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Home , Orciprenaline, Phenylephrine, Thenyldiamine

Thorax: first published as 10.1136/thx.23.6.590 on 1 November 1968. Downloaded from

Thorax (1968), 23, 590.

A comparison of the actions of different in

BERNARD J. FREEDMAN', PETER MEISNER2, AND G. B. HILL3 From Dulwich Hospital, King's College Hospital Group, London, S.E.22,1 and the General Register Office, Somerset House, London, W.C.25

The actions of the following pressurized bronchodilators were compared by administration to 24 asthmatics: (1) Medihaler Iso Forte, (2) Alupent, (3) Medihaler-duo, (4) Bronchilator, and (5) Prenomiser Plus. These contained one or more of the following: , , isoetharine, , methonitrate, and thenyldiamine. The dose was a single discharge from the container. The response was assessed by calculating the mean percentage change in F.E.V. at intervals after inhalation. The mean peak rises were respectively (1) 49 4%, (2) 43 6%, (3) 36-2%, (4) 33 5%, and (5) 23'5 %. The amplitude of peak response to isoprenaline was related to the logarithm of the dose. Weight for weight, orciprenaline had a peak activity 41-5% that of isoprenaline and isoetharine 50%. The preparations did not differ significantly in the time taken to reach maximum response, which varied from 5 to 60 minutes; three-quarters of the maxima occurred

within 15 minutes. copyright. The half-life for Alupent was 2 hours; for Medihaler-duo, which contains 240 /Ag. of -phenyl- ephrine per dose, it was 1* hours; for the remaining preparations it was about 1 hour. The decay rate, after the first half-hour, was 6% of the basal F.E.V. per hour for Medihaler-duo; for the other preparations it was 10-12%. In the doses given, Alupent yielded 20% and 30% increases lasting 130 and 67 minutes; after Medihaler Iso Forte these lasted 78 and 46 minutes. Similar comparative experiments, designed to eliminate effects of dosage difference, are desirable. http://thorax.bmj.com/ Rebound bronchoconstriction occurred in 23% of 92 experiments. There was no response to propellent alone. The mean percentage change in F.E.V. may not be the best way of expressing results.

No fewer than 28 varieties of bronchodilator aero- Isoprenaline and Bronchilator (Jacobsen and sol are available commercially in Britain today. Prime, 1965; El-Shaboury, 1964; Pickworth Eight of these are supplied in solution, and 20 in and Westwood, 1965). pressurized containers. Almost all of them differ Isoprenaline and isoprenaline with phenylephrine on September 29, 2021 by guest. Protected in composition and dosage. The confusion of (Cohen and Hale, 1965; Kal&Is and Kall6s- choice presented by this wide range is scarcely Deffner, 1964). resolved by the published results of numerous Isoprenaline and isoprenaline with drug trials in which two or more bronchodilators (Kennedy, 1965; Prime, 1968). have been compared. Isoprenaline, orciprenaline, and isoprenaline with Some comparative trials that have been pub- atropine (Sinclair, 1966). lished may be quoted: Isoprenaline, orciprenaline, and Bronchilator Isoprenaline and orciprenaline (Woolcock, Tai, (Hoffbrand, Hoffbrand, Hill, and Heaf, 1966). and Pain, 1964; Edwards, 1964; Illig, 1965; Isoprenaline, isoprenaline with atropine, isopren- Fischer and Mielke, 1965). aline with phenylephrine, orciprenaline, and Isoprenaline and atropine (Chamberlain, Muir, Bronchilator (Mattila and Muittari, 1966). and Kennedy, 1962; Kennedy and Thursby- Without exception each trial has differed from Pelham, 1964; Capel and Fletcher, 1964). others in some respect, such as selection ofpatient- groups, dosage of drug, mode of administration, 2 Present address: Lewisham Hospital, London, S.E.13 and method of expressing the amplitude and 590 Thorax: first published as 10.1136/thx.23.6.590 on 1 November 1968. Downloaded from

