Reduced Environmental Impact of the Reusable Respimat® Soft Mist™ Inhaler Compared with Pressurised Metered-Dose Inhalers.

INTRODUCTION: Pressurised metered-dose inhalers (pMDIs) are associated with global warming potential values as they contain a hydrofluoroalkane (HFA) propellant, whereas the Respimat® Soft Mist™ inhaler is propellant-free. The original disposable Respimat has recently been updated to provide a reusable device that is similar in performance and use but is more convenient to patients and reduces environmental impact. This study compared the product carbon footprint (PCF) of Respimat (both disposable and reusable) and pMDIs to understand life cycle hotspots, and also to determine the potential quantitative environmental benefits of a reusable Respimat product. METHODS: PCFs of four inhalation products-tiotropium bromide (Spiriva®) Respimat, ipratropium bromide/fenoterol hydrobromide (Berodual®) Respimat, Berodual HFA pMDI and ipratropium bromide (Atrovent®) HFA pMDI-were assessed across their whole life cycle. RESULTS: Data show that Respimat inhalers have a lower PCF (carbon dioxide equivalent per kilogram) than HFA pMDIs: pMDI Atrovent 14.59; pMDI Berodual 16.48; disposable Spiriva Respimat 0.78; disposable Berodual Respimat 0.78. Approximately 98% of the pMDI life cycle total is due to HFA propellant emissions during use and end-of-life phases. The impact of the material used for the Respimat product outweighs the impact of the material used to make the empty cartridge. Furthermore, compared with the single-use device over 1 month, the PCF of Spiriva Respimat was further reduced by 57% and 71% using the device with refill cartridges over 3 and 6 months, respectively. CONCLUSION: Together, these data suggest that Respimat inhalers, and in particular the new reusable inhaler, can reduce the environmental impact associated with inhaler use. FUNDING: Boehringer Ingelheim.

Drug exposure and the risk of multiple sclerosis: A systematic review.

BACKGROUND: Several environmental and lifestyle factors have been associated with multiple sclerosis (MS) risk, including some pharmacological treatments. We systematically reviewed the literature on prescription drug exposure and MS risk. METHODS: Six databases were searched for original observational studies reporting drug exposure and MS risk published before 2017. RESULTS: Thirteen articles fulfilled inclusion criteria. Exposure to neither amiloride nor valproic acid was associated with MS (adjusted hazard ratio (adj.HR = 1.34;95% CI:0.81-2.20; adj.HR = 1.30;95%CI:0.44-3.80, respectively). Four studies explored oral contraceptive exposure and reported no association with MS; while a single study found an increased risk (odds ratio [adj.OR] = 1.52;95%CI:1.21-1.91). While penicillin exposure was associated with reduced risk of developing MS (adj.OR = 0.5;95%CI:0.3-0.9), a later study observed an elevated risk for penicillin (adj.OR = 1.21;95%CI:1.10-1.27) and all antibiotics (adj.OR = 1.41;95%CI:1.29-1.53), which was potentially attributed to underlying infection. Anti-tumor necrosis factor-alpha (TNFα) was not associated with MS risk in persons with inflammatory bowel disease (standard morbidity ratio = 4.2;95%CI:0.1-23.0) and arthritis (standardized incidence ratio = 1.38;95%CI:0.69-2.77); however, men exposed to anti-TNFα who also had arthritis and individuals with ankylosing spondylitis were at an increased risk (standardized incidence ratios = 3.91;95%CI:1.47-10.42 and 3.48;95%CI:1.45-8.37, respectively). A reduced risk of MS was observed with exposure to the beta2-adrenergic agonist fenoterol (adj.OR = 0.58;95%CI:0.45-0.76), and the sedating histamine 1-receptor antagonists (adj.OR = 0.2;95%CI:0.1-0.8), but not the non-sedating equivalent (adj.OR = 0.8;95%CI:0.4-1.6). CONCLUSIONS: The suggestion that some drugs may prevent MS is intriguing and warrants further study. In addition, further pharmacovigilance is needed to assess the safety of anti-TNFα drugs in specific populations in the context of MS risk.

