Acute Pulmonary Edema Induced by a Low Dose of Ritodrine Hydrochloride: A Case Report.

OBJECTIVE: Acute pulmonary edema associated with ritodrine hydrochloride is a rare, life-threatening complication, and dose and duration of ritodrine use are closely associated with this pathology. We report a case of acute pulmonary edema associated with short-duration infusion of ritodrine hydrochloride in a patient with pectus excavatum as an underlying factor. CASE REPORT: A 30-year-old healthy pregnant woman was treated with oral ritodrine for tocolysis between 31 and 35 weeks of pregnancy. At 36 weeks of gestation, she went into preterm labor, with premature rupture of the membrane and breech presentation, and received an infusion of ritodrine hydrochloride for a few hours. Although she was normotensive until labor onset, mild hypertension and proteinuria were recognized. Intraoperatively, a funnel-chest deformity was observed, and she developed postoperative pulmonary edema associated with dyspnea and wet cough and confirmed on chest radiography and arterial gas analysis, and recovered with supportive care. CONCLUSION: Small-dose infusion of ritodrine hydrochloride might cause pulmonary edema in patients with underlying medical problems, including pectus excavatum.

The safety of ritodrine hydrochloride: Adverse effects on fetuses and newborns.

Prematurely born infants face unique risks, and the treatment of imminent preterm birth is thus an important part of perinatal care. Ritodrine hydrochloride (Rito) is widely used as a therapeutic agent to treat imminent preterm birth in Japan. Following assessment of the risks and benefits of short-acting ß-agonists, including Rito, in Europe, however, the use of Rito has begun to be questioned. Thus, in this study we investigated the safety of Rito in the treatment of imminent preterm birth, with a particular focus on the adverse effects (AEs) on fetuses and newborn infants. Using the Pharmaceuticals and Medical Devices Agency of Japan's Japanese Adverse Drug Event Report (JADER) database, the AEs on fetuses and newborns caused by oral and injected Rito were extracted and analyzed. The reported odds ratios for oral Rito were significantly higher for fetal tachycardia, fetal bradycardia, neonatal hypoglycemia, and neonatal heart failure than for other drugs. The reported odds ratios for Rito injection were significantly higher for fetal tachycardia and neonatal hypoglycemia than for other drugs. Oral drugs had more adverse effect reports than injectable drugs.

Effects of KCNMB2 gene polymorphisms on ritodrine therapy outcomes in women with preterm labor.

OBJECTIVE: The present prospective follow-up study aimed to evaluate the effects of KCNMB2 gene polymorphisms on ritodrine efficacy and adverse drug events (ADEs) in patients with preterm labor. METHODS: A total of 163 preterm labor patients were included in this single-center study. Nine single nucleotide polymorphisms (SNPs) in the KCNMB2 gene (rs10936979, rs7624046, rs7429015, rs7625907, rs6443559, rs9839376, rs9637454, rs11918114, and rs1382045) were assessed. The primary endpoint was time to delivery, and the secondary endpoint was ritodrine-induced ADEs. RESULTS: Patients with variant homozygotes of two SNPs (rs7624046 and rs9839376), which were in linkage disequilibrium, showed 2.06 [95% confidence interval (CI), 1.14-3.73] and 2.68 (95% CI, 1.16-6.20) times the hazard of time to delivery compared to wild-type allele carriers, respectively. Among demographic characteristics, gestational age at start of drug therapy and modified Bishop score were significant factors for time to delivery. Regarding safety outcomes, patients with variant homozygotes of rs7625907 had fewer ADEs compared to those with other genotypes (odds ratio, 0.32; 95% CI, 0.13-0.83). CONCLUSION: This pharmacogenomic study suggests that ritodrine efficacy and ADEs are associated with KCNMB2 gene polymorphisms in patients with preterm labor.

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.

Inappropriate use of ritodrine hydrochloride for threatened preterm birth in Japan: a retrospective cohort study using a national inpatient database.

