High degree atrioventricular block with ventricular asystole in a case of dengue fever.

Cardiac rhythm abnormalities have been uncommonly observed in dengue fever and most of them have been reported in children. We discuss a 30-year-old female with dengue fever, who presented with repeated symptomatic episodes of high degree atrioventricular block with ventricular asystole, which responded to intravenous atropine and oral orciprenaline without recurrence on 6 months follow-up.

Pharmacological Provocation of Outflow-Tract Tachycardia in a Patient With Brugada Syndrome.

We present a case of a symptomatic patient with Brugada syndrome, who had sustained right ventricular outflow tract tachycardia after pronounced exercise-induced ST segment elevation in V1 and V2. In electrophysiological study he developed right ventricular outflow tract tachycardia provoked by combined infusion of ajmaline and orciprenaline. After ablation no further arrhythmia was provoked by pharmacological stimulation.

Residual conduction after pulmonary vein isolation with a circular multielectrode radiofrequency ablation catheter: the role of adenosine and orciprenalin during a prolonged observation time.

INTRODUCTION: Recurrences after pulmonary vein isolation (PVI) in patients (pts) with paroxysmal atrial fibrillation (AF) are mostly due to PV reconnection. The effect of adenosine, orciprenalin and their combination on left atrial PV conduction after PVI with a phased radiofrequency (RF) circular multielectrode ablation catheter (Pulmonary Vein Ablation Catheter, PVAC) was prospectively evaluated during a prolonged waiting time. In addition, it was assessed whether pharmacological reconnection characterizes veins requiring use of an irrigated catheter. METHODS AND RESULTS: In 116 consecutive pts [age 62 (IQR:52,68) years, 46% female], PVI was achieved with the PVAC alone in 114/116 (98%) pts and 461/464 (99%) veins after a median of 26 (IQR:22,32) applications delivering 1782 s (IQR:1518,2197) of RF. Mostly transient PV reconnections were observed in 40/116 (34%) pts and 57/464 (12%) PVs, a median of 44 (IQR:30,58) min after initial isolation. Adenosine, alone (43/57, 75%) or during orciprenalin infusion (7/57, 12%), unmasked residual conduction in the majority of veins (50/57, 88%). Additional PVAC applications less frequently achieved permanent isolation in veins showing reconnection compared to those that didn't (52/57, 91% vs. 404/407, 99%; P < .001). All PVs that could not be isolated with the PVAC were successfully treated with a standard irrigated catheter. CONCLUSIONS: After apparent PVI with the PVAC, drug-challenge after prolonged observation unmasked residual PV conduction in a significant number of pts, and adenosine was the most effective strategy. Drug-induced PV reconnection was difficult to treat with the PVAC. Whether this strategy improves clinical outcome of PVI with phased RF needs to be investigated.

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.

Combined exogenous and endogenous catecholamine release associated with Tako-Tsubo like syndrome in a patient with atrio-ventricular block undergoing pace-maker implantation.

We report the case of a 65-year-old woman with complete atrio-ventricular block who underwent orciprenaline administration and pacemaker implantation. The intervention was complicated by pneumothorax and acute left ventricular systolic dysfunction with typical apical ballooning (Tako-Tsubo like syndrome). The patient was treated with diuretics and calcium-sensitizers and completely recovered. We speculate that both external and internal catecholamine triggered an acute left ventricular impairment with typical Tako-Tsubo features.

Use of ozone-depleting substances; removal of essential-use designation (flunisolide, etc.). Final rule.

The Food and Drug Administration (FDA), after consultation with the Environmental Protection Agency (EPA), is amending FDA's regulation on the use of ozone-depleting substances (ODSs) in self-pressurized containers to remove the essential-use designations for flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil used in oral pressurized metered-dose inhalers (MDIs). The Clean Air Act requires FDA, in consultation with the EPA, to determine whether an FDA-regulated product that releases an ODS is an essential use of the ODS. FDA has concluded that there are no substantial technical barriers to formulating flunisolide, triamcinolone, metaproterenol, pirbuterol, albuterol and ipratropium in combination, cromolyn, and nedocromil as products that do not release ODSs, and therefore they will no longer be essential uses of ODSs as of the effective dates of this rule. MDIs for these active moieties containing an ODS may not be marketed after the relevant effective date.

A new method to quantify the effect after subcutaneous injection of lipolytic substances.

