- Email: [email protected]
A DOUBLE-BLIND TRIAL OF DISODIUM CROMOGLYCATE IN THE TREATMENT OF ALLERGIC BRONCHIAL ASTHMA
539
stringent, criteria were therefore established to assess the results of the experiments; they seem to have been met in this consecutive series: (1) a reliable technique, and (2) a minimum of cell damage during the preservation so that the kidney functions immediately on reimplantation and any damage that does occur is completely reversible within a reasonably short time. The twelve experiments were carried out consecutively and renal preservation and function were successful in each case. Our experience with over eighty extracorporeal perfusions has indicated that undiluted homologous plasma produces the best results (Belzer and Ashby, unpublished).
A DOUBLE-BLIND TRIAL OF DISODIUM CROMOGLYCATE IN THE TREATMENT OF
Arteriovenous oxygen differences at 8° to 12°C showed that more than enough oxygen was available to the kidney in the form of dissolved oxygen. By adjusting the flowrate the venousP02 could always be kept above 100 mm. Hg. But, if the temperature was raised, the venous P02 fell accordingly, indicating that the kidney could extract the oxygen as needed. The pulsatile pump was used, because in our experience survival of the kidney after reimplantation was improved using a pulsatile rather than a non-pulsatile flow. We used a membrane oxygenator to limit the air-fluid interphase-present in all other types of oxygenators and shown to produce denaturing of protein by Dobell et al. (1965). We removed the contralateral kidney immediately before reimplantation of the perfused kidney in order that the functional ability of the implanted organ could be assessed and to mimic the conditions under which a human transplant would be undertaken. With immediate contralateral nephrectomy, seven of the twelve dogs had normal blood-urea nitrogen after 2 weeks, and ten of the twelve had a normal blood-urea nitrogen 5 weeks after reimplantation. This indicates that the cellular damage caused by the period of preservation was slight and rapidly reversible. Although there was more cellular injury in the 72-hour group, function still returned to normal in five out of six dogs within 5 weeks. The period of follow-up is still short, the longest being 13 weeks, but ten of the dogs that survived the immediate postoperative period have survived longer than 9 weeks. The follow-up study will be continued, with long-term observations of renal function and blood-pressure. The results indicate that this method of renal preservation is dependable and inflicts only slight and reversible cell damage on the kidney. Lengthier periods of kidney preservation by means of extracorporeal perfusion are being undertaken, but 24-72 hours seem adequate for preparing human recipients and pre-transplant studies of the donor kidney.
sequential trial a new antiallergic compound, disodium cromoglycate (’ FPL670 ’, ’ Intal ’) was carried out over a period of 6 weeks in ten patients severely disabled with allergic bronchial asthma. There was a significant clinical improvement during administration of FPL670 plus isoprenaline in all patients compared with two periods in which isoprenaline alone was given. Spirometric improvement occurred in only four patients. Subsequent experience over periods up to 26 months with these and other patients has confirmed the therapeutic value and safety of FPL670 in the management of allergic bronchial
ALLERGIC BRONCHIAL ASTHMA
J. B. L. HOWELL M.B., Ph.D. Lond., F.R.C.P. CONSULTANT PHYSICIAN, ROYAL INFIRMARY, MANCHESTER, AND SENIOR LECTURER IN MEDICINE, UNIVERSITY OF MANCHESTER
R. E. C. ALTOUNYAN M.B. Cantab. OF THE RESEARCH
DEPARTMENT, FISONS PHARMACEUTICALS LIMITED, HOLMES CHAPEL, CHESHIRE
A double-blind
Summary of
cross-over
asthma. Introduction
compound, disodium cromoglycate (’ FPL 670 ’,Intal’, 1,3-bis yloxy]-2-hydroxypropane, disodium salt), was found to be effective in reducing the asthmatic response to inhaled antigen in sensitised individuals (Altounyan 1967). The protective effect, which persisted for several hours, was greatest when the compound was inhaled before the antigen challenge; the drug was ineffective when inhaled a few minutes after the antigen challenge. FPL670 has no intrinsic bronchodilator-type or corticosteroid-type activity and it does not antagonise histamine, slow-reacting substance of anaphylaxis (S.R.S.-A.), or other known spasmogens. A preliminary report of the pharmacology and toxicology of FPL670 will be published elsewhere (Cox 1967). These observations suggested that FPL670 might be useful in the prophylaxis and treatment of allergic asthma. The short-term effect was investigated in twelve patients with severe chronic allergic asthma, whose symptoms were poorly controlled by even high doses of corticosteriods, and in whom the dangers of side-effects were causing serious concern. In this pilot study there was rapid, and in some cases striking, symptomatic improvement, particularly in the severity and frequency of acute attacks, We wish to thank Mr. Robert Hoffman and Mr. Glen L. Downes cough, and sputum volume. However, in only five patients for their technical assistance. This work was supported in part by was this improvement accompanied by an increase in the grant AM 09181-02 from the National Institute .of Arthritis and forced expiratory volume in the first second (F.E,V’I) Metabolic Diseases of the National Institutes of Health, Bethesda, U.S.A. B. S. A. is in a of Wellcome Maryland, travelling greater than 20% of control values. receipt grant.
