Abstract
Aims
There is no evidence demonstrating the clinical usefulness of phosphodiesterase (PDE) inhibitors in the treatment of asthma, although PDE3 and 4 inhibitors have received much attention for the treatment of bronchial asthma. We compared the bronchodilator effects of intravenously administered olprinone, a selective PDE3 inhibitor, and aminophylline, a nonselective PDE inhibitor, both alone and concomitantly.
Methods
In 12 patients with mild stable asthma, we compared the acute bronchodilator effects of the following two drugs, alone and together using a double-blind crossover design: intravenous administration of olprinone, 30 µg min−1; aminophylline, 2.25 mg min−1; and olprinone plus aminophylline over a total period of 150 min.
Results
Mean maximal increase (95% confidence interval) in the FEV1 was 7.8% (2.4, 13.2), 17.1% (10.0, 24.2), 16.6% (11.2, 22.0), and 1.0% (−1.1, 3.1) during infusion of aminophylline, olprinone, aminophylline and olprinone, and saline, respectively. The magnitude of bronchodilatation produced by olprinone was greater than that by aminophylline. The combination of aminophylline and olprinone did not produce any greater bronchodilatation than olprinone alone. Olprinone alone or in combination with aminophylline lowered diastolic blood pressure, and increased heart rate.
Conclusions
These results suggest that the intravenous administration of PDE3 inhibitors exhibits a bronchodilatory effect. There are no additive or synergistic effects of administration of olprinone and aminophylline at the same time.
Keywords: aminophylline, asthma, bronchodilatation, olprinone, phosphodiesterase 3 inhibitors
Introduction
National and international guidelines recommend the use of theophylline as second-line or, in most cases, third-line treatment for patients whose symptoms are not adequately controlled with corticosteroids and β2-adrenoceptor agonists [1–3]. Indeed, theophylline is less effective as a bronchodilator than the inhalation of β2-agonists [4], and is less effective as an anti-inflammatory drug than inhaled steroids [5]. Several mechanisms of action have been suggested to explain the therapeutic effectiveness of theophylline. One proposed mechanism is that theophylline, through nonselective phosphodiesterase (PDE) inhibition, raises the intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) concentrations, resulting in relaxation of airway smooth muscle, although a total therapeutic concentration of theophylline inhibits PDE activity in human lung extract by only 5–10% [6]. An improvement in the therapeutic index may, in turn, lead to an improvement in clinical efficacy by permitting greater inhibition of the pertinent PDE isoenzyme(s).
We demonstrated that the orally administered PDE3 inhibitor cilostazol reduces bronchial responsiveness in healthy volunteers [7] and asthmatics [8], and that inhalation of olprinone, a PDE3 inhibitor [9, 10], exhibits a bronchodilator effect in asthmatic patients [11]. Foster and colleagues [12] reported that intravenous AH 21-132, a dual inhibitor of PDE3 and PDE4, exhibits weak and short-lived bronchodilatation in healthy volunteers.
However, there is no evidence demonstrating the clinical usefulness of PDE inhibitors in the treatment of asthma. We undertook the present study to examine the bronchodilating effect of intravenous olprinone in patients with asthma. We also sought to determine whether these two classes of bronchodilators, olprinone and aminophylline, have additive or synergistic effects when used in combination. We compared the acute cardiopulmonary effects of intravenously administered olprinone and aminophylline both alone and concomitantly.
Materials and methods
Subjects
Twelve asthmatic subjects (eight males and four females, aged 21–63 years) were studied (Table 1). None of the patients had ever smoked or experienced any occupational exposure, and each patient satisfied the American Thoracic Society (ATS) definition of asthma, with symptoms of episodic wheezing, cough, and shortness of breath responding to bronchodilators, and reversible airflow obstruction (more than 15% reversibility of FEV1) documented on at least one pulmonary function study [13]. None of the patients had a history of excessive mucus expectoration, and thin-slice chest computed tomography showed no low-attenuation area in any patient. None of the patients had taken theophylline, long-acting β2-agonists, H1-receptor antagonists, sodium cromoglycate, or oral corticosteroids for at least 2 months prior to the study, and none had suffered an upper respiratory tract infection in the preceding month or during the study. Permitted medications, which remained unchanged during the study, included inhaled short-acting β2-agonists and inhaled corticosteroids. This study was conducted while the patients’ symptoms were mild and stable. Informed consent was obtained from all patients. This study was approved by the ethics committee of Kanazawa University Hospital.
Table 1.
