Bronchodilator effect of oral doxofylline and procaterol in asthma: A randomized crossover study

Introduction

Asthma is a chronic respiratory disease characterized by variable airflow limitation due to airway inflammation and hyperresponsiveness, and affects daily activities, social life, performance, and work productivity.¹ The European Respiratory Society (ERS) guidelines recommend spirometry for asthma diagnosis. Inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) are the main medications used for asthma treatment; they can reduce airway inflammation, relieve asthma symptoms, and prevent asthma exacerbations.¹ Oral bronchodilators are options for adjunctive treatment in patients with uncontrolled asthma symptoms despite optimal ICS and LABA therapy, or for patients who do not use their metered-dose inhaler² or dry powder inhaler devices³ properly. Moreover, international guidelines suggest the use of increased ICS doses or the addition of a long-acting muscarinic antagonist (LAMA) to inhaled corticosteroids and long-acting beta2-agonists (ICS/LABA) when disease control is not achieved.¹

Doxofylline is a xanthine molecule with both bronchodilators and anti-inflammatory activities for the treatment of airway diseases.⁴ The main mechanism of action is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE) activity, especially PDE-4, which increases the level of cyclic adenosine monophosphate in smooth muscle cells in bronchial airways, resulting in bronchial dilatation.⁴ In addition, doxofylline can play a role in reducing inflammation, as evidenced by the inhibition of the inflammatory mediator platelet-activating factor and bacterial lipopolysaccharide-induced neutrophil infiltration in animal models.^5,6

Procaterol is an oral, long-acting, and selective beta-2 adrenergic agonist. This medication can increase the affinity for beta-2 adrenergic receptors, stimulating the relaxation of bronchial smooth muscle.^7,8 Moreover, procaterol can stimulate the protein kinase A pathway, causing inhibition of fibroblast cells and resulting in the reduction of airway remodeling. However, the bronchodilating efficacy of procaterol and doxofylline in asthmatic patients has not been investigated.

This study aimed to compare the bronchodilator effects and asthma control of doxofylline and procaterol in adults with asthma.

Methods

Randomization and intervention

Patients were randomly assigned in a 1:1 ratio to receive either doxofylline or procaterol. Randomization was performed using computerized web-based randomization. The flowchart of the study is shown in Figure 1.

Figure 1. Flowchart of prospective, randomized controlled, crossover study in asthmatic patients taking oral doxofylline and procaterol.

Before randomization, asthmatic patients entered a one-week run-in period, after which they were screened for eligibility for the study. Eligible patients were randomly divided into two groups to receive doxofylline at a dose of 400 mg twice daily (800 mg/day) or procaterol at a dose of 50 mcg twice daily (100 mcg/day) for 2 weeks, followed by a 1-week washout period followed by 2 weeks of crossover treatment (doxofylline or procaterol) (Figure 1). Physicians in charge of the study administered the study drug. All patients underwent spirometry with bronchodilator responsiveness (BDR) testing at baseline (visit 1), at the end of period 1 treatment (visit 2), at the start of period 2 (visit 3), and at the end of period 2 treatment (visit 4). BDR testing was performed by inhalation of 400 mcg of salbutamol and repeated spirometry after 15 min. Pulmonary function parameters were recorded by spirometry, including forced vital capacity (FVC), FEV₁, forced expiratory flow rate at 25-75% of FVC (FEF_25-75), peak expiratory flow (PEF), and BDR. Spirometry was performed according to the American Thoracic Society (ATS) and ERS guidelines^9–11 using a PC spirometer (Vyntus® SPIRO, Vyaire Medical, Inc., Mettawa, IL, USA). The complete blood count, blood eosinophil count, urine pregnancy test for women, electrocardiogram, Asthma Control Questionnaire-5 (ACQ-5) scores,¹² and Asthma Control Test (ACT) scores¹³ were also collected at visit 1. Spirometric parameters, ACQ-5 scores, and adverse events were recorded at visits 2, 3, and 4.

