European Journal of Clinical Pharmacology
Eur J Clin Pharmacol (1983) 25:187-193
© Springer-Verlag 1983
Evaluation of Ketotifen (HC20-511) in Bronchial Asthma J. W. Paterson 1, R. H. Yellin 1, and R. A. Tarala 2 1Department of Pharmacology, and 2Department of Medicine, University of Western Australia, Nedlands, Western Australia
Summary. Ketotifen 1 mg b.d. (oral) and sodium cromoglycate 20 mg q.i.d. (inhalation) were compared in a double-blind crossover trial in 43 asthmatic outpatients. Comparison of diary card scores and pulmonary function tests showed significant improvement over a 12week period on each drug. Comparison of the diary card scores and pulmonary function tests showed no significant difference between the drugs after 12 weeks of treatment. Twentysix patients experienced sedation and/or lethargy whilst on ketotifen and 11 patients had similar side effects whilst on cromoglycate. Physician preferences based on diary card and pulmonary function data showed an approximately equal number of preferences for each medication and also a small group of patients in which no preference could be made. The present trial suggests that both ketotifen and cromoglycate are effective in the management of outpatient asthma. When all the patients are considered as a group no distinction can be made between the two drugs; on the basis of physician assessment of each patient, it appears that some patients may do better on ketotifen and others on cromoglycate. Key words: ketotifen, cromoglycate; asthma, physician preference, anti-allergy drugs, side effects, diary card score, pulmonary function test
Ketotifen (HC20-511) is a tricyclic compound belonging to the benzocycloheptathiopene class. It is an antihistamine with 12-24 h duration of action and in conventional dosage has no anticholinergic or antiserotoninergic properties [1]. Antihistamines have been shown to block in vitro release of mediators by antigen in a number of animal models and tricyclic compounds have been shown to be particularly potent in this respect [2]., Ketotifen has the property of
inhibiting the release of mediators from mast cells and has been classified as an anti-allergy compound [3], and has been shown to be active on in vitro preparations of human lung [4]. In man, ketotifen has been shown to prevent bronchospasm due to allergens and histamine in acute bronchial provocation tests [5]. Clinical trials have suggested that ketotifen is effective in longer term treatment of asthma [5, 6] and is well tolerated [6]. Clark and May [7], in a double-blind crossover trial design could find no difference after 12 weeks of treatment between ketotifen and cromoglycate while Lane [8] showed that ketotifen reduced prednisolone requirement. The present study compares ketotifen and sodium cromoglycate in a group of asthmatics, the majority of whom had already been on cromoglycate therapy.
Methods
Patients between the ages of 15-45 years, who had atopic asthma and were being considered for or were already on treatment with cromoglycate were selected for the study. Patients were excluded from taking part in the trial if they were currently on inhaled or oral steroids, if they had asthma precipitated mainly by infection, if they were diabetic or if they were pregnant or lactating. Women patients included in the trial were already on an oral contraceptive. The study had the approval of the University of Western Australia Humans Rights Committee and each patient gave informed consent prior to entry.