BACKGROUND: No study has revealed the effectiveness of long-term tocolysis for patients diagnosed with threatened preterm birth, and the use of betamimetics in these patients has not been recommended in the United States or Europe because of the potential for severe maternal adverse effects. However, long-term tocolysis with intravenous infusion of ritodrine hydrochloride, a betamimetic, can be selected as the first-line tocolytic treatment in Japan. This study was performed to (i) examine the current status of long-term tocolytic treatment, particularly with intravenous infusion of betamimetics, for threatened preterm birth in Japan and (ii) clarify the association between long-term tocolytic treatment and maternal adverse effects. METHODS: This retrospective cohort study was conducted using a national inpatient database for acute-care inpatients in Japan. Among all pregnant women who were diagnosed with threatened preterm birth and admitted to the hospital from July 2010 to March 2016, we identified 134,959 eligible patients. The primary outcome was maternal serious adverse effects during hospitalization. A multivariable logistic regression analysis was performed to evaluate factors associated with maternal adverse effects. RESULTS: Among all patients, 17.2% received intravenous infusion of ritodrine hydrochloride for ≤48 h and 28.7% received this treatment for ≥28 days. The proportion of maternal adverse effects was significantly higher among patients treated for ≥28 days than ≤48 h. A longer duration of tocolysis was significantly associated with increased maternal adverse effects. CONCLUSIONS: Long-term tocolysis was associated with an increased incidence of maternal adverse effects in the current study using real-world data. Japanese clinicians should adjust their tocolytic treatment practices in accordance with the latest scientific evidence or make efforts to verify the effectiveness and safety of long-term tocolysis.

Association between ß2-adrenergic receptor gene polymorphisms and adverse events of ritodrine in the treatment of preterm labor: a prospective observational study.

BACKGROUND: Ritodrine, a tocolytic ß2-agonist, has been used extensively in Europe and Asia despite its safety concerns. This study was designed to identify associations between ß2-adrenergic receptor (ADRB2) polymorphisms and adverse drug events (ADEs) in patients with preterm labor treated with ritodrine. RESULTS: This follow-up study was prospectively conducted at Ewha Womans University Mokdong Hospital in Korea. Five single nucleotide polymorphisms (SNPs) of the ADRB2 gene (rs1042713, rs1042714, rs1042717, rs1042718, and rs1042719) were analyzed in 186 pregnant women with preterm labor. Patients with the AA genotype of rs1042717 had significantly lower incidence of ADEs compared to those with the G allele (p = 0.009). In multivariate analysis, one of the predictors of ADEs was the maximum infusion rate of ritodrine (AOR 4.47, 95% CI 1.31-15.25). Rs1042719 was also a significant factor for ritodrine-induced ADEs. The CC genotype carriers had 78% decreased risk of ADEs compared to those with other genotypes. CONCLUSIONS: This study demonstrates that ADEs induced by ritodrine are associated with ADRB2 gene polymorphisms, as well as the infusion rate of ritodrine in pregnant women with preterm labor.

Association between total dose of ritodrine hydrochloride and pulmonary oedema in twin pregnancy: a retrospective cohort study in Japan.

OBJECTIVE: Pulmonary oedema is recognised as a severe side effect of ritodrine hydrochloride. Recently, the number of twin pregnancies has been increasing. Few studies have reported the association between total dose of ritodrine hydrochloride prior to delivery and pulmonary oedema in twin pregnancy. We aimed to examine this association and determine the optimal cut-off threshold of total ritodrine hydrochloride dose to predict the incidence of pulmonary oedema in twin pregnancy based on obstetric records. DESIGN: Retrospective cohort study. SETTING: Yamanashi Prefectural Central Hospital, Japan. PARTICIPANTS: Two hundred and twenty-six women with twin pregnancy who delivered at Yamanashi Prefectural Central Hospital between September 2009 and November 2016. METHODS: The obstetric records of the participants were analysed. We defined 1 unit of ritodrine hydrochloride as 72 mg per 24 hours continuous transfusion at 50 µg/min to calculate the dose of ritodrine used for tocolysis. OUTCOME MEASURES: Multivariable logistic regression analysis was performed to examine the association between total dose of ritodrine hydrochloride used for threatened preterm labour and pulmonary oedema, while controlling for potential confounding factors. Then, a receiver-operating characteristic curve was used to determine the optimal cut-off of total ritodrine dose to predict pulmonary oedema incidence. RESULTS: Mean maternal age was 32 (range, 18-46) years; 143 participants were nulliparous (63.3%), 109 had (48.2%) term deliveries and 194 (85.8%) had caesarean deliveries. The overall incidence of pulmonary oedema was 13.7% (31/226). Multivariable analysis showed that the total dose of ritodrine was significantly associated with pulmonary oedema (adjusted OR 1.02; 95% CI 1.004 to 1.03). The best cut-off point to predict the incidence of pulmonary oedema was 26 units (1872 mg) (sensitivity, 61.3%; specificity, 87.8%). CONCLUSION: Our results suggest that consideration of the total dose of ritodrine hydrochloride is helpful in the management of patients with threatened preterm labour in twin pregnancy.

