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Cromoglycate (DSCG) inhibits responses to platelet-activating factor (PAF-acether) in man: An alternative mode of action for DSCG in asthma?
European Journal of Pharmacology, 86 (1983) 143-144
143
Elsevier Biomedical Press
Rapid communication C R O M O G L Y C A T E (DSCG) I N H I B I T S R E S P O N S E S T O P L A T E L E T - A C T I V A T I N G FACTOR (PAF-ACETHER) IN MAN: AN A L T E R N A T I V E M O D E OF A C T I O N F O R D S C G IN A S T H M A ? G.S. BASRAN *, C.P. PAGE **. W. PAUL and J. MORLEY
Department of Clinical Pharmacolog~v, Cardiothoracic Institute, Fulham Road, London S W3 6HP and * Ci(v Itospital, Department of Thoracic Medicine, Nottingham NG5 IPD, U.K. Received 15 November 1982. accepted 17 November 1982
The therapeutic efficacy of cromoglycate (DSCG) in asthma has been attributed to stabilisation of mast cells. Although many other drugs share this property of DSCG, none have proved effective in clinical asthma. This anomaly prompted a re-appraisal of the considered view of the mechanism of action of D S C G (Stokes and Morley, 1980) and the shortcomings of the concept of mast cell stabilisation have led us to consider other properties of D S C G which could account for its anti-allergy and anti-asthma properties. The phospholipid, PAF-acether, has properties appropriate to a mediator of asthma and inflammation (Vargaftig et al., 1981). We recently observed that intradermal injection of PAF-acether into the forearm of normal subjects results in an acute inflammatory response that is succeded by a phase of late onset, whose timing is reminiscent of the dual response to allergen in sensitised individuals (Basran et al., 1983). This biphasic response to PAF-acether is unrelated to mast cell degranulation, since inflammatory effects of PAF-acether in guinea-pig or man are not significantly influenced by histamine (H1) antagonists and since, in normal skin, biphasic responses are not a consequence of mast cell degranulation per se (e.g. following codeine or 4 8 / 8 0 injections). In certain asthmatics, allergen inhalation produces both acute and late onset airflow obstruction that is succeded by persistent bronchial hyperreactivity. These responses are usually inhibited by DSCG, an effect which has been assumed to depend on mast
** To whom all correspondence should be addressed. 0014-2999/83/0000 0000/$03.00 © 1983 Elsevier Biomedical Press
cell stabilisation (Pepys et al., 1968). It was of interest, therefore, to ascertain whether D S C G might modify expression of the biphasic reaction to PAF-acether, since this response is independent of mast cell activation. Eight healthy, non-atopic volunteers (aged 20-32 years) gave informed consent to participate in this study. Cutaneous inflammatory responses (wheal and flare) were induced on the volar surface of the forearm by intradermal injection of a fixed volume (50 #1) of coded solutions of phosphate buffered saline (PBS) containing PAF-acether (100 ng/site) either alone, or admixed with D S C G (250 /~g/site), whilst PBS or D S C G (250/~g/site) were used as controls. Cutaneous responses were estimated as wheal and flare areas. Neither PBS nor D S C G produced any significant immediate response. In all eight subjects, intradermal injection of PAF-acether produced immediate wheal and flare responses which were significantly (P < 0.001) reduced by the presence of D S C G (table 1). Neither PBS nor D S C G alone produced any detectable late onset response. However, in 6 of 8 subjects, resolution of the immediate response to PAF-acether (within 1 h) was succeded by a response of delayed onset (3-6 h after intradermal injection), characterised by erythema and hyperalgesia. In these six subjects, a delayed response was not detectable when PAFacether was admixed with D S C G (250/~g/site) at the time of injection (table 1). Other than its well documented effects on mast cell stabilisation, few noteworthy pharmacological properties of D S C G have been identified. This is the first report of an inhibitory action of this drug
144 TABLE l
to b e r e l e a s e d in b o t h allergic a n d n o n - a l l e r g i c
(a) Effect of DSCG on PAF-acether-induced immediate responses.