Requests for reprints
should be addressed to F. 0. B. REFERENCES
Ackermann, J. R. W., Barnard, C. N. (1966) Br. J. Surg. 53, 525. Belzer, F. O., Ashby, B. S. (Unpublished). Dobell, A. R. C., Mitri, M., Galva, R., Sarkozy, E., Murphy, D. R. (1965) Ann. Surg. 161, 617. Humphries, A. L., Russell, R., Ostafin, J., Goodrich, S. M., Moretz, W. H. (1963) Surgery, St. Louis, 54, 136. Gregory, J., Carter, R. H., Moretz, W. H. (1964) Am. Surg. —
—
30, 748. Ladaga, L. G., Nabseth, D. C., Besznyak, I., Hendry, W. F., McLeod, G., Deterling, R. A. (1966) Ann. Surg. 163, 553. Manax, W. G., Bloch, J. H., Longerbeam, J. K., Lillehei, R. C. (1964) Surgery, St. Louis, 56, 275. Eyal, Z., Lyons, G. W., Lillehei, R. C. (1965) J. Am. med. Ass. 192, 755. —
—
IN 1965
a
new
In view of this lack of consistent correlation between the apparent symptomatic improvement and spirometric measurements, it was considered desirable to carry out a double-blind trial to- reduce bias both of patient and of observer. Patients and Methods
Patients Patients
considered suitable for the trial if: (1) severe symptoms persisted despite conventional bronchodilator and corticosteroid therapy; (2) a smear of sputum, stained by the method of Lendrum (1944), contained one or more clumps, each containing at least five eosinophils; (3) they were willing to cooperate in the trial, which necessitated regular and frewere
540 TABLE I-DETAILS OF TEN PATIENTS IN DOUBLE-BLIND TRIAL OF
FPL670
dilator aerosol. Each week the patients were interviewed individually about their symptoms and any untoward effects. They also received a full physical examination. In a separate laboratory the resting PC02 was measured by a rebreathing method (Campbell and Howell 1960), followed by the vital capacity (v.c.), and F.E.V’l> before and after isoprenaline. Sputum smears were examined for eosinophils and polymorphonuclear leucocytes. Blood was taken before and after the trial for routine hxmatological examination, hepaticfunction tests, and determination of serum-electrolytes and blood-urea.
quent attendances for assessment; and (4) they were able to carefully and record symptoms twice daily on a specially
assess
designed questionary. Patients fulfilling these criteria were invited to participate in a trial of a new treatment for asthma. They were told that while short-term toxicity trials of the new compound in animals and in twelve volunteers had shown no toxic effects, long-term investigation had not yet been completed. Of the patients approached, one refused the invitation and one patient who accepted was not included in the final analysis because of a severe exacerbation during the control period. Details of the ten patients in the trial are shown in table i. Experimental Design Statistical.-The restricted sequential procedure employed (Armitage 1960), was designed on the following basis: (1) that the result obtained would be significant at the 5% level (P < 005); (2) that there was a high probability (1-= 0-95) of detecting a true difference between the response to routine treatment and the response to drug; (3) that, in nine cases out of ten, the response would be in favour of drug: (90-90), (4) that patients who showed no preference for either drug or routine treatment would be excluded; (5) that the maximum number of preferences needed to give a result in favour of drug, or in favour of routine treatment, or to show no significant difference between the two is nineteen (N = 19). Procedure.-The trial extended over three consecutive 2 weeks. The patients were instructed to continue their usual treatment throughout the trial and not to alter their steroid dosage other than by increasing it appropriately should a severe exacerbation occur. They were told that they would receive, in addition, capsules containing powder to be inhaled at approximately 6-hourly intervals (4 daily) from a special inhaler (’ Spinhaler’). In the first 2 weeks the powder would contain only a known bronchodilator and the purpose of this initial practice period was to enable them to become proficient in the use of the spinhaler and in the completion of their daily record charts. The capsules for this period were of clear gelatine and contained 0-1 mg. isoprenaline sulphate diluted with lactose. The control period will hereafter be referred to as isoprenaline (control). During each of the next 2-week periods (periods A and B) they would receive pink-coloured capsules which were identical in appearance, but would contain a different preparation. Patients were asked not to comment on any difference which they might notice in the taste or physical properties of each preparation lest this should influence the assessor. Both preparations contained 0-1 mg. isoprenaline in lactose but only one contained FPL670 (20 mg.). The order in which patients received each preparation was randomised. These two periods will hereafter be referred
Assessment of Response to Treatment The design of the trial required one of us (J. B. L. H.) to decide whether each patient was better during period A or period B, or whether there was no significant difference between the two. His decision was based on evidence obtained from interview and from examination of the patient, together with inspection of the daily record charts. It is important to note that the objective laboratory measurements which were made throughout the trial were not known to the physician at the time of his assessment and therefore did not influence his decision.