Subject characteristics.
| Subject no. | Age(years) | Sex | Body weight(kg) | FVC(% predicted) | FEV1 (% predicted) | FEV1/FVC(%) | PC20-MCh(mg ml−1) | Treatment |
|---|---|---|---|---|---|---|---|---|
| 1 | 39 | F | 78 | 108.5 | 86.9 | 72.1 | 0.13 | Sa, Be (800) |
| 2 | 41 | F | 55 | 94.8 | 71.6 | 72.6 | 2.37 | Sa, Be (800) |
| 3 | 22 | M | 67 | 119.4 | 73.9 | 60.9 | 0.52 | Sa, Be (200) |
| 4 | 62 | M | 62 | 112.3 | 90.8 | 65.0 | 3.55 | Sa, Be (200) |
| 5 | 53 | F | 76 | 80.5 | 77.0 | 74.2 | 0.40 | Sa |
| 6 | 63 | F | 56 | 100.3 | 78.1 | 81.7 | 0.14 | Sa, Be (200) |
| 7 | 39 | M | 62 | 126.4 | 115.1 | 82.5 | 0.84 | Sa |
| 8 | 47 | M | 60 | 114.6 | 61.8 | 7.15 | 81.0 | Sa, Be (200) |
| 9 | 33 | M | 76 | 112.1 | 84.1 | 70.5 | 1.58 | Sa |
| 10 | 40 | M | 60 | 107.2 | 83.5 | 66.7 | 0.14 | Sa, Be (400) |
| 11 | 29 | M | 63 | 124.2 | 88.6 | 65.7 | 0.13 | Sa, Be (200) |
| 12 | 21 | M | 66 | 101.9 | 79.8 | 73.4 | 0.86 | Sa |
| Mean ± s.e.m. | 41 ± 4 | 65 ± 2 | 108.5 ± 3.7 | 84.2 ± 3.3 | 70.6 ± 2.0 | 0.638* ± 0.175** |
Be (µg), Beclomethasone dipropionate via metered dose inhaler (daily inhaled dose); Sa, salbutamol via metered dose inhaler on demand; PC20-MCh, methacholine concentration producing a 20% fall in FEV1.
Geometric mean
geometric standard error of the mean.
Study protocol
Intravenous administration of olprinone, aminophylline, both or saline was performed on four occasions, 1 week apart, in a blinded and randomized fashion. All medication or caffeine-containing foods or beverages were stopped at 13.00 h on the previous day to allow a washout time of at least 24 h. On each study day, the forced vital capacity (FVC) and forced expiratory volume in 1s (FEV1) were recorded at 13.00 h. Olprinone and aminophylline were dissolved in physiological saline to form solutions with concentrations of 0.01 and 0.75 mg ml−1, respectively. An 18-G cannula was inserted into an antecubital vein for infusion of each solution. Each solution was administered intravenously at a rate of 3 ml min−1 for 150 min. Inhalation of salbutamol at a dose of 300 µg was performed 120 min after the start of each infusion. Pulmonary function was recorded every 30 min up to 150 min after the start of each infusion. Lastly, blood samples were drawn from an antecubital vein on the contralateral side, and aminophylline and olprinone concentrations were measured by fluorescence polarization immunoassay and high-performance liquid chromatography, respectively. FVC and FEV1 were measured on a dry wedge spirometer (Transfer Test; P.K. Morgan Ltd, Gillingham, Dorset, UK). Subjects performed three FVC manoeuvres in the sitting position. Spirometry was performed and evaluated with ATS criteria for acceptability and reproducibility [14]. Blood pressure and heart rate also were recorded prior to the pulmonary function tests.
Statistical analysis
Repeated-measure analysis of variance (anova) was used to assess differences in baseline pulmonary function, blood pressure and heart rate for each intervention. The degree of bronchodilatation and cardiovascular effects induced by each tested solution was analysed by repeated-measures anova. If significant (P < 0.05), the values were compared using the Fisher's protected least significant difference. Mean maximal increase in FEV1 was calculated based on the highest value of FEV1 among 30, 60, 90 and 120 min after the start of each infusion. Data are expressed as the mean ±s.e.m. or 95% confidence intervals (CI). Differences were regarded as statistically significant at P < 0.05.
Results
The mean baseline values of FEV1 were identical at the start of each of the interventions on the four occasions (aminophylline 2.72 ± 0.25 l; olprinone 2.70 ± 0.23 l; combination 2.70 ± 0.24 l; saline 2.71 ± 0.24 l; anova P = 0.999). Aminophylline and olprinone, either alone or in combination, produced more bronchodilatation than saline (Figure 1). Mean maximal increase (95% CI) in the FEV1 was 7.8% (2.4, 13.2), 17.1% (10.0, 24.2), 16.6% (11.2, 22.0), and 1.0% (−1.1, 3.1) during infusion of aminophylline, olprinone, aminophylline and olprinone, and saline, respectively (anova P < 0.01). During aminophylline infusion, additional administration of inhaled salbutamol caused more increase in FEV1, 7.2% (1.8, 12.6) to 17.3% (9.5, 25.1) (P < 0.01), suggesting that aminophylline is a less effective bronchodilator than inhalation therapy with salbutamol.