A comparison of the actions of different bronchodilators in asthma 591 duration of response. Consequently, the various a more persistent bronchodilator effect than iso- results are not strictly comparable and no very prenaline (Engelhardt, Hoefke, and Wick, 1961), clear picture emerges regarding the relative merits and it was introduced into clinical practice by of the various drugs and their marketed prepara- Spitzbarth and Albers (1961). tions. Phenylephrine, present in Medihaler-duo and In an attempt to resolve the confusion of choice in Bronchilator, is a sympathomimetic arising from this situation, we selected five acting on a-receptors. Its function is to cause pressurized aerosols for comparative trial. The in the bronchial mucosa, delay preparations were Medihaler IsoForte,Medihaler- absorption of the bronchodilator, and so prolong duo, Bronchilator, Prenomiser Plus, and Alupent. its duration of effect. That such prolongation may Table I shows their composition and the dose of occur has been demonstrated by Kall6s and each component drug in micrograms delivered by Kall6s-Deffner (1964) in -induced a single discharge from the container as stated by , and by Cohen and Hale (1965) in the manufacturers.' They were tested with the chronic bronchitis and pulmonary emphysema, following criteria in view: though Mattila and Muittari (1966)didnotachieve 1. Potency of bronchodilator activity, i.e., ampli- this result. Phenylephrine might also have a slight indirect bronchodilator effect by constricting tude of maximum response mucosal blood-vessels whose engorgement con- 2. Time taken to reach maximum response tributes to airway narrowing. Goldfarb and Rom- 3. Extent to which differences in bronchodilator anoff (1962) obtained evidence of bronchodilator activity can be ascribed to differences in dosage action from phenylephrine alone. 4. Duration of effect Atropine methonitrate causes bronchodilatation 5. Influence of adjuvant substances more slowly but more persistently than does iso- 6. Incidence of rebound bronchoconstriction prenaline. When given together with isoprenaline the actions are additive (Capel and Fletcher, 1964) 7. Absence of response to propellent. and the effect is that of prolonging the broncho- copyright. The introduction of isoprenaline marked an dilatation initiated by the isoprenaline (Chamber- important advance on , since it acts ex- lain et al., 1962). Its mode of action is presumably clusively on al-receptors. However, it increases the by the reduction of vagally mediated broncho- force and frequency of the heart-beat and dilates constrictor tone. It reverses bronchoconstriction blood-vessels in skeletal muscle, and hence may caused by inhalation of various dusts (Dautre- cause palpitations, headache, and . http://thorax.bmj.com/ More recently, the occurrence of occasional dan- bande, Lovejoy, and McCredie, 1962; Widdi- gerous cardiovascular effects has been suspected combe, Kent, and Nadel, 1962) and by hypoxia (Lockett, 1965; Greenberg and Pines, 1967, and (Astin and Penman, 1967). subsequent correspondence; Speizer, Doll, Heaf, Thenyldiamine is an . Although and Strang, 1968). relieve histamine-induced broncho- Isoetharine was found by animal experiment spasm (Altounyan, 1964), their effect in naturally to protect guinea-pigs from histamine-induced occurring asthma is dubious. bronchospasm (Siegmund, Granger, and Lands, 1947). Its cardiovascular effects were found to be METHOD on September 29, 2021 by guest. Protected smaller than those of isoprenaline (Lands, The preparations were given to 24 asthmatic subjects, Luduena, Grant, and Ananenko, 1950). It was 18 men and 6 women. The age range was 19 to 70 introduced ino clinical practice by Hersohfus, (mean 43 2) years. The diagnostic criteria were those Bresnick, Levinson, and Segal (1951), who on a of Scadding (1963). Excluded from the trial were weight-for-weight basis found it to have approxi- patients suffering from chronic bronchitis-namely, mately one-third of the bronchodilator effect of those producing sputum on most days for at least isoprenaline. three months in the year and for at least two years, Orciprenaline was also found by animal experi- those prone to recurrent chest infections, and those ment to exert a smaller cardiovascular effect and whose airway obstruction did not vary in severity over short periods of time. Tests were undertaken 1 The dose is estimated by the manufacturer in the following way. when the patients were in a steady state of moderate The concentration of drug in the suspension is assayed chemi- bronchospasm as estimated clinically and by com- cally. A batch of valves is sampled statistically, and the volume parison of the forced expiratory volume in one second of the valve-chamber checked. The proportion of the discharged dose which is retained by the apparatus is measured. The dose (F.E.V.) with each patient's expected value. The pre- delivered is the amount discharged less the amount retained in the treatment F.E.V. was expressed as a percentage of apparatus the expected F.E.V. for each patient. The mean of Thorax: first published as 10.1136/thx.23.6.590 on 1 November 1968. Downloaded from

