........... To::orol, a new long-acting bronchodilator for inhalation

P. Arvidsson, S. Larsson, C-G. Lofdahl, 8. Melander, L. W~hlander, N. Svedmyr

11 1WW long-acting bronchodilaror for inllalario11. P. 1\rvidsson, S. Depts of Pulmonary Medicine and Qinical Phar· macology, Golhenburg University, Medical Dept, CIBA-Geigy, Sweden.

LOfdalll, B. Melandcr, L Wdlrlan.dt~r, N. Svedmyr. The aim or thJs s tudy was to evaluate If treatment with Inhaled

Is appreciated by a.~tbmatlcs and whether lt ClHL'>CS taclty-Conespondence: C-G. Lofdahl, Re~stromska Hospital, Box 17301, S-40264 Goteborg, Sweden.

Twenty s!Jtble asthmatics wen Included In a rnndomlzed, nd, crossover s tudy. They were treated for two weeks either with or snlbutamol, with one week washout lnbetween. T hey were rormoterol or 200 Ill salbutamol twlc:e dally and Instructed to

fdd.IUOn,ru spray doses on demand. On a diary card they recorded the Keywords: Aslhma; fonnotcrol; salbutamol; symptom score; visual analogue scale.

o( doses, asthma symptoms and peak expiratory now rule (PEFR) e-very dose. Forcr.d expiratory volume In one second (FEV

1) dose­

curves ror salbutamol (total dose 1.3 mg) were perrol'!11ed before each treatment perlod to evaluate development or tachyphytuxls.

a !ilgnlnt'8nt di fference In favour of rormoterul concerning P£FR recordings, spray consumption, and prefllrence. Flneen

Received: April, t989; accepted after revision: November 10, 1988.

nr •• r .. rrHI rormoterol and twosalbutamot. The dose-response curves '"· - "'"•" ' and before, as well as after salbutamol were utmost

rormoterol the curve had changed ; both basal and ma:<t· were higher than before. Thus, no evidence Cif tachyphylaxis

compared to the ordinary B-stimulant treatment. f .. 1989, 2, 325-JJO,

nrmn•,.•·n• fumarate (BD-40A, YM-0 8316) is a new ~noc:cptor agonist which has been found in vitro

l 50 limes more potent than salbutamol on smooth muscle (1, 2] and at least as 6-f

salbutamol and terbutaline [2]. In vivo am• gave similar results [3, 4].

1986, formoterol has been registered for oral on in Japan. However, as an inhalant this has not been tested in Japan.

~ier ~tudy performed in Sweden has shown that Jnhalcd, the potency of fonnotcrol is 5-15 Limes

or salbu~nmol , according to a double-blind, cumuJa· ~c:-rcsponse study, and studies in West Germany Slf!lllar resul ts rs, 6]. Mosl important, however, is

mg that the duration of effect or inhaled fomlOt· is much longer than after equipotent doses of

Eight hours after administration, forced . volume in one second (FEY,) was still sig­•ncrcased compared with the basal value. and

approximately 75% of the maximum FEY1

value. lnhalnt•on of salbutamol, FEY, returned to the basal afler <•pproximately 4 h (5, 61. In other studies. a

eftect nfter a single dose of inhaled forrnotcrol shown after 12 h [7, 8).

prolonged bronchoclilating effect of inhaled ~11"da'Oter·nl , which has been demonstrated in studies over

Y ~n~er laboratory conditions, may be of great 81&n•ficance. The aim of the present study was

lO deJ.ennine whet11er patients would notice the prolonged effect and appreciate it when formoterol was given in a controlled study over a longer pcciod of time. We also studied whether this long-lasting stimulation of the .131 adrenoceptors of the bronchi led to development of increased tachyphylaxis during two weeks of treatment, compared to their ordinary treatment with an inhaled 131-

stimulant.

Patients

Twenty one patients with non-allergic bronchial asthma using Bz·agonists by inhalation at least three times daily were included in the trial. A reversibility of FEY 1 of at least 20% after inhalation of a 131-agonist was required on the first day of the investigation. One patient was ex· eluded as his reversibility was less than 20%. Twenty patients are thus presented (table 1). Treatment with lheophyUincs, inhaled steroids and inhaled anticholiner­gics in unchanged dosage was allowed during the trial. Oral 131-agonists we~ withdrown. Thirteen patients used oral theophylline, fifteen patients i nh:~ lcd corticostcroids and two patients inhaled anticholincrgics.