periods, each of
isoprenaline (test) and FPL670, respectively. Clinical and laboratory assessment.-Each morning and evening patients assessed the severity of breathlessness on exertion, frequency of attacks at rest during the day and night, morning tightness, cough, sputum volume and its character, and the number of times they had used their usual broncho-
to as
Results
Physician’s Assessment In each case, the assessing physician had no difficulty deciding that the patient’s condition was better during one period than the other. When ten patients had completed the trial the first analysis was made. It was then found that all the preferences were in favour of FPL670 and it will be seen from the sequential analysis graph (fig. 1) that the sample path crossed the upper boundary at the seventh preference. The exact probability of this result, being due to chance, is 0.016. The trial was therefore terminated.
in
Analysis of Changes
in
Symptoms
Each subjective symptom was recorded on a 5-point scale, except for attacks of breathlessness at rest and bronchodilator-aerosol usage, where actual numbers were recorded. The total score for each item was found for each 2-week period. A difference in the score of 7 or more was arbitrarily chosen as indicative of significant change, except for bronchodilator usage for which a difference of 28 doses was considered to be significant. Results are shown graphically in figs. 2-4 where the number of patients recording a significant change in symptom scores during the three periods of the trial are
541 TABLE
II—F.E.V.i MEASUREMENT
IN TEN PATIENTS
No single patient showed improvement in all of the items assessed, neither did any patient fail to show any improvement in at least 1 item. Morning tightness, nocturnal attacks, attacks at rest during the day, and use of bronchodilator aerosol were the items most frequently improved during FPL670 administration.
Analysis of Laboratory
Measurements
shown in table showed corresponding changes, and are not recorded. Only four of the ten patients showed a change greater than 20%in the F.E.v.i. However, these patients did not show a greater number of symptoms improved during drug administration, when compared with those patients showing little or no change in F.E.v.i. Other tests.-PC02 values showed no significant change throughout the trial. There were no abnormal changes in the biochemical and hxmatological results obtained before and after completion of the trial.
6’p!’ro6fry.—F.E.v.i
11.
Weeks 1 and 2 are control period, weeks 3 and 4 are period A, and weeks 5 and 6 are period B. Figures in italics refer to the period in which FPL670 was given. t % change is calculated from the mean values obtained during each of the two periods:
(test) x 100. change = FPL670Isoprenaline - Isoprenaline (test)
% change=
x
compared. There was no significant difference between the symptom scores during isoprenaline (control) and isoprenaline (test) periods. The ten patients had a total of 19 items which improved during the isoprenaline (test) period and 23 items improved during the control period
(fig. 2). By contrast, a striking difference in the patient’s condition was observed during the period on FPL670 compared with both the isoprenaline periods. Comparing FPL670 with isoprenaline (control) (fig. 3), 39 items improved during FPL670 administration and only 4 items improved during the control period. Similarly, comparing FPL670 with isoprenaline (test) (fig. 4) = 37 items improved during drug period and only 1 during the test period.
Fig. 2-Number of patients showing significant changes in symptom
scores
while
receiving isoprenaline (test and control).
Untoward Events No untoward event was reported by any observed by the physician during the trial.
ficant
FPL670.
patient
or
Discussion
Initially we were concerned lest the difference in taste between isoprenaline (test) and FPL670 (which is slightly bitter) should influence the result. However, we believe that this did not happen, because: by chance, half of the patients received FPL670 in period A yet there was no difference in their symptom response to isoprenaline (test) compared with that in patients receiving FPL670 during period B; the patients derived an immediate subjective response from the isoprenaline content of both preparations, and this was consistent with their original briefing that they were comparing two forms of treatment, both of which were active; and, when questioned after completion of the trial three patients (cases 3, 4, and 5) had not detected any difference in taste between capsules
of patients showing signichanges in symptom scores while receiving isoprenaline (control) and
Fig. 3-Number
measurements are
v.c. measurements
Fig. 4--Number of patients showing significant changes in symptom scores while receiving FPL670 and isoprenaline (test).