592 Bernard J. Freedman, Peter Meisner, and G. B. Hill TABLE I BRONCHODILATOR AEROSOLS: COMPOSITION AND QUANTITY OF COMPONENTS (ug.) DELIVERED IN ONE DOSE, AND NUMBER OF PATIENTS RECEIVING EACH PREPARATION No.A of Isoprenaline Isoetharine Phenylephrine Atropine Orciprenaline Thenyldiamine Patients Sulphate Methonitrate rirnln hnlimn Medihaler Iso Forte (Riker) .. 18 400 Medihaler-duo (Riker) 19 160 - 240 Bronchilator (Bayer) .. .. 18 320 64 27 Prenomiser Plus (Fisons) 18 100 40 Alupent (Boehringer Ingelheim) 19 - - 675

the 24 values was 50-7 %. The F.E.V. was measured RESULTS using a Vitalograph, and the tests were begun at 10 a.m. In order to ensure the absence of residual AMPLITUDE OF MAXIMUM RESPONSE The maximum bronchodilator activity from drugs taken before the percentage increase in F.E.V. above basal level tests, patients were forbidden to use bronchodilators a patient's response to during the preceding six hours except in an was taken as a measure of emergency, in which case the test was postponed. Six a particular aerosol. Because not all patients re- patients were on long-term administra- ceived all five aerosols, it was not possible to use tion. The dose of each preparation was a single dis- simple averages. A more sophisticated method of charge from the cartridge comprising the components analysis is required which separates the effects of and quantities shown in Table I. Immediately before different aerosols from the responses of individual use the operational efficiency of the cartridge was patients (Kendall and Stuart, 1966). This was done checked by inspection of the discharge against a by means of a computer programme which esti- dark ground. All patients were well trained in the mates these various effezts by the method of least copyright. technique of inhalation, and every act of inhalation squares. The mean maximum percentage increases was carefully checked as satisfactory by the person carrying out the test. thus obtained are shown in Table II and Figure 1. The response was assessed by preliminary measure- ment of the F.E.V., which was repeated after inhala- TIME TO REACH MAXIMUM RESPONSE The distribu- at intervals of 5, 15, 30, 60, 90, tion of the time of maximum increase in F.E.V. tion of the aerosol http://thorax.bmj.com/ 120, 150, and 180 minutes, and thereafter hourly until at least one hour after the F.E.V. had returned to the II pre-treatment level (basal). The purpose of continuing TABLE so long (sometimes as much as 6 hours) was to detect MEAN MAXIMUM PERCENTAGE INCREASES IN F.E.V. AFTER INHALATION OF SINGLE DOSES FROM THE any rebound bronchoconstriction. The amplitude of RESPECTIVE PRESSURIZED CONTAINERS. response was expressed as percentage change from -~~~~~~~~ basal. No patient was given a preparation until Medihaler Iso Forte 49 4° several days had elapsed from a previous test with Alupent ...... 43 -6 °' Medihaler-duo .. 36-2%/0 another preparation. Routine inquiry was made Bronchilator 33-5% regarding subjective side-effects. Prenomiser Plus . 23-5% on September 29, 2021 by guest. Protected It was not possible for all patients to receive all five preparations. The distribution of patients in relation to experiments was as follows: 12 patients received 5 preparations Mediholer iso forte 4 patients received 4 preparations 3 patients received 3 preparations Alupent 2 patients received 2 preparations Mediholer-duo- 3 patients received 1 preparation Each preparation was given to 18 or 19 patients Bronchilator - (Table I). A complete control series using inert inhalant was Prenomiser plus not examined, as it has previously been established that the five preparations exert bronchodilator acti- 0 10 20 30 40 50 vity. A small series of nine patients was given inhala- Mean maximum percent increase in FEV. tions of propellent alone, and the F.E.V.s were measured over a period of 3 hours, in order to FIG. 1. Mean maximum percent increase in F.E. V. after confirm that it was inert. inhalation of single doses of bronchodilators. Thorax: first published as 10.1136/thx.23.6.590 on 1 November 1968. Downloaded from