Figure 1.
Time course of FEV1 during intravenous administration of aminophylline (▴), olprinone (•), aminophylline and olprinone (▪), and saline (○) in 12 patients with stable, mild asthma. There was a statistically significant difference when the three curves were compared using repeated-measure anova (P < 0.01). *P < 0.05 and **P < 0.01 compared with saline; †P < 0.05 and ††P < 0.01 compared with aminophylline.
The maximum increase in FEV1 produced by olprinone was significantly (P < 0.01) greater than that produced by aminophylline, and was equal to that achieved by salbutamol during aminophylline infusion; in addition, the onset of action of olprinone was rapid. The combination of aminophylline and olprinone was not more effective than olprinone alone. There was no difference in bronchodilatation 30 min after inhalation of salbutamol between any two groups. The time courses for individual subjects are shown in Figure 2. The bronchodilator effect of olprinone was greater than that of aminophylline in all patients. Blood concentrations were unaffected by concomitant administration (Table 2).
Figure 2.
Time course of FEV1 for each subject following aminophylline (▴), olprinone (♦), aminophylline and olprinone (▪), and saline (○).
Table 2.
Serum aminophylline and olprinone concentrations.
| Subject No. | Aminophylline (µg/ml) | Olprinone (ng/ml) | ||
|---|---|---|---|---|
| Aminophylline day | Combination day | Olprinone day | Combination day | |
| 1 | 9.5 | 9.5 | 65.3 | 51.6 |
| 2 | 12.8 | 12.0 | 43.4 | 36.2 |
| 3 | 10.2 | 7.2 | 38.6 | 39.3 |
| 4 | 13.2 | 13.1 | 57.2 | 55.0 |
| 5 | 9.3 | 10.5 | 50.3 | 57.2 |
| 6 | 14.9 | 17.9 | 65.2 | 66.5 |
| 7 | 9.5 | 9.2 | 44.3 | 41.2 |
| 8 | 11.7 | 10.7 | 40.0 | 34.1 |
| 9 | 8.7 | 6.8 | 37.3 | 15.9 |
| 10 | 9.9 | 12.6 | 31.7 | 33.0 |
| 11 | 8.4 | 11.4 | 52.6 | 52.8 |
| 12 | 12.2 | 11.3 | 42.2 | 45.6 |
| Mean | 10.8 | 11.0 | 47.3 | 44.0 |
| SEM | 0.6 | 0.8 | 3.1 | 3.9 |
Olprinone alone or in combination with aminophylline lowered the diastolic blood pressure, and increased the heart rate compared with saline (Table 3). No subjects reported any adverse effect.
Table 3.
Cardiovascular effect of intravenous olprinone and aminophylline in asthmatic patients.
| Time (min) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Baseline | 30 | 60 | 90 | 120 | 150 | p | anova§ | |
| Systolic blood pressure (mmHg) | ||||||||
| Aminophylline | 130.9 ± 7.1 | 132.6 ± 5.4 | 127.1 ± 5.7 | 125.9 ± 6.3 | 130.4 ± 6.9 | 125.9 ± 5.1 | ||
| Olprinone | 122.4 ± 5.2 | 115.5 ± 5.7 | 113.6 ± 4.1 | 109.4 ± 3.7 | 108.5 ± 4.4 | 116.9 ± 4.8 | 0.2449 | |
| Combination | 129.5 ± 5.0 | 125.0 ± 4.0 | 113.8 ± 4.2 | 114.9 ± 3.1 | 110.5 ± 4.5 | 113.6 ± 4.0 | ||
| Saline | 124.1 ± 2.6 | 123.3 ± 4.7 | 119.1 ± 5.9 | 118.4 ± 3.6 | 118.5 ± 4.5 | 121.5 ± 3.3 | ||
| Diastolic blood pressure (mmHg) | ||||||||
| Aminophylline | 89.5 ± 4.6 | 85.2 ± 4.6 | 85.6 ± 4.9 | 85.2 ± 5.1 | 86.5 ± 5.1 | 83.6 ± 2.9 | ||
| Olprinone | 82.6 ± 4.1 | 73.3 ± 3.2* | 85.6 ± 4.9†† | 67.2 ± 2.9*†† | 63.7 ± 2.6**†† | 63.4 ± 2.9**†† | 0.0174 | |
| Combination | 84.5 ± 3.0 | 78.7 ± 3.0 | 73.6 ± 2.7† | 70.2 ± 2.7*†† | 64.4 ± 3.9*†† | 65.5 ± 2.7**†† | ||
| Saline | 78.5 ± 4.2 | 82.7 ± 5.0 | 77.8 ± 4.7 | 80.5 ± 3.1 | 78.6 ± 3.6 | 80.1 ± 3.9 | ||
| Heart rate (/min) | ||||||||
| Aminophylline | 81.4 ± 2.9 | 74.7 ± 2.4 | 75.5 ± 2.0 | 73.3 ± 2.6 | 71.5 ± 2.4 | 75.7 ± 3.0 | ||
| Olprinone | 83.7 ± 3.4 | 87.9 ± 3.9† | 89.4 ± 4.6*† | 92.9 ± 4.2**†† | 89.2 ± 4.5*†† | 95.4 ± 4.8**†† | 0.0032 | |
| Combination | 79.6 ± 3.0 | 81.5 ± 2.9 | 95.2 ± 3.6**†† | 94.2 ± 3.8**†† | 94.5 ± 4.6**†† | 99.0 ± 5.4**†† | ||
| Saline | 79.7 ± 4.5 | 81.6 ± 5.3 | 76.2 ± 4.1 | 76.0 ± 3.9 | 74.7 ± 3.2 | 76.0 ± 37 | ||
All measurements were expressed as mean ± standard error of the mean (SEM).
