Antenatal exposure to fenoterol is not associated with the development of retinopathy of prematurity in infants born before 32 weeks of gestation.

PURPOSE: Despite safety concerns, ß2-sympathomimetics are still widely used as tocolytic agents. ß-Blockers in turn are used to treat vasculo-proliferative diseases of the newborn such as retinopathy of prematurity (ROP), which may lead to visual impairment and blindness. The scope of this study was to investigate whether antenatal exposure to the ß2-sympathomimetic fenoterol contributes to the development of ROP. METHODS: For this single-center retrospective case-control study of prospectively collected clinical data, all infants born before 32 weeks of gestation between 2001 and 2012 were included. The association of prenatal exposure to fenoterol and the development of ROP were analyzed by multivariate logistic regression. RESULTS: n = 1134 infants < 32 weeks of gestation were screened for eligibility, out of which n = 722 met the inclusion criteria. Exposure to fenoterol (n = 505) was not associated with a higher rate of ROP (OR 0.721, 95% CI 0.463-1.122). Further, duration of exposure (days) did not alter the incidence of ROP (OR 1.001, 95% CI 0.986-1.016). Frequency distribution of different ROP stages and the need for therapeutic intervention was also not affected by prenatal exposure to fenoterol. Risk factors for the development of ROP like low birth weight, low gestational age, prolonged respiratory support and multiple gestation were confirmed in our large study cohort. CONCLUSION: ß2-Sympathomimetic tocolysis does not increase the rate of ROP in premature infants born < 32 weeks of gestation. Our results render fenoterol a safe tocolytic agent regarding neonatal ROP development.

Myoclonus induced by salbutamol: A case report

Salbutamol is a ß2 adrenergic agonist widely prescribed in patients with obstructive and restrictive lung diseases. The main side effects associated with its use are tachycardia and tremor. Myoclonus is an involuntary, irregular, abrupt, brief and sudden muscular contraction, which can be generalized, focal or multifocal. We report the case of a 61-year-old patient presenting with myoclonus difficult to treat who showed improvement only after the definitive discontinuation of the ß2 adrenergic agonist. We describe the clinical findings, the interventions, and the outcomes related to the onset of myoclonus secondary to the use of salbutamol, as well as the possible genesis and importance of this adverse effect. We used the CARE guidelines to delineate the clinical case. Although myoclonus secondary to the use of different drugs has been described in the literature, as far as we know this is the fourth report of salbutamol-induced myoclonus to date.

Mioclonías inducidas por salbutamol / Myoclonus induced by salbutamol: A case report

Resumen El salbutamol es un agonista adrenérgico β2 ampliamente empleado en pacientes con enfermedades pulmonares obstructivas y restrictivas. Sus principales efectos secundarios son la taquicardia y el temblor. Las mioclonías son contracciones musculares involuntarias, irregulares, bruscas, breves y repentinas, y pueden ser generalizadas, focales o multifocales. Se presenta el caso de un paciente de 61 años con mioclonías de difícil manejo que solo presentó mejoría tras la suspensión definitiva del agonista adrenérgico β2. Se describen los hallazgos clínicos, las intervenciones y el resultado en las mioclonías asociadas con el uso de salbutamol y se discuten la posible génesis y la importancia de este efecto adverso. Para documentar el caso, se siguieron las recomendaciones de las guías para el reporte de casos (CAse REport, CARE). Aunque en diversos estudios se han descrito mioclonías secundarias al uso de diferentes fármacos, hasta donde se sabe, este sería el cuarto reporte de un caso asociado específicamente con el uso del salbutamol.

Abstract Salbutamol is a β2 adrenergic agonist widely prescribed in patients with obstructive and restrictive lung diseases. The main side effects associated with its use are tachycardia and tremor. Myoclonus is an involuntary, irregular, abrupt, brief and sudden muscular contraction, which can be generalized, focal or multifocal. We report the case of a 61-year-old patient presenting with myoclonus difficult to treat who showed improvement only after the definitive discontinuation of the β2 adrenergic agonist. We describe the clinical findings, the interventions, and the outcomes related to the onset of myoclonus secondary to the use of salbutamol, as well as the possible genesis and importance of this adverse effect. We used the CARE guidelines to delineate the clinical case. Although myoclonus secondary to the use of different drugs has been described in the literature, as far as we know this is the fourth report of salbutamol-induced myoclonus to date.