A comparison of the actions of different bronchodilators in asthma 593 in the 92 tests is shown in Table HII. Peak response 50 - Medihaler iso forte - occurred at 5 or 15 minutes after aerosol inhala- tion in 69 (75%) of the 92 tests, and in all but one 4) it occurred within an hour. The differences be- 0 AIupent tween the aerosols in this respect is not statistically A40 significant when the results of the 12 patients who C-. Medihaler-duo . L-> received all five preparations are examined by a I),,, Friedman two-way analysis of variance by ranks °ronchilator E c (Friedman, 1937). Mushin (1967) has drawn atten- 30 tion to the need to continue a test for at least half x y=417x-58 3 an hour when measuring the maximum response E to a bronchodilator. By testing for a 2:c Prenomiser plus longer period 4) we have shown that about one patient in eight ..r- 20 . achieved a maximum response one hour after 20 2-1 22 23 214 25 21 ) inhalation. Log. 10 Dose isoprenaline (,ug.)(x)

r . | |~~~~~~~~~~-- TABLE III 100 160 280 400 NUMBER OF PATIENTS OBTAINING PEAK RESPONSE TO AEROSOLS AT DIFFERENT TIMES AFTER INHALATION Dose isoprenaline (pg.) Minutes after Inhalation FIG. 2. Bioassay of bronchodilator aerosols. Solid circles Aerosol represent measured doses and responses. Open circles 5 15 30 60 90 represent measured responses and hypothetical doses. Alupent . . 4 9 3 3 Bronchilator .. . 8 6 2 2 These have been derivedfrom a linefitted to the solid circles Medihaler-duo 11 3 2 3 by the method ofleast squares. Prenomiser Plus 8 5 3 1 1 Medihaler Iso Forte 7 8 1 2 copyright. Total . .. .. 38 31 11 11 1 Hence we conclude that, so far as these three 75% 25% preparations are concerned, differences in maxi- mal response are due to differences in dosage.

DIFFERENCES IN BRONCHODILATOR ACTIVITY DUE TO COMPARATIVE POTENCIES OF ISOETHARINE AND ORCI- DIFFERENCES IN DOSAGE If the maximum per- PRENALINE From the fact that the maximal http://thorax.bmj.com/ centage increase in F.E.V. is regarded as a bronchodilator activity of isoprenaline aerosols is measure of response in a 'bioassay' of broncho- related to the logarithm of the dose, it is possible dilator effect, the results demonstrate that dif- to express the activity of the other two ferences between the aerosols can be ascribed to acting on /3-receptors in terms of isoprenaline dosage. Three of the preparations contain iso- activity when they are administered by inhalation, prenaline as the bronchodilator. again assuming that the adjuvant drugs (phenyl- ephrine and thenyldiamine) exert negligible activity at the early stage of maximal response. Medihaler Iso Forte 400 jug.) isoprenahne The open circles in Fig. 2 show hypothetical posi- on September 29, 2021 by guest. Protected Medihaler-duo 160 gg. per single dose tions for Alupent (orciprenaline 675 ,ug.) and Prenomiser Plus 100 /.g. Bronchilator (isoetharine 320 ,ug.) which evoke responses equal to that given by 280 Mg. and 160 We think we can assume that the adjuvant ,uLg. respectively of isoprenaline. drugs in these preparations (phenylephrine in Weight for weight orciprenaline has 41-5% the Medihaler-duo and atropine in Prenomiser Plus) bronchodilator activity of isoprenaline when given were exerting negligible bronchodilatation at the by inhalation, and isoetharine has 50% its early stage (Table Ill) at which the maximal re- activity (Table IV). sponses were obtained, and hence that these values were solely the effect of isoprenaline. DURATION OF EFFECT The percentage changes in Figure 2 shows the mean maximum percentage in- F.E.V. that occurred at each time interval after crease in F.E.V. produced by these preparations inhalation of the aerosols were averaged, each plotted against the logarithm of the dose of iso- preparation being treated separately. In all indi- prenaline in micrograms (solid circles). The points vidual tests the F.E.V. increased initially, after lie close to a straight line fitted by least squares. which it fell progressively. Occasionally the F.E.V. 2X Thorax: first published as 10.1136/thx.23.6.590 on 1 November 1968. Downloaded from

