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Chapter 9. Pulmonary and Antiallergy Drugs
Chapter 9.
Pulmonary and A n t i a l l e r g y Drugs
Ralph E. Gilesa and David J. Herzig, Dept. of Pharmacol. Warnei-Lambert Research I n s t i t u t e , Morris- P l a i n s , New J e r s e y a P r e s e n t Address: Dept. of Biomed. R e s . , S t u a r t Pharmaceutical Div. I C I United S t a t e s , I n c . , Wilmington, Delaware Asthma may be d e f i n e d a s a t y p e of r e v e r s i b l e , o b s t r u c t i v e pulmonary d i s e a s e due t o widespread narrowing of t h e b r o n c h i a l airways and edema of t h e b r o n c h i a l mucosa, caused by s p e c i f i c a l l e r g i c a n d / o r n o n s p e c i f i c i r r i t a t i v e s t i r n u l i . l s 2 While t h e common endpoint of t h e a s t h m a t i c r e s p o n s e i s airway narrowing and d i f f i c u l t y i n b r e a t h i n g , s e v e r a l f a c t o r s may c a u s e o r p r e d i s p o s e t o t h e c o n d i t i o n . S e v e r a l t h e o r i e s proposing autonomic imbalance i n t h e l u n g of t h e a s t h m a t i c have been suggested. These i n c l u d e a g e n e r a l i z e d d e c r e a s e i n b e t a - a d r e n o c e p t o r r e s p o n s i v e n e s s ,3 an e l e v a t e d ref l e x c h o l i n e r g i c a c t i v i t y 4 and an e l e v a t e d alpha-sympathomimetic a c t i v i t y 5*6; such f a c t o r s could c o n t r i b u t e i n v a r y i n g degree t o t h e a s t h m a t i c response i n d i f f e r e n t p a t i e n t s . This proposed autonomic imbalance need n o t b e confined t o t h e smooth muscle of t h e lung b u t may i n v o l v e o t h e r c e l l s such a s lymphocytes3 and b a s o p h i l s 7 a s w e l l as o t h e r t i s s u e s , such as t h e a d r e n a l medulla and l i v e r . 3 The r e s p o n s i v e n e s s of b r o n c h i o l a r smooth musc l e t o h i s t a m i n e o r slow r e a c t i n g s u b s t a n c e of anaphylaxis (SRS-A), mediat o r s r e l e a s e d f o l l o w i n g a n t i g e n i c p r o v o c a t i o n , i s enhanced i n t h e asthmat i c and t h e t o t a l response may a l s o i n c l u d e t h e d i s c h a r g e of mucus and inflammation. Therapy f o r asthma may b e d i r e c t e d a g a i n s t any o r a l l of these factors. Beta-Adrenoceptor Agonists - S e v e r a l b e t a - a d r e n o c e p t o r a g o n i s t s which sel e c t i v e l y s t i m u l a t e w - 2 r e c e p t o r s (mediating b r o n c h o d i l a t a t i o n ) r e l a t i v e t o b e t a - 1 r e c e p t o r s (mediating c a r d i a c s t i m u l a t i o n ) are b e i n g studied.-Pyrbuterol (1) has been t e s t e d i n man and was a c t i v e o r a l l y a t doses of 2, 5, o r 10 mg f o r up t o 6 h r a f t e r a d m i n i ~ t r a t i o n . ~F u r t h e r work on i s o e t h a r i n e , a s e l e c t i v e b e t a - a d r e n o c e p t o r a g o n i s t known s i n c e 1950, has been d i r e c t e d toward a s e p a r a t i o n of e r y t h r o and t h r e o isomers.1° The racemic e r y t h r o and (-) e r y t h r o isomers were t h e most a c t i v e forms t e s t e d f o r r e l a x a t i o n of t r a c h e a , s t i m u l a t i o n of a t r i a and r e d u c t i o n of r a t p a s s i v e cutaneous anaphylaxis. ~~
A series of 2-, 5-, and 6- c h l o r o s u b s t i t u t e d analogs of i s o p r o t e r e no1 was p r e p a r e d i n an a t t e m p t t o f i n d p o t e n t and b r o n c h o - s e l e c t i v e bronc h o d i l a t o r s w i t h a long d u r a t i o n of a c t i v i t y . ” S u b s t i t u t i o n of p o s i t i o n 2 of i s o p r o t e r e n o l and s e v e r a l N - s u b s t i t u t e d d e r i v a t i v e s g e n e r a l l y a f f o r d e d compounds w i t h g r e a t e r potency than t h e i r n o n c h l o r i n a t e d c o u n t e r p a r t s whereas s u b s t i t u t i o n i n t h e 5 o r 6 p o s i t i o n d e c r e a s e d beta-adrenoceptor potency a s determined i n v i t r o u s i n g r e l a x a t i o n of g u i n e a p i g t r a c h e a and i n c r e a s e d rate of r i g h t a t r i a l c o n t r a c t i o n . A high degree of tracheobronc h i a l v s . c a r d i a c s p e c i f i c i t y was n o t o b t a i n e d . C h l o r i n a t i o n of t h e 2 p o s i t i o n of i s o p r o t e r e n o l d i d n o t alter d u r a t i o n of b r o n c h o d i l a t o r a c t i v i t y . Schwender, e t a1.I2, r e p o r t e d on t h e b r o n c h i a l select i v i t y of ( 2 ) . I n v i v o tests i n dogs and guinea p i g s a s w e l l i n v i t r o
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e v a l u a t i o n u s i n g guinea p i g t r a c h e a and a t r i a i n d i c a t e d t h a t t h i s compound p o s s e s s e d a s e l e c t i v e a c t i o n f o r b r o n c h i o l a r v s . c a r d i a c beta r e c e p t o r s . While t h e potency of t h i s new s e l e c t i v e beta a g o n i s t w a s 1/100 t h a t of s a l b u t a m o l , i t s m a x i m u m e f f i c a c y was similar. S e v e r a l p a p e r s r e p o r t e d on t h e b r o n c h o s e l e c t i v i t y i n man of NAB365 ( c l e n b u t e r o l , 3) which a t an o r a l dose of 10 o r 2Opg was found t o b e s i m i l a r i n b r o n c h o d i l a t i n g potency t o a p . ~ . dose of 2.5 mg of t e r b u t a l i n e o r 2.0 mg of s a l b u t a m o l . 13-15There was a s i g n i f i c a n t b r o n c h o d i l a t o r response f o l l o w i n g a d m i n i s t r a t i o n of each drug. Following an o r a l dose of 20pg, t h e b r o n c h o d i l a t o r r e s p o n s e w a s e v i d e n t a f t e r 15 minutes, reached a maximum a f t e r 2-4 h o u r s and began t o f a l l w i t h i n 5-7 h o u r s . With reg a r d t o c a r d i o v a s c u l a r e f f e c t s , one s t u d y i n d i c a t e d t h a t no i n c r e a s e It" p u l s e o r a r t e r i a l p r e s s u r e o c c u r r e d a f t e r l o n g p e r i o d s of t r e a t m e n t . Another s t u d y i n d i c a t e d a minor d e c r e a s e i n h e a r t rate 1 and 30 minutes a f t e r p.0. a d m i n i s t r a t i o n of e i t h e r NAB365 o r f e n o t e r o l . P5
Although s e v e r a l 8-adrenoceptor a g o n i s t s have s e l e c t i v i t y f o r bronc h i o l a r , b e t a - 2 ( r e l a t i v e t o c a r d i a c o r beta-1) a d r e n o c e p t o r s , t h e s e newer a g e n t s g i v e n p.0. t e n d t o produce tremor. I n c i d e n c e of tremor may b e as h i g h as 40%.16 The tremor r e s p o n s e i s due t o d i r e c t s t i m u l a t i o n of b e t a - a d r e n o c e p t o r s which a p p e a r t o b e of t h e b e t a - 2 type. S e p a r a t i o n between b r o n c h o d i l a t o r and tremorogenic response h a s n o t been r e p o r t e d . F i n a l l y , s i n c e d e c r e a s e d beta r e s p o n s i v e n e s s h a s been i m p l i c a t e d i n asthma f o r c e r t a i n c e l l t y p e s such as lymphocytes3 as w e l l as f o r smooth muscle and s i n c e h i s t a m i n e s y n t h e s i s 1 7 and release from l u n g t i s s u e f o l lowing a n t i g e n i c c h a l l e n g e 1 8 i s d e c r e a s e d by beta a g o n i s t s , t h e b e n e f i c i a l r o l e of t h e s e d r u g s may b e due t o several mechanisms.
