Combination Inhalers Containing Inhaled Corticosteroids and Long-Acting β2-Agonists: Improved Clinical Efficacy and Dosing Options in Patients with Asthma

Combination therapy with inhaled corticosteroids (ICS) and long-acting β₂-agonists (LABA) is a recognized treatment for adults with moderate to severe asthma. The introduction of inhalers containing both an ICS and a LABA simplifies treatment and improves asthma control. This review discusses clinical evidence that budesonide/formoterol and salmeterol/fluticasone are effective and well tolerated in asthma treatment. Moreover, the rapid onset of effect and long duration of action of budesonide and formoterol make once-daily dosing, adjustable maintenance dosing, and the novel treatment strategy of using budesonide/formoterol for maintenance and as needed for symptom relief, valuable treatment options for patients with asthma.     

Addition of Transdermal or Inhaled Long-Acting β 2-Agonists in Adult Asthmatic Patients Treated with Inhaled Corticosteroids: Switchover Study from Tulobuterol Patch to Salmeterol Dry Powder Inhaler

Sixty-four patients with persistent asthma receiving 200 to 800 μ g of fluticasone propionate daily were enrolled in this switchover study. The patients applied a tulobuterol patch 2 mg every 24 hours for 4 weeks followed by inhalation of salmeterol 100 μ g bid for 4 weeks. The mean values for morning and evening peak expiratory flow improved significantly compared with baseline during the 4 weeks of tulobuterol patch treatment. Further improvement was seen on switching to salmeterol treatment, which was significant even in the first week, and continued until the final week of the study. Use of salmeterol alone resulted in a significant increase in the percentage of forced expiratory volume in 1 second %FEV1 from baseline, with 51% of patients feeling that the treatment was effective (vs. 37% on tulobuterol). These data suggest that salmeterol can achieve better control in asthmatic patients after switching from using tulobuterol patches.     

The C523A β2 Adrenergic Receptor Polymorphism Associates with Markers of Asthma Severity in African Americans

Our goal was to explore associations between β₂ adrenergic receptor polymorphisms and markers of asthma severity in African American and Caucasian patients with asthma. Polymorphisms at loci -1023, -654, -47, 46, 79, 491, and 523 were genotyped and haplotypes were imputed in 143 African Americans and 336 Caucasians. C523A genotype associated with percentage of African Americans (but not of Caucasians) having an asthma exacerbation: AA, AC, and CC genotypes were 17, 29, and 40%, respectively (p = 0.018). Symptom scores, pulmonary function, and rescue inhaler use paralleled exacerbation prevalence. We conclude the 523 A allele modifies asthma severity in African Americans.     

Leukotriene Receptor Antagonists: A Good Choice in the Treatment of Premenstrual Asthma?

The aim of this study was to investigate the effects of leukotriene receptor antagonists (LTRAs) on the premenstrual exacerbation of asthma (PMA). Twenty-four female patients with mild asthma were enrolled in the study. Patients were followed for three menstrual cycles and separated into two groups based on whether they exibit premenstrual worsening of asthma symptoms (n = 11) or not (n = 13). During the first month all were treated with only inhaled steroids (IS) (run-in period); during the second month they received IS plus placebo; and during the third month they were given IS plus montelukast. Furthermore, they were advised to use beta ₂ -agonists as needed. Peak expiratory flow rate (PEFR) and symptom scores were recorded during the 3 months. Pulmonary function tests (PFT) and the levels of oestrogen, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured a week before the begining of the menstrual period. At the end of the 3-month period, it was observed that following therapy with montelukast, the patients with PMA showed significant improvement in PEFR variability and symptom scores when compared with the placebo group. Baseline FSH levels were higher, but FSH and other hormone levels and PFTs did not change in these groups. However, in the group without PMA there was no difference between the montelukast or placebo groups in PEFR variability, symptom scores, PFTs, and hormone levels. Based on the data in hand, it could be stated that LTRAs have ensured the control of symptoms and improved PEFR variability in patients with PMA by supressing inflammation. We are of the view that LTRAs would be a right choice in the treatment of patients with PMA.     