542 and there was no difference in their pattern of symptomatic improvement from the other patients. The consistent improvement in subjective symptoms during FPL670 administration contrasts with the variable
This disparity implies due solely to increase in airways resistance; indeed, there is no a priori reason why such symptoms as cough, sputum, morning tightness or intermittent attacks of breathlessness at rest should be reflected in a change in isolated " spot check " values of the F.E.V.I. Furthermore, the persistence of reduced
objective spirometric changes. that the symptoms of asthma
are not
F.E,V’1 values, despite full bronchodilator, corticosteroid, and FPL670 therapy, suggests that factors other than allergy were causing residual airways obstruction. The results of this study indicate that reliance on simple spirometry alone would have led to a failure to recognise the therapeutic value of FPL670 in six of the
patients. Although the primary aim of the trial
ten
was to
study
whether FPL670 was active in the treatment of asthma, it became evident that the compound was of considerable to these patients, at least in the short This was confirmed when all of the patients elected to continue with FPL670 therapy, which they received continuously for the next 12 months. A placebo was then substituted on a single-blind basis, deterioration occurred in all cases, which was reversed when FPL670 therapy was recommenced. Since completing this double-blind trial we have used FPL670 for the treatment of over two hundred patients with mild to severe allergic and non-allergic airway disease. In over a hundred of these patients treatment has extended for periods of 6 to 26 months. The degree of benefit afforded to individual patients has varied considerably. No toxic effects have been noted and we believe that FPL670 is a major advance in the management of allergic airway disease. We thank Dr. A. Adelstein for his help and advice with the statistical aspects of the trial; Dr. J. E. McIver and Mr. H. Varley and their staff at Manchester Royal Infirmary for the haematological
therapeutic value term.
and biochemical measurements; Miss Bernice Coombs for her technical assistance and Dr. J. S. G. Cox, research director, Fisons Pharmaceuticals Limited for his interest and support throughout the studv. REFERENCES
Altounyan, R.
E. C.
(1967) Acta allerg. (in the press). Armitage, P. (1960) Sequential Medical Trials. Oxford. Campbell, E. J. M., Howell, J. B. L. (1960) Br. med. J. i, 458. Cox, J. S. G. (1967) Unpublished. Lendrum, A. C. (1944) J. Path. Bact. 56, 441. "
some of your friends will answer this note, the will be read with interest by many individuals.... In Spain and Portugal, a thin paper, manufactured from straw, and without size, is used for making segars, by rolling up some tobacco in the paper, until the whole is about the size of a common pencil and the length of a finger. The tobacco itself cannot get into the stomach or lungs, as in the case of snufftaking, nor can the raw juice of the tobacco do it, as in the case of quid-chewing; but the mouth, nasal passage, and (I think) the lungs, gullet, and stomach must be powerfully coated with smoke, and whatever that smoke contains. Turks are perpetually smoking; Spaniards and Portuguese use tobacco profusely; and since the army returned from the Peninsula, the habit has become fashionable; the increased number of tobacco shops must be evident to every observer. Now, Sir, I should be glad to know, and I believe a great number of persons besides myself would be glad to know, what effect must be produced upon the structural and functional condition of the stomach and lungs by this habit. I am, rdspectfully, Sir, Your very obedient servant, Cigarro."-Lancet, Dec. 10, 1825, p. 392.
Sir,-If
answer
EFFECT OF VARIATION OF THE INTERVAL BETWEEN VENEPUNCTURE AND MEASUREMENT OF PLATELET ADHESIVENESS BY THE PAYLING WRIGHT METHOD T. FYFE M.B. Glasg., M.R.C.P.G. REGISTRAR
ELEANOR HAMILTON TECHNICIAN
From the Medical Research Council Atheroma Research Western Infirmary, Glasgow W.1
Unit,
Platelet adhesiveness was measured accordto a method based on that of Payling at and 20 minutes after venepuncture in Wright 3, 5, 7, ten subjects, and at 5 and 20 minutes after venepuncture in a further twenty-five subjects. A significant progressive increase in platelet adhesiveness with time after venepuncture was found. It is suggested that in future reports the interval between venepuncture and measurement of platelet adhesiveness should be fixed and should be stated. Summary
ing
Hellem
(1960)
Introduction reported that platelet
adhesiveness,
measured by the glass-bead-column method, tended to increase with time after venepuncture. So far as we are aware the effect of time on platelet adhesiveness as determined by the rotating glass-flask method of Payling Wright (1941) has not previously been reported. Method withdrawn by clean venepuncture into a polystyrene syringe containing 2 ml. of 3-8% sodium-citrate solution. The blood and citrate were gently mixed and transferred into a stoppered polystyrene tube. A stop-watch was started at the time of venepuncture, and platelet adhesiveness was measured according to the rotating glass-flask method of Payling Wright, commencing 3, 5, 7, and 20 minutes after venepuncture in each of ten subjects and 5 and 20 minutes after venepuncture in a further twenty-five subjects. 2 ml. samples of the citrated blood were placed in spherical glass flasks of standard size which were rotated at 31/2 r.p.m. for 20 minutes. Platelets were counted according to the method of Brecher and Cronkite (1950), using phase-contrast microscopy before and after rotation of the blood in the glass flasks. Platelet adhesiveness was expressed as initial count-final count x 100. initial count 18 ml. of blood
was
Results
The results for each of the ten subjects are shown in table 10 The mean results with the standard errors of the means are shown in the accompanying figure. The values TABLE I-PLATELET ADHESIVENESS
(%)
AFTER VENEPUNCTURE
stringent, criteria were therefore established to assess the results of the experiments; they seem to have been met in this consecutive series: (1) a reliable technique, and (2) a minimum of cell damage during the preservation so that the kidney functions immediately on reimplantation and any damage that does occur is completely reversible within a reasonably short time. The twelve experiments were carried out consecutively and renal preservation and function were successful in each case. Our experience with over eighty extracorporeal perfusions has indicated that undiluted homologous plasma produces the best results (Belzer and Ashby, unpublished).
