INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

There is currently considerable interest in the potential use of selective inhibitors of cyclic nucleotide phosphodiesterases (PDEs) in the treatment of asthma (1). Some investigators have identified PDEs of the 1, 2, 3, 4, and 5 families in human tracheal (2) and bronchial (3, 4) smooth muscles. It has been reported that a selective PDE3 inhibitor exhibits a bronchodilator activity in asthmatic patients (5, 6) and inhibits antigen-induced bronchoconstriction in guinea pigs (7) and asthmatics (6). We also demonstrated that the PDE3 inhibitor cilostazol reduces bronchial responsiveness in healthy volunteers (8) and asthmatics (5).

However, PDE3 inhibitors markedly affect heart rate and blood pressure (9). At therapeutic doses, cilostazol also causes headaches, perhaps as a result of cerebral vasodilation (8). Because the airway and cardiovascular effects cannot be separated, systemic PDE3 inhibitors may be of little benefit in the treatment of asthma. On the other hand, it has been reported that when ultrasonically nebulized, the PDE3 inhibitor milrinone has no inhibitory effect on histamine- or antigen-induced bronchoconstriction in cats (10) and that direct injection of the PDE3 inhibitor MKS 492 has no bronchodilator effect in guinea pigs (11), whereas MKS 492 attenuates methacholine-induced bronchoconstriction in guinea pigs (11) and inhaled zardaverine, a dual inhibitor of PDE3 and PDE4, exhibits bronchodilator activity in asthmatic patients (12).

In order to examine the usefulness of inhaled PDE3 inhibitors in the treatment of asthma, we investigated the bronchodilator effect of inhaled olprinone (E-1020: 1,2-Dihydro-6-methyl-2-oxo-5-[imidazo(1,2-a)pyridin-6-yl]-3-pyridine carbonitrile hydrochloride monohydrate), a newly developed PDE3 inhibitor (13, 14), in asthmatic patients.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Subjects

Nine asthmatic subjects (seven males, two females, age 25 to 66 yr) were studied (Table 1). None of the subjects had ever smoked or experienced any occupational exposure, and each subject 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% of reversibility in terms of FEV₁) documented on at least one pulmonary function study (15). None of the subjects had a history of excessive mucus expectoration, and there was no low attenuation area in thin-slice chest computed tomography (CT) among all the subjects. None of the subjects had taken theophylline, antihistamines, sodium cromoglycate, or oral corticosteroids in 2 mo or more prior to the study, and no subject experienced an upper respiratory tract infection in the preceding month or during the study. Permitted medication, which remained unchanged during the study, included inhaled ₂-agonists and inhaled corticosteroids. This study was carried out when the patients' symptoms were mild and stable. Informed consent was obtained from all subjects. This study was approved by the ethics committee of our university hospital.

Study Protocol

Aerosolized administration of olprinone, salbutamol, or vehicle was performed on three occasions 1 wk apart, in a double-blind and randomized fashion. All medication was stopped at 1:00 P.M. on the previous day to allow a washout time of at least 24 h. On each study day, FVC and FEV₁ were recorded at 1:00 P.M. Olprinone and salbutamol were dissolved in D-sorbitol solution (50 mg/ml) to form solutions with concentrations of 1 and 1.25 mg/ml, respectively.

Olprinone at a dose of 2 mg, salbutamol at a dose of 2.5 mg, or vehicle was inhaled from a DeVilbiss 646 nebulizer (DeVilbiss Co., Somerset, PA) operated by compressed air at 5 L/min. The nebulizer output was 0.14 ml/min. The pulmonary functions were recorded 15, 30, 45, and 60 min after each inhalation. FVC and FEV₁ were measured on a dry wedge spirometer (Transfer Test, P.K. Morgan Ltd., UK). Subjects performed three FVC maneuvers in the sitting position. Spirometry was performed and evaluated with ATS criteria for acceptability and reproducibility (16). Blood pressure and heart rate were also recorded before the pulmonary function tests.

