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Molecules (Basel, Switzerland) Jan 2020Mammalian paraoxonase-1 hydrolyses a very broad spectrum of esters such as certain drugs and xenobiotics. The aim of this study was to determine whether carbamates...
Mammalian paraoxonase-1 hydrolyses a very broad spectrum of esters such as certain drugs and xenobiotics. The aim of this study was to determine whether carbamates influence the activity of recombinant PON1 (rePON1). Carbamates were selected having a variety of applications: bambuterol and physostigmine are drugs, carbofuran is used as a pesticide, while Ro 02-0683 is diagnostic reagent. All the selected carbamates reduced the arylesterase activity of rePON1 towards the substrate -phenyl thioacetate (PTA). Inhibition dissociation constants (), evaluated by both discontinuous and continuous inhibition measurements (progress curves), were similar and in the mM range. The rePON1 displayed almost the same values of constants for Ro 02-0683 and physostigmine while, for carbofuran and bambuterol, the values were approximately ten times lower and two times higher, respectively. The affinity of rePON1 towards the tested carbamates was about 3-40 times lower than that of PTA. Molecular modelling of rePON1-carbamate complexes suggested non-covalent interactions with residues of the rePON1 active site that could lead to competitive inhibition of its arylesterase activity. In conclusion, carbamates can reduce the level of PON1 activity, which should be kept in mind, especially in medical conditions characterized by reduced PON1 levels.
Topics: Acetates; Aryldialkylphosphatase; Carbamates; Carbofuran; Carboxylic Ester Hydrolases; Humans; Models, Molecular; Nitrophenols; Phenols; Terbutaline
PubMed: 31947900
DOI: 10.3390/molecules25010211 -
The Cochrane Database of Systematic... Apr 2013Traditionally inhaled treatment for asthma has used separate preventer and reliever therapies. The combination of formoterol and budesonide in one inhaler has made... (Meta-Analysis)
Meta-Analysis Review
Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children.
BACKGROUND
Traditionally inhaled treatment for asthma has used separate preventer and reliever therapies. The combination of formoterol and budesonide in one inhaler has made possible a single inhaler for both prevention and relief of symptoms (single inhaler therapy or SiT).
OBJECTIVES
To assess the efficacy and safety of budesonide and formoterol in a single inhaler for maintenance and reliever therapy in asthma compared with maintenance with inhaled corticosteroids (ICS) (alone or as part of current best practice) and any reliever therapy.
SEARCH METHODS
We searched the Cochrane Airways Group trials register in February 2013.
SELECTION CRITERIA
Parallel, randomised controlled trials of 12 weeks or longer in adults and children with chronic asthma. Studies had to assess the combination of formoterol and budesonide as SiT, against a control group that received inhaled steroids and a separate reliever inhaler.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by The Cochrane Collaboration.
MAIN RESULTS
We included 13 trials involving 13,152 adults and one of the trials also involved 224 children (which have been separately reported). All studies were sponsored by the manufacturer of the SiT inhaler. We considered the nine studies assessing SiT against best practice to be at a low risk of selection bias, but a high risk of detection bias as they were unblinded.In adults whose asthma was not well-controlled on ICS, the reduction in hospital admission with SiT did not reach statistical significance (Peto odds ratio (OR) 0.81; 95% confidence interval (CI) 0.45 to 1.44, eight trials, N = 8841, low quality evidence due to risk of detection bias in open studies and imprecision). The rates of hospital admission were low; for every 1000 people treated with current best practice six would experience a hospital admission over six months compared with between three and eight treated with SiT. The odds of experiencing exacerbations needing treatment with oral steroids were lower with SiT compared with control (OR 0.83; 95% CI 0.70 to 0.98, eight trials, N = 8841, moderate quality evidence due to risk of detection bias). For every 100 adults treated with current best practice over six months, seven required a course of oral steroids, whilst for SiT there would be six (95% CI 5 to 7). The small reduction in time to first severe exacerbation needing medical intervention was not statistically significant (hazard ratio (HR) 0.94; 95% CI 0.85 to 1.04, five trials, N = 7355). Most trials demonstrated a reduction in the mean total daily dose of ICS with SiT (mean reduction was based on self-reported data from patient diaries and ranged from 107 to 385 µg/day). Withdrawals due to adverse events were more common in people treated with SiT (OR 2.85; 95% CI 1.89 to 4.30, moderate quality evidence due to risk of detection bias).Three studies including 4209 adults compared SiT with higher dose budesonide maintenance and terbutaline for