Toward Understanding Myometrial Regulation: Metabolomic Investigation Reveals New Pathways of Oxytocin and Ritodrine Activity on the Myometrium.

In recent times, additional pathways involved in the regulation of the myometrium have been suggested. This also holds true for the effect of drugs such as oxytocin (OT) and ß-adrenergic agonists on the myometrium. Knowledge of these additional pathways will certainly prove useful in designing better therapies for pathologies of the myometrium. This study was therefore aimed at investigating the possibility of other pathways involved in the activities of both OT and ritodrine (RIT; a ß-adrenergic agonist) in the myometrium by utilizing metabolomics and bioinformatics. High-resolution Fourier transform mass spectrometry (HRFTMS) and nuclear magnetic resonance (NMR) spectroscopy coupled with functional uterine assays were used for an innovative assessment. In vitro pharmacological assay of OT (1 nmol/L) and RIT (0.1 nmol/L) on isolated mice uteri mounted in 3 mL organ baths was performed. Mice uteri, treated with OT or RIT, as well as the physiological buffer in which the uterine tissues were immersed, were rapidly collected and analyzed using HRFTMS, proton (1H)-NMR, and bioinformatics. Resulting data were analyzed via pairwise chemometric comparison models, with P ≤ .05 considered statistically significant. In addition to previously known metabolites, nicotinamide adenine dinucleotide, γ-aminobutyric acid, and sphingosine were significantly associated with the activity of OT, whereas the activity of RIT was associated with a downstream involvement of prostaglandin F1 and phosphatidylinositol signaling. These findings add evidence to the reports on additional regulation of myometrial activity by these drugs and suggest newer pathways for therapeutic manipulation.

Comparison of perinatal outcomes between long-term and short-term use of tocolytic agent: a historical cohort study in a single perinatal hospital.

AIM: The aim of this study was to evaluate the effect of long-term use of tocolytic agents to prevent preterm delivery and improve perinatal outcome. METHODS: A historical cohort study was performed in a single perinatal center. The maternal characteristics, frequency of preterm labor and prescribed dose of tocolytic agents were compared before and after changing the management protocol for threatened premature delivery. RESULTS: A total of 1548 deliveries were carried out before changing the protocol for the use of tocolytic agents for threatened premature delivery and 1444 deliveries afterwards. There was no significant difference in the maternal characteristics before and after the revision except for maternal age. The total number of ritodrine hydrochloride ampules used was reduced from 4654 to 514, and the total vials of magnesium sulfate used were reduced from 1574 to 193, but perinatal outcomes, such as rate of preterm birth, neonatal weight, and rate of NICU hospitalization were not different between the groups. CONCLUSION: There was no significant change in the frequency of preterm delivery before and after changing of the protocol for threatened premature delivery. Because a decrease in the given dose of tocolytic agents did not affect the timing of delivery and neonatal outcomes, long-term tocolysis in patients with threatened premature delivery should be restricted to prevent maternal and fetal adverse side-effects.

The Association between Prenatal Yoga and the Administration of Ritodrine Hydrochloride during Pregnancy: An Adjunct Study of the Japan Environment and Children's Study.