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Alpha-Adrenoceptor A n t a g o n i s t s The p r e s e n c e of a l p h a - a d r e n o c e p t o r s medi a t i n g b r o n c h i o l a r smooth muscle c o n t r a c t i o n h a s been r e p o r t e d i n b o t h humans and animals. 19920 The t h e r a p e u t i c u t i l i z a t i o n of t h i s concept w a s f i r s t r e p o r t e d by Marcelle,21 who t r e a t e d s i x r e f r a c t o r y a s t h m a t i c s w i t h phentolamine ( 5 mg by i n h a l a t i o n ) . There w a s improvement i n l u n g funct i o n which l a s t e d f o r 18 h o u r s . I n h i b i t i o n of histamine-induced o r e x e r c i s e - i n d u c e d bronchospasm h a s been r e p o r t e d f o l l o w i n g a d m i n i s t r a t i o n of a1 h a a d r e n o c e p t o r b l o c k i n g a g e n t s s u c h as phenoxybenzamine, i n d o r a m i n ~ ~ e n t o l a r n i n e , 7 , 2 o3r t h y m ~ x a m i n e . ~Also, ~ although a d i r e c t b r o n c h o d i l a t o r r e s p o n s e may n o t b e o b s e r v a b l e , alpha-adrenoceptor blockenhance t h e r e s p o n s e t o --adrenoceptor a g o n i s t s . Thus, Palmer, a s i g n i f i c a n t l y g r e a t e r i n c rease i n forced expirar e p o r t e d t h a t --
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t o r y volume i n one second (FEV1 ) was o b t a i n e d when a l p h a b l o c k i n g drugs were a d m i n i s t e r e d w i t h s d s u t a m o l , than when salbutamol was given a l o n e ; t h e alpha-adrenoceptor b l o c k i n g drugs had no g r e a t e r e f f e c t t h a n d i d t h e placebo. Apart from a l p h a blockade i n smooth muscle, i t has been r e p o r t e d t h a t alpha-adrenergic s t i m u l a t i o n (phenylephrine o r norepinep h r i n e i n t h e presence of p r o p r a n o l o l ) enhanced immunologic release o f h i s t a m i n e and SRS-A from human lung t i s s u e . 26 It is w e l l known t h a t alpha-adrenoceptor b l o c k i n g a g e n t s have severa l pharmacologic a c t i v i t i e s . For example, phenoxybenzamine h a s a n t i h i s taminic and weak a n t i c h o l i n e r g i c p r o p e r t i e s and blocks uptake of c a t e c h o l amines; phentolamine i n c r e a s e s c i r c u l a t i n g catecholamines; and thymoxamine and indoramin have a n t i h i s t a m i n i c r o erties i n t h e same o r d e r of potency as t h e i r alpha-blocking e f f e c t s . 17918 A l l of t h e s e pharmacologic a c t i o n s could c o n t r i b u t e t o t h e observed b e n e f i c i a l response i n histamineo r exercise-induced asthma. A prominent side-ef f e c t of alpha-blockade is p o s t u r a l hypotension.
(*\/\OOH
indoramin
AY 22093
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The exact r o l e of a n t i c h o l i n e r g i c s i n t h e t h e r a p y of Anticholinergics asthma i s s t i l l n o t defined. While b r o n c h o c o n s t r i c t i o n , probably r e f l e x i n n a t u r e , is blocked by a t r o p i n e o r vagotomy i n experimental animals and by a t r o p i n e i n man, t h e d r y i n g e f f e c t s of a n t i c h o l i n e r g i c s remain ikn imp o r t a n t c o n s i d e r a t i o n . Sch 1000 ( i s o p r o p y l a t r o p i n e ) h a s been e v a l u a t e d i n s e v e r a l a c u t e tests. U l m e r 2 9 r e p o r t e d t h a t Sch 1000 had a " b e t t e r t h e r a p e u t i c range" than a t r o p i n e methyl n i t r a t e o r c e r t a i n &-adrenoSch 1000 was c e p t o r s t i m u l a n t s i n " c h r o n i c o b s t r u c t i v e airways disease". r e p o r t e d o b e a more e f f e c t i v e b r o n c h o d i l a t o r t h a n salbutamol i n bronc h i t s, 36 w h i l e t h e reverse r e l a t i o n s h i p w a s r e p o r t e d i n a s t h m a t i c s . 31 Kaik" r e p o r t e d t h a t Sch 1000 and f e n o t e r o l (Th 1165a) had approximately t h e same average b r o n c h o d i l a t o r e f f e c t s i n 20 p a t i e n t s , b u t t h a t t h e two drugs d i d n o t produce similar b r o n c h o d i l a t o r y responses i n t h e same i n d i v i d u a l . This f i n d i n g s u g g e s t s t h a t only c e r t a i n p a t i e n t s may b e n e f i t from a n t i c h o l i n e r g i c therapy. The a c u t e e f f e c t s o f Sch 1000 on p a r o t i d s e c r e t i o n of s a l i v a i n human v o l u n t e e r s h a s been r e p o r ed. Sch 1000 w a s similar i n potency t o a t r o p i n e i n b l o c k i n g s a l i v a t i o n i 3 due t o acetyl-8-methylcholine. Knowl e d g e of t h e e f f e c t s of long term therapy w i t h a n t i c h o l i n e r g i c s such as Sch 1000 i n d i f f e r e n t t y p e s of o b s t r u c t i v e lung d i s e a s e would b e v a l u a b l e .