symptom relief. The studies were considered as low risk of bias. The run-in for these studies involved withdrawal of LABA, and patients were recruited who were symptomatic during run-in. The reduction in the odds of hospitalisation with SiT compared with higher dose ICS did not reach statistical significance (Peto OR; 0.56; 95% CI 0.28 to 1.09, moderate quality evidence due to imprecision). Fewer patients on SiT needed a course of oral corticosteroids (OR 0.54; 95% CI 0.45 to 0.64, high quality evidence). For every 100 adults treated with ICS over 11 months, 18 required a course of oral steroids, whilst for SiT there would be 11 (95% CI 9 to 12). Withdrawals due to adverse events were more common in people treated with SiT (OR 0.57; 95% CI 0.35 to 0.93, high quality evidence).One study included children (N = 224), in which SiT was compared with higher dose budesonide. There was a significant reduction in participants who needed an increase in their inhaled steroids with SiT, but there were only two hospitalisations for asthma and no separate data on courses of oral corticosteroids. Less inhaled and oral corticosteroids were used in the SiT group and the annual height gain was also 1 cm greater in the SiT group, (95% CI 0.3 cm to 1.7 cm).The results for fatal serious adverse events were too rare to rule out either treatment being harmful. There was no significant difference found in non-fatal serious adverse events for any of the comparisons.
AUTHORS' CONCLUSIONS
Single inhaler therapy has now been demonstrated to reduce exacerbations requiring oral corticosteroids against current best practice strategies and against a fixed higher dose of inhaled steroids. The strength of evidence that SiT reduces hospitalisation against these same treatments is weak. There were more discontinuations due to adverse events on SiT compared to current best practice, but no significant differences in serious adverse events. Our confidence in these conclusions is limited by the open-label design of the trials, and by the unknown adherence to treatment in the current best practice arms of the trials.Single inhaler therapy can reduce the risk of asthma exacerbations needing oral corticosteroids in comparison with fixed dose maintenance ICS and separate relief medication. The reduced odds of exacerbations with SiT compared with higher dose ICS should be viewed in the context of the possible impact of LABA withdrawal during study run-in. This may have made the study populations more likely to respond to SiT.Single inhaler therapy is not currently licensed for children under 18 years of age in the United Kingdom and there is currently very little research evidence for this approach in children or adolescents.
Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Adult; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Budesonide; Child; Chronic Disease; Drug Combinations; Ethanolamines; Formoterol Fumarate; Humans; Terbutaline
PubMed: 23633340
DOI: 10.1002/14651858.CD007313.pub3 -
Respiratory Medicine Apr 1996This open randomized, cross-over study compared the clinical efficacy and patient acceptability of the two bronchodilator delivery systems, terbutaline Turbuhaler (0.5... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
This open randomized, cross-over study compared the clinical efficacy and patient acceptability of the two bronchodilator delivery systems, terbutaline Turbuhaler (0.5 mg t.i.d.) and salbutamol Rotahaler (0.4 mg t.i.d.), each given for 3 weeks. Thirty-two adult asthmatics (21 males and 11 females with a mean age of 34 years) who demonstrated at least 15% reversibility in PEF or FEV1 in response to terbutaline, were enrolled for study. The median reversibility in FEV1 was 27.5% for the terbutaline-salbutamol group and 21% for the salbutamol-turbutaline group. Two patients discontinued during terbutaline treatment (one due to respiratory infection and one due to tachycardia, exhaustion and tremor) and five patients were lost to follow-up during salbutamol treatment, leaving data from 25 patients for an 'all patients treated' analysis. Mean morning PEF was 426 l min-1 during terbutaline and 410 l min-1 during salbutamol (difference 16 l min-1, 95% CI of difference 3-28 l min-1, P = 0.016), and mean evening PEF was 446 l min-1 during terbutaline and 428 l min-1 during salbutamol (difference 18 l min-1, 95% CI 5-30 l min-1, P = 0.0076). No significant differences were detected in diary symptom scores or in use of additional study drug during the day or night, and no serious adverse events were reported. When asked to state their treatment preferences on the basis of effects, side-effects and overall, more patients preferred Turbuhaler in each case, although no statistically significant differences were detected. In conclusion, terbutaline via Turbuhaler was significantly more effective than salbutamol via Rotahaler in controlling lung function (mean daily PEF) in adults with mild to moderate asthma, and it was the preferred treatment overall in 44% of patients, compared with 16% for Rotahaler (n.s.).