Cholesterol regulates contractility and inotropic response to ß2-adrenoceptor agonist in the mouse atria: Involvement of Gi-protein-Akt-NO-pathway.

Majority of cardiac ß2-adrenoceptors is located in cholesterol-rich microdomains. Here, we have investigated the underlying mechanisms by which a slight to moderate cholesterol depletion with methyl-ß-cyclodextrin (MßCD, 1 and 5mM) interferes with contractility and inotropic effect of ß2-adrenergic agonist (fenoterol, 50µM) in the mouse atria. Treatment with MßCD itself increased amplitude of Ca2+ transient but did not change the contraction amplitude due to a clamping action of elevated NO. Cholesterol depletion significantly attenuated the positive inotropic response to fenoterol which is accompanied by increase in NO generation and decrease in Ca2+ transient. Influence of 1mM MßCD on the fenoterol-driven changes in both contractility and NO level was strongly attenuated by inhibition of Gi-protein (pertussis toxin), Akt (Akt 1/2 kinase inhibitor) or NO-synthase (L-NAME). After exposure to 5mM MßCD, pertussis toxin or Akt inhibitor could recover the ß2-agonist effects on contractility, NO production and Ca2+ transient, while L-NAME only reduced NO level. An adenylyl cyclase activator (forskolin, 50nM) had no influence on the MßCD-induced changes in the ß2-agonist effects. Obtained results suggest that slight cholesterol depletion upregulates Gi-protein/Akt/NO-synthase signaling that attenuates the positive inotropic response to ß2-adrenergic stimulation without altering the Ca2+ transient. Whilst moderate cholesterol depletion additionally could suppress the enhancement of the Ca2+ transient amplitude caused by the ß2-adrenergic agonist administration in Gi-protein/Akt-dependent but NO-independent manner.

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.

The T/QRS ratio values in pregnancies complicated by threatened preterm labour treated with intravenous infusions of fenoterol.

AIMS: To evaluate values of foetal T/QRS ratios in pregnancies complicated by threatened preterm labour treated with intravenous infusions of fenoterol using non-invasive methods with transabdominal electrodes. MATERIALS AND METHODS: The study group consisted of 451 Caucasian women (63 preterm pregnancies and 327 healthy controls) whose pregnancies ranged from 28 to 37 gestational weeks. Foetal electrocardiograms were recorded and T/QRS ratios were calculated by KOMPOREL software (ITAM, Zabrze, Poland). The first recording was performed 30 min after the start of fenoterol infusion and the second 2 days after finishing tocolysis. T/QRS ratio variables were calculated. One-way analysis of variance was carried out. RESULTS: Significantly higher mean values of the T/QRS ratio were observed in pregnancies during tocolytic treatment in comparison to controls and pregnancies after tocolysis (P=0.0158 and P=0.0071, respectively). The T/QRS ratio values fall again shortly after finishing intravenous tocolysis. CONCLUSIONS: The T/QRS ratio is one of the methods used for non-invasive foetal distress assessment that can be used in antepartum foetal monitoring in complicated pregnancies. Raised values of the T/QRS ratio in the foetus during tocolysis with fenoterol and next its fall to values observed in physiological pregnancies may indicate transient worsening of fetal well-being, however, additional research is required.