A DOUBLE-BLIND TRIAL OF DISODIUM CROMOGLYCATE IN THE TREATMENT OF
Arteriovenous oxygen differences at 8° to 12°C showed that more than enough oxygen was available to the kidney in the form of dissolved oxygen. By adjusting the flowrate the venousP02 could always be kept above 100 mm. Hg. But, if the temperature was raised, the venous P02 fell accordingly, indicating that the kidney could extract the oxygen as needed. The pulsatile pump was used, because in our experience survival of the kidney after reimplantation was improved using a pulsatile rather than a non-pulsatile flow. We used a membrane oxygenator to limit the air-fluid interphase-present in all other types of oxygenators and shown to produce denaturing of protein by Dobell et al. (1965). We removed the contralateral kidney immediately before reimplantation of the perfused kidney in order that the functional ability of the implanted organ could be assessed and to mimic the conditions under which a human transplant would be undertaken. With immediate contralateral nephrectomy, seven of the twelve dogs had normal blood-urea nitrogen after 2 weeks, and ten of the twelve had a normal blood-urea nitrogen 5 weeks after reimplantation. This indicates that the cellular damage caused by the period of preservation was slight and rapidly reversible. Although there was more cellular injury in the 72-hour group, function still returned to normal in five out of six dogs within 5 weeks. The period of follow-up is still short, the longest being 13 weeks, but ten of the dogs that survived the immediate postoperative period have survived longer than 9 weeks. The follow-up study will be continued, with long-term observations of renal function and blood-pressure. The results indicate that this method of renal preservation is dependable and inflicts only slight and reversible cell damage on the kidney. Lengthier periods of kidney preservation by means of extracorporeal perfusion are being undertaken, but 24-72 hours seem adequate for preparing human recipients and pre-transplant studies of the donor kidney.
sequential trial a new antiallergic compound, disodium cromoglycate (’ FPL670 ’, ’ Intal ’) was carried out over a period of 6 weeks in ten patients severely disabled with allergic bronchial asthma. There was a significant clinical improvement during administration of FPL670 plus isoprenaline in all patients compared with two periods in which isoprenaline alone was given. Spirometric improvement occurred in only four patients. Subsequent experience over periods up to 26 months with these and other patients has confirmed the therapeutic value and safety of FPL670 in the management of allergic bronchial
ALLERGIC BRONCHIAL ASTHMA
J. B. L. HOWELL M.B., Ph.D. Lond., F.R.C.P. CONSULTANT PHYSICIAN, ROYAL INFIRMARY, MANCHESTER, AND SENIOR LECTURER IN MEDICINE, UNIVERSITY OF MANCHESTER
R. E. C. ALTOUNYAN M.B. Cantab. OF THE RESEARCH
DEPARTMENT, FISONS PHARMACEUTICALS LIMITED, HOLMES CHAPEL, CHESHIRE
A double-blind
Summary of
cross-over
asthma. Introduction
compound, disodium cromoglycate (’ FPL 670 ’,Intal’, 1,3-bis yloxy]-2-hydroxypropane, disodium salt), was found to be effective in reducing the asthmatic response to inhaled antigen in sensitised individuals (Altounyan 1967). The protective effect, which persisted for several hours, was greatest when the compound was inhaled before the antigen challenge; the drug was ineffective when inhaled a few minutes after the antigen challenge. FPL670 has no intrinsic bronchodilator-type or corticosteroid-type activity and it does not antagonise histamine, slow-reacting substance of anaphylaxis (S.R.S.-A.), or other known spasmogens. A preliminary report of the pharmacology and toxicology of FPL670 will be published elsewhere (Cox 1967). These observations suggested that FPL670 might be useful in the prophylaxis and treatment of allergic asthma. The short-term effect was investigated in twelve patients with severe chronic allergic asthma, whose symptoms were poorly controlled by even high doses of corticosteriods, and in whom the dangers of side-effects were causing serious concern. In this pilot study there was rapid, and in some cases striking, symptomatic improvement, particularly in the severity and frequency of acute attacks, We wish to thank Mr. Robert Hoffman and Mr. Glen L. Downes cough, and sputum volume. However, in only five patients for their technical assistance. This work was supported in part by was this improvement accompanied by an increase in the grant AM 09181-02 from the National Institute .of Arthritis and forced expiratory volume in the first second (F.E,V’I) Metabolic Diseases of the National Institutes of Health, Bethesda, U.S.A. B. S. A. is in a of Wellcome Maryland, travelling greater than 20% of control values. receipt grant.
