCs. Furthermore, Ritodrine ameliorated the H/R-induced higher nuclear level of nuclear factor κ-B (NF-κB) p65 expression and increased luciferase activity of the NF-κB promoter. In addition, we show that Ritodrine mitigated H/R-induced higher estrogen receptor α (ER-α) expression in HESCs. Interestingly, overexpressing ER-α abolished the regulatory effects of Ritodrine on oxidative stress and the NF-κB pathway-mediated inflammation. Collectively, our data reveal that Ritodrine alleviated H/R-induced injury in ESCs by inhibiting the ER-α/NF-κB pathway.

Differences in the effects of beta2- and beta3-adrenoceptor agonists on spontaneous contractions of human nonpregnant myometrium.

OBJECTIVE: This study aimed to compare the relaxant properties of BRL 37344 with p2-adrenoceptors agonist ritodrine on the contractility of human nonpregnant myometrium. MATERIAL AND METHODS: The activity of myometrial strips mounted in an organ bath was recorded under isometric conditions using force transducers with digital output. Contractility before and after cumulative additions of both uterorelaxants and with preincubation with beta-adrenoceptor antagonists bupranolol, propranolol, and butoxamine were studied. RESULTS: Both BRL 37344 (10(-10)-10(-4) mol/L) and ritodrine (10(-10)-10(-5) mol/L) decreased the area under curve, or AUC, value (log/C50 -6.45 +/- 0.18 and -8.71 +/- 0.35, respectively), and the degree of inhibition of spontaneous contractile activity was similar (< 30%). However BRL 37344 decreased the mean frequency of contractions, whereas ritodrine decreased the mean amplitude of contractions. The inhibition of contractions by BRL 37,344 was partially antagonized by bupranolol and propranolol, but not with butoxamine. The inhibition by ritodrine was counteracted by all these antagonists. CONCLUSIONS: The effects of BRL37344 and ritodrine on human nonpregnant myometrium are quantitatively similar in respect to the inhibition of spontaneous contractility yet are also distinct due to their substantially different influences on contraction parameters. Our data indicate that beta3-adrenoceptor activation is not the sole effect of BRL 37,344 on this tissue.

Influence of GRK5 gene polymorphisms on ritodrine efficacy and adverse drug events in preterm labor treatment.

The present prospective follow-up study aimed to evaluate the effects of GRK5 polymorphisms on ritodrine efficacy and adverse drug events (ADEs) in pregnant women undergoing preterm labor. A total of 162 women undergoing preterm labor were included in the study. Seven single nucleotide polymorphisms (SNPs) in the GRK5 gene (rs915120, rs2230345, rs2230349, rs7923896, rs1020672, rs4752308, and rs4752292) were assessed. Homozygous variant carriers of rs4752292 and rs1020672 had 0.6 times the hazard of delivery compared to wild-type allele carriers (95% confidence interval [CI], 0.41~0.99 and 0.38~0.99, respectively). In addition, homozygous variant carriers of rs4752292 and rs1020672 had 2.4-fold more (95% CI, 1.10~4.98) and 2.3-fold more (95% CI, 1.04~5.06) ADEs compared to those with the wild-type homozygotes, respectively. Among demographic variables, gestational age and modified Bishop score were significant factors associated with time to delivery, while body weight and maximum ritodrine infusion rate were significant factors associated with ADEs. In silico analysis showed that both rs4752292 and rs1020672 had the potential to affect mRNA splicing by alteration of splicing motifs. The present study shows that ritodrine efficacy and ADEs are associated with GRK5 gene polymorphisms in pregnant women undergoing preterm labor.

Relaxing effects of clenbuterol, ritodrine, salbutamol and fenoterol on the contractions of horse isolated bronchi induced by different stimuli.