Trial design The trial was a double-blind crossover study with three months on each active treatment. This was considered desirable to allow a washout period in each
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J.W. Paterson et al.: Ketotifen in Bronchial Asthma
Table 1.0-12 week changes for ketotifen and cromoglycate. Diary card parameters 0 vs. 12 weeks Parameter
Ketotifen
Cromoglycate
0
12
Paired test~
0
12
Paired test
bl.67 0.06 42
138 0.06 42
Diff Z2 p
bl.65 0.06 42
1.42 0.06 42
Diff 22 p
0.23 1.73 0.19
Day aerosol use mean + SEM n
4.68 0.47 42
4.35 0.44 42
Diff 0.33 Z2 0.09 p < 0.75 (t= 0.56 p= 0.58)
4.62 0.48 42
4.01 Diff 0.42 Z2 42 p (t= 1.13 p= 0.26)
0.61 0.21 0.63
Night asthma score mean _+SEM n
1.68 0.O7 42
1.40 0.06 42
Diff Z2 p
1.68 0.07 42
1A4 0.06 42
Night aerosol use mean ___SEM n
1.47 0.21 42
0.70 0.12 42
Diff 0.77 2"2 11.4 p < 0.001 (t = 4.25 p < 0.001)
1.49 0.22 42
0.83 Diff 0.14 Z2 42 p (t= 3.62 p < 0.008)
1.51 0.07 42
1.22 0.06 42
Diff p
0.29 11.4 < 0.001
1.5 0.07 42
1.31 0.07 42
Diff 2"2 p
0.t9 7.76 < 0.01
1.46 0.06 41
1.26 0.07 41
Diff Z2 p
0.2 5.3 < 0.05
1.42 0.06 41
1.30 0.06 41
Diff X2
0.12 1.88 0.17
Day asthma score mean
_+SEM n
Cough score mean + SEM n Sputum score mean +__SEM n
22
0.29 11.6 < 0.001
0.28 11.0 < 0.001
Diff 22 p
p
0.24 7.61 < 0.01 0.66 9.26 0.002
a Non parametric test. Paired observations used; sign test i. e. number of rises and number of falls computed 22 carried out. b Note: Mean values at 0 weeks may differ as paired t-tests only carried out on data where second reading available at 12 weeks
p h a s e and to allow sufficient time for a possible effect o f ketotifen to b e c o m e evident as it had been suggested that its m a x i m u m effect might not be seen for several weeks. Because of the different methods o f administering the two trial drugs (oral and spinhaler) a doubled u m m y technique using placebo ketotifen (Sandoz Australia t~y. Ltd.) and placebo cromoglycate (Fisons, U . K . Ltd) was e m p l o y e d allowing a doubleblind design. Each patient was r a n d o m l y allocated to either ketotifen or cromoglycate in the first phase. In the second phase o f the trial the alternative drug was administered. The trial was double-blind and in each phase the patients received both oral and spinhaler therapy. Following admission to the trial, the patients underwent clinical examination and certain baseline data were recorded on a patient data sheet. These data included spirometric m e a s u r e m e n t s p e r f o r m e d by the P u l m o n a r y Physiology D e p a r t m e n t of Sir Charles G a i r d n e r Hospital, readings o f b l o o d pressure and heart rate, weight and the results o f b l o o d
a n d urine tests for toxicity. Prior to entry into the first treatment p h a s e the patients were asked to fill in a diary card daily at h o m e for a fortnight. They then returned to the clinic and the diary card was checked and a new one issued for the first fortnight of treatment, At the time o f the second visit the various clinic parameters were re-measured. During the fortnight run-in period, cromoglycate was withdrawn in the 23 out o f 43 patients w h o were currently taking this medication. During each 12 week treatment phase the patients kept a record card in which they m a d e daily entries of day and night asthma score, day and night aerosol use, cough and sputum score and a list o f other medications taken. During the two week run-in period prior to c o m m e n c e m e n t of active treatment a n d during the last two weeks o f each phase o f active treatment the patients also m e a s u r e d their p e a k flow at h o m e twice daily (Wright Peak Flow gauge) and entered the reading on their record card. During each treatment phase the patient was seen fortnightly at the clinic. At each fortnightly clinic visit the completed record card was inspected and retained for
189
J. W. Paterson et al.: Ketotifen in Bronchial A s t h m a Table 2. L u n g function parameters Parameter
0 vs. 12 weeks ketotifen
0 vs. 12 weeks cromoglycate
0
0
12
12
FEV1 mean ±SEM n
2.74 0.14 42
2.90 0.12 42
Diff t p
0.16 1 95 0,06
2.76 0.14 42
2.86 0.14 42
Diff t p
0.10 1.3 0.2
FVC mean _+SEM n
4.21 0.19 40
4.31 0.16 40
Diff t p
0.10 0.95 0.35
4.20 0.19 42
4.25 0.09 42
Diff t p
0.05 0.56 0.58
PEFR mean ± SEM n
428 28 40
457 23 40
Diff t p
29 1.97 0.06
H o m e P E F R a. m. mean ± SEM n
395 20 40
404 17 40
Diff t p
H o m e P E F R p.m. mean + SEM n
423 19 40
428 17 40
Diff t p
further analysis, a new one being issued for the next fortnight period. Patients were questioned about the state of their asthma and possible side-effects from the drug, were clinically examined, and spirometric measurements were made. Blood and urine specimens were taken for routine toxicology screening. Active sodium cromoglycate treatment consisted of 20 mg four times daily via spinhaler plus a ketotifen placebo capsule orally twice daily and active ketot±fen treatment consisted of ketotifen 1 mg twice daily and one cromoglycate placebo capsule four times daily.