Topics: Adolescent; Adult; Albuterol; Asthma; Bronchodilator Agents; Cross-Over Studies; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Patient Satisfaction; Peak Expiratory Flow Rate; Terbutaline
PubMed: 8736653
DOI: 10.1016/s0954-6111(96)90288-7 -
Annals of Palliative Medicine Sep 2020The pathogenesis of chronic obstructive pulmonary disease (COPD) is complex. Our study aimed to investigate the clinical value of N-acetylcysteine (NAC) combined with...
Clinical value of N-acetylcysteine combined with terbutaline sulfate in elderly patients with chronic obstructive pulmonary disease and its effect on apoptosis/anti-apoptosis mechanism.
BACKGROUND
The pathogenesis of chronic obstructive pulmonary disease (COPD) is complex. Our study aimed to investigate the clinical value of N-acetylcysteine (NAC) combined with terbutaline sulfate in the treatment of COPD in elderly people, and its effect on the apoptosis/anti-apoptosis mechanism.
METHODS
A total of 126 elderly COPD patients in our hospital from December 2017 to June 2019 were recruited and divided into 3 groups. On the basis of conventional treatment, control group A was treated with NAC, control group B with terbutaline sulfate, and combined group with both drugs. Lung function, apoptosis/anti-apoptosis related indexes, oxidative stress indexes, COPD assessment test (CAT) score, 6-min walk distance (6MWD), blood gas indexes, and adverse reactions were measured.
RESULTS
The levels of forced vital capacity (FVC), maximum mid-expiratory flow rate (MMF), peak expiratory flow (PEF), oxygenation index (OI), and blood oxygen saturation (SaO2) in 3 groups were increased after treatment, and were the highest in the combined group. The level of carbon dioxide partial pressure (PaCO2) was decreased, and was the lowest in the combined group. After 2 weeks of treatment, the 6MWD had increased in all 3 groups and was longest in the combined group. The CAT score was decreased and the extent of decrease was the highest in the combined group. After treatment, the levels of Fas receptor/apoptosis antigen 1 (Fas/APO-1), soluble Fas (sFas), malondialdehyde (MDA), and reactive oxygen species (ROS) in the three groups were decreased, and their levels were decreased most markedly in the combined group. Meanwhile, the levels of superoxide dismutase (SOD) and glutathione peroxide enzyme (GSH-PX) were increased after treatment, and their levels were the highest in the combined group. The incidence of dizziness, chest tightness, constipation, and nasal congestion in the combination group were not significantly different from the other two groups.
CONCLUSIONS
The combined use of terbutaline sulfate and NAC in the treatment of elderly patients with COPD can effectively improve their lung function and blood gas status, which can strengthen athletic ability, reduce the oxidative stress response, and regulate apoptotic cytokines.
Topics: Acetylcysteine; Aged; Apoptosis; Humans; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Terbutaline
PubMed: 33065789
DOI: 10.21037/apm-20-1605 -
British Journal of Clinical Pharmacology May 1998To study the pharmacokinetics and bioavailability of the prodrug bambuterol and its bronchodilator moiety terbutaline in healthy subjects. (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
AIMS
To study the pharmacokinetics and bioavailability of the prodrug bambuterol and its bronchodilator moiety terbutaline in healthy subjects.
METHODS
Eight healthy subjects (four women) received intravenous doses of bambuterol and terbutaline. On a third occasion, they, plus another four subjects, ingested oral bambuterol as a single dose followed by repeated doses once daily for 7 days. Plasma concentrations and urinary excretion of bambuterol and terbutaline were measured.