β2-Adrenergic Receptor Polymorphisms Affect Airway Responsiveness to Salbutamol in Asthmatics

We examined the β-adrenergic receptor (β₂AR) polymorphisms (Arg16 → Gly, Gln27 → Glu) and clinical status for 117 asthmatics. Airway responsiveness to methacholine and β₂-agonists was evaluated with Astograph®. The atopic factors, pulmonary function test, and airway responsiveness to methacholine did not differ significantly among the different β₂AR genotypes. Asthmatics homozygous for Glyl 6 showed significantly lower airway responsiveness to inhaled salbutamol than those heterozygous for Arg/Gly16 or homozygous for Arg16. Asthmatics heterozygous for Gln/Glu27 had significantly later asthma onsets than those homozygous for Gln27. These results suggest that β₂AR polymorphisms play an important role in the airway responsiveness to inhaled β₂- agonist and the initial asthma onset.     

Xamoterol,a New Selective β-1-Adrenoceptor Partial Agonist,in the Treatment of Postural Hypotension

ABSTRACT. Three patients severely disabled from postural hypotension were treated with xamoterol, a selective β-1-adrenoceptor antagonist with a high degree of partial agonist activity. Oral treatment (200 mg b.i.d.) was chosen on the basis of the effects of acute intravenous administration of xamoterol and pindolol, a non-selective β-adrenoceptor antagonist with partial agonist activity. In these patients pindolol had a predominantly antagonist effect, whereas xamoterol had a predominantly agonist effect after intravenous administration. Oral treatment was carried out with placebo control in a single-blind fashion. The patients reported gradual improvement during the first days of treatment. After 1 month of oral treatment, heart rate had increased by 15 beats/min, systolic blood pressure from 131 to 170 mmHg, diastolic blood pressure from 77 to 91 mmHg and mean blood pressure by 22 mmHg (mean values, supine). During the placebo period (2 weeks) heart rate decreased to pretreatment levels and mean blood pressure was reduced by only 14 mmHg. The patients reported substantial improvement in their condition during active medication. Xamoterol seems to be a useful alternative in the treatment of postural hypotension.     

A One-Week Dose-Ranging Study of Inhaled Salmeterol in Children with Asthma

This was a 1-week study evaluating the safety and efficacy of two dosage regimens of salmeterol in children with asthma. A total of 243 children, aged 4-11 years, with mild-to-moderate asthma were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating salmeterol xinafoate 21 μg and 42 μg administered via metered-dose inhaler (MDI) twice daily for 1 week. Patients were allowed to use albuterol MDI as needed for relief of acute symptoms. Inhaled corticosteroids and/or cromolyn at fixed dosages could be continued during the study, but theophylline and oral β-agonists were not allowed. Twelve-hour serial spirometry (for patients aged 6-11 years) and serial peak expiratory flow rate (PEFR) (all patients) were performed on days 1 and 8 of treatment; morning and evening PEFR were recorded each day prior to inhalation of the study drug. Safety was assessed by monitoring adverse events, clinical laboratory values, vita signs, electrocardiogram (ECC), and 24-hr ECG (Holter) monitoring. Both the 21 -μg and 42-μg doses of salmeterol produced significantly greater bronchodilation, as measured by 12-hr serial forced expiratory volume in 1 sec (FEV₁) (p ≤ 0.02) and PEFR (p ≤ 0.001), than did placebo on days 1 and 8. A small dose-response was observed, with the 42-μg dosage producing consistently higher serial FEV₁and PEFR than did the 21 -μg dosage, although the differences were not statistically significant. Morning and evening PEFR increased significantly (p ≤ 0.008) with both dosages of salmeterol compared with placebo. Twelve patients (5%) experienced potentially drug-related adverse events, with headache (4% in each salmeterol group) being the most common. There were no clinically significant changes in heart rate as measured by Holter monitoring, ECCs, vital signs, or clinical laboratory values following treatment with either dose of salmeterol. Salmeterol 21 μg or 42 μg twice daily was effective in producing bronchodilation in children aged 4-11 years, and both dosages had good safety profiles. Patients treated with salmeterol 42 μg twice daily showed a trend toward greater improvement in asthma control compared with those who received salmeterol 21 μg.     