BACKGROUND: Increasing numbers of patients request lipolytic injection therapy for aesthetic indications. However, only the clinical results of these therapies have been published to date. In most cases, pre- and postprocedure photographs and measurements have been presented. As with every other medical procedure, it is necessary to ensure that the results of lipolytic injections are quantified on an objective and scientific basis with comparable data. METHODS: In the past, the size of fat tissue could not be measured properly with conventional ultrasound systems. High-resolution, real-time three-dimensional (RT-3D) ultrasound is a fairly new method for measuring the volume of tissue. Therefore, this study aimed to measure the interscapular fat bodies of New Zealand rabbits before and after lipolytic therapy with Lipostabil, phosphatidycholine and orciprenalin (Alupent). RESULTS: The ultrasound-controlled injection of the lipolytic substances into the interscapular fat body ensured a precise injection. The RT-3D ultrasound data were compared with the magnetic resonance imaging (MRI) measurements performed at the same time. The greatest decrease in volume, up to 44%, was measured with orciprenalin (Alupent). There was a significant correlation between the data from ultrasound imaging and MRI. CONCLUSION: The data suggest that RT-3D ultrasound imaging could be a simple and fast method for proving the effects on volume size after lipolytic procedures. Of the three investigated substances, orciprenalin (Alupent) showed the highest lipolytic effect in our animal model.

Effect of reproterol either alone or combined with disodium cromoglycate on airway responsiveness to methacholine.

Regular use of inhaled beta2-agonists might lead to tolerance as reflected in a loss of bronchoprotection. In vitro-data suggest that this might be prevented by disodium cromoglycate (DSCG). Therefore, we studied the effect of the beta2-agonist reproterol in combination with DSCG. In a cross-over design, 19 subjects with airway hyperresponsiveness inhaled either placebo, 1mg reproterol, 2 mg DSCG, or 1mg reproterol plus 2 mg DSCG 4x daily over 2 weeks. Treatment periods were separated by > or = 7 days. Before and at the end of periods, lung function and methacholine responsiveness were determined in the morning, and 6h later the bronchodilator effect and the protection against methacholine-induced bronchoconstriction. Reproterol or DSCG or their combination did not exert detrimental effects on lung function, airway responsiveness, or bronchodilator capacity. However, bronchoprotection was significantly reduced (p < 0.05) after treatment with placebo, reproterol or reproterol plus DSCG, the respective changes being 0.59, 0.96 and 1.37 doubling concentrations. All changes were small as compared to intraindividual variability. In this model all treatments except with DSCG caused a significant but small loss of protection against methacholine-induced bronchoconstriction. Thus, tolerance was not prevented by 2 weeks of additional treatment with DSCG, in contrast to in vitro findings.

Airway reactivity is a determinant of bronchodilator responsiveness after methacholine-induced bronchoconstriction.

Airway hyperresponsiveness (AHR) is one of the characteristics of asthma and a risk factor for persistent airflow limitation. Poor response to bronchodilator may be a cause of persistent airflow limitation. Multiple factors may determine bronchodilator responsiveness, including airway reactivity to nonspecific bronchoconstrictive agents. If patients with AHR have poor bronchodilator responsiveness, then it could be a potential mechanism for asthma and persistent airflow limitation in these patients. The objective of this study is to assess the relationship between airway reactivity to methacholine and responsiveness to beta-agonist and beta-agonist/anticholinergic combination in a large subject population. A retrospective data analysis was undertaken of 764 consecutive subjects with > or = 20% reduction in forced expiratory volume during the first second of exhalation from total lung capacity (FEV1) after < or = 189 cumulative units of methacholine. The first 382 subjects received 3 inhalations of metaproterenol and the second 382 subjects received 3 inhalations of albuterol and ipratropium combination after > or = 20% reduction in FEV1. Bronchodilator responsiveness was measured as the percent increase in FEV1 after the treatment. Airway reactivity was assessed as the log10 of methacholine dose response slope. In a simple linear regression model, airway reactivity was significantly related to bronchodilator responsiveness. The coefficient of determination (r2) was 0.15 for the whole groups; 0.14 for metaproterenol group and 0.18 for albuterol/ipratropium combination group (all p<0.0001). The regression coefficient (beta) was 14.0 for the whole group; 14.8 and 13.2, respectively, for the two bronchodilator groups. Airway reactivity to methacholine is a determinant of airway responsiveness to both beta-agonist and beta-agonist/anticholinergic combination. Subjects with higher airway reactivity have higher bronchodilator responsiveness.