Efectividad del tratamiento de la amenaza de parto pretérmimo con progesterona natural micronizada / Effectiveness of treatment of threatened labor preterm micronized natural progesterone

Objetivo: Evaluar la efectividad de la progesterona natural micronizada administrada vía oral y del fenoterol administrado vía endovenosa, en el tratamiento de las pacientes con diagnóstico de amenaza de parto pretérmino. Métodos: Estudio experimental tipo ensayo terapéutico en pacientes que acudieron al Hospital Universitario de Caracas. Resultados: 15 pacientes del grupo estudio con progesterona presentaron resultados satisfactorios (X² = 155,837, df = 18); del grupo control, 13 pacientes con resultados satisfactorios (X² = 133,093, df = 18). La efectividad absoluta en el grupo de estudio fue de 0,68 contra 0,59 del grupo control (X² = 0,393; df = 1; P < 0,531). Conclusiones: Los tratamientos con progesterona natural micronizada y fenoterol demostraron ser inhibitorios de la dinámica uterina, a partir de la segunda hora de iniciado el tratamiento, evitando su progreso hacia trabajo de parto en un 90 %. La progesterona natural micronizada es efectiva en el tratamiento de la amenaza de parto pretérmino y se debe considerar su uso como alternativa terapéutica.

Objective: To evaluate the effectiveness of micronized natural progesterone administered orally and intravenously administered fenoterol in the treatment of patients with a diagnosis of preterm labor. Method: The type of therapeutic trial in patients attended at the Hospital Universitario de Caracas. Results: 15 patients in the progesterone study showed satisfactory results (X² = 155.837 df = 18); the control group, 13 patients with satisfactory results (X² = 133.093 df = 18). The absolute effectiveness in the study group was 0.68 against 0.59 in the control group (X² = 0.393 df = 1, P < 0.531). Conclusions: Treatment with micronized natural progesterone and fenoterol proved inhibitory uterine dynamics from the second hour of starting treatment preventing its progress toward labor by 90 %. The micronized natural progesterone is effective in the treatment of preterm labor and should be considered as an alternative therapeutic use.

[Tocolysis in preterm labour--current recommendations]. / Tokoliza w porodzie przedwczesnym--aktualne wytyczne.

Common use of tocolytic drugs in preterm labor has not been shown to reduce the rate of neonatal mortality and morbidity Currently tocolytics should be administered in the course of a 48-h administration of antepartum glucocorticoids and/or transfer of the gravida to a center with neonatal intensive care unit. Only oxytocin receptor antagonist--atosiban and short-acting beta-agonists--fenoterol are licensed to reduce preterm uterine activity Owing to its safety and efficacy atosiban should be the first-choice tocolytic, especially in women with other diseases or multiple gestations.

(R,R')-4'-methoxy-1-naphthylfenoterol targets GPR55-mediated ligand internalization and impairs cancer cell motility.

(R,R')-4'-Methoxy-1-naphthylfenoterol (MNF) promotes growth inhibition and apoptosis of human HepG2 hepatocarcinoma cells via cannabinoid receptor (CBR) activation. The synthetic CB1R inverse agonist, AM251, has been shown to block the anti-mitogenic effect of MNF in these cells; however, AM251 is also an agonist of the recently deorphanized, lipid-sensing receptor, GPR55, whose upregulation contributes to carcinogenesis. Here, we investigated the role of MNF in GPR55 signaling in human HepG2 and PANC-1 cancer cell lines in culture by focusing first on internalization of the fluorescent ligand Tocrifluor 1117 (T1117). Initial results indicated that cell pretreatment with GPR55 agonists, including the atypical cannabinoid O-1602 and l-α-lysophosphatidylinositol, dose-dependently reduced the rate of cellular T1117 uptake, a process that was sensitive to MNF inhibition. GPR55 internalization and signaling mediated by O-1602 was blocked by MNF in GPR55-expressing HEK293 cells. Pretreatment of HepG2 and PANC-1 cells with MNF significantly abrogated the induction of ERK1/2 phosphorylation in response to AM251 and O-1602. Moreover, MNF exerted a coordinated negative regulation of AM251 and O-1602 inducible processes, including changes in cellular morphology and cell migration using scratch wound healing assay. This study shows for the first time that MNF impairs GPR55-mediated signaling and, therefore, may have therapeutic potential in the management of cancer.