594 Bernard J. Freedman, Peter Meisner, and G. B. Hill

TABLE IV Alupent maintained a greater rise in F.E.V. after BRONCHODILATOR ACTIVITY OF ORCIPRENALINE AND the first 25 minutes than did the other ISOETHARINE EXPRESSED AS PERCENTAGE OF ISOPRENALINE ACTIVITY preparations. There are several ways of examining and com- Orciprenaline Isoetharine parinig the durations of effect. The percentage Maximal increase in F.E.V. increase in F.E.V. that occurs at any given time (mean) after single dose 43-6% 33 5% Amount of isoprenaline giving after inhalation of a bronchodilator is dependent same increase .. 280 pg. 160 pg. Amount of orciprenaline/iso- inter alia on (a) the size of dose, and (b) the etharine given .. 675 jug. 320 pg. drug's characteristic rate of rise and fall Bronchodilator activity, as of percentage of isoprenaline activity. Whilst the influence of differences in activity .. 415% 50% dosage predominated during the peak period, changes in ranking that occurred subsequently can fell below the basal value and bronchoconstriction be ascribed to a relative increase in the influence was severe enough to curtail the experiment. When of differences in rate of decay of activity of the drugs acting on s-receptors, as well as to the this occurred it was assumed, in calculating the effect of adjuvant drugs (atropine, phenylephrine, averages, that had the experiment continued the and thenyldiamine). AF.E.V...L . V . would have remained at the same value It is instructive to compare the rates of decline as was obtainedObtained when1.1when theX11"A%the eexperimentnwas%Iwas termin-1termin-."in F.E.V., eliminating as far as possible the ated. TIhe same assumption was made if an experi- ment wias concluded at three hours or earlier be- influence of differences in dosage. cause t]he F.E.V. had fallen to, and remained at, The times taken for the mean F.E.V. of each the bas;al level. ' preparation to fall to half its maximum value The mean percentage changes that occurred (half-life) are as follows: Alupent 119 min. ; during the first three hours after inhalation are Medihaler-duo 77 min.; Medihaler Iso Forte, 65 shown in Figure 3. During the first 25 minutes min.; Prenomiser Plus 64 min.; Bronchilator 54copyright. the rarnking order of the five preparations, in min Alupent has the longest half-life (119 terms c)f amplitude of response, was the same as min.). The three isoprenaline preparations have that ofAthe maximum response (Table II), and similar half-lives, with Medihaler Iso Forte (65 differences between them at this stagblear)u to min.) and Prenomiser Plus (64 min.) having the preidominating influence of dosage. Thereafter virtually identical values, and Medihaler-duo the rattdornindecline vary. In the doses given, showing a slight advantage, possibly related to its http://thorax.bmj.com/ phenylephrine content. Inferences about F.E.V. values at times other 50 . *- Medihaler iso forte than the half-life are valid only if one assumes an -o- Alupent exponential rate of fall. A linear decay is a reason- \ A*- Medihaler-duo able approximation after the first half-hour. An 0 40 ° -a- Bronchilator alternative measure to the half-life is the slope of 0 - Prenomiser plus the regression fitted to the mean percentage im- 11 LL:U._ provements from 30 minutes onwards. These on September 29, 2021 by guest. Protected \0\O slopes, expressed as fall in percent basal F.E.V. % 30 a per hour, are: Medihaler-duo 61 ; Prenomiser o Plus 100; Alupent 10-8; Bronchilator 119; Medihaler Iso Forte 12-2. These calculations in- \ dicate\* \an\ for Medihaler-duo c . advantage (6-1% fall 10 per hour). Prenomiser Plus shows a very small and 0~ probably not important advantage over Medihaler Iso Forte (2-2% per hour), possibly related to its X:10 \

A comparison of the actions of different bronchodilators in asthma 595

A clinical approach to the question of duration ment value a state that might be termed 'rebound of effect involves consideration of what consti- bronchoconstriction'. tutes a useful increase in ventilatory capacity. It Table VI shows the number of patients whose is not easy to suggest a percentage rise in F.E.V. F.E.V. fell by 15 % or more below basal at that can be accepted for all patients as clinically various times after inhalation of the five prepara- useful, as there will be individual differences de- tions, and the total number affected in this way pending on the initial level and on the improve- at any time. ment demanded by the circumstances pertaining at the time. Most physicians will probably agree TABLE VI that an increase in F.E.V. of less than 10% is NUMBER OF PATIENTS WHOSE F.E.V. FELL BY 15 ° OR MORE AFTER INHALATION OF FIVE valueless, and that patients are more likely to be BRONCHODILATORS aware of useful improvement when the F.E.V. has increased 20 to 30 Table V Minutes after by % %. shows No. of Inhalation N.o PreparationPeaain Patients Patients at the times after inhalation of single doses of each AyTm preparation during which the mean F.E.V. was 5 15 30 60 90 120 150 180 AnyTime raised by 20% and 30%. Bronchilator.. 18 2 2 1 2 2 | 5 Alupent 19 1 2 4 5 Medihaler-duo 19 2 2 2 1 1 4 Medihaler Iso Forte 18 I 1 1 2 1 2 TABLE V Prenomiser Plus 18 1 3 3 2 2 5 DURATION (MINUTES) OF MEAN INCREASES IN F.E.V. OF AT LEAST 20% AND 30% ABOVE BASAL, OCCURRING Total .. 92 10 2 2 4 7 7 9 10 21 AFTER INHALATION OF SINGLE DOSES OF THE PREPARATIONS Increase above Basal F.E.V. There were no material differences in the time 20% 30% of occurrence of the negative phases: the bulk of