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S i n c e t h e lung i s c a p a b l e of r a p i d s y n t h e s i s of PGF a and Prostaglandins s i n c e a s t h m a t i c s a r e extremely s e n s i t i v e t o t h e bronchocons t r i c t o r e e f e c t s of t h i s p r o s t a g l a n d i n , i t i s tempting t o s p e c u l a t e on t h e importance of t h i s s u b s t a n c e i n t h e p a t h o g e n e s i s of asthma. The major m e t a b o l i t e of PGF2a i n t h e plasma, 15-keto-13,14-dihydro-PGF2a, i n c r e a s e d by up t o 8-fold i n p e r i p h e r a l venous blood f o l l o w i n g antigen-induced a s t h m a t i c a t t a c k s i n 5 s u b j e c t s . 3 4 The i n c r e a s e i n t h e PGF2a m e t a b o l i t e could b e demonstrated w i t h i n a few minutes a f t e r commencing t h e a n t i g e n i c p r o v o c a t i o n and "seemed t o b e c o r r e l a t e d t o t h e s e v e r i t y of t h e a t t a ~ k " ?However, ~ other i n v e s t i g a t o r s r e p o r t e d t h a t indomethacin i n doses r e p o r t e d t o s u p p r e s s over 90% of endogenous p r o s t a g l a n d i n s y n t h e s i s i n man h a s no e f f e c t on e i t h e r antigen-induced o r exercise-induced asthma. 35 I n guinea p i g s sens i t i z e d t o ovalbumin, e l e v a t e d u r i n a r y l e v e l s of a PGF a m e t a b o l i t e , 5a, 7a-dihydroxy-11-ketotetranor p r o s t a n o i c a c i d , are foun% d u r i n g t h e anap h y l a c t i c response. 36 Indomethacin (25-50 mg/kg p. 0.1 reduced t h e b a s a l e x c r e t i o n of t h e PGF m e t a b o l i t e and a l s o a b o l i s h e d t h e expected rise on c h a l l e n g e w i t h a n t i g e n . However, t h e guinea p i g s were n o t p r o t e c t e d from r e s p i r a t o r y d i s t r e s s and c o n v u l s i o n s ; no pulmonary mechanics w e r e measured. I n c o n t r a s t , i n cats, i n h i b i t i o n of p r o s t a g l a n d i n b i o s y n t h e s i s w i t h asp i r i n reduced pulmonary v a s o c o n s t r i c t o r and b r o n c h o c o n s t r i c t o r responses t o hypoxic b r e a t h i n g and i t i s r e p o r t e d t h a t hypoxic v e n t i l a t i o n of i s o l a t e d p e r f u s e d cat lungs caused t h e appearance i n pulmonary p e r f u s a t e s of p r o s t a g l a n d i n - l i k e substance^.^^ I t a p p e a r s t h a t a l t h o u g h PGF2a i s l i b e r a t e d d u r i n g b r o n c h o s p a s t i c c o n d i t i o n s due t o s e v e r a l i n i t i a t i n g f a c t o r s , i t s r o l e a s a primary m e d i a t o r of asthma i s n o t y e t s u b s t a n t i a t e d . A new b r o n c h o d i l a t o r compound, a p r o s t a n o i c a c i d d e r i v a t i v e (AY22093) w a s compared t o i s o p r o t e r e n o l and PGE2 i n s e v e r a l p h a m c o l o g i c tests p r e d i c t i v e of c l i n i c a l l y e f f i c a c i o u s b r o n c h o d i l a t a t i o n . 3 8 AY22093 w a s similar i n p r o f i l e t o PGE2 b u t was less p o t e n t .
S p e c i f i c I n h i b i t o r s of Anaphylactic Mediators - E o s i n o p h i l i a i s a common o c c u r r e n c e i n a t o p i c i n d i v i d u a l s , e s p e c i a l l y a l l e r g i c a s t h m a t i c s . While e a r l y work s u g g e s t e d t h a t antigen-antibody complexes caused e o s i n o p h i l migration,39 l a t e r s t u d i e s showed t h a t s o l u b l e m e d i a t o r s from a n a p h y l a x i s were responsible.40 A s p e c i f i c chemotactic f a c t o r f o r e o s i n o p h i l s (ECF-A) h a s been i d e n t i f i e d 1 9 4 2 from human o r guinea p i g lungs. Wasserman,et G . , have shown t h a t t h e f a c t o r e x i s t s preformed i n t h e mast c e l l g r a n u l e 7
HO '
COONa CH2CH2CH3
FPL 55712
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FPL 55712, a compound t h a t had been shown t o b e a s p e c i f i c b l o c k e r of SRS-A44, h a s now been shown t o b e a n i n h i b i t o r of e o s i n o p h i l chemotaxis by ECF-A45 w i t h an IC50 a l s o of 3 . 8 ~ 1 0 - ~ M . Whether such a compound w i l l have c l i n i c a l u t i l i t y i n asthma i s s t i l l unknown b u t might h e l p t o d e f i n e t h e r o l e of SRS-A and ECF-A i n t h i s d i s e a s e .
Anaphylactic I n h i b i t o r s - With t h e d i s c o v e r y of new m e d i a t o r s of immediate h y p e r s e n s i t i v i t y almost every y e a r i t is c l e a r t h a t t h e mechanism o f all e r g i c asthma i s more complex t h a n t h e concept of h i s t a m i n e impinging on b r o n c h i a l smooth muscle. An a c t i v e r e s e a r c h area is t h e s e a r c h f o r a g e n t s t h a t i n h i b i t t h e a l l e r g i c r e a c t i o n a t i t s i n c e p t i o n . Cromolyn sodium ( a compound t h a t i n h i b i t s t h e release of a l l e r g i c m e d i a t o r s from s e n s i t i z e d t i s s u e s b u t does n o t i n t e r f e r e w i t h t h e combination of a n t i g e n and a n t i body) i s t h e p r o t o t y p e f o r t h i s t y p e of drug b u t s u f f e r s from a l a c k of o r a l a c t i v i t y and from a l i m i t e d s o l u b i l i t y which p r e c l u d e s a e r o s o l i z a t i o n . Three xanthones w i t h similar a n t i a e r g y p r o f i l e s have been s t u d i e d i n v a r i o u s a n i m a l models and man." They are AH 7725, AH 7079, and AH 6556.
R2
R %fJyJR1
(4)
-COOH
AH 7725
-COOH
AH 7079 AH 6556
-COOH
HOCH2 CH2 0 -
CH3 0
-
CH30
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A l l t h r e e compounds i n h i b i t e d antigen-induced h i s t a m i n e release from chopped human l u n g i n v i t r o a t about 1 O 4 ~ . 4 7 They also i n h i b i t e d y l a n t i AH 7079 body-mediated release from guinea p i g l u n g i n v i t r o (IC50'10-5M). w a s about e q u i p o t e n t t o cromolyn in v i t r o a g a i n s t antigen-induced h i s t a m i n e release from r a t p e r i t o n e a l mast cells. When b e e venom w a s used t o release h i s t a m i n e from r a t mast cells AH 7725 w a s e q u i p o t e n t t o cromolyn b u t AH 7079 w a s markedly less s o . AH 7079 as an a e r o s o l p r e p a r a t i o n (15 and 30 mg/ml) was e f f e c t i v e i n a l l e r g i c b r o n c h i a l c h a l l e n g e s i n
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man48 while AH 7725 was orally active at a dose of 500 mg49 in 30 ml of water 2 hours before antigen challenge. Clinical data on the oral activity of a similar compound (4) at 8 mglkg, 2 and 5 hours before testing, showed a statistically significant inhibition of exercise-induced asthma; the clinical utility of this agent is still under study.50 n H
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PR-D-92-EA A tricyclic quinolone acid ICI 74,917 was found to be about 300 times as potent as cromolyn sodium in rat passive cutaneous anaphylaxis (PCA) and devoid of antimediator effect. In the guinea pig it would not block PCA but would inhibit allergic bronchoconstriction while lacking direct bronchodilating activity51 (suggesting tissue specificity for the compound in this species). Another compound, M&B 22,948 an azapurinone, antagonized allergen-induced release of histamine in passively sensitized human lung, PCA in the rat and reagin mediated anaphylactic bronchospasm in the guinea pig.52 This compound does have some direct antimediator activity against histamine, SRS-A and prostaglandin F2a. PR-D-92-FA inhibited PCA in rats and blocked Ascaris-induced bronchospasm in Rhesus monkeys. PR-D-92-EA blocked responses produced by bradykinin, serotonin, SRS-A, PGE2 and PGF2a but not those of histamine on isolated guinea pig ileum.53 Of a series of 2-nitro indan-1,3-diones, (5) was the most potent in rat P C A . ~ ~
CH3 ~ \
~
\
\
3
OH H
\
:
OCH3
(5)
W8011
(6)
4
~
L
~
86 -
Sect. I1
- Pharmacodynamic
Clarke, Ed.
Agents
New s y n t h e t i c methods have p e r m i t t e d t h e e x p l o r a t i o n of 3 - s u b s t i t u t e d chromones. Of a l a r g e series of 3-carboxy,3-hydroxymethyl and 3-formyl chromones t h e most a c t i v e w a s W8011 whi hchad an o r a l ID50 of 2 mglkg and an i . p . ID50 of 1 mglkg i n r t PCA. 55a96’ I n a n o t h e r series (6) was most p o t e n t (ID50
C o r t i c o s t e r o i d s - I n t e r e s t remains h i g h on a e r o s o l i z e d s t e r o i d s f o r treatment of asthma. Two r e c e n t reviews stress t h e a d r e n a l - s p a r i n g e f f e c t of t h e s e p r e p a r a t i o n s . 56,57 S i m i l a r r e s u l t have been found w i t h a e r o s o l i z e d p r e p a r a t i o n s of t r i a m c i n o l o n e a c e t o n i d e 38
.