Role of β-Adrenoceptor Desensitization in Heart Failure

Abstract: Heart failure is characterized by left ventricular dysfunction associated with a complex of symptoms that relate to inadequate perfusion of tissues and pulmonary congestion. When the heart is damaged by an insult, compensatory mechanisms mediated through activation of the sympathetic nervous system are involved to stabilize myocardial performance. Although these mechanisms can sustain cardiac function for a short time, chronic activation of sympathetic activity has adverse biological effects. This review will focus on the changes that occur in the β-adrenergic receptor pathway in the failing heart and will discuss novel approaches to therapy through manipulation of this pathway.     

Peroxisome Proliferator-Activated Receptor γ as a Novel Therapeutic Target in Asthma

Peroxisome proliferator-activated receptor γ (PPARγ) has been characterized as a regulator of adipocyte differentiation and lipid metabolism. However, in the last few years growing evidence indicates that PPARγ plays an important role in controlling immune and inflammatory responses. Upregulation of PPARγ expression is observed in asthmatic airways, and an involvement of PPARγ in airway inflammation and airway hyperresponsiveness in asthma has been reported. Recent studies have demonstrated that PPARγ ligands may have a therapeutic effect in asthma. This article reviews the latest knowledge and studies on the roles and mechanisms of PPARγ and PPARγ ligands in asthma.     

Expression of Transforming Growth Factor β1 in Bronchial Biopsies in Asthma and COPD

The role of transforming growth factor β₁ (TGF β₁) in airway remodeling in asthma and chronic obstructive pulmonary disease (COPD) has not been fully described. To evaluate the possible pathogenetic role of TGF β₁ in asthma and COPD, immunohistochemical expression of TGF β₁ was described in bronchial biopsies from patients with asthma and COPD compared with healthy individuals. Twelve subjects with asthma, 13 subjects with COPD, and 10 healthy individuals enrolled in the study. Bronchial biopsies were stained with hematoxylin and eosin and anti-TGF β₁ antibody. As a result, immunoreactive TGF β₁ was mainly localized in association with connective tissue in all groups. The staining intensity was not statistically different among the groups in bronchial epithelium, whereas it was significantly higher in the group of asthma in the submucosa. Because there is evidence showing a significant increase of staining intensity in the submucosa from asthmatics but not from subjects with COPD, we may conclude that TGF β₁ may play a significant role in pathogenesis of asthma but not in COPD.     

Roles of Genotypes of β2-Adrenergic Receptor in the Relationship Between Eosinophil Counts and Lung Function in Taiwanese Adolescents

To examine the roles of genetic polymorphism of the β₂-adrenergic receptor (β₂AR) in the relationship between eosinophil (EOS) counts and eosinophil cationic protein (ECP) counts and lung function, we recruited a random sample from the 1996 nationwide survey of asthma prevalence in middle school children. A total of 149 subjects—42 asthmatic children, 38 asthmatics in remission (no reported attack for more than 12 months), and 69 nonasthmatics—completed a physical evaluation, pulmonary function test, and determination of EOS, ECP, and β₂AR genotypes at amino acids 16 and 27. Asthmatic children had higher EOS and ECP than did nonasthmatics. No association was found between asthma and β₂AR genotypes. Lung function was significantly and inversely correlated with EOS but not with ECP in asthmatic children. By genotype, an inverse correlation between lung function and EOS was found in asthmatic children with Arg16Arg or Gln27Glu. A nonsignificant but similar inverse correlation was found in asthmatic children with Arg16Gly or Gln27Gln. However, a nonsignificant but positive correlation was found in asthmatic children with Gly16Gly. In conclusion, we suggest that EOS is a better clinical indicator of airway inflammation than ECP when children are not having an asthma attack. The association between an increase of EOS and lower lung function can be differentiated by β₂AR genotypes at amino acid 16.     