RESULTS
After intravenous administration, renal clearances of bambuterol and terbutaline were similar (about 140 ml min(-1)), but there was a five-fold difference in total clearance (bambuterol 1.25 l min(-1), terbutaline 0.23 l min(-1)). Volume of distribution (Vss) was 1.6 l kg(-1) b.w. for both substances. A similar renal clearance of bambuterol was found during oral administration but that of terbutaline decreased (to about 120 ml min(-1)). Mean terminal half-life of bambuterol was 2.6 h after intravenous and 12 h after oral administration, implying that uptake was rate-limiting. Mean residence time of terbutaline generated from oral bambuterol was 34 h compared with 8.0 h when terbutaline as such was infused. Generated terbutaline had a bioavailability of 36% (28-46) after intravenous and 10.2% (6.1-13.2) after oral administration of the prodrug. Bambuterol was well tolerated. The mean activity of plasma cholinesterase, an enzyme catalyzing bambuterol metabolism, was inhibited between 30-60% during repeated oral dosing. It virtually regained original activity within 48 h after the last dose.
CONCLUSIONS
The plasma concentration ofterbutaline fluctuated little during repeated oral administration (mean peak: trough ratio 1.9), as a result of prolonged absorption of bambuterol and slow formation of terbutaline. Thus, the pharmacokinetic properties of bambuterol make it suitable for oral once-daily dosage.
Topics: Administration, Oral; Adult; Area Under Curve; Biological Availability; Bronchodilator Agents; Cholinesterases; Female; Gas Chromatography-Mass Spectrometry; Half-Life; Humans; Injections, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Prodrugs; Terbutaline
PubMed: 9643620
DOI: 10.1046/j.1365-2125.1998.00695.x -
Animal Cells and Systems 2017We examined the role of spinally located β-adrenergic receptors in the regulation of the blood glucose level. The intrathecal (i.t.) injections with dobutamine...
We examined the role of spinally located β-adrenergic receptors in the regulation of the blood glucose level. The intrathecal (i.t.) injections with dobutamine (β-adrenergic receptor agonist) or terbutaline (β-adrenergic receptor agonist) caused an elevation of the blood glucose level, whereas metoprolol (β-adrenergic receptor antagonist) or butoxamine (β-adrenergic receptor antagonist) did not. In addition, i.t. pretreatment with pertussis toxin (PTX) attenuated the hyperglycemic effect induced by dobutamine or terbutaline. Moreover, plasma insulin level was increased by dobutamine but not by terbutaline, and PTX reduced dobutamine-induced up-regulation of the plasma insulin level. Terbutaline significantly increased plasma corticosterone level, and PTX further enhanced terbutaline-induced corticosterone level. Furthermore, intraperitoneal (i.p.) pretreatment with hexamethonium- (a preganglionic blocker) attenuated dobutamine- and terbutaline-induced hyperglycemic effects. Our results suggest that activation of spinal β- and β-adrenergic receptors produces hyperglycemic effects in a different manner. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by terbutaline. Furthermore, dobutamine- or terbutaline-induced hyperglycemia appears to be mediated through the spinal nerves.
PubMed: 30460079
DOI: 10.1080/19768354.2017.1345788 -
Journal of Applied Physiology... Nov 2013Repeated injury of the airway epithelium caused by hyperpnoea of poorly conditioned air has been proposed as a key factor in the pathogenesis of exercise-induced... (Randomized Controlled Trial)
Randomized Controlled Trial
Repeated injury of the airway epithelium caused by hyperpnoea of poorly conditioned air has been proposed as a key factor in the pathogenesis of exercise-induced bronchoconstriction (EIB) in athletes. In animals, the short-acting β2-agonist terbutaline has been shown to reduce dry airflow-induced bronchoconstriction and the associated shedding of airway epithelial cells. Our aim was to test the efficacy of inhaled terbutaline in attenuating hyperpnoea-induced bronchoconstriction and airway epithelial injury in athletes. Twenty-seven athletes with EIB participated in a randomized, double-blind, placebo-controlled, crossover study. Athletes completed an 8-min eucapnic voluntary hyperpnoea (EVH) test with dry air on two separate days 15 min after inhaling 0.5 mg terbutaline or a matching placebo. Forced expiratory volume in 1 s (FEV1) and urinary concentration of the club cell (Clara cell) protein 16 (CC16, a marker of airway epithelial perturbation) were measured before and up to 60 min after EVH. The maximum fall in FEV1 of 17 ± 8% (SD) on placebo was reduced to 8 ± 5% following terbutaline (P < 0.001). Terbutaline gave bronchoprotection (i.e., post-EVH FEV1 fall <10%) to 22 (81%) athletes. EVH caused an increase in urinary excretion of CC16 in both conditions (P < 0.001), and terbutaline significantly reduced this rise (pre- to postchallenge CC16 increase 416 ± 495 pg/μmol creatinine after placebo vs. 315 ± 523 pg/μmol creatinine after terbutaline, P = 0.016). These results suggest that the inhalation of a single therapeutic dose of terbutaline offers significant protection against hyperpnoea-induced bronchoconstriction and attenuates acute airway epithelial perturbation in athletes.