Inhibition by reproterol of cAMP PDE in intact mastocytoma P-815 cells.

In vitro studies in rat mastocytes and human monocytes suggested that reproterol (a selective beta(2)-adrenoceptor agonist with a theophylline moiety) exerts anti-inflammatory actions through inhibition of cyclic AMP (cAMP) PDE activity. Thus, reproterol was tested for its ability to inhibit cAMP PDE in cultured mouse mastocytoma P-815 cells. cAMP PDE activity was measured in intact cells by spectrofluorometry using the fluorescent substrate 2'-O-anthraniloyl cAMP. Reproterol was more potent than theophylline to inhibit cAMP PDE (pIC(50)=4.28+/-0.25 vs. 3.16+/-0.05). This contrasted with disrupted cells, where the PDE inhibitory potency of reproterol was low (pIC(50)=2.85+/-0.03) and similar to that of theophylline (pIC(50)=2.66+/-0.19). No cAMP PDE inhibition was found with other beta(2)-agonists tested (fenoterol, salbutamol, salmeterol and formoterol). Finally, the selective PDE inhibitors calmidazolium (100 nM), milrinone (5 microM) and rolipram (50 microM) inhibited cAMP PDE activity by approximately 20, 30 and 25% respectively. In conclusion, reproterol potently and non-specifically inhibited intracellular cAMP phosphodiesterases in intact mastocytoma cells. This can explain the previously reported beta(2)-adrenoceptor-independent anti-inflammatory actions of reproterol in vitro. Further studies are required to define the anti-inflammatory potential of reproterol in asthma.

Chronic beta-adrenoreceptor stimulation in vivo decreased Bcl-2 and increased Bax expression but did not activate apoptotic pathways in mouse heart.

Prolonged activation of the sympathetic nervous system is deleterious to heart function. In vitro beta1-adrenergic activation promotes apoptosis, whereas beta2-adrenergic activation reduces apoptosis in cultured adult cardiomyocytes. To determine the effect of chronic catecholamine infusion in vivo, we measured apoptosis marker expression in C57Bl/6 and catecholamine-sensitive Egr-1 deficient mice after treatment with the nonspecific beta-adrenergic agonist, isoproterenol, the beta1-specific agonist, dobutamine, or the beta2-specific agonist, metaproterenol. Antiapoptotic and proapoptotic protein expression, cytochrome c release and caspases 3, 9, and 12 activation products were measured on immunoblots. Catecholamine-treated mice had decreased Bcl-2 and increased Bax and BNIP1 expression, suggesting mitochondria-dependent apoptosis pathway activation. However, cytosolic cytochrome c or caspase 3 or 9 activation products were not detected. In mice, increased molecular chaperone expression and caspase 12 activation characterize endoplasmic-reticulum-driven apoptosis. Clusterin expression was increased in catecholamine-treated mice, but GRP78 expression was not increased, and caspase 12 activation products were not detected. Thus, neither the mitochondrial nor the endoplasmic apoptotic pathway was fully activated. Further, Egr-1 deficiency did not increase cardiac apoptosis. We conclude that although chronic in vivo infusion of beta1- or beta2-adrenergic receptor agonists partially activates the apoptosis program, full activation of the caspase cascade requires more, or other, cardiac insults.

Aging does not affect beta-agonist responsiveness after methacholine-induced bronchoconstriction.

OBJECTIVES: To assess the response to an inhaled beta-agonist alone or in combination with an anticholinergic agent after methacholine-induced bronchoconstriction in four age groups. DESIGN: Retrospective analysis. SETTING: Pulmonary function laboratory in a university-affiliated hospital. PARTICIPANTS: Seven hundred sixty-four consecutive subjects with a 20% reduction or more in forced expiratory volume during the first second (FEV1) of exhalation from total lung capacity after inhaling 189 or fewer cumulative units of methacholine were included in the analysis. INTERVENTION: The first 382 subjects received three inhalations of metaproterenol (total of 1.95 mg), and the other 382 subjects received three inhalations of albuterol and ipratropium combination (total of 309 microg of albuterol and 54 microg of ipratropium) after methacholine-induced bronchoconstriction. MEASUREMENTS: The response to bronchodilators was assessed as the postbronchodilator percentage change in FEV1 and the percentage of subjects recovering to 90% or better of baseline FEV1 after the use of bronchodilator. RESULTS: The percentage change in FEV1 postbronchodilator in the elderly was similar to that of the younger subjects. The percentage of subjects who recovered to 90% or better of their baseline FEV1 postbronchodilator was also similar in the elderly and younger age groups. Response to metaproterenol was similar to that of the albuterol/ipratropium combination in all age groups (all P>.05). CONCLUSION: Aging does not affect bronchodilator response to beta-agonist after methacholine-induced bronchoconstriction. The responsiveness to beta-agonist alone is similar to the responsiveness to the combination of beta-agonist and anticholinergic agent in all age groups.