In vitro synthesis and characterisation of three fenoterol sulfoconjugates detected in fenoterol post-administration urine samples.

Fenoterol, a fast-acting ß2-adrenergic agonist, is used in the therapy of obstructive pulmonary diseases and for the inhibition of premature labour obstetrics. Doping control for ß2-agonists, which are prohibited in sports by the World Anti-Doping Agency, is commonly performed by liquid chromatography/mass spectrometry after hydrolysis of phase II metabolites. The continuing development of analytical procedures has led to direct injection of urine samples without sample preparation becoming a viable tool. For the detection of substances without sample preparation, including hydrolysis, detailed information of the phase II metabolism of the substances is essential. In this study, human S9 fractions of different tissues and two recombinant sulfotransferases were investigated for their potential to form fenoterol sulfoconjugates, which were characterised in detail. Two mono-sulfoconjugates and one bis-sulfoconjugate were synthesised and their structures confirmed by liquid chromatography­high-resolution/high-accuracy mass spectrometry. All of the metabolites were identified as esterified phenolic compounds. Excretion studies with orally and inhalatively administered fenoterol proved the occurrence of the sulfoconjugates in vivo. Inhalatively administered fenoterol resulted in the detection of the two monosulfoconjugates in low amounts in urine due to the lower inhalation dose of fenoterol compared to the oral dose. After oral uptake of fenoterol, the two mono-sulfoconjugates and a fenoterol bis-sulfoconjugate were detected in urine. This is the first report of the bis-sulfoconjugate.

Factors affecting the stability and performance of ipratropium bromide; fenoterol hydrobromide pressurized-metered dose inhalers.

The aim of the study was to investigate the factors affecting the stability and performance of ipratropium bromide and fenoterol hydrobromide in a pressurized-metered dose inhaler (pMDI). A factorial design was applied to investigate the effects of three parameters (propellant, water, and ethanol) on the performance of 27 designed formulations of a solution-based pMDI. The formulations that contained a hydrofluoroalkane (HFA) propellant lower than 72% v/v and an ethanol concentration higher than 27% v/v remained as clear solutions. Nine formulations that contained the HFA propellant higher than 74% v/v precipitated. The results indicated that it was not only the HFA propellant content of the formulations that was related to the formulation instability but also ethanol content. Only six formulations from the 18 formulations, that did not precipitate, produced drug contents that were within the acceptable range (80-120%). These six formulations generated aerosols with mass median aerodynamic diameters (MMAD) of approximately 2 µm with a fine particle fraction (FPF; particle size, <6.4 µm) between 45% and 52%. The MMAD and FPF did not change significantly after 6 months of storage (P > 0.05).

48-hours administration of fenoterol in spontaneous preterm labor - does it affect fetal preload?

OBJECTIVE: to investigate whether any changes in the preload index (PLI) occur within the first 48 hours of fenoterol intravenous tocolysis. MATERIAL AND METHODS: Doppler evaluation of placental and fetal circulation was performed in 36 pregnant women prior to fenoterol administration and after 24/48 hours. Measurements were obtained from a longitudinal section of the inferior vena cava (IVC) and preload index was calculated. To determine changes over time, an all study variable analysis of variance (ANOVA) for repeated measurements, followed by Tukey-Kramer's multiple comparison test was used. The effects of additional clinical covariates were checked. RESULTS: The maternal heart rate values were significantly increased after 24 hours and 48 hours in comparison to pre-treatment values. No significant changes in fetal heart rate were observed during treatment. The fetal IVC PLI values were significantly reduced after 24 hours and 48 hours of treatment. The increase in PLI values when comparing 24 and 48 hours results were not statistically significant. These observations were consistent with ANOVA post-hoc analysis. CONCLUSIONS: 48 hours intravenous administration of fenoterol appears not to alter inferior vena cava blood flow by itself. The reduction in PLI values may reflect lower fetal preload conditions during the course of successful tocolytic treatment. Therefore, Doppler IVC PLI measurement should be considered as a possible additional assessment method of effectiveness of treatment. However, other Doppler venous blood flow parameters should be assessed to confirm the results and clarify whether maternal corticosteroids administration may be interfering with the results.

