PREVENTION OF EXERCISE-INDUCED BRONCHOCONSTRICTION BY INHALED FRUSEMIDE

252

PREVENTION OF EXERCISE-INDUCED BRONCHOCONSTRICTION BY INHALED FRUSEMIDE S. BIANCO1 M. ROBUSCHI3

A. VAGHI2 M. PASARGIKLIAN3

Institute of Lung Diseases, University of Siena,1 Siena; Pneumology Division, Hospital of Garbagnate Milanese,2 Milan; and Institute of Lung Diseases, University of Milano,3 Milan, Italy

To determine whether inhaled frusemide, a diuretic able to interfere with ion and water across airway epithelium, can modify exercise-

Summary movement

induced bronchoconstriction,

three-part randomised, double-blind, placebo-controlled study was done in asthmatic patients who had a fall in FEV1 of at least 20% after running up and down a corridor. In the first part the effect of approximately 28 mg frusemide given as an aerosol was compared with that of a placebo. In the second part two a

doses of inhaled frusemide (approximately 14 mg and 28 mg) were examined. In the third part the effect of 20 mg oral frusemide was tested. Inhaled frusemide had a good and dose-related protective effect, whereas oral frusemide was ineffective. The mean (95% CI) maximum percentage falls in the FEV1 were: 11·5 (14·3-8·7) with frusemide and 33·8 (39·1-28·5) with placebo in the first part of the study, 13·6 (21·6-6·0) with 28 mg frusemide, 19·7 (28·2-11·3) with 14 mg frusemide, and 34·6 (39·4-30·0) with placebo in the second part of the study; and 15·2 (19·9-10·5) with inhaled frusemide, 38·2 (47·1-29·3) with oral frusemide, and 35·3 (45·9-24·7) with placebo in the last part of the study. The findings lend support to the hyperosmolarity hypothesis of exercise-induced asthma and may have therapeutic

implications.

been free of symptoms of respiratory infections for at least 6 weeks and were well controlled with inhaled &bgr;2-stimulants; only 7 also needed inhaled corticosteroids. Both drugs were withheld for at least 8 h before each exercise challenge. The subjects had undergone two screening tests 2 days apart to qualify for entry to the study. On the first occasion, after resting for 20 min and after wearing a nose clip, patients were invited to run at regular and sub-maximum speed back and forth along a 60 m straight corridor near the laboratory for 5-9 min; they could stop at any time during this interval if tired. Number of corridor lengths run and duration of exercise were recorded. FEV was measured at rest and 5 and 10 min after excercise. Arterial pressure and pulse rate were taken immediately before and immediately after exercise. The second screening test was done to confirm that FEV fall was at least 20%; on this occasion FEV was measured at the same time intervals as in the study days and this was taken as the control test. The study was done on 2 consecutive days 3-5 days after the second screening test. At the same time on each of the 2 days subjects were asked to inhale frusemide or placebo before exercise. These agents were given in random order and double blind. Frusemide (’Lasix’ Hoechst, as a 10 mg/ml solution containing NaCl7-0 mg, NaOH to reach pH 9, and water to make up 1 ml)and placebo (the diluent solution) were given by means of a jet nebuliser driven by a small compressor (’Flatus’, MEFAR, 20073 Bovezzo, Brescia, Italy). Patients inhaled from the nebuliser for 20 min, during which time the mean amount of frusemide delivered to the mouth (calculated on five occasions by differential weighing after placing 4 ml frusemide solution in the reservoir) was 28-3 (SEM 06) mg. For ease of data presentation this dose was designated F 28. Patients were connected to the nebuliser through a plastic cylindrical mouth-piece and asked to breathe normally wearing a

nose-clip. measured with a water-sealed spirometer (Warren E. duplicate and the better value was recorded. Measurements were done immediately before and after aerosol inhalation and then at 2, 4, 6, 8, 10, 15, and 30 min after exercise.

