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BRONCHODILATOR AEROSOLS
838 in insects and recognised in amphibia, has been overlooked in man. This hypothesis will be presented in detail in the near future. New York Medical College, HARRY WIENER. New York 10029.
thoroughly studied
ASSESSMENT OF VALUE OF DISODIUM CROMOGLYCATE BY COMPARISON OF CONDITION OF 62 PATIENTS WITH ASTHMA DURING PERIODS A
AND B
(see text)
DISODIUM CROMOGLYCATE IN ASTHMA SiR,-On reviewing the careful observations, both animal and clinical, by Altounyanand the pilot clinical trials by Altounyan and Howell,2 it seemed fully justifiable to embark on a formal double-blind trial to assess this form of treatment
independently. A double-blind trial, carried out in 1967 between January and April, consisted of two periods of six weeks (period A and period B). During period A half the patients inhaled capsules containing 20 mg. disodium cromoglycate (’ FPL 670’) together with 0-1 mg. isoprenaline and 14-0 mg. lactose, whilst the other half of the patients inhaled a placebo powder containing 0-1 mg. isoprenaline, 5 mg. anhydrous sodium sulphate, and 35 mg. lactose. During period B of the trial, those patients who had been having the placebo capsules during period A were issued with active capsules, and vice versa. No-one concerned with the management of the patients had any idea which capsules were active and which were inactive. Sixty-two patients were selected for this trial from a group of four hundred patients for whom detailed records, going back for some one to ten years, were available. Most of the patients chosen for the trial had various types of labile allergic asthma, but there were also a few patients in whom . there was evidence of very advanced irreversible lung damage. Before, during, and after the trial, serial assessments were carried out on all patients-these included daily symptomatic records, and weekly physiological measurements of ventilatory capacity and sputum cytology-and radiological, hsematological and physical examinations were made. All relevant findings were plotted on annual asthma charts. From the scrutiny of these data, individuals were assessed as worse, or as showing no change, marginal improvement, definite improvement, or pronounced improvement during either period A or period B. This assessment was made prior to breaking the code, and the results are summarised in the accompanying table. On breaking the code it was found that forty of the fortyfive patients who showed improvement during period A or B, including all the eleven patients judged to have shown pronounced improvement, had been receiving disodium cromoglycate. It was concluded that these findings were highly significant and that, in the treatment of certain individuals with allergic airway disease, disodium cromoglycate showed a considerable advantage over the placebo. As a result of this investigation, further open trials with disodium cromoglycate are now in progress on more than a hundred patients. It is, as yet, premature to fully assess these further results. However, ten of the eleven patients who showed pronounced improvement during the original double-blind trial have been given further treatment. Seven of these ten patients showed pronounced improvement (objective and subjective) on resuming treatment. In two of the remaining three patients, the asthma condition has been adequately controlled (with less steroid therapy than in previous years) since disodium-cromoglycate therapy has been resumed. Most of those showing pronounced improvement have had temporary mild relapses, especially at times when there has been an exceptionally high antigen challenge (e.g., the pollen seasons). Thus, on reviewing the findings of Dr. Grant and his colleagues (S’ept. 23, p. 673), I wonder whether their results are quite so bad as they suggest, since ten out of the thirty-two patients who were treated and suitable for analysis showed both objective and subjective improvement (i.e., roughly 1. 2.
Altounyan, R. Altounyan, R.