Data Analysis Global Preference by Physician. An assessment sheet was drawn up for each patient in which both diary card and clinic data were presented in tabular form for each fortnight of each treatment phase. The sheet was prepared before the trial code was broken. Data presented were day, and night time asthma scores, day and night aerosol use, cough and sputum scores, and other medications used. The spirometric readings obtained at the clinic were also entered and the incidence of side-effects listed at clinic visits was entered. These sheets were evaluated blind by two experienced chest physicians and each patient allocated to one of three groups. Treatment Period 1 preferred, treatment Period 2 preferred, or neither period preferred. Following analysis of all the sheets the
432 26,7 42
454 24.1 42
Diff t p
22 1.55 0.13
9 0.96 0.34
402 20 41
410 19 41
Diff t p
8 0.84 0.41
5 0.68 0.5
431 19.5 41
440 18.5 41
Diff t p
9 1.I 0,27
code was broken and the preferences expressed as follows: A - physician preference for ketotifen, B physician preference for cromoglycate, and C - no physician preference. In the event of a disagreement the data were re-evaluated.
Baseline Parameters. These were compared for the 25 patients starting cromoglycate (Group 1) and the 19patients starting ketotifen (Group2) using unpaired t test for lung function and cardiovascular measurements and Mann Whitney U test for diary card data. Statistical Analysis of Patient Data. Data obtained from the patient diary cards and at the clinic visits were processed and analysed. The t2 week clinic readings for FEV1, FVC, PEFR, blood pressure, heart rate, weight, were compared for the period on ketotifen and the period on cromoglycate. The diary card data over the last four weeks on each drug were tabulated for each patient. Paired analyses were then done between the ketotifen and sodium cromoglycate periods using the Wilcoxon-Matched Pairs Signed Ranks test. Comparison of Oand 12 Weeks. Paired analyses were done between the readings obtained at 0 weeks (i. e. after two week run-in period) and those obtained at 12 weeks, or over the last four weeks in the case of diary card data, for ketotifen and for cromoglycate.
190
J.W. Paterson et al.: Ketotifen in Bronchial Asthma
Physician's Preference
Table 3. FEV1 Measurements 0 v. 12 weeks 0
12
Difference
Group A Ketotifen Cromoglycate
2.82 (0.24) 2.84 (0.25)
2.93 (0.23) 2.71 (0.25)
+0.11 (0.11) -0.13 (0.13)
Group B Ketotifen Cromoglycate
3.02 (0.2) 3.02 (0.2)
2.87 (0.17) 3.11 (0.2)
-0.15 (0.12) + 0.09 (0.08)
Group C Ketotifen Cromoglycate
2.04 (0.24) 2.04 (0.24)
2.88 (0.23) 2.65 (0.3)
~+ 0.84 (0.13) b+0.61 (0.18)
a p<0.001, b p<0.05 FEV1 Ketotifen v. Cromoglycate at 12 weeks
Group A Group B Group C
Ketotifen
Cromoglycate
Difference
2.93 (0.23) 2.87 (0.17) 2.88 (0.23)
2.71 (0.25) 3.11 (0.2) 2.65 (0.3)
c0.22 (0.14) d0.24 (0.12) 0.23 (0.14)
cp = 0.036 one tailed test; dp = 0.029 one tailed test; mean readings with _+SEM in parenthesis
Further Analysis of Diary Card and Spirometric Data Based on Physicians' Preference. The patients were sub-divided into three groups. Group A - ketotifen preferred by physician, Group B - cromoglycate preferred by physician, and Group C - no drug preferred by physician. Similar analyses of the 0-12 weeks parameters and 12 week ketotifen vs. cromoglycate parameters were carried out for these sub-groups.