I n a d i f f e r e n t approach t h e macrolide a n t i b i o t i c troleandomycin (TAO) w a s used t o reduce t h dose of o r a l methyl p r e d n i s o l o n e needed by s t e r o i d dependent asthmatics.” With 250 t o 500 mglday of TAO, about 70% of t h e p a t i e n t s s i g n i f i c a n t l y reduced t h e i r s t e r o i d requirements w i t h no untoward side-effects. This a c t i v i t y of TAO i s u n r e l a t e d t o i t s a n t i b i o t i c activity.
-
Emphysema Emphysema i s an anatomic a l t e r a t i o n of t h e l u n g c h a r a c t e r i z e d by an abnormal enlargement of t h e a i r spaces d i s t a l t o t h e t e r m i n a l , nonr e s p i r a t o r y b r o n c h i o l e , accompanied by d e s t r u c t i v e changes of a l v e o l a r walls. S e v e r a l a g e n t s have been used t o produce emphyse - l i k e condit i o n s i n animals, w i t h papain being t h e a g e n t most used.
fY
Progesterone, which p r e v e n t s papain-induced emphysema i n r a t s , h a s now been e v a l u a t e d i n a n e x i s t i n g emphysema-condition i n r a t s and w a s found t o have a t h e r a p e u t i c a l l y b e n e f i c i a l e f f e c t .60 The mechanism of t h e benef i c i a l response, whether p r o p h y l a c t i c o r t h e r a p e u t i c , i s unknown. Although p r o g e s t e r o n e e l e v a t e s a - a n t i t r y p s i n i n humans and a d e f i c i e n c y of a j a n t i t r y p s i n has been a s s o c i a t e d w i t h p a n l o b u l a r emphysema i n man, t h e mechanism of p r o g e s t e r o n e p r o p h y l a x i s i n rats does n o t appear t o b e due t o a l t e r a t i o n s of serum a n t i t r y p s i n . 6 1 I n o t h e r s t u d i e s , Martorana, e t a l . fi2 r e p o r t e d t h a t i n t r a c a r d i a c a d m i n i s t r a t i o n of human a - a n t i t r y p s i n 1 hour p r i o r t o exposure t o papain i n hamsters d i d n o t p r e v e n i emphysemal i k e changes, b u t t h a t i n t r a t r a c h e a l i n s t i l l a t i o n of a j a n t i t r y p s i n 1 hour b e f o r e exposure s i g n i f i c a n t l y prevented t h e development of t h e l e s i o n . T h i s f i n d i n g g i v e s f u r t h e r support t o t h e concept of an i n t r a a l v e o l a r ( r a t h e r than c i r c u l a t i n g ) a n t i p r o t e a s e as a f a c t o r i n t h e pathog e n e s i s of emphysema. A lung a n t i p r o t e i n a s e , p r e s e n t a t t h e a i r - l u n g i n t e r f a c e , h a s been i s o l a t e d by s a l i n e lavage of f r e s h l y e x c i s e d dog lungs. Immunologic techniques demonstrated t h a t t h e r e were d i f f e r e n c e s between t h i s l u n g a n t i p r o t e i n a s e and serum a n t i p r o t e i n a s e . The serum and lung a n t i p r o t e i n a s e showed d i f f e r e n t i a l i n h i b i t i o n s of e l a s t a s e and t r y p s i n . 63
--
References
1. W.B. Sherman I n Cecil-Loeb Textbook of Medicine, P.B. Beeson and W. McDermott, Eds., W.B. Saunders Co., P h i l a d e l p h i a , 1973, pp. 538-539. 2 . A.W. Frankland I n C l i n i c a l Aspects of Immunology, P.G.H. Gel1 and R.A.
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Coombs, Eds., F.A. Davis Co., P h i l a d e l p h i a , 1968, p. 649. C.W. P a r k e r I n Asthma: P h y s i o l o g y , Immunopharmacology and Treatment, K.F. Austen and L.M. L i c h t e n s t e i n , Eds., Academic P r e s s , N.Y., 1973, p. 185. W. Gold I n Asthma: P h y s i o l o g y , Immunopharmacology and T r e a t m e n t , K.F. Austen and L.M. L i c h t e n s t e i n , Eds., Academic P r e s s , N.Y., 1973, p . 169. J . W . Kerr, M. Govindaraj and K.R. P a t e l , B r i t . Med. J. 2, 139 (1970). E. Middleton, Jr., Adv. I n t e r n . Med. 2, 177 (1972). L.M. L i c h t e n s t e i n I n Asthma: P h y s i o l o g y , Immunopharmacology and Treatment, K.F. Austen and L.M. L i c h t e n s t e i n , Eds., Academic P r e s s , N.Y. 1973, p. 91. R.E. G i l e s and D . J . H e r z i g , I n Annual R e p o r t s i n M e d i c i n a l Chemistry, v. 9, R.V. Heinzelman, Ed., Academic P r e s s , N.Y., 1974, p. 85. S.N. S t e e n , I. Ziment and J . S . Thomas, Curr. Ther. R e s . 16,1077(1974). M . J . Mardle, H. Smith, B.A. S p i c e r and R.H. P y s e r , J. Med. Chem. 513 (1974). C. Kaiser, D.F. C o l e l l a , A.M. P a v l o f f and J . R . W a r d e l l , J r . , J. Med. Chem., l7, 1 0 7 1 (1974). C.F. Schwender, B.R. Sunday, J. S h a v e l , Jr., and R.E. G i l e s , J. Med. Chem., 2, 1112 (1974). D. N o l t e , W.T. U l m e r and E. K r i e g e r , A r z n e i m i t t e l - F o r s c h . , 2, 858 (1974). P.C. C u r t i , I n t e r n . J. C l i n . Pharmacol. Ther. T o x i c o l . 9, 305 (1974). 0. LJhl, A r z n e i m i t t e l - F o r s c h . , 24, 855 (1974). S.W. E p s t e i n , J . A . Barnard and T.T. Z s o t e r , h e r . Rev. Resp. D i s . , 108, 1367 (1973). E . K . Assem and J . J . I . Feigenbaum, B r . J. Pharmacol., 46, 519 (1972). E.S.K. A s s e m and H.O. S c h i l d , N a t u r e (London), 102F(1969). A.A. Math&, A. Astrom and N.A. P e r s s o n , J. Pharm. Pharmacol., 23, 905 (1971). R. C a s t r o d e l a Mata, M. Penna and D.M. Aviado, J. Pharmacol. Exp. Ther., 135, 197 (1962). R. Marcelle, Acta A l l e r g o l . , 24, 432 (1969). S. Bianco, J.P. G r i f f i n , P.L. Kamburoff and F.J. P r i m e , B r i t . Med. J. 4, 1 8 (1974). 5.N. Gross, J . F . Souhrada and R.S. F a r r , C h e s t , 66, 4 (1974). Legge, G. P e t r i e , B r . J. D i s . C h e s t , 66, 1 4 1 (1972). J. Gaddie, J . S . K.N.V. Palmer, J . Gaddie and C. S k i n n e r , B r i t . Med. J . , 4 , 409 (1974). M. K a l i n e r , R.P. Orange and K.F. Austen, J. Exp. Med., 556 (1965). A.T. Birmingham and J. S z o l c s a n y i , J. Pharm. Pharmacol., 17,449 (1965). B . J . Alps, M. H i l l , E.S. Johnson and A.B. Wilson, B r . J . Pharmacol., 44, 5 2 (1972). T T . U l m e r , J. Dorsch and J. I r a v a n i , A r z n e i m i t t e l - F o r s c h . , 2, 468 (1973). H. Poppius and Y. S a l o r i n n e , B r i t . Med. J., 134 (1973). A. Lahdensuo, A.A. V i l j a n e n and A. M u i t t a r i , Scand. J. C l i n . Lab. I n v e s t . , 2, S u p p l . 13, 1 6 (1973). G. Kaik, Therapiewoche, 23, 3260 (1973). H. Diament, T. E k s t r a n d and J . Rydnert, A r z n e i m i t t e l - F o r s c h . , 24, 573 (19 74).