ß2-adrenoceptor agonists are considered the most effective drugs to counteract bronchoconstriction in horses with asthma, but only clenbuterol is commonly employed in clinical practice. We evaluated the effects of different selective ß2 agonists: clenbuterol, ritodrine, salbutamol, and fenoterol on the contractions of isolated bronchial muscle of horses induced by electrical field stimulation (EFS), carbachol, histamine, and KCl. All ß2 agonists reduced the amplitude of contraction induced by the different stimuli but with variable efficacy and potency. Fenoterol and salbutamol were more effective than clenbuterol in relaxing the bronchial contractions induced by EFS and histamine, and were able to completely abolish carbachol-induced contractions, unlike clenbuterol and ritodrine. The respective potency values (pEC50) of clenbuterol, ritodrine, salbutamol, and fenoterol were 7.74 ±â€¯0.20, 7.77 ±â€¯0.17, 7.30 ±â€¯0.23, 8.01 ±â€¯0.13, for EFS-induced contractions; 8.39 ±â€¯0.26, 5.49 ±â€¯0.28, 6.63 ±â€¯0.14, 7.68 ±â€¯0.11, for carbachol-induced contraction; 7.39 ±â€¯0.27, 7.04 ±â€¯0.28, 6.45 ±â€¯0.34, 7.34 ±â€¯0.22, for histamine-induced contraction; 7.15 ±â€¯0.06, 6.07 ±â€¯0.20, 6.48 ±â€¯0.14, 6.70 ±â€¯0.18, for KCl-induced contraction. Salbutamol and fenoterol showed a higher efficacy than clenbuterol in relaxing horse bronchial muscle pre-contracted by most stimuli. Clenbuterol displayed a good potency but a rather low efficacy, and this may be due to its partial agonist nature; ritodrine showed lower or not significantly different efficacy and potency compared to the other agonists. An evaluation of the clinical efficacy by fenoterol and salbutamol in horses with asthma could be of great interest to assess if they could represent more effective bronchodilators compared to clenbuterol.

Thyroid hormone modulates the responsiveness of rat aorta to alpha1-adrenergic stimulation: an effect due to increased activation of beta2-adrenergic signaling.

AIM: The ability of the thyroid hormone to increase cardiac output and to lower systemic vascular resistance may provide a novel treatment for cardiovascular diseases. Therefore, understanding the mechanisms of thyroid hormone action on the heart and peripheral vasculature could be of clinical importance. We previously found that thyroid hormone modulates the alpha1-adrenergic effect on vascular reactivity of rat aortas. In the present study we further investigated possible mechanisms of this response. METHODS: Hyperthyroidism was induced on Wistar-Kyoto male rats with L-Thyroxine, (THYR) treatment for two weeks, N.=18 while untreated rats used as controls (NORM), N.=16. The thoracic aorta was dissected and cut into rings that were suspended in an isolated organ bath with Krebs-Henseleit buffer. Maximal tension, Tmax, in g was measured in response to Potassium Chloride (KCl) and Phenylephrine (PE) in rings in the presence of Ritodrine, a beta-2 agonist (NORM-RITO, N:=8, THYR-RITO, N.=9), or in the absence of Ritodrine (THYR, N.=9, NORM, N.=8). RESULTS: With KCL, Tmax was not different between the THYR, NORM, NORM-RITO, and THYR-RITO groups. With PE, there was a difference in Tmax between NORM-RITO and NORM, 0.66 (0.056) g vs 1.00 (0.066) g, P<0.05 and THYR and NORM, 0.75 (0.055) g vs 1.00 (0.066) g, P<0.05. No significant difference was observed between THYR-RITO AND THYR. Furthermore, Relax % was not significantly different between the NORM and the THYR, NORM-RITO, and THYR-RITO groups, 64.5%(3.7) vs 67.3%(6.7), 73.5% (4.3) and 81.8 %(4.7), P>0.05. CONCLUSIONS: PE induced vasoconstriction in isolated rat aortic rings was reduced after both ritodrine and thyroxine treatment. However, co-administration of thyroid hormone and ritodrine did not result in a synergistic reduction of PE induced vasoconstriction. Thus, thyroxine may modulate the alpha1-adrenergic vascular responsiveness by enhancing beta2-adrenergic stimulation.

A prospective randomized trial of acute tocolysis in term labour with atosiban or ritodrine.

OBJECTIVE: To study the effects of the tocolytics atosiban and ritodrine in term labour. STUDY DESIGN: Women in term labour, requiring acute tocolysis, were prospectively randomized for treatment with either atosiban i.v. (n=70) or ritodrine i.v. (n=70). There were three indications for acute tocolysis: (1) fetal distress followed by continuation of labour, (2) fetal distress followed by emergency caesarean section (CS), and (3) arrest of contractions in women waiting for a secondary CS in the absence of fetal distress. Primary endpoints were maternal blood pressure (MBP) and maternal heart rate (MHR). Secondary endpoints were intra-uterine pressure, fetal heart rate (FHR), 5'-Apgar score and umbilical arterial pH. RESULTS: Baseline characteristics did not differ between the study groups. The ritodrine group showed a significant rise in MHR (p<0.001), MHR remained unaltered in the atosiban group (p=0.31). No significant changes occurred in systolic and diastolic BP in either group. FHR rose by a maximum of 11.6 bpm (8.5%) in the ritodrine group (p<0.001) compared to a rise of 4.9 bpm (4.8%) in the atosiban group (p=0.27). No differences were found in blood loss and fetal outcome. Compared to baseline, uterine pressure was reduced by a maximum of 55% (p<0.001) after ritodrine administration, compared to a maximal reduction of 54% (p<0.001) after atosiban administration. These effects did not differ between the two treatment groups. CONCLUSION: Considering the maternal effects, our results suggest a possible role for atosiban bolus in acute tocolysis in term labour.