Pregnant women, patients with serious diseases and asthmatics on oral steroids or B-bloc.kers were excluded from participation. Patients who were considered unable to comply with the study protocol were not included.

326 P. ARV!DSSON ET Al.

Table 1. - Patient characteristics (n-20)

Mean

Age yrs 48 Duration of disease yrs 16 Basal FEY

1 % predicted 44

Reversibility % 44

Range

43~6 2-42

14-78 20-80

Seventeen of the patients were men and five were smokers. Three patients had hypertension treated with diuretics or vera­pamil. One patient had experienced slight cardiac decompensa­tion, treated with a diuretic. FEY

1: forced expiratory volume in

one second.

Methods

The study was carried out as a randomized, double­blind crossover study with two weeks of treatment with either inhaled salbutamol or inhaled formoterol and with a washout period. of one week between treatment peri­ods. The patients were examined before and after each treatment period, with FEV1 dose-response curves for salbutamol to evaluate tachyphylaxis. During the treat­ment periods peak expiratory flow rate (PEFR) was recorded by the patients themselves before each dose of the study medication. They also recorded on a diary card additional doses of the tested drugs and symptom scores. Asthma symptoms were also recorded using visual ana­logue scales at each visit, when side-effects were also recorded. At the last visit, the patients were asked about their treatment preference.

The study was approved by the Ethical Committee at the University of Gothenburg.

PEFR values and need for additional doses ofbronchodi­lators

PE~ was measured every morning and evening dur­ing the study before lhe prescribed study medication was taken. Recordings were also made before every addi­tional dose (two puffs) of the study medication. A Wright

mini peak_-flow ~eter was used. The patients were thorough InStructions about the recording technique. best of two values was recorded on a diary cant ln way every additional dose was recorded. The vat the last 10 days of each treatment were evalua~

Continuous recording of symptoms

The patients made subjective recordings of lhe ity of their asthma every morning and evening on diary card by using a four-grade scale: 0 = No symptoms, undisturbed sleep; 1 = Mild asthma, symptoms not interfering with or sleep; 2 = Moderate asthma, symptoms only slightly ..... ,11arm with activities and sleep; 3 = Severe asthma symptoms making daily ooutvtliiMII

impossible and seriously disturbing sleep. Recordings made during the 10 last days of the

ment periods were used for the calculations.

Visual analogue scales

Before and after each treatment period the patients asked about their subjective view of symptoms duration of effect of the sn1dy medication. Visual logue scales were used for this investigation. The tients were asked to give their answers by on a lOO mm long horizontal line. Separate paper were used for each question. The four l•u~:.:~u~~J~t.; asked are presented in figure 1.

Further interviews

At each visit the patients were asked for any effects that they considered attributable to the tested They were also asked to give their opinion ,., ... ,N•mnrw.-:

the duration of the effect by using a five-grade scale the following alternatives; 0-2 h, 2-4 h, 4-6 h, 6-8 b. and more than 8 h. At the last visit the patients welt asked which treatment period they preferred.

How has your asthma been during the last 2 weeks, compared with what lt Is usually like?

Much worse 1--------------------1 Much better

A lot

Have you had problems with shortness of breath during the last 2 weeks?

1--------------------1 Not at all

How have you slept during the last 2 weeks?

Very badly

Very short

How long-lasting has the effect of the spray been during the last 2 weeks?

Fig. I. - Visual analogue scales {0-1 00 mm).

Very well

Very long

FORMOTEROL: A NI!W INHALED DRONCHOOILATOR 327

patieniS were treated with either salbut.amol from 8erosol delivering I 00 ).1.8 per puff or formoterol

. Two puffs were given regularly morning A spacer, Volumatic4P, was used for the

The patients were taught the correct inhala­ue by an experienced assistant The patients

msiiJU~··"" to use additional inhalations when needed. the washout period, the patients used their ordi­

medication.

studY the possibility of tachyphylaxis of the bron­enCICCJ>tor·s, FEY1 dose-response curves for

butamol were recorded before and after each period. The patieniS were asked to absmin

....... -,~ bronchodilators during 12 h before the dose­tests and from oml theophyllines for 36 h before They arrived at the laboratory at 7.30 am after

breakfast without coffee or tea. The patients rested for 50 min and. basal values for FEY l were then

Two measurements were made wtth 20 rnin Salbut.amol was then given in three doses

300 and 900 ).l.g, respectively) at intervals of 20 The inhaled doses were given by a dose aerosol

to a Volumatic~ spacer. Only 100 ).l.g salbutn­cet(:asc:a illlo the space before each inhalation.

unrmJauorts were supervised by an experienced ass is-and the patient's mouth was rinsed with water after inhalation. FEV

1 was recorded 12 min after each

dose with a Yitalograph spirometer. The best of three values was used for calculations. lf the patient could not abstain from inhaled bronchodilators during the night before !he test, this was postponed .