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K. Green, P. Hedqvist and N. Svanborg, Lancet, 2, 1419 (1974). A.P. Smith and L. Dunlop, Lancet, 1,39 (1975). K.Strandberg and M. Hamberg, P r o s t a g l a n d i n s , 6, 159 (1974). S . I . S a i d , T. Yoshida, S. Kitamura and C. V r e i m , S c i e n c e , 1181 (19 74) 38. R. Greenberg and G. B e a u l i e u , Can. J. P h y s i o l . Pharmacol., 52, 1 (1974). 39. M. L i t t , J. Immunol., 87, 522 (1961). 40. S.G. Cohen, T.M. Sapp and A. Gallia, Proc. SOC. Exp. B i o l . Med., 29 (1963). 41. A.B. Kay and K.F. Austen, J . Immunol., 107, 899 (1971). 42. A.B. Kay, D . J . S t e c h s c h u l t e and K.F. Austen, J. Exp. Med., 607 (1971). 43. S.I. Wasserman, E . J . G o e t z l and K.F. Austen, J. Immunol., 351 (1974). 44. J. Augstein, J . B . Farmer, T.B. Lee and M.T. Tattersall, N a t u r e New B i o l . , 245, 215 (1973). 45. D.G. J o n e s and A.B. Kay, J. Pharm. Pharmacol., 26, 218 (1974). 46. J. F u l l a r t o n , L.E. M a r t i n and C. Vardey, I n t . Arch. A l l e r g y , 45, 84 (1973). 47. E.S.K. A s s e m , I n t . Arch. A l l e r g y , 45, 708 (1973). 48. E.S.K. A s s e m and M.K. McAllen, I n t . Arch. A l l e r g y , 45, 697 (1973). 49. E.S.K. A s s e m , J.A. Evans and M.K. McAllen, B r i t . Med. J., 2, 9 3 (1974). 50. A.C. S p r e n k l e , P.P. van A r s d a l e , Jr., and C.W. Bierman, J. A l l e r g y C l i n . Immunol., 55, 118 (1975). 51. D.P. Evans, D. J. Gilman, D.S. Thomson and W.S. Waring, N a t u r e , 592 (1974). 52. B . J . Broughton, P. Chaplin, P. Knowles, E. Lunt, D.L. P a i n , K.R.H. Woolridge, R. Ford, S. M a r s h a l l , J . L . Walker and D.R. Maxwell, Nature, 251, 650 (1974). 198 53. G.J. Possanga, A. Bauen and P.B. S t e w a r t , The P h a r m a c o l o g i s t , (1974). 54. D.R. Buckle, N . J . Morgan, J . W . Ross, H. Smith and B.A. S p i c e r , J. Med. Chem., 16,1334 (1973). 55a. M. von Strandtmann, S. Klutchko, M.P. Cohen, and J. S h a v e l , J r . , J. H e t e r o c y c l . Chem., 2, 1 7 1 (1972). 55b. S. Klutchko, M.P. Cohen, J. S h a v e l , Jr., and M. von Strandtmann, J. H e t e r o c y c l . Chem., 2, 183 (1974). 55c. D . J . H e r z i g , P.R. Schumann, E.J. Kusner, L. Robichaud, R.E. Giles B. Dubnick, M. von Strandtmann, S. Klutchko, M.P. Cohen and J. Shavel, Jr., I n Immunopharmacology, M.E. R o s e n t h a l e and H.C. Mansmann, Eds., University Park Press, Baltimore ( i n press). 55d. A. Nohara, H. K u r i k i , T. S a i j o , K. Ukawa, T. Murato, M, Kauno and Y. Sanno, J. Med. Chem., 18,34 (1975). 122 (1974). 56. M.H. W i l l i a m s , Amer. Rev. R e s . D i s . , 57. M. Turner-Warwick, P o s t g r a d . Med. J., 50, Suppl. 4, 50 (1974). 58. M.H. Williams, Jr., C. Kane and C.S. Shim, Amer. Rev. Resp. D i s . , 109, 538 (1974). 59. S X S p e c t o r , F.H. Katz and R.S. F a r r , J. A l l e r g y C l i n . Immunol., 54, 367 (1974).
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60. R.E. Giles, M.P. F i n k e l and J.C. W i l l i a m s , Proc. SOC. Exp. B i o l . Med., 147, 489 (1974). 61. R X G i l e s , J . C . Williams and M.P. F i n k e l , P r o c . SOC. Exp. B i o l . Med., 144, 487 (1973). 62. P x Martorana, N.W. McKeel, J . W . R i c h a r d and N.N. S h a r e , The P h a r m a c o l o g i s t , l6, 299 (1974). 63. G. Weinbaum, M. Tahamoto, B. S l o a n and P. Kimbel, Chest ( I n P r e s s ) .
Pulmonary and A n t i a l l e r g y Drugs
Ralph E. Gilesa and David J. Herzig, Dept. of Pharmacol. Warnei-Lambert Research I n s t i t u t e , Morris- P l a i n s , New J e r s e y a P r e s e n t Address: Dept. of Biomed. R e s . , S t u a r t Pharmaceutical Div. I C I United S t a t e s , I n c . , Wilmington, Delaware Asthma may be d e f i n e d a s a t y p e of r e v e r s i b l e , o b s t r u c t i v e pulmonary d i s e a s e due t o widespread narrowing of t h e b r o n c h i a l airways and edema of t h e b r o n c h i a l mucosa, caused by s p e c i f i c a l l e r g i c a n d / o r n o n s p e c i f i c i r r i t a t i v e s t i r n u l i . l s 2 While t h e common endpoint of t h e a s t h m a t i c r e s p o n s e i s airway narrowing and d i f f i c u l t y i n b r e a t h i n g , s e v e r a l f a c t o r s may c a u s e o r p r e d i s p o s e t o t h e c o n d i t i o n . S e v e r a l t h e o r i e s proposing autonomic imbalance i n t h e l u n g of t h e a s t h m a t i c have been suggested. These i n c l u d e a g e n e r a l i z e d d e c r e a s e i n b e t a - a d r e n o c e p t o r r e s p o n s i v e n e s s ,3 an e l e v a t e d ref l e x c h o l i n e r g i c a c t i v i t y 4 and an e l e v a t e d alpha-sympathomimetic a c t i v i t y 5*6; such f a c t o r s could c o n t r i b u t e i n v a r y i n g degree t o t h e a s t h m a t i c response i n d i f f e r e n t p a t i e n t s . This proposed autonomic imbalance need n o t b e confined t o t h e smooth muscle of t h e lung b u t may i n v o l v e o t h e r c e l l s such a s lymphocytes3 and b a s o p h i l s 7 a s w e l l as o t h e r t i s s u e s , such as t h e a d r e n a l medulla and l i v e r . 3 The r e s p o n s i v e n e s s of b r o n c h i o l a r smooth musc l e t o h i s t a m i n e o r slow r e a c t i n g s u b s t a n c e of anaphylaxis (SRS-A), mediat o r s r e l e a s e d f o l l o w i n g a n t i g e n i c p r o v o c a t i o n , i s enhanced i n t h e asthmat i c and t h e t o t a l response may a l s o i n c l u d e t h e d i s c h a r g e of mucus and inflammation. Therapy f o r asthma may b e d i r e c t e d a g a i n s t any o r a l l of these factors. Beta-Adrenoceptor Agonists - S e v e r a l b e t a - a d r e n o c e p t o r a g o n i s t s which sel e c t i v e l y s t i m u l a t e w - 2 r e c e p t o r s (mediating b r o n c h o d i l a t a t i o n ) r e l a t i v e t o b e t a - 1 r e c e p t o r s (mediating c a r d i a c s t i m u l a t i o n ) are b e i n g studied.-Pyrbuterol (1) has been t e s t e d i n man and was a c t i v e o r a l l y a t doses of 2, 5, o r 10 mg f o r up t o 6 h r a f t e r a d m i n i ~ t r a t i o n . ~F u r t h e r work on i s o e t h a r i n e , a s e l e c t i v e b e t a - a d r e n o c e p t o r a g o n i s t known s i n c e 1950, has been d i r e c t e d toward a s e p a r a t i o n of e r y t h r o and t h r e o isomers.1° The racemic e r y t h r o and (-) e r y t h r o isomers were t h e most a c t i v e forms t e s t e d f o r r e l a x a t i o n of t r a c h e a , s t i m u l a t i o n of a t r i a and r e d u c t i o n of r a t p a s s i v e cutaneous anaphylaxis. ~~