Requests for reprints
should be addressed to F. 0. B. REFERENCES
Ackermann, J. R. W., Barnard, C. N. (1966) Br. J. Surg. 53, 525. Belzer, F. O., Ashby, B. S. (Unpublished). Dobell, A. R. C., Mitri, M., Galva, R., Sarkozy, E., Murphy, D. R. (1965) Ann. Surg. 161, 617. Humphries, A. L., Russell, R., Ostafin, J., Goodrich, S. M., Moretz, W. H. (1963) Surgery, St. Louis, 54, 136. Gregory, J., Carter, R. H., Moretz, W. H. (1964) Am. Surg. —
—
30, 748. Ladaga, L. G., Nabseth, D. C., Besznyak, I., Hendry, W. F., McLeod, G., Deterling, R. A. (1966) Ann. Surg. 163, 553. Manax, W. G., Bloch, J. H., Longerbeam, J. K., Lillehei, R. C. (1964) Surgery, St. Louis, 56, 275. Eyal, Z., Lyons, G. W., Lillehei, R. C. (1965) J. Am. med. Ass. 192, 755. —
—
IN 1965
a
new
In view of this lack of consistent correlation between the apparent symptomatic improvement and spirometric measurements, it was considered desirable to carry out a double-blind trial to- reduce bias both of patient and of observer. Patients and Methods
Patients Patients
considered suitable for the trial if: (1) severe symptoms persisted despite conventional bronchodilator and corticosteroid therapy; (2) a smear of sputum, stained by the method of Lendrum (1944), contained one or more clumps, each containing at least five eosinophils; (3) they were willing to cooperate in the trial, which necessitated regular and frewere
540 TABLE I-DETAILS OF TEN PATIENTS IN DOUBLE-BLIND TRIAL OF
FPL670
dilator aerosol. Each week the patients were interviewed individually about their symptoms and any untoward effects. They also received a full physical examination. In a separate laboratory the resting PC02 was measured by a rebreathing method (Campbell and Howell 1960), followed by the vital capacity (v.c.), and F.E.V’l> before and after isoprenaline. Sputum smears were examined for eosinophils and polymorphonuclear leucocytes. Blood was taken before and after the trial for routine hxmatological examination, hepaticfunction tests, and determination of serum-electrolytes and blood-urea.
quent attendances for assessment; and (4) they were able to carefully and record symptoms twice daily on a specially
assess
designed questionary. Patients fulfilling these criteria were invited to participate in a trial of a new treatment for asthma. They were told that while short-term toxicity trials of the new compound in animals and in twelve volunteers had shown no toxic effects, long-term investigation had not yet been completed. Of the patients approached, one refused the invitation and one patient who accepted was not included in the final analysis because of a severe exacerbation during the control period. Details of the ten patients in the trial are shown in table i. Experimental Design Statistical.-The restricted sequential procedure employed (Armitage 1960), was designed on the following basis: (1) that the result obtained would be significant at the 5% level (P < 005); (2) that there was a high probability (1-= 0-95) of detecting a true difference between the response to routine treatment and the response to drug; (3) that, in nine cases out of ten, the response would be in favour of drug: (90-90), (4) that patients who showed no preference for either drug or routine treatment would be excluded; (5) that the maximum number of preferences needed to give a result in favour of drug, or in favour of routine treatment, or to show no significant difference between the two is nineteen (N = 19). Procedure.-The trial extended over three consecutive 2 weeks. The patients were instructed to continue their usual treatment throughout the trial and not to alter their steroid dosage other than by increasing it appropriately should a severe exacerbation occur. They were told that they would receive, in addition, capsules containing powder to be inhaled at approximately 6-hourly intervals (4 daily) from a special inhaler (’ Spinhaler’). In the first 2 weeks the powder would contain only a known bronchodilator and the purpose of this initial practice period was to enable them to become proficient in the use of the spinhaler and in the completion of their daily record charts. The capsules for this period were of clear gelatine and contained 0-1 mg. isoprenaline sulphate diluted with lactose. The control period will hereafter be referred to as isoprenaline (control). During each of the next 2-week periods (periods A and B) they would receive pink-coloured capsules which were identical in appearance, but would contain a different preparation. Patients were asked not to comment on any difference which they might notice in the taste or physical properties of each preparation lest this should influence the assessor. Both preparations contained 0-1 mg. isoprenaline in lactose but only one contained FPL670 (20 mg.). The order in which patients received each preparation was randomised. These two periods will hereafter be referred
Assessment of Response to Treatment The design of the trial required one of us (J. B. L. H.) to decide whether each patient was better during period A or period B, or whether there was no significant difference between the two. His decision was based on evidence obtained from interview and from examination of the patient, together with inspection of the daily record charts. It is important to note that the objective laboratory measurements which were made throughout the trial were not known to the physician at the time of his assessment and therefore did not influence his decision.