FEV1

Collins)

was

in

Two-dose

Study

clinically stable non-smokers (7 men, 1 woman), aged 13-38 17), with a typical history of exercise-induced wheezing participated in this study. All were taking inhaled (32 stimulants 8

years (mean

INTRODUCTION

WATER loss and hyperosmolarity of the fluid bathing the mucosa are important initiating factors in exerciseinduced bronchoconstriction.1-4 Therefore drugs such as frusemide, which can interfere with ion and water translocation across airway epithelium may modify the bronchial response to exercise. We have tested this idea and describe our findings here.

airway

SUBJECTS AND

METHODS

Single-dose Study clinically stable non-smokers (15 men, 3 women), aged 10-40 (mean 20), with a typical history of exercise-induced wheezing and no other diseases gave informed consent for the study. All had 18

J. WIRIMA: REFERENCES 1 Gilles HM The treatment and prophylaxis of malana Ann

Trop Med Parasitol 1987;

81: 607-18

WM, Oloo JA, Lury JD, et al. Efficacy of multiple-dose halofantrme chloroquine-resistant falciparium malaria m children in Kenya. Lancet

treatment of

1988;

ii:

the F28 dose.

Oral Frusemide The

years

2. Watkins

and 4 also needed inhaled corticosteroids. The admission criteria the same as for the single-dose study. The protocol differed from the previous one only in that two doses of frusemide--14 mg (F14) and 28 mg were tested. Thus there were 3 study days instead of two. Both volume of liquid in the reservoir (4 ml) and nebulisation time (20 min) were kept constant; the frusemide preparation for the F14 dose contained half the amount of drug for were

247-50.

Cosgriff TM, Boudreau EF, Pamplin CL, Dobertsyn EB, Desjardins RE, Canfield CJ. Evalaution of the anti-malarial activity of the phenanthrene methanol halofantrine (WR 171669). Am J Trop med Hyg 1982; 31: 1075-79 4. Boudreau EF, Pang LW, Dixon KE, et al. Comparable efficacy of halofantrine and mefloquine in the treatment of drug resistant P falciparum malana on the Thai-Kampuchean border Presented at the Annual Meeting of the American Society of Tropical Medicine and Hygiene San Antonio, Texas, December, 1983. 5 Edington GM, Gilles HM. Pathology in the Tropics. London; Edward Arnold, 1979 3.

29.

6 Khoramana C, Campbell CC, Wirima JJ, Heyman DL. In vivo efficacy of chloroquine treatment for Plasmodium falciparum in Malawian children under five years of age. Am JTrop Med Hyg 1986; 35: 465-71

Study

of frusemide delivered to the mouth in the single-dose study was 28 mg. Since approximately 20 % of this dose would have been exhaled and no more than 10% would have been deposited in the bronchial tree,9,10 approximately 20 mg would have been ingested. To ascertain whether 20 mg frusemide given orally could, at least in part, account for the observed protective effect, 8 clinically stable non-smokers (all men), 16 to 30 years of age (mean 21), who fulfilled the same selection criteria as for the single and two-dose studies, were investigated. Before exercise, subjects were given, in random order and double blind, (a) inhaled frusemide (F 28) + oral placebo (three sips, each of 3 ml, of the diluent solution, one at the beginning, one in the middle, and one at the end of the nebulisation period); (b) inhaled placebo + oral frusemide (20 mg in 9 ml-three 3 ml sips--of the diluent solution); (c) inhaled palcebo + oral placebo. All measurements (arterial pressure, pulse rate, and FEV 1) were made at the same time intervals as in the amount

previous tests. In all the phases of the study a variability of baseline FEV, was kept at less than 10 % during the study days by admitting only stable patients and by excluding those who after the preliminary tests showed a variability of more than 10%. 11 patients in the first

253 TABLE I- EFFEC’I’OF

28 mg FRUSEMIDE GIVEN AS AEROSOL ON POST-EXERCISE FEV,

FEV, expressed in litres; *Change from post-treatment values. Numbers in parentheses refer to TABLE II-EFFECT OF

second, and 2 in the third were atopic, with positive skin tests to Dermatophagoides pteronyssinus and/or grass mixture. Those allergic to the grass mixture (patients 10, 4, and 2, respectively) were examined out of the pollen season. group, 4 in the

Analysis of Data Baseline

(before and after treatment) values (mean 95% CI) of expressed in absolute terms and as percentage of predicted,"postexercise values were expressed as absolute and were

percentage changes from post-treatment baseline at individual time points. Also the maximum percentage falls in FEV1 from posttreatment baseline values were calculated. The paired Student’s t test was used for comparison. A value of p < 0 05

was

considered

significant. RESULTS

Single-dose Study before and

immediately after treatment on the study days remained similar to those recorded during the preliminary control test (table I). For every patient, distance

FEV

18 ASTHMATIC PATIENTS

predicted. p calculated by

14 mg OR 28 mg FRUSEMIDE GIVEN AS AEROSOL ON POST-EXERCISE FEV,

FEV, expressed in litres; *Change from post-treatment values. Numbers in parentheses refer to

FEV1

%

IN

%

IN

paired Student’s

t test.