reactions. I n h i b i t i o n of P A F - a c e t h e r r e s p o n s e s by
P alone P+ D
D S C G , therefore, suggests an alternative m e c h a n i s m f o r t h e a n t i - a s t h m a e f f i c a c y o f this d r u g . T h i s
Wheal area
Flare area
p r o p e r t y o f D S C G w o u l d b e e x p e c t e d to c o n t r i b -
84 _+8 53_+8
1030 + 130 380_+ 140
ute, n o t o n l y to i n h i b i t i o n o f a l l e r g e n - i n d u c e d e x p e r i m e n t a l a s t h m a , b u t also to i n h i b i t i o n o f experimental asthma
(b) Effect of DSCG on PAF-acether-induced late responses. Incidence of late response
P alone P+D
Present
Absent
6 0
2 8
The effect of DSCG (D 250 p~g/site) on (a) early and (b) late cutaneous responses to PAF-acether (P 100 ng/site) in 8 subjects. In (a), the wheal and flare responses to PAF-acether were significantly reduced by DSCG (P < 0.001, paired t-test). In (b) the incidence of late onset responses was significantly reduced in the presence of DSCG (P < 0.005, x
o n a c h e m i c a l l y d e f i n e d m e d i a t o r in m a n . T h e p r o p e r t i e s o f P A F - a c e t h e r are c o n s i s t e n t w i t h a n i n v o l v e m e n t in a s t h m a a n d P A F - a c e t h e r is k n o w n
of non-allergic origin and
m a y a c c o u n t f o r t h e c a p a c i t y o f D S C G to r e d u c e t h e b r o n c h i a l h y p e r r e a c t i v i t y t h a t c h a r a c t e r i s e s this disease.
References Basran, G.S., C.P. Page, W. Paul and J. Morley, 1983~ Platelet activating factor: A possible mediator of the dual response to allergen, Clin. Allergy (in press). Pepys, J., F.E. Hargreave, M. Chan and D.S. McCarthy, 1968. Inhibitory effects of disodium cromoglycate on allergen-inhalation tests, Lancet 2, 134. Stokes, T.C. and J. Morley, 1981, Prospects for an Oral Intal, Br. J. Dis. Chest. 75, 1. Vargaftig, B.B., M. Chignard, J. Benveniste~ J. Lefort and F. Wal, 1981, Background and present status of research on platelet-activating factor (PAF-acether), Ann. N.Y. Acad. Sci. 370. 119.
143
Elsevier Biomedical Press
Rapid communication C R O M O G L Y C A T E (DSCG) I N H I B I T S R E S P O N S E S T O P L A T E L E T - A C T I V A T I N G FACTOR (PAF-ACETHER) IN MAN: AN A L T E R N A T I V E M O D E OF A C T I O N F O R D S C G IN A S T H M A ? G.S. BASRAN *, C.P. PAGE **. W. PAUL and J. MORLEY
Department of Clinical Pharmacolog~v, Cardiothoracic Institute, Fulham Road, London S W3 6HP and * Ci(v Itospital, Department of Thoracic Medicine, Nottingham NG5 IPD, U.K. Received 15 November 1982. accepted 17 November 1982
The therapeutic efficacy of cromoglycate (DSCG) in asthma has been attributed to stabilisation of mast cells. Although many other drugs share this property of DSCG, none have proved effective in clinical asthma. This anomaly prompted a re-appraisal of the considered view of the mechanism of action of D S C G (Stokes and Morley, 1980) and the shortcomings of the concept of mast cell stabilisation have led us to consider other properties of D S C G which could account for its anti-allergy and anti-asthma properties. The phospholipid, PAF-acether, has properties appropriate to a mediator of asthma and inflammation (Vargaftig et al., 1981). We recently observed that intradermal injection of PAF-acether into the forearm of normal subjects results in an acute inflammatory response that is succeded by a phase of late onset, whose timing is reminiscent of the dual response to allergen in sensitised individuals (Basran et al., 1983). This biphasic response to PAF-acether is unrelated to mast cell degranulation, since inflammatory effects of PAF-acether in guinea-pig or man are not significantly influenced by histamine (H1) antagonists and since, in normal skin, biphasic responses are not a consequence of mast cell degranulation per se (e.g. following codeine or 4 8 / 8 0 injections). In certain asthmatics, allergen inhalation produces both acute and late onset airflow obstruction that is succeded by persistent bronchial hyperreactivity. These responses are usually inhibited by DSCG, an effect which has been assumed to depend on mast