Is electrical stimulation during administration of catecholamines required for the evaluation of success after ablation of atrioventricular node re-entrant tachycardias?

OBJECTIVES: The purpose of this study was to answer the question of whether stimulation after administration of catecholamines is mandatory for identifying unsuccessful ablations of atrioventricular node re-entrant tachycardia (AVNRT). BACKGROUND: The success of radiofrequency (RF) catheter ablation in AVNRT is confirmed in many centers by noninducibility of tachycardias during stimulation after the administration of catecholamines. METHODS: A total of 131 patients (81 women and 50 men; mean age 53.6 +/- 13.7 years [range 20 to 77]) were studied. Electrical stimulation was performed without and with the beta-adrenergic amine Orciprenaline (metaproterenol) before and after RF catheter ablation. RESULTS: In 100 patients (76.3%; confidence interval [CI] 68.1% to 83.3%) an AVNRT was inducible without administration of Orciprenaline. Thirty minutes after the initially successful ablation in 95 patients, tachycardia was inducible in none of these patients, not even after Orciprenaline administration. In the 31 patients (23.7%; CI 16.7% to 31.9%) in whom there was no tachycardia inducible before ablation, Orciprenaline was given, and the stimulation protocol was repeated. In only five patients (3.8%; CI 1.3% to 8.7%) was there still no tachycardia inducible. After an initially successful ablation in the 26 patients who had inducible tachycardias with Orciprenaline before ablation, no tachycardia could be re-induced. After Orciprenaline, the tachycardia was inducible again in only one patient. CONCLUSIONS: Only patients who require catecholamines for tachycardia induction before ablation need catecholamines for control of the success of the ablation of AVNRT.

Dietary adrenergic active compounds and the response of broilers to isoproterenol and cyclic adenosine monophosphate in vitro.

Broiler chickens, growing from 7-28 days of age, were fed diets containing 18% protein and 0, 1, 10 or 100 mg/kg yohimbine (alpha 2-adrenergic antagonist) or metaproterenol (beta-adrenergic agonist) to determine the role of adrenergic agents in the regulation of feeding behavior and metabolism. Data from this experiment suggest that beta-adrenergic agonists have slight effects on feed intake, growth and more pronounced effects on metabolism in the broiler chicken. In vitro lipogenesis (IVL) was determined by incubating liver explants for 2 h at 37 degrees C in the presence of cAMP or isoproterenol (ISO) and [2-14C]acetate and by measuring acetate incorporation into total hepatic lipid. Metaproterenol and yohimbine (100 mg/kg) depressed growth from 7 to 28 days. Both metaproterenol and yohimbine (100 mg/kg) decreased (P < 0.05) IVL compared to controls. These dietary additions also decreased (P < 0.05) hepatic malic enzyme activity without affecting the activities of either isocitrate dehydrogenase or aspartate aminotransferase.

Spatial and temporal heterogeneity of depolarization and repolarization may complicate implantable cardioverter defibrillator therapy in Brugada syndrome.

INTRODUCTION: Dynamic variations in electrophysiologic phenomena inherent to the Brugada syndrome may complicate therapy with implantable cardioverter defibrillators (ICDs). METHODS AND RESULTS: Between 1997 and 1999, 3 of 7 patients with Brugada syndrome (1 man and 2 women, mean age 42 years) received an ICD. During follow-up, 2 patients experienced multiple inappropriate shocks. Simultaneously with dynamic changes in the surface ECG, endocardial ECGs revealed a dynamic decrease in the right ventricular R wave and an increase in the corresponding T wave, resulting in T wave oversensing. With ajmaline administration, these dynamic changes in endocardial signals were reproducible at different right ventricular sites, whereas left ventricular epicardial signals remained stable. Incremental AAI pacing and exercise stress testing resulted in similar changes in right ventricular endocardial signals, but normalization of the surface ECG apart from progressively increasing S waves in leads II, V5, and V6. Orciprenaline administration had no effect on ECG phenomena. After implantation of a left ventricular epicardial lead for sensing and pacing, no inappropriate tachycardia detection recurred. CONCLUSION: These findings demonstrate that, in Brugada syndrome, spontaneous or ajmaline-induced changes in the surface ECG may be paralleled by significant variations in the right ventricular endocardial electrogram that may result in ICD malfunction. Implantation of a left ventricular epicardial lead for sensing and pacing may be the ultimate successful approach in certain patients. To assure proper ICD function, ajmaline testing during ICD implantation appears to be helpful.