INTRODUCTION: While the beneficial effects of prenatal yoga have been reported in recent years, little is known about its effectiveness in pregnant Japanese women. Despite several adverse effects, ritodrine hydrochloride is frequently prescribed to suppress preterm labor in Japan, and its usage may therefore indicate cases of preterm labor. This study aimed to clarify the association between prenatal yoga and ritodrine hydrochloride use during pregnancy. METHODS: An observational study was conducted as an adjunct study by the Hokkaido unit of the Japan Environment and Children's Study. Information on prenatal yoga practice was collected using a self-questionnaire between March 21, 2012, and July 7, 2015, targeting women who had recently delivered. Ritodrine hydrochloride use was identified from medical records. A total of 2,692 women were analyzed using logistic regression models that adjusted for possible confounders. RESULTS: There were 567 (21.1%) women who practiced prenatal yoga, which was associated with a lower risk of ritodrine hydrochloride use (adjusted odds ratio [OR] 0.77; 95% CI 0.61-0.98). This was especially evident in women with a total practice duration that exceeded 900 minutes throughout their pregnancy (adjusted OR 0.54; 95% CI 0.38-0.76). A sensitivity analysis that excluded patients with threatened abortion during the study period produced similar results. CONCLUSIONS: Prenatal yoga was associated with a lower risk of ritodrine hydrochloride use, particularly in women with more than 900 minutes of practice time over the course of their pregnancy. Prenatal yoga may be a beneficial option for pregnant women in the selection of alternative therapies.

Genotoxic effect of tocolytic drug ritodrine in combination with smoking during pregnancy.

OBJECTIVE: Tocolytic drugs are used widely in order to prevent preterm birth. Ritodrine, is the only food and drug administration (FDA) approved drug for tocolytic use. We estimated the cytogenetic effect of ritodrine administered as maternal therapy, alone or in combination with smoking, in women and their neonates. METHODS: Lymphocyte and fibroblasts cultures were evaluated and three indices were analyzed; sister chromatid exchanges (SCEs), proliferation rate index (PRI) and mitotic index (MI) as well as average generation time (AGT) and population doubling time (PDT). Campothacin (CPT-11) was used as a positive control. RESULTS: Administration of ritodrine up to a month revealed significant reduction of SCEs/cell in neonates in the presence or absence of the mutagenic agent. A statistical significant increase on SCEs, for mothers and neonates, was noticed in neonate's lymphocytes when tocolytic therapy was over a month. Ritodrine revealed a cytoprotective action against smoking when the two factors were combined, but the synergistic action of ritodrine with smoking increased genotoxicity, cytostaticity and cytotoxicity of neonates after long administration (1-3 months). CONCLUSIONS: The time-depended genotoxic, cytostatic and cytotoxic action of ritodrine alone or in combination with smoking suggests that its administration should not exceed the time period of a month.

Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy.