The two physicians agreed on 29 of the 43 assessments (67%) on the first attempt and agreed on a further 11 patients on the second attempt. They then discussed the final three patients and reached agreement. Change in assessment occurred approximately equally with each physician (physician A - six changes, physician B - eight changes) but on no occasion was there a reversal of drug preference. All the changes were either from no difference detected to a particular drug preferred or vice versa. The final analysis showed 18 patients in which ketotifen was preferred = Group A. Seventeen patients in which cromoglycate was preferred = Group B and eight patients in whom no drug was preferred -- Group C. Thus there was no significant difference between the two drugs in terms of physician preference. Further analysis showed that drug order had no effect on the physicians' preference. Thus in the 18 patients in which ketotifen was preferred 13 finished on ketotifen and in the 17 patients in which cromoglycate was preferred 7 finished on ketotifen. A Chi square test showed no significant difference between the 2 groups (X 2= 0.24, p: 0.75 - 0.5).
Comparison of Baseline Parameters No significant differences were found in the baseline parameters between Group 1 and Group 2.
Analysis of Paired Data at 12 Weeks Results
Forty-six asthmatics entered the study and three were withdrawn. One patient was entered twice because of a drug rash caused by coincidental administration of an antibiotic at the time of first entry. The three patients were withdrawn from the trial by the investigators for reasons unassociated with efficacy or drug side-effects. Forty-three patients completed the study, of whom 26 were males with mean age + SD = 29.6 + 8.5 years and 17 were females with mean age _+ SD = 28.5 _+8.4 years. Of the 43 patients, seven had never taken cromoglycate before and 23 of the remaining 36 patients were currently using cromoglycate when selected into the trial. Of the 36 patients known to have used it in the past, 31 (86%) stated they had found it effective and three (12%) stated they had not found it effective whereas three patients were uncertain whether it had much effect.
The 12 week clinic readings for FEV1, FVC, PEFR, blood pressure, and heart rate were compared for the period on ketotifen and the period on cromoglycate. No significant difference was found in any of these parameters. The home peak flow rates measured over the last two weeks of each treatment phase were not significantly different. Day and night asthma scores, day and night aerosol use, cough and sputum scores obtained over the last four weeks on each drug showed no significant difference between ketotifen and sodium cromoglycate.
Comparison 0-12 Weeks on Each Drug Tables 1 and 2 show the diary card parameters and pulmonary function tests 0 vs. 12 weeks for ketotifen and cromoglycate. All diary card parameters except day aerosol use improved significantly between 0 and 12weeks on ketotifen. In contrast, improvements were only significant on cromoglycate for night asthma score, night aerosol use and cough
J. W. Paterson et al.: Ketotifen in Bronchial Asthma
191
Table 4. Night aerosol use 0 vs. 12 weeks 0
12
Diff
Group A Ketotifen Cromoglycate
1.55 (0.39) 1.69 (0.43)
0.70 (0.24) 1.19 (0.28)
b0.85 (0.26) 0.50 (0.38)
Group B Ketotifen Cromoglycate
1.51 (0.32) 1.51 (0.32)
0.82 (0.15) 0.69 (0.16)
0.69 (0.35) b0.82 (0.23)
Group C Ketotifen Cromoglycate
1.05 (0.15) 1.05 (0.15)
0.36 (0.15) 0.38 (0.14)
"0.69 (0.22) c0.67 (0.22)
ap<0.05:
bp<0.01;
Cp=0.02
Night aerosol use ketotifen vs, cromoglycate at 12 weeks
Group A Group B Group C
Ketotifen
Cromoglycate
Difference
0.70 (0.24) 0.82 (0.15) 0.36 (0.15)
1.19 (0.28) 0.69 (0.16) 0.38 (0.14)
d0.49 (0.23) 0.13 (0.23) 0.02 (0.06)
dp = 0.027 (one tailed t test); mean readings with _+_SEM in parenthesis, no significant differences between three groups
score. There were no significant improvements in lung function between 0 and 12 weeks on either drug although the trend for FEV1 and peak flow almost reached significance at a p value of 0.06 when the patients were on ketotifen. Thus there are clear indications that the patients improved between 0 and 12 weeks on active therapy, although there is no overall difference between the two drugs at 12weeks. Preferences show however that individual patients respond better to one or other drug.