Alupent . .. 130 67 the negative phases occurred between 90 and 180 copyright. Medihaler Iso Forte .. 78 46 Medihaler-duo .. 54 10 minutes. A few occurred after that time, up to Bronchilator .. 28 - five hours, but the numbers were few and some Prenomiser Plus .. .. 12 patients who suffered rebound bronchoconstric- tion withdrew at an earlier stage. Hence, there are no useful data about the incidence at a very

THE EFFECT OF PROPELLENT In order to check late stage. Only two patients had negative phases http://thorax.bmj.com/ that the freon propellent was devoid of activity after Medihaler Iso Forte, compared with four or on the bronchi, nine patients were given inhala- five with the other preparations. The total inci- tions of propellent alone from containers which dence of negative phases in the 92 experiments were indistinguishable from those containing was 21 (23%). There were three patients whose bronchodilator. The changes that occurred during F.E.V. fell to 40% below -basal and two to 50%, the three hours after inhalation of propellent were but the numbers are too small to implicate the small, showing apparently random rises and falls. preparations that were used. The mean changes in F.E.V. from basal levels lay As there was a very low incidence of rebound between -3-6% and +8-1%. These were com- bronchoconstriction occurring soon after inhala- on September 29, 2021 by guest. Protected parable to those obtained by Edwards (1964), tion (less than 60 min.), none of the preparations El-Shaboury (1964), Jacobsen and Prime (1965), appeared likely to induce patients to make fre- Kennedy (1965), Hoffbrand et al. (1966), and quent use of the inhaler, and over-use from this Mattila and Muittari (1966). Of these nine patients, cause is unlikely to occur. five were taking steroids and four were not. There Subjective side-effects attributable to cardio- was no difference between these two groups in the vascular stimulation were absent throughout. pattern of response to inhalations of propellent. DISCUSSION THE NEGATIVE PHASE-REBOUND BRONCHOCON- STRICTION An important aspect of the action of Direct comparisons made between the five pre- bronchodilators, and one which appears to have parations as regards amplitude of peak activity received little if any attention in similar trials, is and duration of effect are valid only in relation the occasional occurrence, after the F.E.V. has to the doses given. Altering the dose alters the returned to the basal level, of a negative phase peak response and must similarly alter the dura- during which the F.E.V. is less than its pre-treat- tion of effect. If the preparations had been Thorax: first published as 10.1136/thx.23.6.590 on 1 November 1968. Downloaded from

596 Bernard J. Freedman, Peter Meisner, and G. B. Hill

50

>: ,, 40- U' E .E a 4 - E FIG. 4. Hypothetical mean percent increases 0 a 30 in F.E. V. adjusted to give equal maxima. E_ These curves are calculatedon the assumption c > that the bronchodilator response to all U 20 components, varies directly as the logarithm of the dose, and that thepreparations have 0 0 been given in doses that yield identical u, peak values. E cX 10.