Differential Hemodynamic Effects of β-Adrenoceptor Blockers,Ca Antagonists and Combined α-β-Receptor Blockade in Ischemic Heart Disease

ABSTRACT. The hemodynamic responses to 3 different therapeutical regimens: β-adrenoceptor blockade, calcium inflow inhibition and combined α-β-blockade were evaluated in 3 matched randomized groups of patients with ischemic heart disease and typical exercise-induced angina. The groups consisted of 22, 16 and 15 men, mean age 55–59 years. They were studied at rest and during ischemia-inducing exercise, before and after single oral doses of 100 mg metoprolol, 10 mg nifedipine and 200 mg labetalol. Pressures in the brachial artery and the pulmonary circulation were recorded by means of percutaneously introduced catheters. Cardiac output was determined according to the Fick principle. Metoprolol reduced mean arterial pressures, heart rate and cardiac output. Systemic vascular resistance and left ventricular filling pressure increased. Nifedipine resulted under all conditions in a distinct reduction of systemic vascular resistance and arterial pressures and a slight increase in heart rate and cardiac output. Left ventricular filling pressure was significantly lowered, the more the higher the initial level. The effect of labetalol was similar to that of nifedipine; however, cardiac output was unchanged and heart rate was slightly reduced. Left ventricular filling pressure was significantly lower. It is apparent that suppression of adrenergic stimulation by β-receptor blockade alone may have adverse hemodynamic effects in ischemic heart disease and prompt further functional deterioration. Conversely, both calcium and combined α-β-receptor blockade tend to improve left ventricular function by lowering both left ventricular preload and total systemic vascular resistance. The results strongly suggest that in patients in whom β-receptor blockers appear indicated, their adverse hemodynamic effects can be offset by concomitant α₁-receptor blockade or vasodilation without losing symptomatic efficacy. Combined α-β-receptor blockade has the advantage over calcium antagonists alone to prevent any increase in adrenergic activity and related hyperkinetic response.     

Duration of Action of Inhaled vs. Intravenous β2-Adrenoceptor Agonists in an Anaesthetized Guinea-pig Model

We compared the duration of action of the short-acting α₂-adrenoceptor agonist salbutamol and the long-acting α₂-adrenoceptor agonists salmeterol and formoterol when administered iv or by inhalation in a histamine-induced bronchoconstriction model in the guinea-pig. Following aerosol dosing, maximal bronchoprotector effects were seen for salbutamol, salmeterol and formoterol at concentrations of 1 mg/ml, 100 μ g/ml and 30 μ g/ml respectively, giving a potency order of formoterol > salmeterol > salbutamol. All displayed similar maximum effects in this system. A maximal concentration of salbutamol showed bronchoprotection at 1 h but not at 3 h post-dosing whereas maximal concentrations of formoterol and salmeterol showed protection up to 5 h post-aqueous-aerosol dosing, giving a duration order of salmeterol > formoterol > salbutamol. All three α₂-adrenoceptor agonists showed dose-dependent bronchoprotection and duration of action following intravenous administration; salbutamol and salmeterol were equipotent and both were less potent than formoterol. Bronchoprotection obtained with sub-maximal concentrations of all three α₂-adrenoceptor agonists faded within 30 min following iv administration, but this could be extended by increasing the doses. These results demonstrate that the route of administration is important in determining the duration of action of α₂-adrenoceptor agonists in the lung. Furthermore, such findings lend support to the suggestion that the physico-chemical characteristics of salmeterol govern its duration of action rather than sustained binding of this agonist to a α₂-adrenoceptor exo-site.     