Analysis of Patients Grouped According to Physicians' Preference A detailed analysis for FEV1 (Table 3) and Night Aerosol Use (Table4) is presented and then the trends for the other lung function and diary card parameters are outlined. The FEV1 readings subdivided by groups in Table 3 show an interesting trend, with the mean baseline FEV1, for the whole group being 73.5% of predicted normal. There was no difference between this and the baseline FEV~ in Group A or Group B. There was a trend for FEV1 to be somewhat higher in Group B although this did not reach significance. A more interesting finding was that the Group C patients had an FEV1 significantly lower than that of the other groups. In the Group C patients there were large and significant improvements in FEV1 on both drugs. The 12 week FEV1 in Group C was not significantly different from that measured in the other two
groups at 12 weeks. There were small changes in favour of the drug preferred in both Groups A and B but these did not achieve statistical significance. However, When a paired t test was done on the 12 week readings there were differences in favour of ketotifen in Group A patients and cromoglycate in Group B patients. Table 4 shows night aerosol use analysed in the same way. There was no significant difference in aerosol use at 0 weeks between the three groups nor were there any differences between the 12 week readings for the three groups. The reduction in aerosol use in Group A patients whilst on ketotifen reached statistical significance and similarly the reduction in Group B patients whilst on cromoglycate reached statistical significance. In Group C patients the reduction in aerosol use was significant on both drugs. Comparison of the 12week readings showed a reduction in favour of ketotifen in Group A patients. The other parameters were analysed in a similar way.
Lung Function The FVC results showed similar trends to the FEV1 readings but none of the changes reached statistical significance except the improvement between 0 and 12 weeks on ketotifen in Group C. The home peak flow readings improved significantly only in Group C patients whilst on cromoglycate. The clinic peak flow readings showed similar trends as seen for the FEV1 i.e. the baseline readings were lower in Group C and improved to readings that were not significantly different from the other Groups at week 12. The changes in Groups A and B between 0 to 12weeks did not achieve statistical significance for either drug. Comparison of the 12 week readings of peak flow showed significant differences in favour of ketotifen in Group A patients and cromoglycate in Group B patients.
Diary Card Parameters The day asthma score changed significantly between 0 and 12 weeks in Group A patients whilst on ketotifen and Group B patients whilst on cromoglycate. There were no significant differences when the 12week cromoglycate and ketotifen readings were compared in each group. The night asthma score showed similar trends to the day asthma score. Comparison of the 12 week readings showed a significant change in favour of ketotifen in Group A patients. There were reductions in day aerosol use between 0 and 12 weeks in all three groups but none achieved statistical significance. Comparison of ke-
192
totifen and cromoglycate at 12 weeks showed significant reduction in day aerosol use in Group A whilst on ketotifen and Group B whilst on cromoglycate. The cough and sputum scores fell significantly between 0 and 12 weeks for Group A patients whilst on ketotifen. There were no other significant changes for these parameters.
Side Effects Twenty-six of the 43 patients noticed sedation a n d / or lethargy whilst on ketotifen whereas 11 patients had similar side effects whilst on cromoglycate. No patient considered the effect serious enough to stop medication, although two patients found it sufficiently unpleasant to reduce ketotifen dosage or take the total dose at night over the first week. There were no significant changes seen in blood pressure or cardiac rate. There was no significant change in body weight on either drug although the body weight at 12weeks on ketotifen was 0.7kg higher than at 12 weeks on cromoglycate and this was statistically significant (p = 0.04). No significant change due to drug therapy was seen in urine analysis, blood count, serum electrolytes, urea, creatinine or liver function tests.