Deleterious genetic variants in ciliopathy genes increase risk of ritodrine-induced cardiac and pulmonary side effects.

BACKGROUND: Ritodrine is a commonly used tocolytic to prevent preterm labour. However, it can cause unexpected serious adverse reactions, such as pulmonary oedema, pulmonary congestion, and tachycardia. It is unknown whether such adverse reactions are associated with pharmacogenomic variants in patients. METHODS: Whole-exome sequencing of 13 subjects with serious ritodrine-induced cardiac and pulmonary side-effects was performed to identify causal genes and variants. The deleterious impact of nonsynonymous substitutions for all genes was computed and compared between cases (n = 13) and controls (n = 30). The significant genes were annotated with Gene Ontology (GO), and the associated disease terms were categorised into four functional classes for functional enrichment tests. To assess the impact of distributed rare variants in cases with side effects, we carried out rare variant association tests with a minor allele frequency ≤ 1% using the burden test, the sequence Kernel association test (SKAT), and optimised SKAT. RESULTS: We identified 28 genes that showed significantly lower gene-wise deleteriousness scores in cases than in controls. Three of the identified genes-CYP1A1, CYP8B1, and SERPINA7-are pharmacokinetic genes. The significantly identified genes were categorized into four functional classes: ion binding, ATP binding, Ca2+-related, and ciliopathies-related. These four classes were significantly enriched with ciliary genes according to SYSCILIA Gold Standard genes (P < 0.01), thus representing ciliary genes. Furthermore, SKAT showed a marginal trend toward significance after Bonferroni correction with Joubert Syndrome ciliopathy genes (P = 0.05). With respect to the pharmacokinetic genes, rs1048943 (CYP1A1) and rs1804495 (SERPINA7) showed a significantly higher frequency in cases than controls, as determined by Fisher's exact test (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: Ritodrine-induced cardiac and pulmonary side effects may be associated with deleterious genetic variants in ciliary and pharmacokinetic genes.

Arrest of preterm labor in rat and mouse by an oral and selective nonprostanoid antagonist of the prostaglandin F2alpha receptor (FP).

OBJECTIVE: The purpose of this study was to assess the tocolytic effect of AS604872, an orally active, potent, and selective prostanoid prostaglandin F2alpha receptor (FP) antagonist. STUDY DESIGN: Compound AS604872 was characterized and tested for its ability to block uterine contraction and delay preterm parturition in rodent models. RESULTS: AS604872 inhibited spontaneous uterine contractions in pregnant rat near term. In pregnant mouse, AS604872 delayed parturition induced by either the antiprogesterone RU-486 or the endotoxin lipopolysaccharide. Pups from treated mothers were delivered alive. The efficacy of AS604872 was superior to the beta-mimetic drug ritodrine. Combination of AS604872 and ritodrine showed an additive inhibitory effect on spontaneous uterine contractions in rat. CONCLUSION: A selective antagonist of the FP receptor suppresses uterine contractility and delays labor. Our findings identify a new potential modality for the pharmacological management of preterm labor.

The effects and selectivity of beta-adrenoceptor agonists in rat myometrium and urinary bladder.