a

Minutes after inhalation administered in doses that yielded identical peak maximum response. The best method of assessing values, the resulting mean percentage increase duration of effect also requires further study. copyright. curves would be the result of their respective There is evidence to suggest that bronchitics decay characteristics alone, uninfluenced by the may respond better than asthmatics to effect of differences in Since it has atropine. dosage. been Altounyan (1964) described a group of shown that related patients the response is to the logarithm who were unresponsive to steroids and whom he of the it is to from dose, possible calculate, the regarded as primarily chronic bronchitics (Altoun- data shown in Fig. 3, hypothetical curves with yan, 1968); their response to atropine was greater http://thorax.bmj.com/ identical peak values These curves (Fig. 4). show than that of a group of asthmatics. Crompton an advantage to to 165 Alupent up min. and (1968) reported a rise in F.E.V. following sub- thereafter to Medihaler-duo. this com- However, cutaneous injection of atropine, which was greater putation needs experimental confirmation, and in bronchitics than in asthmatics. However, accordingly it is proposed to undertake a similar Kennedy and Thursby-Pelham (1964), who used comparative trial in which the doses of the dif- Prenomiser Plus in the same dosage as ourselves ferent are preparations standardized to yield and an almost identical method of assessment, identical or closely similar peak bronchodilator obtained similar responses in asthmatics and bron- responses. Such an should on September 29, 2021 by guest. Protected experiment make chitics. These responses were well maintained for a possible valid comparison of durations of effect 31 hours and did not fall away from the and of side-effects. peak as occurred in our series. In a personal series of The percentage increase over basal is most 13 bronchitics with severe emphysema the re- commonly used as a measure of bronchodilator sponse to Prenomiser Plus was smaller than that effectiveness, and this tradition has been followed of the asthmatics in this trial; the mean basal in this paper. There are, however, theoretical dis- F.E.V. of the bronchitics was, however, lower advantages to the use of the percentage increase than that of the asthmatics. which we propose to discuss elsewhere (see also Feinmann and Newell (1963)). One major draw- We thank the Bayer Products Company, Boeh- back is that the distribution of this statistic tends ringer Ingelheim Limited, Fison Pharmaceuticals to be so that the Limited, Riker Laboratories, and Vitalograph Limited positively skewed, arithmetical for of mean is at the of a few supplies the preparations used, loan of equip- mercy high readings. This ment and financial support, Mr. J. is evidenced the fact that the mean S. Bass, of Riker by F.E.V. is Laboratories, for clerical assistance, and the considerably greater than the median F.E.V. Board for of Governors of King's College Hospital for a grant some preparations, especially around the time of towards expenses. Thorax: first published as 10.1136/thx.23.6.590 on 1 November 1968. Downloaded from