Statistics

The results were analysed with regard to interactions, period and treatment effects according to Hiu..s and ARMrrAGE (9]. Thus, while all the results given are based on the actually recorded unadjustcd figures, the p-values presented for treatment effects ore adjusted for period effects. Wilcoxon's mid rank-sum test was used for comparisons between the sequences and p <0.05 was chosen as the level of significance. The SAS programme package was used for all the calculations.

Results

PEFR measurements

The highest and lowest PEFR values on each treat­ment day were used in the calculation of data presented in table 2. The table presents mean values for lhe last 10 days of each treatment period. Maximum and minimum values were significantly higher during formoterol treatment and the difference between maximum and minimum values decreased significantly during formot­erol treatment, showing a decrease in diurnal variation during that treatment.

Table 2.- Daily PEFR values, number of additional doses and symptoms, during salbutamol and formoterol treatment periods (mean±sEM)

Daily PEFR /·min·1

Additional doses (2 puffs each)

Maximal Minimal

"Diurnal variation"

Day Night Total

Symptom score (0-3) Day Night Total

Visual analogue scales (0-100 mm)

Asthma severity

Shortness of breath

Quality of sleep

Duration of spray effect

PEFR: peak expiratory flow rate.

Salburamol

344±22 287±21

57±8

).55±0.33 0.39±0.10 1.94±0.35

1.11±0.17 1.12±0.18 1.11±0.16

55±5

52±5

64±6

55±4

Formoterol

357±21 320±22

37±4

0.78±0.32 0.15±0.07 0.92±0.33

0 .77±0.13 0.62±0.16 0.69±0.14

71±3

74±4

77±5

78±3

Significance

p<0.05 p<O.Ol p<0.02

p<0.001 p<0.05 p<O.Ol

p<0.05 p<0.001 p<O.Ol

p<O.Ol

p<O.OOl

p<0.05

p<O.OOl

328 P. ARVIDSSON ET AL.

Additional doses

Besides the regular inhalations of 2 puffs b.i.d. the patients took. on average, 2 additional puffs 1.9 times during 24 h when treated with salbutamol, whereas their average number of additional dosage occasions during 24 h was 0.9 with formoterol. The number of additional doses (2 puffs each) both at night and day was signifi­cantly smaller during the formoterol treatment period (table 2).

Symptom evaluation

Mean values for each patient during the last 10 days of each treatment period were used for calculations of the values presented in table 3. When treated. these patients had mild symptoms. reflected in low symptom scores. During both day and night. the symptom scores were significantly better dwing the formoterol lreatmenL pe­riod. The effect was most pronounced at night.

Table 3. - Subjective evaluation of spray duration (number of patients)

Spray duration Salbulamol Formoterol

0-2 h 1 0 2-4 h 6 1 4-c6 h 6 3 6-8 h 4 8

>8 h 3 8

Difference between drugs (p<O.OOl).

Mean values for visual analogue scale recordings before and after each treatment are presented in table 2. The parameters, asthma severity, quality of night sleep, and breathlessness were significantly better during formot­erol treatment.

FEV1

2.2

1.7

1.2

Salbutamol

Durcstion of effect

The patient's awn opinion concerning the effect of the tested drugs was estimated using -both··· .. u~ .....

analogue scales and a fi ve-grade scale. Acco~:ding vL~ual analogue scales. the patients experienced cantJy longer duration of effect with formotcrol salbutnmol (table 2). There was also a significant ence in favour of formoterol when the five-grade was analysed (table 3). During formot.erol treatment, patients estimated the duratiOn to be more lha:n whereas during salbutamol treatment only three P3tillllfi!411 gave the same estimate.

Side-effects

The patients had only slight complajnts. One on salbutamol complained of slight tachycardia, and another patient on salbutamol of ncss and coughing. On formoterol one patient cornpiJliftl• of dryness of the mouth in the morning.