48-hours administration of fenoterol in spontaneous preterm labor - Doppler blood flow assessment of placental and fetal circulation.

OBJECTIVES: The aims were to investigate whether any changes in placental and fetal circulation were observed during fenoterol tocolysis within the first 48 hours of therapy. MATERIAL AND METHODS: Doppler evaluation of placental and fetal circulation was performed prior to fenoterol administration and then after 24 and 48 hours. Maternal heart rate and pulsatility index (PI) in uterine arteries were assessed. FHR, RI and PI of umbilical artery and middle cerebral artery were measured. E/A ratio for A-V valves, the myocardial performance index (MPI) and shortening fraction (SF) were calculated for both ventricles independently. The blood flow pattern in DV was assessed using PI, S/a ratio and peak velocity index for the vein. To determine changes over time in all study variable analysis of variance (ANOVA) for repeated measurements followed by Tukey-Kramer's multiple comparison test was used. The effects of additional clinical covariates were checked. RESULTS: Uterine and fetal arterial blood flow patterns were not altered significantly during 48 hours of tocolysis. No significant changes were observed in fetal cardiac function parameters as well. The evaluation of Doppler parameters in the DV revealed a significant increase in PVIV after 48 hours. Additionally after 48 hours of successful tocolysis S/a ratio values were significantly lower. CONCLUSIONS: Short term intravenous administration of fenoterol seems not to alter uterine and fetal arterial blood flow pattern. Direct fetal cardiac function remained unaffected. However significant changes of selected Doppler parameters in DV may suggest further studies should be performed to assess more precisely fetal venous blood flow.

[Paradoxical reaction to salbutamol in an asthma patient]. / Reactie paradoxala la salbutamol la un pacient astmatic.

Bronchial asthma is a disease with increasing incidence worldwide, being an important cause of morbidity and mortality. The diagnosis and management of the disease are subject to international guidelines, GINA being updated periodically, according to the latest findings about the disease. The recommendations include the use in all severity stages of short acting beta-2-agonists as reliever of asthma symptoms. We present the case of an asthma patient presenting a life-threatening paradoxical bronchospasm at salbutamol, as well as discussions on the possible pathogenesis of this situation. Paradoxical bronchospasm to salbutamol is a rare situation but can turn into a serious problem for the patient, as well as for the physicians who underestimate this possibility.

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.

Semi-automated in vivo solid-phase microextraction sampling and the diffusion-based interface calibration model to determine the pharmacokinetics of methoxyfenoterol and fenoterol in rats.

In vivo solid-phase microextraction (SPME) can be used to sample the circulating blood of animals without the need to withdraw a representative blood sample. In this study, in vivo SPME in combination with liquid-chromatography tandem mass spectrometry (LC-MS/MS) was used to determine the pharmacokinetics of two drug analytes, R,R-fenoterol and R,R-methoxyfenoterol, administered as 5 mg kg(-1) i.v. bolus doses to groups of 5 rats. This research illustrates, for the first time, the feasibility of the diffusion-based calibration interface model for in vivo SPME studies. To provide a constant sampling rate as required for the diffusion-based interface model, partial automation of the SPME sampling of the analytes from the circulating blood was accomplished using an automated blood sampling system. The use of the blood sampling system allowed automation of all SPME sampling steps in vivo, except for the insertion and removal of the SPME probe from the sampling interface. The results from in vivo SPME were compared to the conventional method based on blood withdrawal and sample clean up by plasma protein precipitation. Both whole blood and plasma concentrations were determined by the conventional method. The concentrations of methoxyfenoterol and fenoterol obtained by SPME generally concur with the whole blood concentrations determined by the conventional method indicating the utility of the proposed method. The proposed diffusion-based interface model has several advantages over other kinetic calibration models for in vivo SPME sampling including (i) it does not require the addition of a standard into the sample matrix during in vivo studies, (ii) it is simple and rapid and eliminates the need to pre-load appropriate standard onto the SPME extraction phase and (iii) the calibration constant for SPME can be calculated based on the diffusion coefficient, extraction time, fiber length and radius, and size of the boundary layer. In the current study, the experimental calibration constants of 338.9±30 mm(-3) and 298.5±25 mm(-3) are in excellent agreement with the theoretical calibration constants of 307.9 mm(-3) and 316.0 mm(-3) for fenoterol and methoxyfenoterol respectively.