periods, each of
isoprenaline (test) and FPL670, respectively. Clinical and laboratory assessment.-Each morning and evening patients assessed the severity of breathlessness on exertion, frequency of attacks at rest during the day and night, morning tightness, cough, sputum volume and its character, and the number of times they had used their usual broncho-
to as
Results
Physician’s Assessment In each case, the assessing physician had no difficulty deciding that the patient’s condition was better during one period than the other. When ten patients had completed the trial the first analysis was made. It was then found that all the preferences were in favour of FPL670 and it will be seen from the sequential analysis graph (fig. 1) that the sample path crossed the upper boundary at the seventh preference. The exact probability of this result, being due to chance, is 0.016. The trial was therefore terminated.
in
Analysis of Changes
in
Symptoms
Each subjective symptom was recorded on a 5-point scale, except for attacks of breathlessness at rest and bronchodilator-aerosol usage, where actual numbers were recorded. The total score for each item was found for each 2-week period. A difference in the score of 7 or more was arbitrarily chosen as indicative of significant change, except for bronchodilator usage for which a difference of 28 doses was considered to be significant. Results are shown graphically in figs. 2-4 where the number of patients recording a significant change in symptom scores during the three periods of the trial are
541 TABLE
II—F.E.V.i MEASUREMENT
IN TEN PATIENTS
No single patient showed improvement in all of the items assessed, neither did any patient fail to show any improvement in at least 1 item. Morning tightness, nocturnal attacks, attacks at rest during the day, and use of bronchodilator aerosol were the items most frequently improved during FPL670 administration.
Analysis of Laboratory
Measurements
shown in table showed corresponding changes, and are not recorded. Only four of the ten patients showed a change greater than 20%in the F.E.v.i. However, these patients did not show a greater number of symptoms improved during drug administration, when compared with those patients showing little or no change in F.E.v.i. Other tests.-PC02 values showed no significant change throughout the trial. There were no abnormal changes in the biochemical and hxmatological results obtained before and after completion of the trial.
6’p!’ro6fry.—F.E.v.i
11.
Weeks 1 and 2 are control period, weeks 3 and 4 are period A, and weeks 5 and 6 are period B. Figures in italics refer to the period in which FPL670 was given. t % change is calculated from the mean values obtained during each of the two periods:
(test) x 100. change = FPL670Isoprenaline - Isoprenaline (test)
% change=
x
compared. There was no significant difference between the symptom scores during isoprenaline (control) and isoprenaline (test) periods. The ten patients had a total of 19 items which improved during the isoprenaline (test) period and 23 items improved during the control period
(fig. 2). By contrast, a striking difference in the patient’s condition was observed during the period on FPL670 compared with both the isoprenaline periods. Comparing FPL670 with isoprenaline (control) (fig. 3), 39 items improved during FPL670 administration and only 4 items improved during the control period. Similarly, comparing FPL670 with isoprenaline (test) (fig. 4) = 37 items improved during drug period and only 1 during the test period.
Fig. 2-Number of patients showing significant changes in symptom
scores
while
receiving isoprenaline (test and control).
Untoward Events No untoward event was reported by any observed by the physician during the trial.
ficant
FPL670.
patient
or
Discussion
Initially we were concerned lest the difference in taste between isoprenaline (test) and FPL670 (which is slightly bitter) should influence the result. However, we believe that this did not happen, because: by chance, half of the patients received FPL670 in period A yet there was no difference in their symptom response to isoprenaline (test) compared with that in patients receiving FPL670 during period B; the patients derived an immediate subjective response from the isoprenaline content of both preparations, and this was consistent with their original briefing that they were comparing two forms of treatment, both of which were active; and, when questioned after completion of the trial three patients (cases 3, 4, and 5) had not detected any difference in taste between capsules
of patients showing signichanges in symptom scores while receiving isoprenaline (control) and
Fig. 3-Number
measurements are
v.c. measurements
Fig. 4--Number of patients showing significant changes in symptom scores while receiving FPL670 and isoprenaline (test).