Comparison of two regimens of beta-adrenergics in acute asthma.

BACKGROUND AND METHODS: Inhaled adrenergics and steroids are the main agents used in acute asthma. Dosing recommendations for adrenergics, while generally becoming more aggressive, lack prospective validation. A double blind, randomized trial of two regimens of nebulized metaproterenol was conducted in patients presenting to an Emergency Department with an acute asthma exacerbation. Asthmatics age 16-55, with no other cardio-pulmonary disease, presenting with peak expiratory flow rate (PEFR) < 30% of predicted and greater than 80 L/m were enrolled. All patients received 125 mg of methylprednisolone and theophylline, if needed, to reach therapeutic levels. The experimental group received 0.3 cc metaproterenol in 2.5 cc of saline at times 0, 20", 40", 1', 2', 3', 4', 5', 6', and 7'. The control group received metaproterenol at times 0, 1 hr, and hours 3, 5, and 7. Placebo was given to control group patients at 20", 40", 2', 4', and 6'. PEFR and vital signs were measured 10 min after each treatment. Study end points included discharge upon reaching set criteria or admission if patients were not discharged following the hour 7 treatment. RESULTS: Seventy one patients were enrolled, 40 in experimental group and 31 in the control group. The group characteristics did not differ at entry in any significant way, and the groups began with mean expected PEFR of 23.4% and 24.5%, respectively. There were no significant differences at any point in PEFR outcomes, time to discharge, or admission rate. The experimental group showed a greater increase in pulse rate and a reduced diastolic blood pressure at 20, 40 and 60 min. The experimental group had a 12- and 8-fold increase in the risk of a pulse rate > 140 at 40 and 60 min, respectively. This group also had two moderate complications, both near the 60-minute mark. These were an induction of atrial fibrillation in one patient and ischemic electrocardiographic changes in another. CONCLUSION: Three treatments in the first hour, and hourly thereafter showed no benefit over treatments initially, at one hour, and every other hour in acute, moderate, or severe exacerbation of asthma. Side effects were markedly increased in the control group. Such dosing should not be recommended as routine therapy.

Sympathetic modulation of lipolysis in subcutaneous adipose tissue: effects of gender and energy restriction.

To investigate the differences in the regulation of lipolysis between male and female obese subjects in vivo, we used an in situ microdialysis technique before and after 3 weeks of energy restriction. Using this method, we examined glycerol, glucose, and lactate responses after 5 minutes of epinephrine stimulation in the adipose tissues. Glycerol releases after the perfusion of phentolamine, orciprenaline, and propranolol were also studied. Sixteen subjects were studied (8 men, 8 women, 35 to 45 years of age, body mass index 38 to 50 kg/m2). In women, epinephrine provoked a greater glycerol release than in men in both abdominal and femoral regions (P < .05). In men and women there was a significant decrease in the concentration of glucose and a significant increase in lactate concentration after epinephrine stimulation (P < .001). After 3 weeks of energy restriction, glycerol release after epinephrine stimulation was greater in both sexes than that observed before energy restriction (P < .05). Both phentolamine and orciprenaline stimulated the release of glycerol (P < .01); phentolamine had a higher effect in women, while propranolol had no effect on glycerol release in both sexes. In summary, we have demonstrated that epinephrine provoked a greater lipolytic response in obese women in both abdominal and femoral adipose tissues. The lipolytic response was further enhanced after 3 weeks of energy restriction in each gender. The decrease in glucose concentration suggests that glucose may be reutilized for synthesis into new triacylglycerol. Knowledge about the sensitivity to lipolytic agents in subcutaneous adipose tissue may provide potential new approaches for modulating the lipolytic responses of subcutaneous adipose tissue differently in men and women.