Topics: Administration, Inhalation; Adolescent; Adult; Asthma, Exercise-Induced; Athletes; Bronchoconstriction; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; England; Female; Forced Expiratory Volume; Humans; Hyperventilation; Lung; Male; Pulmonary Ventilation; Respiratory Mucosa; Terbutaline; Time Factors; Treatment Outcome; Uteroglobin; Young Adult
PubMed: 24030662
DOI: 10.1152/japplphysiol.00716.2013 -
The Journal of Physiological Sciences :... Feb 2021Currently available tocolytic agents are not effective treatment for preterm labor beyond 48 h. A major reason is the development of maternal side effects which...
BACKGROUND
Currently available tocolytic agents are not effective treatment for preterm labor beyond 48 h. A major reason is the development of maternal side effects which preclude the maintenance of an effective steady-state drug concentration. One strategy that can mitigate these side effects is utilizing synergistic drug combinations to reduce the drug concentrations necessary to elicit a clinical effect. We have previously shown that three anoctamin 1 (ANO1) antagonists mediate potent relaxation of precontracted human uterine smooth muscle (USM). In this study, we aimed to determine whether a combination of sub-relaxatory doses of tocolytic drugs in current clinical use [the L-type voltage-gated calcium channel (VGCC) blocker, nifedipine (NIF); and the β-adrenergic (β2AR) agonist, terbutaline (TRB)] will potentiate USM relaxation with two ANO1 antagonists [benzbromarone (BB) and MONNA (MN)].
OBJECTIVE
This study sought to examine the synergistic potency and mechanistic basis of two ANO1 antagonists with currently available tocolytic drugs. Functional endpoints assessed included relaxation of pre-contracting pregnant human USM tissue, inhibition of intracellular calcium release, and reduction of spontaneous transient inward current (STIC) recordings in human uterine smooth muscle cells.
METHODS
Human myometrial strips and primary human USM cells were used in organ bath and calcium flux experiments with different combinations of sub-threshold doses of ANO1 antagonists and terbutaline or nifedipine to determine if ANO1 antagonists potentiate tocolytic drugs.
RESULTS
The combination of sub-threshold doses of two ANO1 antagonists and current tocolytic drugs demonstrate a significant degree of synergy to relax human pregnant USM compared to the effects achieved when these drugs are administered individually.
CONCLUSION
A combination of sub-threshold doses of VGCC blocker and β2AR agonist with ANO1 antagonists potentiates relaxation of oxytocin-induced contractility and calcium flux in human USM ex vivo. Our findings may serve as a foundation for novel tocolytic drug combinations.
Topics: Anoctamin-1; Benzbromarone; Female; Gene Expression Regulation; Humans; Muscle Relaxation; Muscle, Smooth; Nifedipine; Pregnancy; Terbutaline; Tissue Culture Techniques; Tocolytic Agents; Uricosuric Agents; Uterus; ortho-Aminobenzoates
PubMed: 33618673
DOI: 10.1186/s12576-021-00792-3 -
The Cochrane Database of Systematic... Jun 2014Preterm birth, defined as birth between 20 and 36 completed weeks, is a major contributor to perinatal morbidity and mortality globally. Oxytocin receptor antagonists... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Preterm birth, defined as birth between 20 and 36 completed weeks, is a major contributor to perinatal morbidity and mortality globally. Oxytocin receptor antagonists (ORA), such as atosiban, have been specially developed for the treatment of preterm labour. ORA have been proposed as effective tocolytic agents for women in preterm labour to prolong pregnancy with fewer side effects than other tocolytic agents.