A series of 2-, 5-, and 6- c h l o r o s u b s t i t u t e d analogs of i s o p r o t e r e no1 was p r e p a r e d i n an a t t e m p t t o f i n d p o t e n t and b r o n c h o - s e l e c t i v e bronc h o d i l a t o r s w i t h a long d u r a t i o n of a c t i v i t y . ” S u b s t i t u t i o n of p o s i t i o n 2 of i s o p r o t e r e n o l and s e v e r a l N - s u b s t i t u t e d d e r i v a t i v e s g e n e r a l l y a f f o r d e d compounds w i t h g r e a t e r potency than t h e i r n o n c h l o r i n a t e d c o u n t e r p a r t s whereas s u b s t i t u t i o n i n t h e 5 o r 6 p o s i t i o n d e c r e a s e d beta-adrenoceptor potency a s determined i n v i t r o u s i n g r e l a x a t i o n of g u i n e a p i g t r a c h e a and i n c r e a s e d rate of r i g h t a t r i a l c o n t r a c t i o n . A high degree of tracheobronc h i a l v s . c a r d i a c s p e c i f i c i t y was n o t o b t a i n e d . C h l o r i n a t i o n of t h e 2 p o s i t i o n of i s o p r o t e r e n o l d i d n o t alter d u r a t i o n of b r o n c h o d i l a t o r a c t i v i t y . Schwender, e t a1.I2, r e p o r t e d on t h e b r o n c h i a l select i v i t y of ( 2 ) . I n v i v o tests i n dogs and guinea p i g s a s w e l l i n v i t r o
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e v a l u a t i o n u s i n g guinea p i g t r a c h e a and a t r i a i n d i c a t e d t h a t t h i s compound p o s s e s s e d a s e l e c t i v e a c t i o n f o r b r o n c h i o l a r v s . c a r d i a c beta r e c e p t o r s . While t h e potency of t h i s new s e l e c t i v e beta a g o n i s t w a s 1/100 t h a t of s a l b u t a m o l , i t s m a x i m u m e f f i c a c y was similar. S e v e r a l p a p e r s r e p o r t e d on t h e b r o n c h o s e l e c t i v i t y i n man of NAB365 ( c l e n b u t e r o l , 3) which a t an o r a l dose of 10 o r 2Opg was found t o b e s i m i l a r i n b r o n c h o d i l a t i n g potency t o a p . ~ . dose of 2.5 mg of t e r b u t a l i n e o r 2.0 mg of s a l b u t a m o l . 13-15There was a s i g n i f i c a n t b r o n c h o d i l a t o r response f o l l o w i n g a d m i n i s t r a t i o n of each drug. Following an o r a l dose of 20pg, t h e b r o n c h o d i l a t o r r e s p o n s e w a s e v i d e n t a f t e r 15 minutes, reached a maximum a f t e r 2-4 h o u r s and began t o f a l l w i t h i n 5-7 h o u r s . With reg a r d t o c a r d i o v a s c u l a r e f f e c t s , one s t u d y i n d i c a t e d t h a t no i n c r e a s e It" p u l s e o r a r t e r i a l p r e s s u r e o c c u r r e d a f t e r l o n g p e r i o d s of t r e a t m e n t . Another s t u d y i n d i c a t e d a minor d e c r e a s e i n h e a r t rate 1 and 30 minutes a f t e r p.0. a d m i n i s t r a t i o n of e i t h e r NAB365 o r f e n o t e r o l . P5
Although s e v e r a l 8-adrenoceptor a g o n i s t s have s e l e c t i v i t y f o r bronc h i o l a r , b e t a - 2 ( r e l a t i v e t o c a r d i a c o r beta-1) a d r e n o c e p t o r s , t h e s e newer a g e n t s g i v e n p.0. t e n d t o produce tremor. I n c i d e n c e of tremor may b e as h i g h as 40%.16 The tremor r e s p o n s e i s due t o d i r e c t s t i m u l a t i o n of b e t a - a d r e n o c e p t o r s which a p p e a r t o b e of t h e b e t a - 2 type. S e p a r a t i o n between b r o n c h o d i l a t o r and tremorogenic response h a s n o t been r e p o r t e d . F i n a l l y , s i n c e d e c r e a s e d beta r e s p o n s i v e n e s s h a s been i m p l i c a t e d i n asthma f o r c e r t a i n c e l l t y p e s such as lymphocytes3 as w e l l as f o r smooth muscle and s i n c e h i s t a m i n e s y n t h e s i s 1 7 and release from l u n g t i s s u e f o l lowing a n t i g e n i c c h a l l e n g e 1 8 i s d e c r e a s e d by beta a g o n i s t s , t h e b e n e f i c i a l r o l e of t h e s e d r u g s may b e due t o several mechanisms.
-
Alpha-Adrenoceptor A n t a g o n i s t s The p r e s e n c e of a l p h a - a d r e n o c e p t o r s medi a t i n g b r o n c h i o l a r smooth muscle c o n t r a c t i o n h a s been r e p o r t e d i n b o t h humans and animals. 19920 The t h e r a p e u t i c u t i l i z a t i o n of t h i s concept w a s f i r s t r e p o r t e d by Marcelle,21 who t r e a t e d s i x r e f r a c t o r y a s t h m a t i c s w i t h phentolamine ( 5 mg by i n h a l a t i o n ) . There w a s improvement i n l u n g funct i o n which l a s t e d f o r 18 h o u r s . I n h i b i t i o n of histamine-induced o r e x e r c i s e - i n d u c e d bronchospasm h a s been r e p o r t e d f o l l o w i n g a d m i n i s t r a t i o n of a1 h a a d r e n o c e p t o r b l o c k i n g a g e n t s s u c h as phenoxybenzamine, i n d o r a m i n ~ ~ e n t o l a r n i n e , 7 , 2 o3r t h y m ~ x a m i n e . ~Also, ~ although a d i r e c t b r o n c h o d i l a t o r r e s p o n s e may n o t b e o b s e r v a b l e , alpha-adrenoceptor blockenhance t h e r e s p o n s e t o --adrenoceptor a g o n i s t s . Thus, Palmer, a s i g n i f i c a n t l y g r e a t e r i n c rease i n forced expirar e p o r t e d t h a t --
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t o r y volume i n one second (FEV1 ) was o b t a i n e d when a l p h a b l o c k i n g drugs were a d m i n i s t e r e d w i t h s d s u t a m o l , than when salbutamol was given a l o n e ; t h e alpha-adrenoceptor b l o c k i n g drugs had no g r e a t e r e f f e c t t h a n d i d t h e placebo. Apart from a l p h a blockade i n smooth muscle, i t has been r e p o r t e d t h a t alpha-adrenergic s t i m u l a t i o n (phenylephrine o r norepinep h r i n e i n t h e presence of p r o p r a n o l o l ) enhanced immunologic release o f h i s t a m i n e and SRS-A from human lung t i s s u e . 26 It is w e l l known t h a t alpha-adrenoceptor b l o c k i n g a g e n t s have severa l pharmacologic a c t i v i t i e s . For example, phenoxybenzamine h a s a n t i h i s taminic and weak a n t i c h o l i n e r g i c p r o p e r t i e s and blocks uptake of c a t e c h o l amines; phentolamine i n c r e a s e s c i r c u l a t i n g catecholamines; and thymoxamine and indoramin have a n t i h i s t a m i n i c r o erties i n t h e same o r d e r of potency as t h e i r alpha-blocking e f f e c t s . 17918 A l l of t h e s e pharmacologic a c t i o n s could c o n t r i b u t e t o t h e observed b e n e f i c i a l response i n histamineo r exercise-induced asthma. A prominent side-ef f e c t of alpha-blockade is p o s t u r a l hypotension.