BACKGROUND: Twin pregnancies are associated with a high risk of neonatal mortality and morbidity due to an increased rate of preterm birth. Betamimetics can decrease contraction frequency or delay preterm birth in singleton pregnancies by 24 to 48 hours. The efficacy of oral betamimetics in women with a twin pregnancy is unproven. OBJECTIVES: To assess the effectiveness of prophylactic oral betamimetics for the prevention of preterm labour and birth for women with twin pregnancies. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (21 September 2015), MEDLINE (January 1966 to 31 July 2015), EMBASE (January 1985 to 31 July 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials in twin pregnancies comparing oral betamimetics with placebo or any intervention with the specific aim of preventing preterm birth. Quasi-randomised controlled trials, cluster-randomised trials and cross-over trials were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two authors assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Overall, the quality of evidence is low for the primary outcomes. All of the included trials had small numbers of participants and few events. Preterm birth, the most important primary outcome, had wide confidence intervals crossing the line of no effect.Six trials (374 twin pregnancies) were included, but only five trials (344 twin pregnancies) contributed data. All trials compared oral betamimetics with placebo.Betamimetics reduced the incidence of preterm labour (two trials, 194 twin pregnancies, risk ratio (RR) 0.37; 95% confidence interval (CI) 0.17 to 0.78; low quality evidence). However, betamimetics did not reduce prelabour rupture of membranes (one trial, 144 twin pregnancies, RR 1.42; 95% CI 0.42 to 4.82; low quality evidence), preterm birth less than 37 weeks' gestation (four trials, 276 twin pregnancies, RR 0.85; 95% CI 0.65 to 1.10; low quality evidence), or less than 34 weeks' gestation (one trial, 144 twin pregnancies, RR 0.47; 95% CI 0.15 to 1.50; low quality evidence). Mean neonatal birthweight in the betamimetic group was significantly higher than in the placebo group (three trials, 478 neonates, mean difference 111.22 g; 95% CI 22.21 to 200.24). Nevertheless, there was no evidence of an effect of betamimetics in reduction of low birthweight (two trials, 366 neonates, average RR 1.19; 95% CI 0.77 to 1.85, random-effects), or small-for-gestational age neonates (two trials, 178 neonates, average RR 0.90; 95% CI 0.41 to 1.99, random-effects). Two trials showed that betamimetics significantly reduced the incidence of respiratory distress syndrome (388 neonates, RR 0.30; 95% CI 0.12 to 0.77), but the difference was not significant when the analysis was adjusted to account for the non-independence of twins (194 twins, RR 0.35; 95% CI 0.11 to 1.16). Three trials showed no evidence of an effect of betamimetics in reducing neonatal mortality, either with the unadjusted analysis, assuming twins are completely independent of each other (452 neonates, average RR 0.90; 95% CI 0.15 to 5.37, random-effects), or in the adjusted analysis, assuming non-independence of twins (226 twins, average RR 0.74; 95% CI 0.23 to 2.38, random-effects). A maternal death was reported in one trial without a significant difference between the groups (144 women, RR 2.84; 95% CI 0.12 to 68.57). AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the use of prophylactic oral betamimetics for preventing preterm birth in women with a twin pregnancy.

Pregnant Woman Bitten by a Japanese Mamushi (Gloydius blomhoffii).

We herein report the fourth case of a pregnant woman bitten by a mamushi. A 33-year-old pregnant woman in the 25th week of gestation was bitten by a mamushi. Her vital signs were stable; however, biochemical analyses of the blood showed mild deterioration of anemia and hypoproteinemia. The effects of envenomation were limited to the extremities, the administration of supportive therapy without antivenom fortunately resulted in a favorable outcome. As there are differences in the maternal medical condition and weeks of gestation, further research is needed to clarify the optimal management strategy for administering antivenom in pregnancy.

In vitro and in vivo evaluations of buccal tablet formulations of ritodrine hydrochloride.

Buccal tablets of ritodrine (RD) hydrochloride (HCl), called RD-HCl, were prepared using the direct compression method with alginate (AL), lactose (LC), magnesium stearate (ST), and microcrystalline cellulose (MC) as excipients. The tablets were evaluated based on hardness, and tablets weighing 80 mg and with hardness of greater than 30 N were chosen as appropriate ones. As a result, tablets composed of RD-HCl (4 mg)/LC (38.5 mg)/ST (0.5 mg)/MC (37 mg) and RD-HCl (4 mg)/AL(7 mg)/LC (28.5 mg)/ST (0.5 mg)/MC (37 mg), called D9 and D10, respectively, were selected. These tablets were further evaluated based on in vitro dissolution and in vivo absorption studies in rats. D9 rapidly released RD, achieved an effective plasma concentration from 15 min to 7 h after its buccal administration, and did not exceed the toxic plasma level of 80 ng/mL. D10 gradually released RD, and maintained an effective concentration from 1 h to 7 h after its buccal administration, without exceeding the toxic plasma level. The absorption was more prolonged in D10 than D9. Their in vivo release was considered to be caused gradually from the amount of RD remaining in the oral cavity at 7 h, in particular D10. The superior retention of D10 in plasma and oral cavity appeared to be related to its higher mucoadhesive properties. Although these results were obtained using rats, they suggest that the chosen tablets should have adequate characteristics from the viewpoints of plasma levels.

Preparation and evaluation of ritodrine buccal tablets for rational therapeutic use.