Preferences

After the last treatment period. we asked the which of the two treatment periods they preferred_. teen patients preferred the fonnoterol treatment two patients preferred the salbutamol period and patients could not state a preference (p<O.O I).

Studies of tachyphylaxis.

Figure 2 shows the mean FEV 1

dose-response curvetl• for 20 patients. The curves before and after the ~alb•il.l mol treatment period are almost identical, showing indication of a change in the 62-adrenoceptor resJpoll~!l

Formoterol

0 100 400 1300 0 100 400 1300

Cumulative dose (J.!Q)

Pig. 2. - Mean dose-response curves for cumulative doses of s~Jbutamol perfonned before (o ) and after (•) 2 weeks of trealtllent with salbutamol or fonnoterol. FEV

1: forced expiratol}' volume in one second.

FORMOTEROL: A NP.W INHALP.D BRONCHODILAT0R 329

thl} fomlotcrol treatment period lhc FEY, curve approximately the same level as the curves re­before and after the salbutamol treatment period.

treatment for two weeks with fonnoterol both tlte and maximal FEY, value were higher than the values

before the fonnotcrol treatment pedod. TI1Us, was no indication that fonnoterot produced a more

Ulchyphylrut is to B2-adrcnoceptor stimulation

bronchial muscle of asthmatics than the B'l· agonists normally used. e.g. salbutamol.

stuctied separately the live patients who were with inhaled corticosteroids. Their dose­

curves showed the same pattcm as those of the group, i.e there was no indication of tac.hyphy-

ln thl'se patients either.

Discussion

study has demonslrated that the prolonged effect formoterol shown in acute studies is also

longer periods or clinical use. The pa­the long duration of effect and stated !hat

lasted considerably longer than that of salbu­also noted the longer duration of action or

os a need for fewer additional inhalations. patients included in this study had moderate to

severe asthma as evidenced by basal FEY, values, no bronchodilators had been given since the previ­

No patients with the most severe form of ipated, as patients on oral steroids were not

The reason for their exclusion was the diffi-ot studying patients with very severe asthma. as rend to be unstable and unable to complete a

study. This means, however. that we do not whether patients with more severe asthma will find

as advantageous as the patients in the present

lll'nranht~ilators with a prolonged effect on the bron­.::~tt,r.•n.nr~>ntnr~ may involve a greater risk of ylaxis compared to the short-acting drugs. Stud­tachyphylaxis to this new bronchodilator are

essential. In this study, with a limited number , no evidence of tachyphylaxis to formoterol compared to their ordinary treatment with a Fourteen days of treatment is a rather short probably long enough for a study of tachy­

Tachyphylaxis to 62-agonists develops very after the start of ttcatment in almost all re­studied, except the bronchial 6

2-adrenoceptors

patients (11- 15]. It has been shown that healthy develop tachyphylaxis to the bronchial effects of lsts (contrary to asthmatics) even after one week

I 12). It is therefore likely that tachyphylaxis . developed in this group of patients within 14 •f such a development were to occur. The patients study are now on continuous formoterol therapy

one year and will be followed with repeated dose­curves to elucidate this matter further. patients were treated with inhaled corticostcr-

>Which is the standard treatment of asthma of this

severity in Sweden. Inhaled corticostcroids are the rec­ommended second choice after inhaled B1 adrenoceptor ogonists for the treatment of asthma. This may have blunted the development of tachyphylaxis [ 12]. How­ever, separate evatuntion of patients without inhaled corticosteroid treatment did not indicate tachyphylaxis. Moreover. as this is the recommended treatment for this type of patiem. our data elucidate the most important question, namely, whether a long-acting B.z-adrenoceplor agonist such as fonnoterol induces tachyphylaxis in the clinical situation. However, studies of tachyphylaxis to t11is dntg in mild asthmatics without previous steroid or Bz-stimulanl therapy would be of interest.