(*\/\OOH
indoramin
AY 22093
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The exact r o l e of a n t i c h o l i n e r g i c s i n t h e t h e r a p y of Anticholinergics asthma i s s t i l l n o t defined. While b r o n c h o c o n s t r i c t i o n , probably r e f l e x i n n a t u r e , is blocked by a t r o p i n e o r vagotomy i n experimental animals and by a t r o p i n e i n man, t h e d r y i n g e f f e c t s of a n t i c h o l i n e r g i c s remain ikn imp o r t a n t c o n s i d e r a t i o n . Sch 1000 ( i s o p r o p y l a t r o p i n e ) h a s been e v a l u a t e d i n s e v e r a l a c u t e tests. U l m e r 2 9 r e p o r t e d t h a t Sch 1000 had a " b e t t e r t h e r a p e u t i c range" than a t r o p i n e methyl n i t r a t e o r c e r t a i n &-adrenoSch 1000 was c e p t o r s t i m u l a n t s i n " c h r o n i c o b s t r u c t i v e airways disease". r e p o r t e d o b e a more e f f e c t i v e b r o n c h o d i l a t o r t h a n salbutamol i n bronc h i t s, 36 w h i l e t h e reverse r e l a t i o n s h i p w a s r e p o r t e d i n a s t h m a t i c s . 31 Kaik" r e p o r t e d t h a t Sch 1000 and f e n o t e r o l (Th 1165a) had approximately t h e same average b r o n c h o d i l a t o r e f f e c t s i n 20 p a t i e n t s , b u t t h a t t h e two drugs d i d n o t produce similar b r o n c h o d i l a t o r y responses i n t h e same i n d i v i d u a l . This f i n d i n g s u g g e s t s t h a t only c e r t a i n p a t i e n t s may b e n e f i t from a n t i c h o l i n e r g i c therapy. The a c u t e e f f e c t s o f Sch 1000 on p a r o t i d s e c r e t i o n of s a l i v a i n human v o l u n t e e r s h a s been r e p o r ed. Sch 1000 w a s similar i n potency t o a t r o p i n e i n b l o c k i n g s a l i v a t i o n i 3 due t o acetyl-8-methylcholine. Knowl e d g e of t h e e f f e c t s of long term therapy w i t h a n t i c h o l i n e r g i c s such as Sch 1000 i n d i f f e r e n t t y p e s of o b s t r u c t i v e lung d i s e a s e would b e v a l u a b l e .
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S i n c e t h e lung i s c a p a b l e of r a p i d s y n t h e s i s of PGF a and Prostaglandins s i n c e a s t h m a t i c s a r e extremely s e n s i t i v e t o t h e bronchocons t r i c t o r e e f e c t s of t h i s p r o s t a g l a n d i n , i t i s tempting t o s p e c u l a t e on t h e importance of t h i s s u b s t a n c e i n t h e p a t h o g e n e s i s of asthma. The major m e t a b o l i t e of PGF2a i n t h e plasma, 15-keto-13,14-dihydro-PGF2a, i n c r e a s e d by up t o 8-fold i n p e r i p h e r a l venous blood f o l l o w i n g antigen-induced a s t h m a t i c a t t a c k s i n 5 s u b j e c t s . 3 4 The i n c r e a s e i n t h e PGF2a m e t a b o l i t e could b e demonstrated w i t h i n a few minutes a f t e r commencing t h e a n t i g e n i c p r o v o c a t i o n and "seemed t o b e c o r r e l a t e d t o t h e s e v e r i t y of t h e a t t a ~ k " ?However, ~ other i n v e s t i g a t o r s r e p o r t e d t h a t indomethacin i n doses r e p o r t e d t o s u p p r e s s over 90% of endogenous p r o s t a g l a n d i n s y n t h e s i s i n man h a s no e f f e c t on e i t h e r antigen-induced o r exercise-induced asthma. 35 I n guinea p i g s sens i t i z e d t o ovalbumin, e l e v a t e d u r i n a r y l e v e l s of a PGF a m e t a b o l i t e , 5a, 7a-dihydroxy-11-ketotetranor p r o s t a n o i c a c i d , are foun% d u r i n g t h e anap h y l a c t i c response. 36 Indomethacin (25-50 mg/kg p. 0.1 reduced t h e b a s a l e x c r e t i o n of t h e PGF m e t a b o l i t e and a l s o a b o l i s h e d t h e expected rise on c h a l l e n g e w i t h a n t i g e n . However, t h e guinea p i g s were n o t p r o t e c t e d from r e s p i r a t o r y d i s t r e s s and c o n v u l s i o n s ; no pulmonary mechanics w e r e measured. I n c o n t r a s t , i n cats, i n h i b i t i o n of p r o s t a g l a n d i n b i o s y n t h e s i s w i t h asp i r i n reduced pulmonary v a s o c o n s t r i c t o r and b r o n c h o c o n s t r i c t o r responses t o hypoxic b r e a t h i n g and i t i s r e p o r t e d t h a t hypoxic v e n t i l a t i o n of i s o l a t e d p e r f u s e d cat lungs caused t h e appearance i n pulmonary p e r f u s a t e s of p r o s t a g l a n d i n - l i k e substance^.^^ I t a p p e a r s t h a t a l t h o u g h PGF2a i s l i b e r a t e d d u r i n g b r o n c h o s p a s t i c c o n d i t i o n s due t o s e v e r a l i n i t i a t i n g f a c t o r s , i t s r o l e a s a primary m e d i a t o r of asthma i s n o t y e t s u b s t a n t i a t e d . A new b r o n c h o d i l a t o r compound, a p r o s t a n o i c a c i d d e r i v a t i v e (AY22093) w a s compared t o i s o p r o t e r e n o l and PGE2 i n s e v e r a l p h a m c o l o g i c tests p r e d i c t i v e of c l i n i c a l l y e f f i c a c i o u s b r o n c h o d i l a t a t i o n . 3 8 AY22093 w a s similar i n p r o f i l e t o PGE2 b u t was less p o t e n t .