542 and there was no difference in their pattern of symptomatic improvement from the other patients. The consistent improvement in subjective symptoms during FPL670 administration contrasts with the variable
This disparity implies due solely to increase in airways resistance; indeed, there is no a priori reason why such symptoms as cough, sputum, morning tightness or intermittent attacks of breathlessness at rest should be reflected in a change in isolated " spot check " values of the F.E.V.I. Furthermore, the persistence of reduced
objective spirometric changes. that the symptoms of asthma
are not
F.E,V’1 values, despite full bronchodilator, corticosteroid, and FPL670 therapy, suggests that factors other than allergy were causing residual airways obstruction. The results of this study indicate that reliance on simple spirometry alone would have led to a failure to recognise the therapeutic value of FPL670 in six of the
patients. Although the primary aim of the trial
ten
was to
study
whether FPL670 was active in the treatment of asthma, it became evident that the compound was of considerable to these patients, at least in the short This was confirmed when all of the patients elected to continue with FPL670 therapy, which they received continuously for the next 12 months. A placebo was then substituted on a single-blind basis, deterioration occurred in all cases, which was reversed when FPL670 therapy was recommenced. Since completing this double-blind trial we have used FPL670 for the treatment of over two hundred patients with mild to severe allergic and non-allergic airway disease. In over a hundred of these patients treatment has extended for periods of 6 to 26 months. The degree of benefit afforded to individual patients has varied considerably. No toxic effects have been noted and we believe that FPL670 is a major advance in the management of allergic airway disease. We thank Dr. A. Adelstein for his help and advice with the statistical aspects of the trial; Dr. J. E. McIver and Mr. H. Varley and their staff at Manchester Royal Infirmary for the haematological
therapeutic value term.
and biochemical measurements; Miss Bernice Coombs for her technical assistance and Dr. J. S. G. Cox, research director, Fisons Pharmaceuticals Limited for his interest and support throughout the studv. REFERENCES
Altounyan, R.
E. C.
(1967) Acta allerg. (in the press). Armitage, P. (1960) Sequential Medical Trials. Oxford. Campbell, E. J. M., Howell, J. B. L. (1960) Br. med. J. i, 458. Cox, J. S. G. (1967) Unpublished. Lendrum, A. C. (1944) J. Path. Bact. 56, 441. "
some of your friends will answer this note, the will be read with interest by many individuals.... In Spain and Portugal, a thin paper, manufactured from straw, and without size, is used for making segars, by rolling up some tobacco in the paper, until the whole is about the size of a common pencil and the length of a finger. The tobacco itself cannot get into the stomach or lungs, as in the case of snufftaking, nor can the raw juice of the tobacco do it, as in the case of quid-chewing; but the mouth, nasal passage, and (I think) the lungs, gullet, and stomach must be powerfully coated with smoke, and whatever that smoke contains. Turks are perpetually smoking; Spaniards and Portuguese use tobacco profusely; and since the army returned from the Peninsula, the habit has become fashionable; the increased number of tobacco shops must be evident to every observer. Now, Sir, I should be glad to know, and I believe a great number of persons besides myself would be glad to know, what effect must be produced upon the structural and functional condition of the stomach and lungs by this habit. I am, rdspectfully, Sir, Your very obedient servant, Cigarro."-Lancet, Dec. 10, 1825, p. 392.
Sir,-If
answer
EFFECT OF VARIATION OF THE INTERVAL BETWEEN VENEPUNCTURE AND MEASUREMENT OF PLATELET ADHESIVENESS BY THE PAYLING WRIGHT METHOD T. FYFE M.B. Glasg., M.R.C.P.G. REGISTRAR
ELEANOR HAMILTON TECHNICIAN
From the Medical Research Council Atheroma Research Western Infirmary, Glasgow W.1
Unit,
Platelet adhesiveness was measured accordto a method based on that of Payling at and 20 minutes after venepuncture in Wright 3, 5, 7, ten subjects, and at 5 and 20 minutes after venepuncture in a further twenty-five subjects. A significant progressive increase in platelet adhesiveness with time after venepuncture was found. It is suggested that in future reports the interval between venepuncture and measurement of platelet adhesiveness should be fixed and should be stated. Summary
ing
Hellem
(1960)
Introduction reported that platelet
adhesiveness,
measured by the glass-bead-column method, tended to increase with time after venepuncture. So far as we are aware the effect of time on platelet adhesiveness as determined by the rotating glass-flask method of Payling Wright (1941) has not previously been reported. Method withdrawn by clean venepuncture into a polystyrene syringe containing 2 ml. of 3-8% sodium-citrate solution. The blood and citrate were gently mixed and transferred into a stoppered polystyrene tube. A stop-watch was started at the time of venepuncture, and platelet adhesiveness was measured according to the rotating glass-flask method of Payling Wright, commencing 3, 5, 7, and 20 minutes after venepuncture in each of ten subjects and 5 and 20 minutes after venepuncture in a further twenty-five subjects. 2 ml. samples of the citrated blood were placed in spherical glass flasks of standard size which were rotated at 31/2 r.p.m. for 20 minutes. Platelets were counted according to the method of Brecher and Cronkite (1950), using phase-contrast microscopy before and after rotation of the blood in the glass flasks. Platelet adhesiveness was expressed as initial count-final count x 100. initial count 18 ml. of blood
was
Results
The results for each of the ten subjects are shown in table 10 The mean results with the standard errors of the means are shown in the accompanying figure. The values TABLE I-PLATELET ADHESIVENESS
(%)
AFTER VENEPUNCTURE