Before and during the study, the patients were allowed to take inhaled short-acting beta-agonists if they had asthma symptoms. During the study, the patients were permitted to ingest oral study medications in the morning when spirometry was performed.

Results

Thirty-three patients were screened, and 21 eligible patients were randomized into the study. After randomization, no patient was lost to follow-up (Figure 1). The baseline demographic and pulmonary function data of asthmatic patients are shown in Table 1. Twenty-one patients (23.8% males) were aged 53.0±14.8 years. All the patients had allergic rhinitis. ICS combined with LABA or LABA plus LAMA was used as the main treatment in all patients. Mean ACQ-5 was 1.38±1.12.

Secondary outcomes

ACQ-5 scores improved significantly from baseline in both groups (-0.381±0.740, P=0.029 and -0.476±0.873, P=0.021 for the doxofylline and procaterol groups, respectively) (Table 3, Figure 2). None of the patients experienced asthma exacerbations during the study period.

Figure 2. Asthma Control Questionnaire-5 (ACQ-5) scores before and after 2-week doxofylline and procaterol treatment in asthmatic patients.

Patients in the doxofylline group experienced dizziness, headaches, and insomnia (Table 4). Patients in the procaterol group had eight palpitations (Table 4), however they recovered from symptoms after 3-5 days of treatment.

Table 4. Adverse events of doxofylline and procaterol treatment in asthmatic patients.

Adverse events	Doxofylline (N=21)	Procaterol (N=21)
Asthma exacerbation	0	0
Adverse drug reaction
Dizziness	1 (4.8)	0
Headache	1 (4.8)	0
Insomnia	1 (4.8)	0
Palpitation	0	8 (38.1)

Discussion

This study is the first crossover randomized trial to compare two oral bronchodilators for the treatment of asthma. We found no differences in pulmonary function, asthma symptoms, or exacerbation between doxofylline and procaterol in asthma treatment. Our results showed that both doxofylline and procaterol significantly improved asthma symptoms, although baseline pulmonary function remained unaffected.

The GINA guidelines recommend ICS-containing controller treatment of asthma in adults and adolescents to reduce serious exacerbations and control asthma symptoms.¹ In addition, low-dose sustained-release theophylline might be another option for asthma treatment at step 3 or higher.^1,16 ICS-containing regimens are still the main asthma therapy; however, various inhalation devices and hand-breath coordination are crucial issues, especially in patients with insufficient inspiratory effort or in patients with hand-mouth incoordination, leading to incorrect use of inhalation devices and uncontrolled asthma.^3,17 Incorrect inhaler use was observed in 70% of asthmatic patients.¹⁸ Therefore, other treatments, such as oral xanthine, are alternative options for controlling asthma symptoms.¹

The guidelines for adult asthma management in Thailand recommend sustained-release xanthine in patients with severe, uncontrolled asthma despite taking a high dosage of ICS/LABA (step 4 asthma treatment).¹⁹

A real-world study by Racine G and coworkers²⁰ reported that adherence to asthma treatment was very low in patients with (44.4%) and without (37.5%) asthma exacerbation. A study by Staehr Holm F and colleagues²¹ found that hospital admission with asthma exacerbation did not increase patient adherence to controller medication.

Doxofylline is an orally active novofylline attributed to the class of methylxanthine, which is characterized by both anti-inflammatory and bronchodilator activities.²² In adults, the peak serum doxofylline concentration is observed after oral administration of 400 mg twice daily for 5 days.²³ Doxofylline 400 mg twice daily is as effective as theophylline 400 mg sustained release once daily,²⁴ but doxofylline shows safer profiles with fewer adverse events and a larger therapeutic index.⁴ A study by Goldstein MF and coworkers²⁵ showed that FEV₁ improvement 2 h after the oral administration of treatments in asthmatic patients exhibited significant differences between doxofylline 400 mg three times daily (t.i.d.) and placebo and between theophylline 250 mg t.i.d. and placebo; however, patients in both the high-dose doxofylline and theophylline groups had to interrupt treatment because of adverse events. A pooled analysis of DOROTHEO 1 and DOROTHEO 2 studies by Calzetta L and colleagues²⁶ demonstrated that both doxofylline 400 mg t.i.d. and theophylline 250 mg t.i.d. significantly increased FEV₁, reduced the rate of asthma events, and reduced the use of salbutamol to relieve asthma symptoms compared with placebo. Doxofylline did not significantly increase the risk of adverse events compared with placebo; however, theophylline had a significantly higher risk of adverse events. A systematic review of 15 studies by Nair P and coworkers²⁷ revealed that intravenous aminophylline had no additional benefit on inhaled beta 2-agonists for the treatment of asthma exacerbation, but had more serious side effects than placebo. Nevertheless, doxofylline showed no serious adverse effects in our study.