Increased Systemic Exposure and Stronger Cardiovascular and Metabolic Adverse Reactions to Fenoterol in Individuals with Heritable OCT1 Deficiency.

Fenoterol is a widely used anti-asthmatic and tocolytic agent, but high plasma concentrations of fenoterol may lead to severe and even fatal adverse reactions. We studied whether heritable deficiency of the liver organic cation transporter 1 (OCT1), a trait observed in 3% of Europeans and white Americans, affects fenoterol plasma concentrations and toxicity. OCT1 transported fenoterol with high affinity, and OCT1 inhibition in human hepatocytes reduced fenoterol uptake threefold. After administration of 180 µg of fenoterol to 39 healthy individuals, the OCT1-deficient individuals (zero active OCT1 alleles; n = 5) showed 1.9-fold greater systemic fenoterol exposure (P = 4.0 × 10-5 ) and 1.7-fold lower volume of distribution (P = 8.0 × 10-5 ). Correspondingly, the OCT1-deficient individuals had a 1.5-fold stronger increase in heart rate (P = 0.002), a 3.4-fold greater increase in blood glucose (P = 3.0 × 10-5 ), and significantly lower serum potassium levels. In conclusion, heritable OCT1 deficiency significantly increases plasma concentrations of fenoterol and may be an important factor underlying the excess mortality associated with fenoterol.

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.

[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.

[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.

Fenoterol did not enhance glucocorticoid-induced skeletal changes in male rats.

Glucocorticoids and ß(2)-adrenergic receptor agonists are the most commonly used drugs in the treatment of asthma. Both therapies are potentially dangerous to the skeletal system. The aim of the present study was to investigate the effects of fenoterol, a ß(2)-receptor agonist, on the development of bone changes induced by glucocorticoid (prednisolone) administration in mature male rats. The experiments were carried out on 24-week-old male Wistar rats. The effects of prednisolone 21-hemisuccinate sodium salt (7 mg/kg s.c. daily) or/and fenoterol hydrobromide (1.4 mg/kg i.p. daily), administered for 4 weeks, on the skeletal system were studied. Bone turnover markers, geometric parameters, mass, mass of bone mineral in the tibia, femur and L-4 vertebra, bone histomorphometric parameters and mechanical properties of tibial metaphysis, femoral diaphysis and femoral neck were determined. Both prednisolone and fenoterol had damaging effects on the skeletal system of mature male rats. However, concurrent administration of fenoterol and prednisolone did not result in the intensification of the deleterious skeletal effect of either drug administered separately.

beta2-Agonist modulates epithelial gene expression involved in the T- and B-cell chemotaxis and induces airway sensitization in human isolated bronchi.

Regular use of beta(2)-adrenoceptor agonists may enhance non-specific airway responsiveness and inflammation. In earlier experimental studies, we showed that prolonged in vitro fenoterol exposure induced airway sensitization via perturbed epithelial regulation of bronchoconstriction. The aim of the present work was to examine the involvement of inflammatory mediator genes and proinflammatory cells and to investigate the role of the bronchial epithelium in these untoward effects. Bronchial tissues were surgically removed from 17 ex-smokers. Bronchial rings and primary cultures of bronchial epithelial cells were incubated with 0.1microM fenoterol for 15h. Levels of mRNA-expression were analyzed using a real-time quantitative reverse transcription-polymerase chain reaction array. Bronchial rings were contracted with endothelin-1 and immune cell infiltration was assessed by immunohistochemistry. Compared to paired controls, fenoterol up-regulated the mRNAs of cytokines/proteins implicated in the recruitment of T and B cells or the activation and proliferation of bronchial epithelial cells (CCL20/MIP-3alpha, FOXA2, PPAR-gamma) in isolated bronchi and in cultured epithelial cells. Fenoterol exposure significantly enhanced CD8(+)-T and differentiated CD138(+)-B-cells infiltration into the bronchi, especially the subepithelial area. Increase in CD8 or CD138 labeling-intensity strongly correlated with rise in maximal contraction to endothelin-1 induced by fenoterol exposure. In summary, our results show that fenoterol modulates the T and B cells chemotaxis possibly via the epithelial chemokine secretion in isolated bronchi from ex-smokers. They also suggest that the infiltration of resident T and B cells into the subepithelial area is associated with an increase in airway responsiveness due to fenoterol exposure.

