European Journal of Clinical Pharmacology

Eur J Clin Pharmacol (1986) 31: 105-106

© Springer-Verlag 1986

Long-Term Treatment with Oral Nifedipine Plus Theophylline in the Management of Chronic Bronchial Asthma C. Spedini and C. Lombardi Department of Internal Medicine, S. Orsola-FatebenefratelliHospital, Brescia, Italy

Summary. The effect on bronchial smooth muscle of slow release theophylline plus placebo and theophylline plus slow release nifedipine administered for a prolonged period to 12 asthmatic and hypertensive patients has been studied. Both combinations led to a significant improvement in respiratory function parameters when compared to baseline values. No additional improvement in pulmonary function was found on long term treatment with theophylline plus nifedipine. A reduction in the number of asthmatic attacks, in the use of inhaled beta2-agonists and better control of arterial blood pressure resulted from use of theophylline plus nifedipine. That drug combination is safe and valuable in patients with chronic bronchial obstruction and cardiovascular disease. Key words: theophylline, nifedipine; bronchial asthma

Transmembrane passage of calcium ions underlies activation of the cellular response in several biological systems, including the release of chemical mediators from mast cells and the contraction of bronchial smooth muscle. A possible bronchodilator activity of Calcium Entry Blockers (CEBs) has been suggested [1, 2]. Thus, when administered sublingually nifedipine showed mild, not significant bronchodilator action [3]. There does not appear to be clinical information about the long term effects of CEBs on spontaneously occurring exacerbations of bronchial asthma. Ethical problems connected with the use of CEBs alone in the therapy of bronchial obstruction are the cause of the lack of such information. In vitro studies have revealed that nifedipine can potenciate the bronchodilator effects of theophylline

(Daya S. and Jonkert R H. 1984, personal communication). An investigation has now been made into the effect on bronchial smooth muscle of slow release theophylline and theophylline plus slow release nifedipine administered for a prolonged period to patients with chronic bronchial asthma. Patients and Methods Twelve patients were studied, aged 53-69years (4 males and 8 females) with stable chronic asthma and a history of arterial hypertension. All subjects gave their informed consent and the protocol was approved by the Hospital Research Ethics Committee. After a 48-h period for wash-out of previously administered drugs, each subject received, in a double-blind randomized sequence, slow release theophylline (200-300mg b.d., according to body weight) plus placebo for 30days (Group T + P ) or slow release theophylline (same dose) plus slow release nifedipine (20mg b.i.d.) for 30days (Group T + N). Both active and placebo tablets had the same appearance. Using a dry spirometer, measurements were made of forced expiratory volume in one second (FEVI), vital capacity (VC) and maximal mid-expiratory flow (MMEF). The measurements were taken before starting the therapy and after 30 and 60 days. All tests in each subject were performed at the same time of the day. The patients were instructed to record daily heart rate and blood pressure, reporting values on a personal schedule, and to note on a dial~j card the number of exacerbations of asthma, including the use of concomitant inhaled beta-2-adrenoceptor agonists. During the investigation, all patients took a low sodium diet. Results in the treatment groups were compared with the t-test.

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C. Spedini and C. Lombardi: Nifedipine plus Theophytline in Asthma

Table 1. Mean (_+SD) changes in lung function tests, inhaled beta2-adrenergic agonist use, heart rate and blood pressure Control (t3days) FEV1 VC MMEF beta2-agonist (puffs/day) Heart rate (beats/rain) Blood pressure systolic (mmHg) Diastolic

T+ P (30 days)

1.17 + 0.21 2.74 + 0.23 0.76 ___0.17

T+ N (30 days)

al.76 _ 0.16 a3.414- 0.25 q.20 4- 0.15

-N. S.-N. S.-N.S.- N.S.-

80.8 _ 4.3

- N.S.-

3.0___0.9 84.6 4-4.7

176.6 _+7.0 104.2 _+6.3

-N.S.-N.S.-

161.4_+4.6 92.0_+3.3

1.78 + 0.17~ 3.47 + 0.24a 1.21 ___0.17a 2.1 +0.7 b 86.2 + 4.8 144.1 +3.1 c 80.0 -+3.6c

a p< 0.01 (vs control) b p< 0.05 (T+ N vs T+ P) c p< 0.01 (vs T+ P and control)

Results N o subject c o m p l a i n e d o f any side-effect. The resuits are reported in Table 1. There was a significant increase between spirometric baseline values and values after the T + P a n d T + N t h e r a p y (p<0.01). Statistical analysis did not show a significant difference between T + P a n d T + N values. The T + N g r o u p revealed a significant decrease in the BP values a n d a small increase in the heart rate. The n u m b e r o f exacerbations o f a s t h m a and use o f the inhaled beta2-agonist was lower in the T + N group.

Discussion The study has s h o w n that nifedipine c o m b i n e d with theophylline in the treatment o f chronic stable asthm a causes an i m p r o v e m e n t in the respiratory function parameters. The i m p r o v e m e n t , however, was not as significant as that f o u n d o n testing theophylline plus a placebo, as already s h o w n b y results o b t a i n e d after single doses o f nifedipine [3]. At the clinical level a reduction in exacerbations a n d in beta2-agonist inhalation was observed. Better control o f arterial b l o o d pressure also resulted. It is considered that this d e m o n s t r a t e s that the c o m b i n a t i o n o f nifedipine plus theophylline m a y safely be given to patients with airways obstruction, especially if they are hypertensive or suffer f r o m is-

chaemic heart disease. The reduction in the arterial pressure should not be underestimated at the level o f the p u l m o n a r y system [4]. Therefore, patients with chronic bronchial obstructions a n d cardiovascular disease can safely benefit f r o m the c o m b i n a t i o n o f nifedipine and theophylline, since this combination o f drugs has n o w been s h o w n not to be hazardous. Acknowledgment. We t h a n k Dr. L. Pasquale, Institute o f Health Science University o f Brescia, Italy, for the statistical analysis.

References 1. Spedini C, Lombardi C (1986) Calcium antagonists in COPD. Chest 89:315-316 2. Lombardi C, Spedini C, Govoni S (I985) Effect of calcium entry blockade on ethanol-induced changes in bronchomotor tone, Eur J Clin Pharmacol 28:221-222 3. Williams DO, Barnes PJ, Vickers HP, Rudolf M (1981) Effect of nifedipine on bronchomotor tone and histamine reactivity in asthma. Br Med J 283: 348 4. Sturani C, Bassein L, Schiavina M, Gunella G (1983) Oral nifedipine in chronic cor pulmonale secondary to severe chronic obstructive pulmonary disease. Short and long-term hemodynamic effects. Chest 84:135 Received: February 27, 1986 accepted in revised form: June 2, 1986 Dr. Cesare Spedini Via Einaudi, 26 1-25122 Brescia, Italy