Ritodrine hydrochloride (RD-HCl) tablets containing alginate (AL) and lactose (LC) with or without microcrystalline cellulose (MC) as excipients were produced as a buccal dosage form. The RD-HCl (2 mg) tablets with AL/LC but no MC swelled and dissolved gradually in the in vitro dissolution test. The tablet showing the fastest dissolution and highest drug release rate, called Tablet A1, was selected as a tablet to show rapid and prolonged absorption. However, in the in vivo buccal absorption test using rats, it could not give a plasma concentration over the human minimal effective level (15 ng/mL). The modified tablet containing AL, LC, MC and RD-HCl (4 mg), named Tablet B/MC, showed better hardness and faster drug release. Tablet B/MC gave a plasma concentration over the human effective level within 15 min, and the plasma concentration was maintained at >15 ng/mL over 4 h. Moreover, the deconvolution analyses demonstrated that a prolonged high absorption rate could be achieved in vivo best with Tablet B/MC. Tablet B/MC improved the pharmacokinetic profile in comparison with Tablet A1 and the solution dosage form. The RD-HCl buccal tablets with AL, LC and MC as excipients are suggested to be possibly useful for the treatment of premature labor.

The influence of ritodrine alone or in combination with nifedipine on maternal cardiovascular side effects and pregnancy outcomes.

OBJECTIVE: To compare the influence of ritodrine alone or in combination with nifedipine on maternal side effects and suppressing preterm labor. MATERIALS AND METHODS: This retrospective study included 213 pregnancies with preterm labor (20-34 weeks) from May 2002 to April 2010 in Kyungpook National University Hospital in Daegu, Korea. Obstetric medical records were reviewed for both maternal characteristics and neonatal outcomes, including birth weight, Apgar score, admission to neonatal intensive care unit (NICU), ventilator support, and neonatal mortality. Maternal side effects such as tachycardia, pulmonary edema, and hyperglycemia were also reviewed. RESULTS: Of 213 patients, 109 received ritodrine only and 104 were given ritodrine and nifedipine. There was no statistical difference between the two groups with regards to pregnancy outcomes and neonatal complications. Pregnancy prolongation over seven days was achieved more in the combination therapy group, with borderline statistical significance (59.6% vs. 72.1%, p = 0.055). Sixty-nine cases experienced maternal side effects; four cases were categorized as serious and 65 cases were mild. CONCLUSION: In the treatment of preterm labor, the combination regimen of ritodrine and nifedipine can be more effective than ritodrine alone for prolonging gestation over seven days. Moreover, as the combination did not cause severe maternal side effects, it may be considered as a safe and effective method to prolong gestation in patients with preterm labor.

In vivo absorption study of ritodrine hydrochloride in the buccal administration to rats.

BACKGROUND: Although ritodrine (RD)-hydrochloride (HCl), named RD-HCl, is widely used in the treatment of premature labor by intravenous prolonged infusion or frequent oral dosing of tablets, those administrations often lower patients' quality of life (QOL) or cause undesirable side effects, such as tachycardia; therefore, in this study, the potential usefulness of buccal administration as a novel administration method was examined in vivo. METHOD: First, the HPLC method was assessed for the determination of plasma RD concentration. Then, after RD-HCl solution in saline was administered intravenously (1 mg/kg), intragastrically (10 mg/kg) or buccally (10 mg/kg) in rats, the plasma concentration-time profiles were investigated, and the absorption extent and rate compared. RESULTS: The present modified determination method by HPLC with fluorescence detection (Ex. 278 nm, Em. 306 nm) was suitable to analyze the plasma level at 8-200 ng/mL. Buccal administration gave the best plasma concentration-time profile for maintenance of an effective plasma level and fewer side effects. Absorption rates calculated by deconvolution also supported better sustained absorption in buccal dosing. CONCLUSION: Buccal application of RD-HCl was demonstrated to be a potentially useful dosing method in the treatment of premature labor with RD-HCl.

Oral betamimetics for maintenance therapy after threatened preterm labour.