Neonatal exposure to fenoterol and betamethasone: effects on the behavioral development in the rat.

We investigated longitudinally the behavioral development in the rat following exposure to beta-agonists and glucocorticoids (GC). Neonatal rats received either 1 mg/kg fenoterol (FEN), 0.3 mg/kg betamethasone (BET), or saline (SAL). Weanling and young adult rats were tested in the open field, the elevated-plus maze, and the water maze. FEN-treated as well as BET-treated animals displayed increased anxiety-like behavior. Furthermore, BET-treated adult animals showed a reduced locomotor activity. An enhanced 24-h memory in the water maze in both treatment groups may be facilitated by emotional arousal due to the increased anxiety levels. The possible neurobiological underpinnings are discussed in detail.

[Effectiveness and safety of atosiban vs. pulsatile administration of fenoterol in the treatment of preterm labour]. / Wirksamkeit und Sicherheit von Atosiban vs. pulsatiler Applikation von Fenoterol bei der Behandlung vorzeitiger Wehen.

BACKGROUND: The aim of this study was to compare the efficacy and side effects of atosiban with those of fenoterol (pulsatile administration) for acute tocolysis. METHODS: A prospective, open-label, randomised controlled trial was performed. Patients in preterm labour at 24+0 to 33+6 weeks of gestation were randomised to receive atosiban (A) or fenoterol (F) pulsatile administration. Primary outcome was the arrest of preterm labour. RESULTS: The proportion of woman remaining undelivered at 48 hours (86.3% atosiban group and 79.6% fenoterol group) and at 7 days (78.4% vs. 66.7%) was comparable. The incidence of maternal cardiovascular side effects was lower in the atosiban group (4% vs. 78%, p=0.0). Tocolysis was terminated as a result of maternal adverse effects in the fenoterol group (9%). Fetal tachycardia was lower in the atosiban group (2% vs. 22%). The mean duration of tocolytic administration was lower in the atosiban group (19 h vs. 24.5 h, p<0.05). DISCUSSION: The adverse effects in the pulsatile administration of fenoterol for short duration were only dependent on the initial dosage for the arrest of preterm labour. Neonatal outcome were similar between the treatment groups and were rather related to the gestational age not to the tocolytic agent. CONCLUSIONS: Atosiban was comparable in clinical effectiveness and was associated with fewer maternal and fetal adverse effects, so that fenoterol cannot be recommended. Completion of tocolytic therapy 12 hours after arrest of preterm labour is effective and associated with a short mean duration.

Diagnosis, treatment, observation and outcome of fetal supraventricular tachycardia in a twin pregnancy.

BACKGROUND: Magnetocardiography and M-mode fetal echocardiography are non-invasive techniques capable of identifying fetal arrhythmias. The STAN-fetal scalp electrode system can record the fetal echocardiogram in labor. CASE: A patient was admitted to hospital with preterm contractions and cervical insufficiency at 28 weeks of gestation. After treatment with a beta-sympathomimetic drug (Partusisten) one fetus developed supraventricular tachycardia. After terminating the Partusisten medication, there was no effect on the fetal arrhythmia and flecainide therapy was initiated. Maintenance dosages controlled the condition thereafter. Cardiac time intervals of a fetus in labor can be presented, which did not change significantly throughout the first stage of labor. CONCLUSION: Flecainide is an effective therapy for supraventricular tachycardias in a twin pregnancy. Analyzing the cardiac time intervals during pregnancy can improve perinatal outcome.

Tocolysis and delayed delivery versus emergency delivery in cases of non-reassuring fetal status during labor.