Repeated-measure anova was used for differences between four time courses.
P < 0.05
P < 0.01 compared with saline.
p < 0.05
p < 0.01 compared with aminophylline.
Discussion
The present study compared the cardiopulmonary effects of olprinone and aminophylline alone and in combination in a double-blind crossover fashion over a total period of 150 min. Olprinone produced a greater increase in the FEV1 than aminophylline or saline. It has been reported that olprinone inhibits guinea pig heart PDE3 and increases the cyclic AMP content of isolated guinea pig papillary muscle [9], and that the IC50 of olprinone for inhibition of PDE1, PDE2, PDE3, and PDE4 are 150 ± 25, 100 ± 13, 0.35 ± 0.03, and 14 ± 0.4 µm, respectively [10]. In this study, we used olprinone at a maximum dose, which has been demonstrated to be safe in healthy volunteers [15]. The serum concentration of olprinone was 47.3 ± 3.1 ng ml−1 (approx. 0.16 µm). These observations suggest that PDE3 inhibitors may be effective as bronchodilators in asthmatics.
Although the mean effect of olprinone on the FEV1 was significantly larger than the mean effect induced by aminophylline, there were important differences between the different study subjects. In patients 1, 3, 7, 9 and 12, the effect of aminophylline was similar to placebo. These patients could be regarded as nonresponders to aminophylline. In the other patients, the effect of aminophylline was very similar to olprinone, which indicates a relevant response to aminophylline. From this point of view, one could suggest that the difference in the mean bronchodilatation between olprinone and aminophylline is due to an increased response rate to olprinone than to aminophylline rather than a difference in bronchodilatory capacity. In this study, the mean aminophylline concentration (10.8 µg ml−1) is low compared with the recommended concentration (10–20 µg ml−1). Significant correlation was observed between the aminophylline concentration and patient's body weight (r = −0.64, P < 0.05), suggesting that the body weight may be a reason why the aminophylline concentration was low in some subjects. Furthermore, in patients 1, 3, 7, and 9, who did not have bronchodilator response to aminophylline, aminophylline concentration was low. Therefore, the lower concentration of aminophylline would be a possible reason why the bronchodilator effect of intravenous aminophylline was observed in only a proportion of the patients.
During a severe acute attack, national and international guidelines recommend the use of intravenous aminophylline as second- or third-line treatment for patients whose symptoms are inadequately controlled by corticosteroids and β2-adrenoceptor agonists [1–3]. In stable and well-controlled asthmatic patients, the present study confirmed that aminophylline is a less effective bronchodilator than inhalation therapy with salbutamol, and demonstrated that olprinone has no additional effect on salbutamol-induced bronchodilatation. These findings suggest that the addition of aminophylline or olprinone to this regimen does not enhance efficacy and is unwarranted in well-controlled asthmatics. However, the present study does not provide any information on the use of intravenous aminophylline or olprinone during a severe acute asthma attack.
In conclusion, intravenous PDE3 inhibitors exhibit bronchodilatory effect. There are no additive or synergistic effects of administration of olprinone and aminophylline at the same time. A more extensive study is needed to examine the clinical value of PDE3 inhibitors.
Acknowledgments
We thank Eisai Co., Ltd. (Tokyo, Japan) for measuring the olprinone concentration.
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