Effects of a beta2-agonist on airway hyperreactivity in subjects with cervical spinal cord injury.

STUDY OBJECTIVE: Aerosolized ipratropium bromide or orally administered baclofen or oxybutynin chloride (Ditropan) block methacholine-associated airway hyperreactivity in subjects with chronic cervical spinal cord injury (SCI), whereas these agents do not inhibit airway hyperreactivity associated with the inhalation of histamine. The present study was performed to determine whether pretreatment with a beta2-agonist attenuates airway hyperresponsiveness in these subjects. PARTICIPANTS: Subjects with chronic cervical SCI previously demonstrating airway hyperreactivity were challenged with methacholine (n = 9) or histamine (n = 16) alone and, on a separate day, 25 min following inhalation of nebulized metaproterenol sulfate. RESULTS: Inhalation of the beta2-agonist was associated with an increase in provocative concentration causing a 20% decrease in FEV1 (PC20) values (geometric mean) from 1.01+/-2.76 to 20.54+/-6.24 mg/mL for methacholine and from 2.29+/-2.26 to 19.82+/-5.93 mg/mL for histamine. No correlation was found between specific PC20 values for individual subjects and percentage improvement in FEV1 (liter) following inhalation of metaproterenol sulfate and between PC20 values and baseline FEV1 percent. CONCLUSION: These data, combined with findings that patients with chronic high cervical SCI experience increased breathlessness following exposure to exogenous agents, suggest that long-term prophylactic beta2-agonist therapy may reduce respiratory symptoms associated with airway hyperreactivity in these patients.

Tolerability and in vivo performance of a novel freon-free metered dose inhaler for a fixed combinational product of reproterol and disodium cromoglycate.

The present study was conducted to describe and compare the in vivo performance (systemic exposure), clinical and laboratory safety of a fixed combinational product of inhaled reproterol (CAS 54063-54-6) plus disodium cromoglycate (DSCG; CAS 15826-37-6) using a novel freon (CFC)-free metered dose inhaler (MDI), which uses 1,1,1,2,3,3,3-heptafluoropropane (HFA-227; CAS 431-89-0) as propellant and polyoxyethylene glyceryl trioleate (Tagat TO; CAS 68958-64-5) as surfactant relative to the conventional freon-driven MDI Allergospasmin in healthy male and female volunteers. Twenty-four young male and female healthy subjects were randomly allocated in gender-balanced fashion to 4 parallel treatment groups with single and repeated dosing of either reproterol + DSCG by HFA- or CFC-MDI (each time N = 8) or placebo by HFA- or CFC-MDI (each time N = 4) using matched placebo devices thus allowing a double-blind (with regard to placebo) approach. Treatments consisted of a single morning dose of 2 actuations followed 4 days later by a 1 week treatment course of 2 actuations four times daily. Subjects were investigated extensively in terms of blood pressure, pulse rate, electrocardiography, spirometry, respiratory rate, body temperature, laboratory safety (haematology, clinical chemistry, urinalysis) and clinical well-being. There were no treatment, compound or device related effects for any of the tolerability and safety end points. The treatments were well tolerated. In particular, there was no irritative cough or any sign of broncho-irritation on application. Adverse events were reported in a total of 9 subjects: 3/8, 4/8, 0/4 and 2/4 subjects treated with reproterol + DSCG by HFA-MDI, reproterol + DSCG by CFC-MDI, placebo by HFA-MDI and placebo by CFC-MDI, respectively. Of these, 6 events in 6 subjects receiving the active treatments were considered probably or definitely related to the test drug administration (i.e. adverse drug reactions): after reproterol + DSCG one subject in each treatment group (HFA-MDI and CFC-MDI) complained of an unpleasant bitter taste immediately after application; one further subject in each group complained of headache. Under treatment with reproterol + DSCG by CFC-MDI one male subject complained of mild transient nausea with onset on day 5. Under treatment with reproterol + DSCG by HFA-MDI one female subject complained of mild dizziness and mildly disturbed (blurred) vision with onset on day 1. All adverse events occurred only transitory and required no treatment. Systemic exposure, evaluated by the plasma concentrations of DSCG at 1 h after application, was slightly higher with the HFA-MDI compared to the CFC-MDI. It is concluded that the safety, tolerability and in vivo performance of the newly developed freon-free MDI is at least as well tolerable as the already marketed freon-driven conventional formulation.