Statistical Analysis

Repeated-measures analysis of variance (ANOVA) was used to assess differences in baseline FVC, FEV₁, blood pressure, and heart rate on the three occasions. The degrees of bronchodilation and cardiovascular effects induced by each tested solution were analyzed by repeated-measures ANOVA for three occasions. If significant (p < 0.05), the values were compared using the Bonferroni test. All results were expressed as mean ± SEM and differences were regarded as statistically significant at p < 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The mean baseline values of FVC and FEV₁ were identical among the three occasions. Although the time course of FVC after inhalation of olprinone or salbutamol was not significantly different from that after inhalation of vehicle (Figure 1), there was a significant difference in the time courses of FEV₁ after inhalation of olprinone, salbutamol, and vehicle (Figure 2). Significant increases in FEV₁ were observed until 45 min and at least 60 min after inhalation of olprinone and salbutamol, respectively. Mean maximal increases in FEV₁ were 16.0 ± 4.0 and 20.5 ± 4.2% after inhalation of olprinone and salbutamol, respectively (p = 0.28). The time courses for individual subjects are shown in Figure 3. The bronchodilator effect of olprinone was greater than that of salbutamol in four (Patients 1, 2, 3, and 5) of the nine patients, and no effect was observed after olprinone inhalation in only one patient (Patient 9).

View larger version (16K): [in this window] [in a new window]   Figure 1.   Time courses of FVC after inhalation of olprinone (closed squares), salbutamol (closed circles), and vehicle (open triangles) in nine asthmatic patients. There was no statistically significant difference when the three curves were compared using repeated-measures ANOVA (p > 0.1).

View larger version (15K): [in this window] [in a new window]   Figure 2.   Time courses of FEV1 after inhalation of olprinone (closed squares), salbutamol (closed circles), and vehicle (open triangles) in nine asthmatic patients. There was a statistically significant difference when the three curves were compared using repeated-measures ANOVA (p < 0.01). *p < 0.05 and **p < 0.01 compared with vehicle.

View larger version (30K): [in this window] [in a new window]   Figure 3.   The individual time courses of FEV1 after inhalation of olprinone (closed squares), salbutamol (closed circles), and vehicle (open triangles) in nine asthmatic subjects.

As shown in Table 2, there were no significant differences in time course of blood pressure among three occasions. A significant increase in heart rate was observed after inhalation of salbutamol but not after inhalation of olprinone. None of the subjects complained of adverse effects.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

In this study, we investigated the effect of inhaled olprinone on the airway caliber in nine asthmatic patients. Our results show that olprinone has a bronchodilator effect in terms of FEV₁. It has been reported that olprinone inhibits guinea pig heart PDE3 and increases cyclic AMP contents of isolated guinea pig papillary muscles (13), and that the inhibitory concentration of 50% (IC₅₀) values of olprinone inhibition of PDE1, PDE2, PDE3, and PDE4 are 150 ± 25, 100 ± 13, 0.35 ± 0.03, and 14 ± 0.4 µmol/L, respectively (14). The dose of olprinone inhaled in this study was 2 mg (6.6 µmol). These observations suggest that inhalation of PDE3 inhibitors has a bronchodilator effect in asthmatic patients.

PDE3 inhibitors have been shown previously to exert bronchodilator action after intravenous and oral administration (5, 6, 17). This study shows that PDE3 inhibitors can also be effective with no cardiovascular side effects when administered by inhalation. Although a previous study (12) has shown a weak and transient bronchodilator action of inhaled zardaverine, a combined PDE3 and PDE4 inhibitor, the bronchodilation caused by olprinone in the present study is both more substantial and more prolonged.

At the moment, the therapeutic usefulness of PDE3 inhibitors in bronchial asthma is unclear. However, elevation of cyclic adenosine monophosphate (cAMP) by -agonists may result in increased PDE activity, thus limiting the bronchodilator effect of -agonists. Indeed, there is evidence that alveolar macrophages from asthmatic patients have increased PDE activity (18). It is necessary to assess the various effects of PDE inhibitors, such as the synergistic effect with -agonists. Furthermore, it is necessary to evaluate the long-term effect of olprinone.

In conclusion, inhaled PDE3 inhibitors may be useful as airway smooth muscle relaxants in the treatment of asthma.