The dose of formoterol used in this study, 12 ~g. was chosen to be approximately equipotent with 200 ll& of salbutamol, with regard to the maximum bronchodilating effecL Actually, 200 J.L& salbutamot is somewhat more potent. This has been shown in a double-blind cumula­tive dose-response comparison to salbutamol in asthmat­ics [5). Available data indicate tllatthe duration of effect of l2 jlg fonnoterol would be I 2 h [7, 8]. For this reason two administrations a day were chosen for continuous use in this study. On average, the patients used formot­crol once more per day. Our patients are used to talring bronchodilators pr:ophylacticaJly when attacks can be anticipated, as for example before physical exercise. The dose used may, therefore, have been slightly higher than was actually needed. However. on the basis of data from this study. regular dosage of 12 Jl& formoterol 3 times dally can be expected to be a reasonable recommenda­tion for asthmatics witll moderate to severe asthma. However, several patients in this study felt well on only two doses of fonnoterol a day. lt was not the original intention of the present study to compare formoterot with recommended salbutamol dosage. Such a comparison seems possible, however. since the patients in this study took 200 J.L& salbutamot approximately 4 times daily, on average, which is in fact the recommended regular dose [16J. Our results indicate that 12 1.18 fonnoterol 3 times daily is clearly superior to 200 jlg salbutamol 4 times daily with regard to symptom relief and improved PEFR values.

The crossover design may give rise to certain prob­lems [9, lOJ. In this study a tendency towards interaction between treatment and treatment order was noticed, witll respect to the dose-response recordings. This means that it cannot be ascertained that the change toward.-; "im­provement'' of the dose-response curves for FEY after the rormotcrot treatment period wns in fact caused by the therJpy. However. this is highly likely, since the same pattern wa$ evident when tlte results from Ule lirst treat· mcnt period were analysed as a study with parallel groups. We are therefore inclined to believe !hat tlle high bnS31 values for FEV 1 after formoterol thernpy were caused by remaining bronchodilatalion after the last dose. given about 12 h before the test.

It has been stated that a long-acting inhaled bronchocli­huor would improve astllma therapy significantly I 171. This p::tpcr supports this assumption. The patients did not only notice the prolonged erfect of fomloterol, but also sUited that tlleir asthma was better controlled during both

330 P. ARVIDSSON ET AL.

night and day. Furthermore, they slept better and it was objectively demonstrated that their pulmonary function was improved. The view that long-acting bronchodila­tors are a major improvement appeared to be shared by the patients, as they strongly preferred this therapy. Such clear-cut results are uncommon even in placebo­controlled studies and it should be borne in mind that the comparison made in this study was with an active treat­ment, once a therapeutic breakthrough.

Acknowlrdgernents: We \hank B. Boquist and B. Oiofsson for e:~~pert technical assistance during \he study.

References

I. ldo H. - Comparison of oction of BD 40A and some other B-adrcnoceplor stimul1111ts on the isolated ltnchea. 1111d alrin of the guinea-pig. Arz~im-Forsch ( D,ug Res). 1976, .526, 839-842. 2. Decker N. Quennedey MC, Rouo1 B, Schwnrt7. I, Velly J. - Effect of N-amkyl :;ubstitution of ll agonisls on alpha nnd beta-odrenoccptor sublypes: phamu1cologic.1J studies ond bind­ing nssoys. J Phrnm Pharmocol. 1982, 34, 107- 112. 3. Id a H. - Cardiorcspimtory activities of 3-formyl:unino-4-hydroxy-aJpha-(N -1-methyl-2 -p-melhoxyphcnetylamin· omethyl)-ben7.yhdcohol-hemifumamt (BD 40A) and some other B-adrcnoceptor stimulants in conscious guine:~-pigs. Arzm:im­Forscll (Drug Res), 1916, 726, 1337-1340. 4. Wasserman MA, Griffm RL. - A new and highly potent bronchoselective beta-adrenergic stimulant. Pharmacologist, 1980, 22, 202. 5. Lofdahl CG, Svedmyr N. - Formotcrol fumarate, a new 31-adrenoceptor agonist. 6. Lofdahl CG, Svedmyr N. - Effcel and dunnion of inhaled fonnoterol, a new Bt·adrenoceptor agonist, compBTed tO S11lbu­tamol in asthmatic patients. Acta PJrarmacol Toxicol, 1986. (Suppl. 52), 229. 7 . .....:: Bcrg A, Bcrdel D. - In: Comparison of a new B­ugomsl with snlbutnmol in the treatment of bronchospasm in asthmatic children. XIT World Congress lnterasma. Barcelona, 1987, Abstract. 8. Noho D. Rolke M. - In: Compt~tison of the bronchodi­lator effect or fomtoterol and fenoterol over a 12-hour period. XIT World Congress 1nrcrasma. fbrcelonu. 1987, Abstract. 9. Hills M, Armitagc P. - The tWo·pcriod cross-over tri;1l. Br J C/in Plwmtlcol, 1979. 8, 7-20. 10. V ere DW. -Validity of cross-over trials. Br J Clin Phar­mocol, 1979, 8, 5-6. ll. Svedmyr N. - Is belo-adrcnoceplor sensitivity a limiting factor in asthma thernpy? In: Perspectives in asthma U. Bcta­adrenoceptors in asthma. J. Moreley cd., Academic Press, Lon­don. 1984, pp. 181-199.