Procaterol is a beta 2-selective adrenergic receptor agonist characterized by a direct bronchodilating effect. A study in 20 asthmatic patients by Tukiainen H and coworkers²⁸ showed that oral procaterol 100 mcg twice daily had a more potent bronchodilator effect of increasing PEF than salbutamol, but there was more palpitations than placebo. A study in 24 asthmatic patients by Crowe MJ and colleagues¹⁵ reported that procaterol and salbutamol were clinically similar in terms of improvement in lung function (FEV₁ and FVC) and adverse events such as headache and tremor. The authors suggested that the maximum effective dose of procaterol was less than 50 mcg.¹⁵

Although pulmonary function parameters were not different after oral bronchodilator treatment in our study, asthma symptoms significantly improved. The improvement of symptoms by oral bronchodilators might be explained by other mechanisms, including anti-inflammatory effects^26,29,30 via inhibition of eosinophil functions,^31,32 reducing cough,³³ and increasing airway secretion clearance by enhancing the mucociliary transport of the airway.³⁴

Our asthmatic patients were already well-controlled according to their ACT and ACQ-5 scores. However, the ACQ-5 scores improved significantly after treatment with oral bronchodilators (0.38 and 0.47 points for the doxofylline and the procaterol groups, respectively). They almost achieved a minimal clinically important ACQ-5 difference of 0.5 points.³⁵

This study had some limitations. First, our patients had well-controlled asthma symptoms and normal baseline pulmonary function at study enrollment. Consequently, these results may not demonstrate significant differences in spirometry parameters after oral bronchodilator treatment. Second, this study was conducted during the COVID-19 pandemic period. This situation might have affected clinical outcomes such as asthma exacerbation rates, which might have been lower than expected due to preventive measures for respiratory infection (e.g., mask wearing). Third, a single- or double-blind method could not be implemented in this study due to differences in the packaging of both medications. However, we attempted to minimize the bias by employing a crossover design. Therefore, physicians and patients could identify the study drugs, potentially leading to a bias in clinical outcomes. Lastly, our short-term follow-up period of 2 weeks might not have been long enough to observe changes in pulmonary function and clinical outcomes, especially asthma exacerbations. A longer prospective study is required to investigate the efficacy of oral bronchodilators on pulmonary function and asthma outcomes.

Conclusions

Doxofylline and procaterol can improve asthma symptoms in asthmatic patients with normal baseline pulmonary function, although they are not able to enhance lung function. There were relatively few adverse drug events and they were not serious. These oral bronchodilators can be used as adjunctive therapies to improve asthma symptoms.

Software availability

Statistical analyses were performed using SPSS version 24.0 (IBM Corp., Armonk, NY, USA). https://www.ibm.com/support/pages/downloading-ibm-spss-statistics-24.

Ethics and consent

Ethical approval was obtained from the Human Research Ethics Committee of the Thammasat University (Medicine), Thailand (IRB No. MTU-EC-IM-0-095/64, COA No.174/2021, Date of approval on July 19, 2021), in full compliance with international guidelines such as the Declaration of Helsinki, Belmont Report, CIOMS Guidelines, and International Conference on Harmonization–Good Clinical Practice (ICH-GCP). All methods were performed in accordance with the guidelines and regulations. All the participants provided written informed consent.