OBJECTIVES
To assess the effects on maternal, fetal and neonatal outcomes of tocolysis with ORA for women with preterm labour compared with placebo or any other tocolytic agent.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 December 2013).
SELECTION CRITERIA
We included all randomised controlled trials (published and unpublished) of ORA for tocolysis of labour between 20 and 36 completed weeks' gestation.
DATA COLLECTION AND ANALYSIS
Two review authors independently evaluated methodological quality and extracted trial data. When required, we sought additional data from trial authors. Results are presented as risk ratio (RR) for categorical and mean difference (MD) for continuous data with the 95% confidence intervals (CI). Where appropriate, the number needed to treat for benefit (NNTB) and the number needed to treat for harm (NNTH) were calculated.
MAIN RESULTS
This review update includes eight additional studies (790 women), giving a total of 14 studies involving 2485 women.Four studies (854 women) compared ORA (three used atosiban and one barusiban) with placebo. Three studies were considered at low risk of bias in general (blinded allocation to treatment and intervention), the fourth study did not adequately blind the intervention. No difference was shown in birth less than 48 hours after trial entry (average RR 1.05, 95% CI 0.15 to 7.43; random-effects, (two studies, 152 women), perinatal mortality (RR 2.25, 95% CI 0.79 to 6.38; two studies, 729 infants), or major neonatal morbidity. ORA (atosiban) resulted in a small reduction in birthweight (MD -138.86 g, 95% CI -250.53 to -27.18; two studies with 676 infants). In one study, atosiban resulted in an increase in extremely preterm birth (before 28 weeks' gestation) (RR 3.11, 95% CI 1.02 to 9.51; NNTH 31, 95% CI 8 to 3188) and infant deaths (up to 12 months) (RR 6.13, 95% CI 1.38 to 27.13; NNTH 28, 95% CI 6 to 377). However, this finding may be confounded due to randomisation of more women with pregnancy less than 26 weeks' gestation to atosiban. ORA also resulted in an increase in maternal adverse drug reactions requiring cessation of treatment in comparison with placebo (RR 4.02, 95% CI 2.05 to 7.85; NNTH 12, 95% CI 5 to 33). No differences were shown in preterm birth less than 37 weeks' gestation or any other adverse neonatal outcomes. No differences were evident by type of ORA, although data were limited.Eight studies (1402 women) compared ORA (atosiban only) with betamimetics; four were considered of low risk of bias (blinded allocation to treatment and to intervention). No statistically significant difference was shown in birth less than 48 hours after trial entry (RR 0.89, 95% CI 0.66 to 1.22; eight studies with 1389 women), very preterm birth (RR 1.70, 95% CI 0.89 to 3.23; one study with 145 women), extremely preterm birth (RR 0.84, 95% CI 0.37 to 1.92; one study with 244 women) or perinatal mortality (RR 0.55, 95% CI 0.21 to 1.48; three studies with 816 infants). One study (80 women), of unclear methodological quality, showed an increase in the interval between trial entry and birth (MD 22.90 days, 95% CI 18.03 to 27.77). No difference was shown in any reported measures of major neonatal morbidity (although numbers were small). ORA (atosiban) resulted in less maternal adverse effects requiring cessation of treatment (RR 0.05, 95% CI 0.02 to 0.11; NNTB 6, 95% CI 6 to 6; five studies with 1161 women).Two studies including (225 women) compared ORA (atosiban) with calcium channel blockers (CCB) (nifedipine only). The studies were considered as having high risk of bias as neither study blinded the intervention and in one study it was not known if allocation was blinded. No difference was shown in birth less than 48 hours after trial entry (average RR 1.09, 95% CI 0.44 to 2.73, random-effects; two studies, 225 women) and extremely preterm birth (RR 2.14, 95% CI 0.20 to 23.11; one study, 145 women). No data were available for the outcome of perinatal mortality. One small trial (145 women), which did not employ blinding of the intervention, showed an increase in the number of preterm births (before 37 weeks' gestation) (RR 1.56, 95% CI 1.13 to 2.14; NNTH 5, 95% CI 3 to 19), a lower gestational age at birth (MD -1.20 weeks, 95% CI -2.15 to -0.25) and an increase in admission to neonatal intensive care unit (RR 1.70, 95% CI 1.17 to 2.47; NNTH 5, 95% CI 3 to 20). ORA (atosiban) resulted in less maternal adverse effects (RR 0.38, 95% CI 0.21 to 0.68; NNTB 6, 95% CI 5 to 12; two studies, 225 women) but not maternal adverse effects requiring cessation of treatment (RR 0.36, 95% CI 0.01 to 8.62; one study, 145 women). No longer-term outcome data were included.