18 ASTHMATIC PATIENTS

predicted.

of exercise, and heart-rate increase remained similar for each bout of exercise. There was no significant difference in postexercise changes in FEV values-both absolute (table I) and percent (fig 1) between control and placebo, whereas the difference between placebo and frusemide was highly significant at all time points. The mean (95% CI) maximum percent FEV1 fall was 34-1 (38-3-29-8) in the control test, 33-8 (39-1-28 5) after placebo, and 11 5 (14-3-8-7) after frusemide. run, duration

Two-dose

Study

Again, baseline values remained stable (table II), as did distance run, duration of exercise, and heart-rate increase. Post-exercise changes in FEV—absolute (table 11) and percentage (fig 2)--for the control test were similar to those

occurring after placebo. The effects of 14 or 28 mg frusemide differed significantly from those of placebo. The effects of 14 mg frusemide also differed from those of 28 mg frusemide. The mean (95% CI) maximum percent fall was

254

Fig

given by inhalation on (95% CI) post-exercise percentage changes in FEV, from

2-Effect of approx 28 mg or 14 mg frusemide given by inhalation on mean (95 % CI) post-exercise percentage changes in FEV from baseline in 8 asthmatic patients.

l-Effect of approx 28 mg frusemide

mean

Fig

baseline in 18 asthmatic patients. Vertical lines represent 9?% CI. ***p < 0 001(paired Student’s t test) for difference between inhaled frusemide at individual points.

36-2

(44-2-28-7) in the control test,

placebo, 19-7 (28-2-11-3) after 14 (21-2-6-0) after 28 mg frusemide.

placebo

Vertical lines represent 95% CI. Asterisks refer to differences between placebo and frusemide 14 mg, solid triangles refer to differences between the two doses of frusemide. or *p < 005; 11 or **p < 001; *** p < 0001.

and

(39-4-30-0) after frusemide, and 13-6

34-6

mg

Side-effects In all the three studies frusemide was tolerated well; it did induce changes in blood pressure or pulse rate.

not

Oral F

Study

There

significant differences between control, placebo, and oral frusemide in the effects on absolute (table III) or percentage (fig 3) changes in FEV1 after exercise, . whereas inhaled frusemide showed a protective effect. The mean (95% CI) maximum percentage fall was 37-8 in the control test, 35-3 (45-9-24-7) after placebo, (46-2-29-4) 38-2 (47-1-29-3) after oral frusemide, and 15-2 (19-9-10-5)

DISCUSSION

were no

after inhaled frusemide.

TABLE III-EFFECT OF

20 mg ORAL

FRUSEMIDE OR

FEV, expressed in litres, *Change from post-treatment values.

Our study has shown that inhaled frusemide prevents exercise-induced bronchoconstriction in asthmatic patients. The protection is dose-dependent and is not accompanied by any direct bronchodilator effect. Oral frusemide, in the dose given in our study (20 mg), was ineffective. Thus, the protection is probably the result of a local effect of inhaled frusemide on the bronchial mucosa.

28 mg INHALED

Numbers

in

FRUSEMIDE POST-EXERCISE

parentheses refer to % predicted.

FEV,

IN

8 ASTHMATIC

PATIENTS

255

Reviews of Books Contemporary Obstetrics and Gynaecology Edited by Geoffrey Chamberlain. Guildford: Butterworth. 1988. Pp 434. 27.50. ISBN 0-407015809.