AIM: To determine whether fetal intrauterine resuscitation using tocolysis and delayed delivery is better for the fetus than emergency delivery when fetal hypoxia is suspected because of a non-reassuring fetal heart-rate (FHR) pattern using conventional heart rate monitoring. METHODS: This was a prospective and randomized study, conducted between 2001 and 2004 at Pereira Rossell Hospital, Montevideo, Uruguay. The population consisted of 390 fetuses, in which intrauterine distress was diagnosed using electronic FHR monitoring. Of these, 197 were randomly assigned to the emergency delivery group and 193 to the fetal intrauterine resuscitation group. The inclusion criteria were: term singleton pregnancy, in labor, cephalic presentation, and no placental accidents. RESULTS: The time between randomization and birth was 16.9 +/- 7.6 min (mean +/- SD) for the emergency delivery group, and 34.5 +/- 11.7 min (mean +/- SD) for the resuscitation group. The relative risk (RR) of acidosis in the umbilical artery (pH < 7.1) in the emergency delivery group was 1.47 (0.95-2.27). The RR of base deficit < or =12 mEq/L in the emergency delivery group was higher than in the resuscitation group (RR = 1.48 [1.0-2.2], P = 0.04). When considering the need for admission to the neonatal care unit, the relative risk was higher in the emergency delivery group than in the resuscitation group (RR = 2.14 [1.23.3.74], P = 0.005). No maternal adverse effects were reported. CONCLUSION: Tocolysis and delayed delivery renders better immediate neonatal results than emergency delivery when fetal distress is suspected because of a non-reassuring fetal heart pattern. In addition, it may decrease the need for emergency delivery without increasing maternal and fetal adverse side-effects.

Myocardial ischemia induced by nebulized fenoterol for severe childhood asthma.

We examined for myocardial ischemia induced by continuous inhalation of fenoterol in children with severe acute asthma. Thirty children with severe acute asthma were evaluated for signs of myocardial ischemia when treated with 0.5 mg kg dose (maximum 15 mg) of inhaled fenoterol for one hour. The heart rate was measured before and after inhalation. Cardiac enzymes (creatine kinase, creatine kinase MB fraction and troponin levels) were measured at admission and 12 hours later. An EKG was recorded before inhalation was started and immediately after its completion to detect the presence of any evidence of myocardial ischemia. All patients developed significant increase in heart rate. Six patients showed EKG changes compatible with myocardial ischemia, despite normal enzyme levels. Patients with severe acute asthma show tachycardia and may show EKG changes of myocardial ischemia.

Short-acting inhaled beta-2-agonists increased the mortality from chronic obstructive pulmonary disease in observational designs.

OBJECTIVE: The effect of short-acting inhaled beta(2)-agonists on mortality from chronic obstructive pulmonary disease (COPD) is controversial. Different observational designs were used to investigate about this topic. STUDY DESIGN AND SETTING: A population-based case-control design was performed, by linking automated health databases from the Varese Province of Italy. Deaths of COPD generated from the cohort of 135,871 patients for whom at least one prescription for drugs used to treat COPD had been dispensed between 1997 and 1999 entered into the study as cases. Up to 20 controls were randomly selected for each case from the cohort after matching on gender, age, and date of cohort entry. Risk ratios were estimated using the case-control, case-crossover, and case-time-control approaches. RESULTS: A total of 222 cases and 3022 controls met the inclusion criteria. Odds ratios (and corresponding 95% confidence intervals) corresponding to more than 0.5 defined-daily-doses were 2.6 (1.7, 4.0), 1.9 (1.1, 3.3), 2.1 (1.1, 4.0), and 2.3 (1.2, 4.6) by using crude and adjusted case-control, case-crossover, and case-time-control estimates, respectively. CONCLUSION: Evidence that higher doses of short-acting inhaled beta(2)-agonists are associated with higher mortality from COPD was consistently supplied by three observational approaches.

A review of ipratropium bromide/fenoterol hydrobromide (Berodual) delivered via Respimat Soft Mist Inhaler in patients with asthma and chronic obstructive pulmonary disease.