E. C. Acta allerg. (in the press). E. C., Howell, J. B. L. Personal communication.
in three). Perhaps some of the temporary responses that they report may well have been due to the varying antigen challenge to which some of their patients might have been subjected. Altounyanfound disodium cromoglycate to reduce the asthmatic response to inhaled antigen, but the degree of protection depended mainly on the severity of the antigen challenge. Thus it is not surprising that the individual response varies when the antigen challenge is continually changing throughout the year. At the moment, my overall impression is that disodium cromoglycate is an effective, useful, protective agent in certain asthmatics. It certainly does not afford 100% protection in all cases, and Dr. Howell and Dr. Altounyan, as they point out last week (p. 777), did not imply this in their paper (Sept. 9, p. 539). However, it is clear that a great deal more work needs to be done to evaluate further this new preparation and to learn how to apply it. Variables such as dose, frequency of administration, and when to give and when to withdraw the drug all require investigation. The investigation becomes one
difficult in view of the fact that certain asthmatics will continue to require spasmolytic, adrenergic, and steroid treatment as well. Certainly the design and analysis of clinical trials for this form of treatment, which acts differently from anti-inflammatory and spasmolytic drugs, will require further thought. Probably the most important prerequisite in evaluating this drug or any other drug used in the treatment of asthma is to map out, accurately, objectively and subjectively, the pattern of behaviour before treatment. Department of Respiratory Physiology, City General Hospital, M. C. S. KENNEDY. Stoke-on-Trent. even more
BRONCHODILATOR AEROSOLS
SIR,-I read with interest about Dr. Plaut’s patient (Sept. 30, p. 721) whose forced expiratory volume in one second (F.E.V.!) fell from 1-49 to 1-06 litres after inhalation of an aerosol propellant. The act of forced expiration induces bronchospasm in some asthmatics. In such cases a truly inert propellant, inhaled after an initial F.E.V. measurement, might be wrongly blamed for causing a fall in value. I have encountered several asthmatics who on occasion respond to a bronchodilator aerosol with a fall in F.E.v., and who on other occasions respond with a rise after inhalation of the same aerosol. It seems that this unexpected response might be due to some transitory change in the individual’s reactivity. Before concluding that the propellant alone caused bronchoconstricdon in Dr. Plaut’s test subject, one needs an assurance that he (a) maintains his F.E.v. at the same level after repeated measurement without prior inhalation, and (b) responds to propellant with a fall in F.E.v. on each occasion that it is inhaled. Dulwich Hospital, BERNARD I. FREEDMAN. London S.E.22.
thoroughly studied
ASSESSMENT OF VALUE OF DISODIUM CROMOGLYCATE BY COMPARISON OF CONDITION OF 62 PATIENTS WITH ASTHMA DURING PERIODS A
AND B
(see text)
DISODIUM CROMOGLYCATE IN ASTHMA SiR,-On reviewing the careful observations, both animal and clinical, by Altounyanand the pilot clinical trials by Altounyan and Howell,2 it seemed fully justifiable to embark on a formal double-blind trial to assess this form of treatment
independently. A double-blind trial, carried out in 1967 between January and April, consisted of two periods of six weeks (period A and period B). During period A half the patients inhaled capsules containing 20 mg. disodium cromoglycate (’ FPL 670’) together with 0-1 mg. isoprenaline and 14-0 mg. lactose, whilst the other half of the patients inhaled a placebo powder containing 0-1 mg. isoprenaline, 5 mg. anhydrous sodium sulphate, and 35 mg. lactose. During period B of the trial, those patients who had been having the placebo capsules during period A were issued with active capsules, and vice versa. No-one concerned with the management of the patients had any idea which capsules were active and which were inactive. Sixty-two patients were selected for this trial from a group of four hundred patients for whom detailed records, going back for some one to ten years, were available. Most of the patients chosen for the trial had various types of labile allergic asthma, but there were also a few patients in whom . there was evidence of very advanced irreversible lung damage. Before, during, and after the trial, serial assessments were carried out on all patients-these included daily symptomatic records, and weekly physiological measurements of ventilatory capacity and sputum cytology-and radiological, hsematological and physical examinations were made. All relevant findings were plotted on annual asthma charts. From the scrutiny of these