AUTHORS' CONCLUSIONS
This review did not demonstrate superiority of ORA (largely atosiban) as a tocolytic agent compared with placebo, betamimetics or CCB (largely nifedipine) in terms of pregnancy prolongation or neonatal outcomes, although ORA was associated with less maternal adverse effects than treatment with the CCB or betamimetics. The finding of an increase in infant deaths and more births before completion of 28 weeks of gestation in one placebo-controlled study warrants caution. However, the number of women enrolled at very low gestations was small. Due to limitations of small numbers studied and methodological quality, further well-designed randomised controlled trials are needed. Further comparisons of ORA versus CCB (which has a better side-effect profile than betamimetics) are needed. Consideration of further placebo-controlled studies seems warranted. Future studies of tocolytic agents should measure all important short- and long-term outcomes for women and infants, and costs.
Topics: Albuterol; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Obstetric Labor, Premature; Oligopeptides; Pregnancy; Randomized Controlled Trials as Topic; Receptors, Oxytocin; Ritodrine; Terbutaline; Tocolytic Agents; Vasotocin
PubMed: 24903678
DOI: 10.1002/14651858.CD004452.pub3 -
British Journal of Pharmacology Apr 19991. The effect of the alpha2-adrenoceptor agonist, terbutaline, was investigated on simultaneously measured force and intracellular free calcium ([Ca2+]i) in intact rat...
1. The effect of the alpha2-adrenoceptor agonist, terbutaline, was investigated on simultaneously measured force and intracellular free calcium ([Ca2+]i) in intact rat soleus muscle fibres, and on contractile protein function and Ca2+ content of the sarcoplasmic reticulum (SR) in skinned fibres. 2. Terbutaline (10 microM) had no significant effect on either resting force or [Ca2+]i. Exposure to terbutaline increased both the integral of the indo-1 ratio transient and peak twitch force by 37%. 3. At sub-maximal (10 Hz) stimulation frequencies, terbutaline accelerated force relaxation but had highly variable effects on tetanic force amplitude. The corresponding indo-1 ratio transients were significantly larger, and faster to decay than the controls. 4. Terbutaline increased tetanic force at near maximal stimulation frequencies (50 Hz) by increasing tetanic [Ca2+]i. Force relaxation was accelerated at this frequency with no significant change in the indo-1 ratio transient decay rate. 5. All of terbutaline's effects on force and indo-1 ratio transients in intact fibres were completely blocked and reversed by ICI 118551 (1 microM). 6. Mechanically skinned fibres isolated from intact muscles pre-treated with terbutaline showed no significant changes in SR Ca2+ content, myofilament [Ca2+]i-sensitivity or maximum force generating capacity. 7. The results suggest that terbutaline primarily modulates force by altering the amplitude and decay rate of the [Ca2+]i transient via phosphorylation of both the ryanodine receptor (RR) and the SR pump regulatory protein, phospholamban (PLB). The high variability of responses of slow-twitch muscles to beta2-agonists probably reflects individual differences in basal phosphorylation levels of PLB relative to that of RR.
Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Calcium; Drug Interactions; In Vitro Techniques; Male; Muscle Contraction; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Propanolamines; Rats; Rats, Wistar; Sarcoplasmic Reticulum; Terbutaline
PubMed: 10372813
DOI: 10.1038/sj.bjp.0702482