12. Holgatc ST. Baldwin CJ, Tattcrsfield AE. _ B-ac~ten agonist resislance in normal human airways. Lancet

1917 375-377. ' • 13. Harvey JE, Baldwin CJ, Wood PJ, Albcni KO T altersfield AE. - Airway and metabolic rc.~ponsiv intravenous salbutamol in asthma: effect of regular~ salbutamol. Clin Sci. 1981, 60, 579-585. 14. Harvey JE. Taucrsfield AE. - Airway response

10 lam.ol: o(fcct or regular salbutamol inhalnt.ions in normli) and nsthmntic subjects. Thorax, 1982, 37, 280-287. 15. Larsson S, Svcdmyr N. 'T'hiringer G. - L:\Ck of br B1-adrcnoceptor resi~tnnce in nsthmatics during long-term ment with tcrbutnline. J Allergy Clin lmm.unol, 19n, 59, 93-~ 16. Ulfdnhl CG, Svedmyr N . - Bronchodil:l[ors. /n: Ph cotherpy of respiratory disea.tes. J. Wilson ed., WiUiarna llill WUkins. Sydn.ey, 1987, pp. 60-77. 17. Svcdmyr N, Ulfdahl CO.- Physiology and ph.umacoltt;. nctics or bcln-odrcnergic agonist$./n: Drug therapy rur IISI!una. J.W. Jcnnc and S. Murphy eds, Ockkcr, New York, l987 - · 177-211. • ..,...

Le formt)le:ro/, UII II()UVeau brondwdilatateur a action proro,~; en inlwlotion. Um! comparoison pendOJIJ deux j'eiTUJines, ~ etude de la tachypllylaxie. P. Arvidsson, S. Lor.rso11, C.(f. LO[dahl, 8 . MeiOJuler. L. W4Jrlander. N. Sved.myr. RESUME: L'objcctif de COliC etude est d'c!va.luer si lo lta!to. mcnt nu moyen du fonnoterol en inhalation est bien nppr6ci6 par les asthmatiqucs, et s'i l provoque une tnchyphyhuie. Noua nvons introduit 20 osthmatiqucs en etat sLoblc dans w1c &ucll rnndomis~. en double anonymot, ayee permutation CTOis~c. 0. ont ete trru l~ pendnnr deux sem aincs, soit pnr le fomtoL«<~ soil par le salbutamol, ovec une semaine intcmHI<II~tlrc cfe wa.shout. On leur a donne 12 ~g de formoterol ou 200 J.l& cfl salbutnmol deux fols par jour et on leur a doMe corrune struction d'utiliser des doses complementaires d'aerosols a 11 dcmandc. lis ont note sur uno fiche d'observation quotidiCIUIJ le nombre de doses utilis~es. les symptOmes nsthmatiques, ainsl que le DEP avant chaque dose. Les courbes dose-rl!ponse du YEMS pour le salbutamol (dose totale l.3 mg) ont e~ real is&~ avant et apres chaque periode de traitement, pour evaluet .. devcloppement d'une tachyphylaxie. On a note une dlff~ signilicative en favcur du fonnotcrol en cc qui conceme let symptomes, les enregisltemenlS du DEP, la consomnnllion d'acrosols, et la preference. Quinze patients preferaient le formo­terol et deux le salbutamol. Les courbes dose-rcponse real~ avant formoterol ainsi qu'avant et apres salbutamol, s'av~re:nl quasiment identiques. Apres formoterol, la courbe s'est modi· fice, Ios valeurs basales et maximales elant plus 6Jev6el qu'auparavant. On n'a done trouve aucune preuve de tochyphY• laxie par comparaison avec un traitement beta-stimulant clll• sique. Eur Respir J., 1989, 2, 325-330.