A comparison of the actions of different bronchodilators in asthma 597

REFERENCES Jacobsen, M., and Prime, F. J. (1965). Comparisons of isoprenaline with a new bronchodilator combination (Bronchilator). Clin. Altounyan, R. E. C. (1964). Variation of drug action on airway Trials J., 2, 297. obstruction in man. Thorax, 19, 406. Kall6s, P., and Kall6s-Deffner, L. (1963). Comparison ofthe protective (1968). Personal communication. effect of isoproterenol and isoproterenol-phenylephrine aerosols Astin, T. W., and Penman, R. W. B. (1967). Airway obstruction due in asthmatics. Int. Arch. Allergy, 24, 17. to hypoxemia in patients with chronic lung disease. Amer. Rev. Kendall, M. G., and Stuart, A. (1966). The Advanced Theory of resp. Dis., 95, 567. Statistics, Vol. 3, pp.1-56. Griffin, London. Capel, L. H., and Fletcher, E. C. (1964). Spirometric integrals after Kennedy, M. C. S. (1965). "Bronchodilator" action of deptropine isoprenaline and atropine in asthma. Brit. J. Dis. Chest, 58, 174. citrate with and without isoprenaline by inhalation. Brit. med. Chamberlain, D. A., Muir, D. C. F., and Kennedy, K. P. (1962). J., 2, 916. Atropine methonitrate and isoprenaline in bronchial asthma. -and Thursby-Pelham, D. C. (1964). Some drugs and Lancet, 2, 1019. atropine methonitrate given by inhalation for asthma: a com- Cohen, A. A., and Hale, F. C. (1965). Comparative effects of iso- parative study. Ibid., 1, 1018. proterenol aerosols on airway resistance in obstructive pulmonary Lands, A. M., Luduena, F. P., Grant, J. I., and Ananenko, E. (1950). diseases. Amer. J. med. Sci., 249, 309. The pharmacologic action of some analogs of 1-(3,4-dihydroxy- Crompton, G. K. (1968). A comparison of responses to bronchodilator phenyl)-2- amino -1- butanol (ethylnorepinephrine). J. Pharmacol drugs in chronic bronchitis and chronic asthma. Thorax, 23, 46. exp. Ther., 99, 45. Dautrebande, L., Lovejoy, F. W., and McCredie, R. M. (1962). Lockett, M. F. (1965). Dangerous effects of isoprenaline in myo- Effects of atropine micro-aerosols on airway resistance in cardial failure. Lancet, 2, 104. man. Arch. int. Pharmacodyn., 139, 198. Mattila, M., and Muittari, A. (1966). The effect of bronchodilator Edwards, G. (1964). Orciprenaline in treatment of airways obstruction aerosols on the peak expiratory flow rate in asthmatic patients. in chronic bronchitis. Brit. med. J., 1, 1015. Acta med. scand., 180, 421. El-Shaboury, A. H. (1964). Controlled study of a new inhalant in Mushin, G. J. (1967). Time factor in the measurement of response to asthma and bronchitis. Ibid., 2, 1037. bronchodilators. Thorax, 22, 538. Engelhardt, A., Hoefke, W. and Wick, H. (1961). Zur Pharmakologie Pickworth, K. H., and Westwood, J. (1965). Use of the Wright peak des Sympathomimeticums 1-(3,5-Dihydroxyphenyl)-1-hydroxy- flow meter. A double-blind trial of two bronchodilator aerosols. 2-isopropylaminoathan. Arzneimittel-Forsch., 11, 521. Practitioner, 194, 260. Feinmann, L., and Newell, D. J. (1963). Isoprenaline in the treatment Prime, F. J. (1968). The relief of airways obstruction by deptropine of chronic bronchitis. Brit. J. Dis. Chest, 57, 140. citrate and isoprenaline. Brit. J. Dis. Chest, 62, 81. Fischer, M., and Mielke, U. (1965). Vergleichende Untersuchungen Scadding, J. G. (1963). The meaning of diagnostic terms in broncho- uber die Wirkung von Aludrin und Alupent als Spruh-Aerosole. pulmonary disease. Brit. med. J., 2, 1425. Med. Klin., 60, 1824. Siegmund, 0. H., Granger, H. R., and Lands, A. M. (1947). The Friedman, M. (1937). The use of ranks to avoid the assumption of bronchodilator action of compounds structurally related to normality implicit in the analysis of variance. J. Amer. Statist. epinephrine. J. Pharmacol. exp. Ther., 90, 254. Soc., 32, 675., Sinclair, J. D. (1966). The response of asthmatics to bronchodilator Goldfarb, A. A., and Romanoff, A. (1962). Clinical evaluations of a aerosols. N.Z. med. J., 65, 524. new triple drug aerosol for asthma. Ann. Allergy, 20, 307. Speizer, F. E., Doll, R., Heaf, P., and Strang, L. B. (1968). Investiga- copyright. Greenberg, M. J., and Pines, A. (1967). Pressurized aerosols in asthma. tion into use of drugs preceding death from asthma. Brit. med. J., (Correspondence.) Brit. med. J., 1, 563. 1, 339. Herschfus, J. A., Bresnick, E., Levinson, L., and Segal, M.S. (1951). Spitzbarth, H., and Albers, P. (1961). Beobachtungen uber Verander- A new sympathomimetic amine ("Neosuprel") in the treatment ungen der physikalischen Kreislaufgrossen beim Menschen nach of bronchial asthma. Ann. Allergy, 9, 769. Verabreichung von 1-(3,5-Dihydroxyphenyl)-1-hydroxy-2-isopro- Hoffbrand, B. I., Hoffbrand, M. I., Hill, I. D., and Heaf, P. J. D. pylaminoathan. Arzneimittel-Forsch., 11, 528. (1966). Trial of bronchodilator drugs given by a metered aerosol Widdicombe, J. G., Kent, D. C., and Nadel, J. A. (1962). Mechanism with a comparison of two bedside methods of estimating airway ofbronchoconstriction during inhalation of dust. J. appl. Physiol.,

resistance. Brit. med. J., 1, 1014. 17, 613. http://thorax.bmj.com/ Illig, H. (1965). Die Wirkung verschiedener Dosier-Aerosole auf die Woolcock, A. J., Tai, E. H., and Pain, M. C. F. (1964). Assessment of asthmatische Dyspnoe (Doppelblindversuch). Med. Klin., 60, orciprenaline ("Alupent"), a long-acting bronchodilator. Med. J. 1452. Aust., 2, 89. on September 29, 2021 by guest. Protected