data, individuals were assessed as worse, or as showing no change, marginal improvement, definite improvement, or pronounced improvement during either period A or period B. This assessment was made prior to breaking the code, and the results are summarised in the accompanying table. On breaking the code it was found that forty of the fortyfive patients who showed improvement during period A or B, including all the eleven patients judged to have shown pronounced improvement, had been receiving disodium cromoglycate. It was concluded that these findings were highly significant and that, in the treatment of certain individuals with allergic airway disease, disodium cromoglycate showed a considerable advantage over the placebo. As a result of this investigation, further open trials with disodium cromoglycate are now in progress on more than a hundred patients. It is, as yet, premature to fully assess these further results. However, ten of the eleven patients who showed pronounced improvement during the original double-blind trial have been given further treatment. Seven of these ten patients showed pronounced improvement (objective and subjective) on resuming treatment. In two of the remaining three patients, the asthma condition has been adequately controlled (with less steroid therapy than in previous years) since disodium-cromoglycate therapy has been resumed. Most of those showing pronounced improvement have had temporary mild relapses, especially at times when there has been an exceptionally high antigen challenge (e.g., the pollen seasons). Thus, on reviewing the findings of Dr. Grant and his colleagues (S’ept. 23, p. 673), I wonder whether their results are quite so bad as they suggest, since ten out of the thirty-two patients who were treated and suitable for analysis showed both objective and subjective improvement (i.e., roughly 1. 2.
Altounyan, R. Altounyan, R.
E. C. Acta allerg. (in the press). E. C., Howell, J. B. L. Personal communication.
in three). Perhaps some of the temporary responses that they report may well have been due to the varying antigen challenge to which some of their patients might have been subjected. Altounyanfound disodium cromoglycate to reduce the asthmatic response to inhaled antigen, but the degree of protection depended mainly on the severity of the antigen challenge. Thus it is not surprising that the individual response varies when the antigen challenge is continually changing throughout the year. At the moment, my overall impression is that disodium cromoglycate is an effective, useful, protective agent in certain asthmatics. It certainly does not afford 100% protection in all cases, and Dr. Howell and Dr. Altounyan, as they point out last week (p. 777), did not imply this in their paper (Sept. 9, p. 539). However, it is clear that a great deal more work needs to be done to evaluate further this new preparation and to learn how to apply it. Variables such as dose, frequency of administration, and when to give and when to withdraw the drug all require investigation. The investigation becomes one
difficult in view of the fact that certain asthmatics will continue to require spasmolytic, adrenergic, and steroid treatment as well. Certainly the design and analysis of clinical trials for this form of treatment, which acts differently from anti-inflammatory and spasmolytic drugs, will require further thought. Probably the most important prerequisite in evaluating this drug or any other drug used in the treatment of asthma is to map out, accurately, objectively and subjectively, the pattern of behaviour before treatment. Department of Respiratory Physiology, City General Hospital, M. C. S. KENNEDY. Stoke-on-Trent. even more
BRONCHODILATOR AEROSOLS
SIR,-I read with interest about Dr. Plaut’s patient (Sept. 30, p. 721) whose forced expiratory volume in one second (F.E.V.!) fell from 1-49 to 1-06 litres after inhalation of an aerosol propellant. The act of forced expiration induces bronchospasm in some asthmatics. In such cases a truly inert propellant, inhaled after an initial F.E.V. measurement, might be wrongly blamed for causing a fall in value. I have encountered several asthmatics who on occasion respond to a bronchodilator aerosol with a fall in F.E.v., and who on other occasions respond with a rise after inhalation of the same aerosol. It seems that this unexpected response might be due to some transitory change in the individual’s reactivity. Before concluding that the propellant alone caused bronchoconstricdon in Dr. Plaut’s test subject, one needs an assurance that he (a) maintains his F.E.v. at the same level after repeated measurement without prior inhalation, and (b) responds to propellant with a fall in F.E.v. on each occasion that it is inhaled. Dulwich Hospital, BERNARD I. FREEDMAN. London S.E.22.