** To whom all correspondence should be addressed. 0014-2999/83/0000 0000/$03.00 © 1983 Elsevier Biomedical Press
cell stabilisation (Pepys et al., 1968). It was of interest, therefore, to ascertain whether D S C G might modify expression of the biphasic reaction to PAF-acether, since this response is independent of mast cell activation. Eight healthy, non-atopic volunteers (aged 20-32 years) gave informed consent to participate in this study. Cutaneous inflammatory responses (wheal and flare) were induced on the volar surface of the forearm by intradermal injection of a fixed volume (50 #1) of coded solutions of phosphate buffered saline (PBS) containing PAF-acether (100 ng/site) either alone, or admixed with D S C G (250 /~g/site), whilst PBS or D S C G (250/~g/site) were used as controls. Cutaneous responses were estimated as wheal and flare areas. Neither PBS nor D S C G produced any significant immediate response. In all eight subjects, intradermal injection of PAF-acether produced immediate wheal and flare responses which were significantly (P < 0.001) reduced by the presence of D S C G (table 1). Neither PBS nor D S C G alone produced any detectable late onset response. However, in 6 of 8 subjects, resolution of the immediate response to PAF-acether (within 1 h) was succeded by a response of delayed onset (3-6 h after intradermal injection), characterised by erythema and hyperalgesia. In these six subjects, a delayed response was not detectable when PAFacether was admixed with D S C G (250/~g/site) at the time of injection (table 1). Other than its well documented effects on mast cell stabilisation, few noteworthy pharmacological properties of D S C G have been identified. This is the first report of an inhibitory action of this drug
144 TABLE l
to b e r e l e a s e d in b o t h allergic a n d n o n - a l l e r g i c
(a) Effect of DSCG on PAF-acether-induced immediate responses.
reactions. I n h i b i t i o n of P A F - a c e t h e r r e s p o n s e s by
P alone P+ D
D S C G , therefore, suggests an alternative m e c h a n i s m f o r t h e a n t i - a s t h m a e f f i c a c y o f this d r u g . T h i s
Wheal area
Flare area
p r o p e r t y o f D S C G w o u l d b e e x p e c t e d to c o n t r i b -
84 _+8 53_+8
1030 + 130 380_+ 140
ute, n o t o n l y to i n h i b i t i o n o f a l l e r g e n - i n d u c e d e x p e r i m e n t a l a s t h m a , b u t also to i n h i b i t i o n o f experimental asthma
(b) Effect of DSCG on PAF-acether-induced late responses. Incidence of late response
P alone P+D
Present
Absent
6 0
2 8
The effect of DSCG (D 250 p~g/site) on (a) early and (b) late cutaneous responses to PAF-acether (P 100 ng/site) in 8 subjects. In (a), the wheal and flare responses to PAF-acether were significantly reduced by DSCG (P < 0.001, paired t-test). In (b) the incidence of late onset responses was significantly reduced in the presence of DSCG (P < 0.005, x
o n a c h e m i c a l l y d e f i n e d m e d i a t o r in m a n . T h e p r o p e r t i e s o f P A F - a c e t h e r are c o n s i s t e n t w i t h a n i n v o l v e m e n t in a s t h m a a n d P A F - a c e t h e r is k n o w n
of non-allergic origin and
m a y a c c o u n t f o r t h e c a p a c i t y o f D S C G to r e d u c e t h e b r o n c h i a l h y p e r r e a c t i v i t y t h a t c h a r a c t e r i s e s this disease.
References Basran, G.S., C.P. Page, W. Paul and J. Morley, 1983~ Platelet activating factor: A possible mediator of the dual response to allergen, Clin. Allergy (in press). Pepys, J., F.E. Hargreave, M. Chan and D.S. McCarthy, 1968. Inhibitory effects of disodium cromoglycate on allergen-inhalation tests, Lancet 2, 134. Stokes, T.C. and J. Morley, 1981, Prospects for an Oral Intal, Br. J. Dis. Chest. 75, 1. Vargaftig, B.B., M. Chignard, J. Benveniste~ J. Lefort and F. Wal, 1981, Background and present status of research on platelet-activating factor (PAF-acether), Ann. N.Y. Acad. Sci. 370. 119.