Other Therapy Prior to inclusion in the trial all but one patient was using a pressurised multi-dose aerosol dispensing a beta adrenergic drug, the most common being salbutamol. Twenty-three of the 46 patients were taking cromoglycate at the time of entry to the trial and this was withdrawn for the first two week period. Twenty of the patients were taking a theophylline preparation prior to the trial. The other drugs included oral beta adrenergic drugs and antihistamines.
Other Drugs used During the Trial Steroids. There were no obvious differences in steroid use between the two active treatment periods. Two patients required oral steroids at some time during the pre-trial period and in both of these patients, steroids were also used at some time during both treatment phases. Of the other patients, four required oral steroids whilst on ketotifen and four whilst on cromoglycate. Theophylline. Nineteen patients required theophylline for the two week pre-trial period. Twenty-four patients required theophylline during ketotifen therapy and 22 during cromoglycate therapy. Fifteen of these patients had theophylline during both phases
J.W. Paterson et al.: Ketotifen in Bronchial Asthma
of therapy. Thus there was no significant difference as regards theophylline use between ketotifen and cromoglycate.
Antibiotics. Five patients required antibiotics during both phases of the trial. An additional nine had antibiotics during the ketotifen phase and another four required antibiotics during the cromoglycate phase. Six patients required an additional antihistamine during ketotifen treatment and six during cromoglycate. Four patients required beclomethasone diproprionate nasal spray during ketotifen treatment whereas eight required this medication during cromoglycate treatment. Discussion
There is still considerable controversy about the role of ketotifen in the treatment of asthma. Craps et al. [5] and Pauwels et al. [9] found that ketotifen prevented bronchospasm due to inhalation of allergens. Two studies have suggested it is ineffective in exercise induced bronchoconstriction [10, 111. Although Craps et al. [51 and Weheba [6] showed a beneficial effect in adult asthma, Groggins et al. [12] failed to show an effect in childhood asthma. Dyson and Mackay [13] reported a multicentre study involving 38 extrinsic asthmatics. These patients were allocated in random order to one month of placebo, one month of treatment with ketotifen in a dose of 1 mg twice daily and one month of ketotifen 2 mg twice daily. Assessment by patient diary card, and thrice daily spirometry showed that on the higher dose of ketotifen, patients not already on steroid aerosols reported a significant reduction of inhaled bronchodilator drugs. Nine of the 38 patients noticed significant drowsiness on the higher dose of ketotifen. Monie et al. [14] carried out a double-blind, double-dummy crossover study comparing ketotifen 1 mg twice daily, with disodium cromoglycate 20 mg four times daily, each drug taken for eight weeks. The patients reported a significant improvement with cromoglycate, but ketotifen was not significantly superior to placebo. Lane [8] reported 86 patients studied in a multicentre trial, and demonstrated a small but significant reduction in oral steroid requirement in 44 subjects on ketotifen 1 mg twice daily compared with 42 patients on placebo. The present trial had a similar design to that of Clark and May [7]. There was a similar overall result in terms of efficacy, in that there were no significant differences between diary card scores and spiromettic data after 12 weeks of therapy with cromoglycate
J.W. Paterson et al.: Ketotifen in Bronchial Asthma
as compared to ketotifen. One possible explanation of this result was that none of our patients responded to cromoglycate, and the study was thus a comparison of two ineffective medications. However, in the present trial comparison of diary card scores at 0 and 12 weeks showed a significant improvement suggesting that active treatment was being given, particularly in the case of ketotifen. Pulmonary function tests also showed improvement although this did not reach statistical significance. It is possible that analysis of the mean data could be obscuring very considerable individual differences in patient response, e.g. a small subgroup of patients may show a greater response to one drug or the other, and this effect may not be evident from inspection of mean data for the whole group. Our analysis of patient responses by means of 