Asthma and chronic obstructive pulmonary disease (COPD) can be effectively treated by the use of bronchodilator therapies delivered by inhalation. Berodual is a fixed combination of the anticholinergic agent ipratropium bromide (IB) and the beta2-adrenergic agonist fenoterol hydrobromide (FEN). IB/FEN has been available for the treatment of asthma and COPD in a pressurised metered dose inhaler (MDI) [pMDI] formulation for many years. The pMDI is the most widely used device for the delivery of inhaled medications, such as IB/FEN. However, most conventional pMDIs contain chlorofluorocarbon (CFC) propellants, which are currently being withdrawn because of their detrimental effects on the environment. This has resulted in alternative methods of drug delivery being developed. Respimat Soft Mist Inhaler (SMI) is a new generation, propellant-free inhaler that generates a fine, slow-moving cloud (the Soft Mist) which can be easily inhaled. Scintigraphic studies have shown that this improves deposition of drugs in the lung and results in less oropharyngeal deposition than the CFC-MDI. A clinical development programme has been conducted to compare the efficacy and safety of IB/FEN delivered via Respimat SMI with that of IB/FEN via CFC-MDI in the treatment of patients with asthma or COPD. Five clinical studies (two phase II and three phase III) investigated dosages of IB/FEN 5/12.5 microg to 320/800 microg via Respimat SMI in single and multiple dose administration regimens. Four of the trials were conducted in patients with asthma (three in adults and one in children), while one phase III trial was conducted in patients with COPD. In phase III, 2058 patients participated, with a total of 1112 patients treated with IB/FEN via Respimat SMI. In the phase III studies, each dose from Respimat SMI was given in one actuation compared with two actuations with the CFC-MDI. In the paediatric asthma phase III study, all CFC-MDI doses were delivered via a spacer device. The results of the trials demonstrated that IB/FEN via Respimat SMI allows a reduction in the nominal dose of IB/FEN, while offering similar therapeutic efficacy and safety to a CFC-MDI. In children, Respimat SMI obviates the need for a spacer.

[Comparison of the cost of treatment of premature labor with atosiban or beta-sympathomimetics from the perspective of the health care payer--a pharmacoeconomic model]. / Srovnání nákladu na lécbu predcasného porodu atosibanem nebo beta-sympatomimetiky z perspektivy plátce zdravotní péce--farmakoekonomický model.

OBJECTIVE: To evaluate the cost of treating premature delivery with atosiban or beta-sympatomimetic drugs (fenoterol and hexoprenalin) from the perspective of health care payer--the medical insurance company. DESIGN: A pharmaco-economic model based on the results of randomized, controlled clinical study. SETTING: Hospital Pharmacy at Vitkovice Hospital of Blessed Mary Antonia, Ostrava. METHODS: The study is based on the application of clinical decision-making analysis, which includes results of a randomized controlled clinical study as well as data on the cost of clinical interventions and cost of drug therapy. The pharmaco-economic model was created from the perspective of the payer of health care--the insurance company. This model presumes the administration of atosiban or beta-sympatomimetic drugs (fenoterol and hexoprenalin) for the period of 18 and 48 h and the therapy of possible untoward effects for the next 72 h after the administration of the drugs. The analysis of sensitivity of pharmacokinetic model also employs so called low and high estimate of supplementary cost for the treatment of untoward effects. RESULTS: After the administration of the drugs for the period of 18 h the total cost of the payer of medical care was in the range of 21,914.5-21,974.4 CKr in atosiban, 19,878.7-22,661.4 CKr in fenoterol and 19,942.9-21,974.4 CKr in hexoprenalin. In the administration of the drugs for 48 h, the overall cost of the payer of medical care was in the range of 43,082.5-43,142.4 CKr in atosiban, 19,960.3-23,150.7 CKr in fenoterol and 20,131.3-23,574.0 in hexoprenalin. CONCLUSIONS: This study compared overall cost associated with hospitalization of a premature delivery from the perspective of the medical care payer, i.e. the health insurance company. The authors applied a pharmaco-economic model evaluating hospitalization for the period of 48 h and subsequent therapy of possible untoward effects for the period of up to 72 h. In case of a shorter administration of atosiban (up to 18 h) the overall cost of hospitalization for premature delivery for the period of 48 h from the point of view of medical insurance company is basically comparable with the administration of beta-sympatomimetic drugs. If atosiban is administered for more than 18 h, the overall cost of hospitalization is higher than with beta-sympatomimetic drugs, and the cost increases in relation to the duration of atosiban administration.