I SEEM to recall that the first Contenaporary Obstetrics and Gynaecology comprised a collection of reviews, often by junior hospital doctors, which had already been published in a medical magazine. The reviews in the present edition were

Fig 3-Effect of frusemide, approx 28 mg given as aerosol or 20 mg given orally in post-exercise percentage changes in FEV, from baseline in 8 asthmatic patients. ***p < 0-001(paired Student’s inhaled frusemide.

t

test) for difference between placebo and

How the protective effect is brought about remains to be established. In-vitro frusemide inhibits Cl- secretion into the bronchial lumen by blocking an electrically neutral Na Cl- co-transport process in the basolateral membrane of epithelial cells.5-8 Thus changes in the osmotic and ionic epithelial environment probably either dampen the responsiveness of sensory epithelial receptors and so inhibit the reflex vagally mediated component of the reaction, or reduce the local release of mediators.2-4 Some caution is, however, needed with this interpretation because frusemide inhibits Cl- secretion only when added to the submucosal +

side of the epithelium,5-8whereas in our experiments it reached the epithelium from the luminal side. Nonetheless, the ion-osmolarity mechanism remains the most likely explanation for our results, which add support to the osmotic theory of exercise-induced bronchoconstriction. As additional possibility to consider is that frusemide might alter the reactivity of the bronchial vessels, so influencing the normal events--cooling and rewarmingthat take place within the airways during and after (rewarming) the performance of the exercise.H2 It has been recently proposed that frusemide may release a hormone from the kidney which inhibits vasoconstriction.13 This hormone is unlikely to account for the antireactive effects observed by us since oral frusemide was ineffective. In any case, whatever the mechanism, inhaled frusemide seems to offer the possibility of a new approach to the treatment of asthmatic syndromes. It is not new in medicine for existing drugs to reveal unexpected properties that make them suitable for new applications. Our results so far show that frusemide has protective effects against bronchoconstriction induced by ultrasonically nebulised hypotonic and hypertonic solutions and by allergen extracts (immediate and late reactions). We thank Mrs Donatella Mariotti for

typing the manuscript.

Correspondence should be addressed to S. B., Institute of Lung Diseases, University of Siena, Siena, Via Tufi, 1-53100 Siena, Italy.

written for it at the invitation of the editor after Professor Chamberlain had heard the authors present their work at scientific meetings. Most of the 26 contributions are by senior personnel but good work by registrars, senior registrars, and lecturers is included and remains an attractive and distinguishing feature of the book. In the preface, Professor Chamberlain says that he chose his subjects idiosyncratically from the growing edge of obstetrics and gynaecology. This may give potential readers the wrong impression. The great majority of the articles are at the sharp end of clinical practice even if their titles suggest a more comfortable read. For example, Fetal Physiology in Labour is about the recognition of fetal distress, while Prostaglandins, Preterm Labour and Infection is about the prevention of preterm labour and its often baleful Fetal and Growth Achievement consequences. cerebral is about Neurodevelopmental Disability spastics, palsy, and mental retardation. The gynaecology papers also deal with matters of daily relevance to the clinician-for instance, the medical treatment of menorrhagia, whether to preserve the ovaries at hysterectomy, and how to react to the current spate of cervical smear tests showing human papillomavirus infection and other abnormalities. All the reviews are detailed, compact, and very well referenced. Sometimes they provide an answer-nuclear magnetic resonance has laid to rest the controversy of "placental migration"-but where there is a definite answer the question was usually relatively trivial. Most of them

S. BIANCO AND OTHERS REFERENCES

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2. 3. 4. 5.

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8

1986, 7: 299-305. 9. Lewis RA. Therapeutical aerosols. In: Cummings G, Bonsignore G, eds. Drugs and lung E. Maioraria International Science Series, Life Sciences vol 14, New York: Plenum, 1983, 63-83 Med 1986; 10. Newhouse MT, Dolovich MB. Control and asthma by aerosols. N Engl J 315: 870-74. 11. Bates DV, Macklem PT, Christie RV Respiratory function m disease. 2nd ed. Philadelphia. Saunders, 1971: 93-94. 12. MacFadden ER Jr, Lenner KAM, Stroll KP. Postexertional airway rewarming and thermally induced asthma New insights into the pathophysiology and possible pathogenesis. J Clin Invest 1986; 78: 18-25. Does furosemide have vasodilator activity? Trends Pharmacol Sci 1987; 8: 13 Gerkens JF 254-57