[Right ventricular hypertrophic cardiomyopathy in the fetus --may it be caused by chronic oral tocolysis with fenoterol?]. / Kardiomiopatia przerostowa prawej komory u plodu--czy przewlekla doustna tokoliza fenoterolem moze byc jej przyczyna?

The use of fenoterol in the treatment of preterm labor is associated with the risk of many complications in the mother and the fetus. We present a case of a multipara treated with oral fenoterol due to threatening preterm labor 14 weeks. At 35 weeks of gestation the fetus was diagnosed with hypertrophic cardiomyopathy with severe impairment of the right ventricle. The only factor that might have caused such a state of the fetal circulatory system was fenoterol, used from 21 weeks of gestation. After the withdrawal of the fenoterol the fetal right ventricular function improved gradually. However fetal cardiac hypertrophy persisted until the birth at 39 weeks of gestation. Concentric hypertrophy of the right ventricular wall and interventricular septum were confirmed in the newborn.

Anticholinergic therapy for acute asthma in children.

BACKGROUND: Inhaled anticholinergics as single agent bronchodilators (or in combination with beta(2)-agonists) are one of the several medications available for the treatment of acute asthma in children. OBJECTIVES: To determine the effectiveness of only inhaled anticholinergic drugs (i.e. administered alone), compared to a control in children over the age of two years with acute asthma. SEARCH METHODS: The Cochrane Register of Controlled Trials (CENTRAL), and the Cochrane Airways Group Register of trials were searched by the Cochrane Airways Group. The latest search was performed in April 2011. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) in which inhaled anticholinergics were given as single therapy and compared with placebo or any other drug or drug combinations for children over the age of two years with acute asthma. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, extracted data and assessed trial quality. MAIN RESULTS: Six studies met the inclusion criteria but were limited by small sample sizes, various treatment regimes used and outcomes assessed. The studies were overall of unclear quality. Data could only be pooled for the outcomes of treatment failure and hospitalisation. Other data could not be combined due to divergent outcome measurements. Meta-analysis revealed that children who received anticholinergics alone were significantly more likely to have treatment failure compared to those who received beta(2)-agonists from four trials on 171 children (odds ratio (OR) 2.27; 95% CI 1.08 to 4.75). Also, treatment failure on anticholinergics alone was more likely than when anticholinergics were combined with beta(2)-agonists from four trials on 173 children (OR 2.65; 95% CI 1.2 to 5.88). Data on clinical scores/symptoms that were measured on different scales were conflicting. Individual trials reported that lung function was superior in the combination group when compared with anticholinergic agents used alone. The use of anticholinergics was not found to be associated with significant side effects. AUTHORS' CONCLUSIONS: In children over the age of two years with acute asthma exacerbations, inhaled anticholinergics as single agent bronchodilators were less efficacious than beta(2)-agonists. Inhaled anticholinergics were also less efficacious than inhaled anticholinergics combined with beta(2)-agonists. Inhaled anticholinergic drugs alone are not appropriate for use as a single agent in children with acute asthma exacerbations.