BACKGROUND: Some women who have threatened to give birth prematurely, subsequently settle. They may then take oral tocolytic maintenance therapy to prevent preterm birth and to prolong gestation. OBJECTIVES: To assess the effects of oral betamimetic maintenance therapy after threatened preterm labour for preventing preterm birth. SEARCH METHODS: We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 9 November 2012. SELECTION CRITERIA: Randomised controlled trials comparing oral betamimetic with alternative tocolytic therapy, placebo or no therapy, for maintenance following treatment of threatened preterm labour. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the selection criteria and carried out data extraction and quality assessment of studies. MAIN RESULTS: We did not identify any new trials from the updated search so the results remain unchanged as follows.We included 13 randomised controlled trials (RCTs) with a total of 1551 women. We found no differences for admission to the neonatal intensive care unit when betamimetics were compared with placebo (risk ratio (RR) 1.28, 95% confidence interval (CI) 0.68 to 2.41; two RCTs of terbutaline with 2600 women) or with magnesium (RR 0.80, 95% CI 0.43 to 1.46; one RCT of 137 women). The rate of preterm birth (less than 37 weeks) showed no significant difference in six RCTs, four comparing ritodrine with placebo/no treatment and two comparing terbutaline with placebo/no treatment (RR 1.11, 95% CI 0.91 to 1.35; 644 women). We observed no differences between betamimetics and placebo, no treatment or other tocolytics for perinatal mortality and morbidity outcomes. Some adverse effects such as tachycardia were more frequent in the betamimetics groups than the groups allocated to placebo, no treatment or another type of tocolytic. AUTHORS' CONCLUSIONS: Available evidence does not support the use of oral betamimetics for maintenance therapy after threatened preterm labour.

Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy.

BACKGROUND: Twin pregnancies are associated with a high risk of neonatal mortality and morbidity due to an increased rate of preterm birth. Betamimetics can decrease contraction frequency or delay preterm birth in singleton pregnancies by 24 to 48 hours. The efficacy of oral betamimetics in women with a twin pregnancy is unproven. OBJECTIVES: To assess the effectiveness of prophylactic oral betamimetics for the prevention of preterm labour and birth for women with twin pregnancies. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (31 January 2012), the Central Register of Controlled Trials (The Cochrane Library 2012, Issue 2), MEDLINE (January 1966 to 1 February 2012) and EMBASE (January 1985 to 1 February 2012). SELECTION CRITERIA: Randomised controlled trials in twin pregnancies comparing oral betamimetics with placebo or any intervention with the specific aim of preventing preterm birth. Quasi-randomised controlled trials, cluster-randomised trials and cross-over trials were not included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and trial quality. Two review authors extracted data. Data were checked for accuracy. MAIN RESULTS: Six trials (374 twin pregnancies) were included, but only five trials (344 twin pregnancies) contributed data. All trials compared oral betamimetics with placebo.Betamimetics reduced the incidence of preterm labour (one trial, 50 twin pregnancies, risk ratio (RR) 0.40; 95% confidence interval (CI) 0.19 to 0.86). However, betamimetics did not reduce preterm birth less than 37 weeks' gestation (four trials, 276 twin pregnancies, RR 0.85; 95% CI 0.65 to 1.10) or less than 34 weeks' gestation (one trial, 144 twin pregnancies, RR 0.47; 95% CI 0.15 to 1.50). Mean neonatal birthweight in the betamimetic group was significantly higher than in the placebo group (three trials, 478 neonates, mean difference 111.22 g; 95% CI 22.2 to 200.2). Nevertheless, there was no evidence of an effect of betamimetics in reduction of low birthweight (two trials, 366 neonates, average RR 1.19; 95% CI 0.77 to 1.85, random-effects) or small-for-gestational age neonates (two trials, 178 neonates, RR 0.92; 95% CI 0.52 to 1.65). Two trials (388 neonates) showed that betamimetics significantly reduced the incidence of respiratory distress syndrome but the difference was not significant when the analysis was adjusted for correlation of babies from twins. Three trials (452 neonates) showed no evidence of an effect of betamimetics in reducing neonatal mortality (RR 0.80; 95% CI 0.35 to 1.82). AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the use of prophylactic oral betamimetics for preventing preterm birth in women with a twin pregnancy.