Recent evidence supports a role for beta(3)-adrenoceptors in human non-pregnant and pregnant myometrium. The present study was designed to characterize the pharmacology of beta-adrenoceptors involved in the function of non-pregnant rat myometrium by comparison of the activity of several beta-adrenoceptor agonists and antagonists in isolated rat uterus and urinary bladder. Contractions of myometrial and detrusor strips were induced by adding 1 nM oxytocin and 15 mM KCl respectively. Cumulative concentration-response curves to the selective beta(3)-adrenoceptor agonists, CL 316243 and BRL 37344 and the selective beta(2)-adrenoceptor agonist ritodrine were obtained in the presence and absence of the selective beta(2)-adrenoceptor antagonist ICI 118551 and the non-selective beta-adrenoceptor antagonist bupranolol. Both BRL 37344 (pD(2)=6.79+/-0.09) and ritodrine (pD(2)=6.89+/-0.19) produced potent inhibition of oxytocin-induced contractions in myometrial strips; CL 316243 was inactive at concentrations up to 10 microM. Concentration effect curves to both BRL 37344 and ritodrine were shifted (10 to 30-fold) to the right in the presence of ICI 118551 (10 nM). BRL 37344 (pD(2)=8.51+/-0.21) and CL 316243 (pD(2)=8.61+/-0.24) produced potent inhibition of detrusor strips, while ritodrine was almost 100-fold less potent (pD(2)=5.83+/-0.17). The response to all agonists was significantly attenuated by pretreatment with bupranolol (10 microM), but only ritodrine was affected by ICI 118551 (1 microM). These results demonstrate that relaxation of rat myometrium is mediated by beta(2)-adrenoceptors while, consistent with previous reports, the beta(3)-subtype is primarily responsible for relaxation of rat detrusor.

Preterm labour. Myometrial function in prematurity.

The primary function of the uterus during gestation is to harbour the growing conceptus in a largely quiescent environment. Upon maturation of the fetus to a point sufficient for extrauterine survival, the uterus must remodel itself sufficiently to generate forceful contractions during labour. During preterm delivery, the process of remodelling of the myometrium occurs early due to a number of different causes, although the underlying basis for myometrial contraction remains the same. This review summarises the anatomical, physiological and molecular basis for contraction. We describe the fibre structure of the human uterus and how this relates to the spread of electrical excitation during a contraction. The process of excitation within a single myometrial cell is described, as well as how this relates to contraction. We then focus on how excitation-contraction coupling is modulated by intercellular communication, pharmacomechanical-coupling and hormonal milieu. Lastly, we consider the actions of the commonly accepted uterine agonists oxytocin, prostaglandin F(2alpha), and prostaglandin E(2), and the tocolytic ritodrine.

Effects of ritodrine hydrochloride tocolysis on echocardiographic parameters.

OBJECTIVE: Preterm delivery is a leading cause of perinatal mortality and morbidity. The aim of this study was to determine the effect of ritodrine hydrochloride, used for tocolysis and having serious cardiovascular side effects, on echocardiographic parameters. METHODS: Sixty-two pregnant women were included in our study. The study and control groups were composed of patients with preterm labor (group A, N = 30) and patients with uneventful pregnancies (group B, N = 32), respectively. While the patients in group A were evaluated before and during treatment, those in group B were evaluated only once for ejection fraction and fractional shortening of the left side of the heart with echocardiography and for the regional systolic and diastolic functions with the tissue Doppler technique. One-way ANOVA and a t-test (paired comparison) were used for statistical purposes. RESULTS: For the left side of the heart, it was shown that while fractional shortening increased with tocolysis (p < 0.05), neither the ejection fraction nor E/A ratio, showing diastolic function, changed significantly (p < 0.01). While systolic function parameters (S(asep) and S(alat)) increased due to the inotropic and chronotropic actions of the beta-mimetic agents (p < 0.05), regional diastolic function parameters (E(asep)/A(asep) and E(alat)/A(alat)) did not change (p > 0.05). CONCLUSIONS: Due to its potent inotropic and chronotropic effects, ritodrine hydrochloride increases myocardial oxygen demand significantly. Therefore, it should be used sparingly or avoided altogether in patients with ischemic or structural heart disease.

In vitro effects of ritodrine, magnesium sulfate and their combination on spontaneous contractions of myometrial strips of pregnant rat uteri.

OBJECTIVE: To investigate in vitro effects of ritodrine, magnesium sulfate and their combination on spontaneous contractions of myometrial strips obtained from pregnant rat uteri. METHOD: A total of 13 pregnant Sprague Dawley rats with weights between 180-200 g were used in this study. Three strips from each rat were kept in an organ bath containing 20 ml Krebs-Henseleit solution (pH: 7.4 and 37 degrees C). 10(-8) 10(-6) and 10(-4) M concentrations of ritodrine, magnesium sulfate and the combination was applied over myometrial strips in Groups I (n: 10), II (n: 10) and III (n: 8), respectively. Amplitude and frequency of spontaneous myometrial contractions, which were recorded at the beginning of each experiment, were considered as reference values. Amplitude and frequency changes in spontaneous myometrial contractions were calculated at approximately ten-minute intervals right after the application of drugs as the percentage of difference at the first reference response. RESULTS: Magnesium sulfate application did not lead to any significant difference on the amplitude and frequency of contractions at any of its concentrations. 10 and 10(-4) M concentrations of ritodrine caused a significant decrease in the amplitude of contractions. It was also found that ritodrine significantly decreased the frequency values at all concentrations. A significant decrease in amplitude was observed at 10(-8) and 10(-6) M concentrations in the combination group. No significant decrease in frequency values was found at any concentration in the combination group. CONCLUSION: The tocolytic effect of ritodrine is superior to that of magnesium sulfate.