Reduction of the Pyrexial Response to Acute Myocardial Infarction by β-Adrenoceptor Blockade

ABSTRACT. We have studied the effect of β-adrenoceptor blockade on the pyrexial response to acute myocardial infarction (AMI). Temperatures of 22 patients treated with timolol, 20 mg daily, in the acute phase of AMI were compared to temperatures of 22 patients not receiving timolol treatment. Fever response after AMI was significantly reduced in the timolol-treated patients, maximal and mean temperature in the febrile period being lower and the febrile period being shorter. Reduction of fever in AMI may be of importance as a higher body temperature increases the risk of developing heart failure and arrhythmias. The study lends support to the use of β-adrenoceptor blockade in AMI. It also substantiates a possible role of β-adrenergic receptors in the regulation of body temperature during fever.     

Addition of Transdermal or Inhaled Long-Acting β 2-Agonists in Adult Asthmatic Patients Treated with Inhaled Corticosteroids: Switchover Study from Tulobuterol Patch to Salmeterol Dry Powder Inhaler

Sixty-four patients with persistent asthma receiving 200 to 800 μ g of fluticasone propionate daily were enrolled in this switchover study. The patients applied a tulobuterol patch 2 mg every 24 hours for 4 weeks followed by inhalation of salmeterol 100 μ g bid for 4 weeks. The mean values for morning and evening peak expiratory flow improved significantly compared with baseline during the 4 weeks of tulobuterol patch treatment. Further improvement was seen on switching to salmeterol treatment, which was significant even in the first week, and continued until the final week of the study. Use of salmeterol alone resulted in a significant increase in the percentage of forced expiratory volume in 1 second %FEV1 from baseline, with 51% of patients feeling that the treatment was effective (vs. 37% on tulobuterol). These data suggest that salmeterol can achieve better control in asthmatic patients after switching from using tulobuterol patches.     

Effect of β-Agonists on Production of Cytokines by Activated T Cells Obtained from Asthmatic Patients and Normal Subjects

Intracellular levels of cAMP were found to regulate T cell activity. We examined whether β₂-agonists altered cytokine production and cyclic adenosine monophosphate (cAMP) accumulation in concanavalin A (ConA)-activated peripheral T cells from asthmatic patients. Procaterol and isoproterenol weakly decreased the ConA-elicited interleukin (IL)-4 and IL-5 secretion; however, the inhibitory effect of procaterol on the ConA-induced IL-2 secretion was inferior to that of isoproterenol in normal controls and was little in asthmatics. The intracellular accumulation of cAMP by procaterol was not altered compared with that by isoproterenol. Results suggest that there is a qualitative difference between procaterol- and isoproterenol-induced cAMP accumulation in T cells.     

Depressed Melatonin Secretion in Patients with Nightmares Due to β-Adrenoceptor Blocking Drugs

ABSTRACT. Nocturnal urinary melatonin excretion was evaluated in six patients with nightmares and hallucinations during treatment with β-adrenoceptor blocking agents, and compared to six control patients with similar diagnoses and treatment but without such symptoms from the central nervous system (CNS). Nightly melatonin excretion was lower in all cases with nightly CNS-symptoms than in the control patients. The results also suggest drug differences and dose dependency. It is concluded that in predisposed patients CNS side-effects induced by β-adrenoceptor antagonists are related to depressed nightly melatonin secretion.     

Potential Use of β3‐Adrenoceptor Antagonists in Heart Failure Therapy

Recently, a functional, negatively inotropic, β₃‐adrenoceptor was characterized in the human heart. Several studies now suggest that this receptor might play an important role in the pathophysiology of heart failure, by counterbalancing the effects of a β₁ and β₂‐stimulation. Therefore, this review summarizes the rationale and effects of β‐adrenergic blockade in chronic heart failure and specifically addresses the question of the potential use of β₃‐adrenoceptor antagonists in the treatment of heart failure and other pathophysiological conditions associated with a decreased cardiac contractility.