'physician preference' showed that 18 subjects appeared better on ketotifen, 17 on cromoglycate and in eight no preference could be made. Once delineated by 'physician preference', analysis of the numerical data within these categories confirmed this 'preference'. Thus in Group A, FEV1 between 0 and 12 weeks rose on ketotifen and fell on cromoglycate (Table 3); the reverse effect occurring in Group B. Similarly, comparison of the mean values for FEV1 at 12 weeks shows a trend for the 'preferred' drug in categories A and B. Table 4 shows similar results for night aerosol score in Groups A and B. Our 'physician preference' analysis showed a small group of eight patients (Group C) in whom no 'preference' could be made. However, this group showed the greatest drug effect, having a significant rise in FEV1 on both ketotifen and cromoglycate. This group is distinguished from Groups A and B in that they had the lowest pre-treatment FEV1 of all three groups (Table 3). The present trial suggests that in a small group of patients, characterised in our subjects by the lowest pre-treatment FEV1, ketotifen and cromoglycate are both equally effective agents. In the remainder, 35 out of 43 subjects in our study, particular patients may do better on one or other drug; comparison of the mean data at 12 weeks for all patients loses this information. A possible explanation for the difference between the response to ketotifen in the present trial, and those of Dyson and Mackay [13] and Monie et al. [14] is that the drug was given for 12 weeks in the present trial but for only four weeks in the trial of Dyson and Mackay [13] and for eight weeks in the trial of Monie eta]. [14]. The maximal effect of ketotifen may take several weeks to develop and so shorter duration trials may tail to detect it. In the present
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study, none of the patients was taking steroid aerosol and accordingly the effect reported by Dyson and Mackay [13] could not be tested. The present trial suggests that in younger allergic asthmatics ketotifen has a definite role in therapy. It is of particular interest that some patients appear to do better on ketotifen and others on cromoglycate. Accordingly, a patient who fails on cromoglycate may nevertheless respond to ketotifen.
References 1. Martin U, R6mer D (1978) The pharmacological properties of a new orally active antianaphylactic compound: Ketotifen, a benzocycloheptathiopene. Arzneimlttelforsch/Drug Res 28: 770-782 2. Lichtenstein LM, Gillespie E (1975) The effects of the H1 and H2 antihistamines on 'allergic" histamine release and its inhibition by histamine. J Pharmacol Exp Ther 192:441-450 3. Martin U, Rrmer D (1978) Anti-anaphylactic properties of ketotifen in animal experiments. Triangle 17 [3-4]: 141-147 4. Church MK, Gradidge CF (1980) Inhibition of histamine release from human lung in vitro by antihistamines and related drugs. Br J Pharmacol 69: 663-667 5. Craps L, Greenwood C, Radielovic P (1978) Clinical investigation of agents with prophylactic anti-allergic effects in bronchial asthma. Clin Allergy 8:373-382 6. Weheba AF (1978) Clinical assessment of the efficacy and tolerance of ketotifen in bronchial asthma. Pharmatherapeutica 2:85-90 7. Clarke CW. May CS (1980) A comparison of the efficacy of ketotifen (HC20-511) with sodium cromoglycate (SCG) in skin test positive asthma. Br J Clin Pharmacol 10:473-476 8. Lane DJ (1980) A steroid sparing effect of ketotifen in steroiddependent asthmatics. Clin Allergy 10:519-525 9. Pauwels R, Lamont H, Van Der Straeten M (1978) Comparison between ketotifen and DSCG in bronchial challenge. Clin Allergy 8:289-293 10. Kennedy JD, Hasham F, Clay MJD, Jones RS (1980) Comparison of actions of disodium cromoglycate and ketotifen on exercise-induced bronchoconstriction in childhood asthma. Br MedJ 281:1458 11. Tanser AR, Elmes J (1980) A controlled trial of ketotifen in exercise induced asthma. Br J Chest 74:398-401 12. Groggins RC, Hiller EJ, Milner AD, Stokes GM (1981) Ketotifen in the prophylaxis of childhood asthma. Arch Dis Child 56:304-305 13. Dyson AJ, Mackay AD (1980) Ketotifen in adult asthma. Br Med J 280:360-361 14. Monie RDH, Smith AP, Leopold JD, Anderson EG, Davies BH, Thomas GO (1981) Double blind clinical trial of ketotifen and disodium cromoglycate in bronchial asthma. Thorax 36: 234 Received: October 12, 1982 accepted: April 8, 1983 James W. Paterson, M.D. Department of Pharmacology University of Western Australia Nedlands, Western Australia 6009