Altered uterine contractility in response to ß-adrenoceptor agonists in ovarian cancer.

We aimed to prospectively examine ß-adrenoceptor-mediated uterine contractility in women suffering from gynecological malignancies. Myometrial specimens were obtained from non-pregnant women undergoing hysterectomy for benign gynecological disorders, and ovarian, endometrial, synchronous ovarian-endometrial, and cervical cancer. Contractions of myometrial strips in an organ bath before and after cumulative dosages of ß2- and ß3-adrenoceptor agonists with preincubation of propranolol, SR 59230A, and butoxamine were studied. All agonists induced a dose-dependent attenuation for uterine contractility in endometrial or cervical cancer, similar to that observed in the reference group. Contradictory effects were observed for ovarian cancer alone or in combination with endometrial cancer. CL 316243 or ritodrine abolished the relaxation, whereas BRL 37344 increased the uterine contractility in ovarian cancer. Moreover, ß-adrenoceptor antagonists caused varied effects for ß2- or ß3-adrenoceptor agonists. Our experiments demonstrate that ovarian cancer, alone or as synchronous ovarian-endometrial cancer, substantially alters uterine contractility in response to ß-adrenoceptor agonists.

The Synergic In Vitro Tocolytic Effect of Nifedipine Plus Ritodrine on Human Myometrial Contractility.

Many pharmacological agents have been investigated to manage preterm labor; we postulate that a combination of tocolytic drugs may achieve a better effect in the prevention of uterine contractions without dose-dependent adverse effects. The aim of this study was to evaluate the inhibitory effect of dual combinations of tocolytics in vitro. Human myometrium was obtained during elective cesarean sections (term without labor; n = 40). Myometrial strips were placed in organ baths for the measurement of isometric tension. Contractile activity was induced by oxytocin (10-8 mol/L), then a concentration-response curve to single or dual combinations of tocolytics was started. All studied tocolytics (nifedipine, ritodrine, nitroglycerin, atosiban, and NS-1619), when used alone, significantly inhibited myometrial contractions. When combined, nifedipine plus ritodrine produced a significantly greater inhibition of contractility than each drug alone in the midrange of concentrations. The combination of nifedipine plus nitroglycerin or nifedipine plus atosiban produced a significantly greater inhibition than nitroglycerin or atosiban alone but not greater than nifedipine. The combination of nifedipine plus NS-1619 (Ca+2-activated K+ [BKCa] channel opener) reduced the inhibitory effect of each drug. We concluded that a selected combination of tocolytics (nifedipine plus ritodrine) produced a significantly greater inhibitory effect on contractility than each drug alone at intermediate concentrations. Thus, specific combinations of tocolytics with different intracellular signaling pathways may have a synergic effect constituting a provocative new option for preterm labor treatment.

Neonatal neurodevelopmental outcomes following tocolysis with glycerol trinitrate patches.

OBJECTIVE: The object of this study was to determine the effects of maternal tocolysis with glycerol trinitrate (GTN) patches on the neurodevelopment of infants. STUDY DESIGN: This was a randomized, multicenter, controlled trial comparing the efficacy of GTN patches with standard beta2 agonist as tocolytic therapy. The previously reported outcomes of this study indicated no difference in neonatal mortality or morbidity to hospital discharge. One hundred fifty-six surviving infants from 2 Australian centers were psychometrically assessed using the Griffiths Mental development Scales (revised) at 18 months of age. RESULTS: There was no difference in psychometric performance between those infants enrolled in either the GTN (81 infants) or beta2 agonist (75 infants) arm of the study. CONCLUSION: This randomized trial supports no significant difference between GTN patches in comparison with standard beta2 agonist for tocolytic therapy. The results underscore the association between premature labor and adverse infant outcomes.