S p e c i f i c I n h i b i t o r s of Anaphylactic Mediators - E o s i n o p h i l i a i s a common o c c u r r e n c e i n a t o p i c i n d i v i d u a l s , e s p e c i a l l y a l l e r g i c a s t h m a t i c s . While e a r l y work s u g g e s t e d t h a t antigen-antibody complexes caused e o s i n o p h i l migration,39 l a t e r s t u d i e s showed t h a t s o l u b l e m e d i a t o r s from a n a p h y l a x i s were responsible.40 A s p e c i f i c chemotactic f a c t o r f o r e o s i n o p h i l s (ECF-A) h a s been i d e n t i f i e d 1 9 4 2 from human o r guinea p i g lungs. Wasserman,et G . , have shown t h a t t h e f a c t o r e x i s t s preformed i n t h e mast c e l l g r a n u l e 7
HO '
COONa CH2CH2CH3
FPL 55712
S e c t . I1
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FPL 55712, a compound t h a t had been shown t o b e a s p e c i f i c b l o c k e r of SRS-A44, h a s now been shown t o b e a n i n h i b i t o r of e o s i n o p h i l chemotaxis by ECF-A45 w i t h an IC50 a l s o of 3 . 8 ~ 1 0 - ~ M . Whether such a compound w i l l have c l i n i c a l u t i l i t y i n asthma i s s t i l l unknown b u t might h e l p t o d e f i n e t h e r o l e of SRS-A and ECF-A i n t h i s d i s e a s e .
Anaphylactic I n h i b i t o r s - With t h e d i s c o v e r y of new m e d i a t o r s of immediate h y p e r s e n s i t i v i t y almost every y e a r i t is c l e a r t h a t t h e mechanism o f all e r g i c asthma i s more complex t h a n t h e concept of h i s t a m i n e impinging on b r o n c h i a l smooth muscle. An a c t i v e r e s e a r c h area is t h e s e a r c h f o r a g e n t s t h a t i n h i b i t t h e a l l e r g i c r e a c t i o n a t i t s i n c e p t i o n . Cromolyn sodium ( a compound t h a t i n h i b i t s t h e release of a l l e r g i c m e d i a t o r s from s e n s i t i z e d t i s s u e s b u t does n o t i n t e r f e r e w i t h t h e combination of a n t i g e n and a n t i body) i s t h e p r o t o t y p e f o r t h i s t y p e of drug b u t s u f f e r s from a l a c k of o r a l a c t i v i t y and from a l i m i t e d s o l u b i l i t y which p r e c l u d e s a e r o s o l i z a t i o n . Three xanthones w i t h similar a n t i a e r g y p r o f i l e s have been s t u d i e d i n v a r i o u s a n i m a l models and man." They are AH 7725, AH 7079, and AH 6556.
R2
R %fJyJR1
(4)
-COOH
AH 7725
-COOH
AH 7079 AH 6556
-COOH
HOCH2 CH2 0 -
CH3 0
-
CH30
-
A l l t h r e e compounds i n h i b i t e d antigen-induced h i s t a m i n e release from chopped human l u n g i n v i t r o a t about 1 O 4 ~ . 4 7 They also i n h i b i t e d y l a n t i AH 7079 body-mediated release from guinea p i g l u n g i n v i t r o (IC50'10-5M). w a s about e q u i p o t e n t t o cromolyn in v i t r o a g a i n s t antigen-induced h i s t a m i n e release from r a t p e r i t o n e a l mast cells. When b e e venom w a s used t o release h i s t a m i n e from r a t mast cells AH 7725 w a s e q u i p o t e n t t o cromolyn b u t AH 7079 w a s markedly less s o . AH 7079 as an a e r o s o l p r e p a r a t i o n (15 and 30 mg/ml) was e f f e c t i v e i n a l l e r g i c b r o n c h i a l c h a l l e n g e s i n
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man48 while AH 7725 was orally active at a dose of 500 mg49 in 30 ml of water 2 hours before antigen challenge. Clinical data on the oral activity of a similar compound (4) at 8 mglkg, 2 and 5 hours before testing, showed a statistically significant inhibition of exercise-induced asthma; the clinical utility of this agent is still under study.50 n H
’
PR-D-92-EA A tricyclic quinolone acid ICI 74,917 was found to be about 300 times as potent as cromolyn sodium in rat passive cutaneous anaphylaxis (PCA) and devoid of antimediator effect. In the guinea pig it would not block PCA but would inhibit allergic bronchoconstriction while lacking direct bronchodilating activity51 (suggesting tissue specificity for the compound in this species). Another compound, M&B 22,948 an azapurinone, antagonized allergen-induced release of histamine in passively sensitized human lung, PCA in the rat and reagin mediated anaphylactic bronchospasm in the guinea pig.52 This compound does have some direct antimediator activity against histamine, SRS-A and prostaglandin F2a. PR-D-92-FA inhibited PCA in rats and blocked Ascaris-induced bronchospasm in Rhesus monkeys. PR-D-92-EA blocked responses produced by bradykinin, serotonin, SRS-A, PGE2 and PGF2a but not those of histamine on isolated guinea pig ileum.53 Of a series of 2-nitro indan-1,3-diones, (5) was the most potent in rat P C A . ~ ~
CH3 ~ \
~
\
\
3
OH H
\
:
OCH3
(5)
W8011
(6)
4
~
L
~
86 -
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Agents
New s y n t h e t i c methods have p e r m i t t e d t h e e x p l o r a t i o n of 3 - s u b s t i t u t e d chromones. Of a l a r g e series of 3-carboxy,3-hydroxymethyl and 3-formyl chromones t h e most a c t i v e w a s W8011 whi hchad an o r a l ID50 of 2 mglkg and an i . p . ID50 of 1 mglkg i n r t PCA. 55a96’ I n a n o t h e r series (6) was most p o t e n t (ID50
C o r t i c o s t e r o i d s - I n t e r e s t remains h i g h on a e r o s o l i z e d s t e r o i d s f o r treatment of asthma. Two r e c e n t reviews stress t h e a d r e n a l - s p a r i n g e f f e c t of t h e s e p r e p a r a t i o n s . 56,57 S i m i l a r r e s u l t have been found w i t h a e r o s o l i z e d p r e p a r a t i o n s of t r i a m c i n o l o n e a c e t o n i d e 38
.
I n a d i f f e r e n t approach t h e macrolide a n t i b i o t i c troleandomycin (TAO) w a s used t o reduce t h dose of o r a l methyl p r e d n i s o l o n e needed by s t e r o i d dependent asthmatics.” With 250 t o 500 mglday of TAO, about 70% of t h e p a t i e n t s s i g n i f i c a n t l y reduced t h e i r s t e r o i d requirements w i t h no untoward side-effects. This a c t i v i t y of TAO i s u n r e l a t e d t o i t s a n t i b i o t i c activity.
-
Emphysema Emphysema i s an anatomic a l t e r a t i o n of t h e l u n g c h a r a c t e r i z e d by an abnormal enlargement of t h e a i r spaces d i s t a l t o t h e t e r m i n a l , nonr e s p i r a t o r y b r o n c h i o l e , accompanied by d e s t r u c t i v e changes of a l v e o l a r walls. S e v e r a l a g e n t s have been used t o produce emphyse - l i k e condit i o n s i n animals, w i t h papain being t h e a g e n t most used.
fY
Progesterone, which p r e v e n t s papain-induced emphysema i n r a t s , h a s now been e v a l u a t e d i n a n e x i s t i n g emphysema-condition i n r a t s and w a s found t o have a t h e r a p e u t i c a l l y b e n e f i c i a l e f f e c t .60 The mechanism of t h e benef i c i a l response, whether p r o p h y l a c t i c o r t h e r a p e u t i c , i s unknown. Although p r o g e s t e r o n e e l e v a t e s a - a n t i t r y p s i n i n humans and a d e f i c i e n c y of a j a n t i t r y p s i n has been a s s o c i a t e d w i t h p a n l o b u l a r emphysema i n man, t h e mechanism of p r o g e s t e r o n e p r o p h y l a x i s i n rats does n o t appear t o b e due t o a l t e r a t i o n s of serum a n t i t r y p s i n . 6 1 I n o t h e r s t u d i e s , Martorana, e t a l . fi2 r e p o r t e d t h a t i n t r a c a r d i a c a d m i n i s t r a t i o n of human a - a n t i t r y p s i n 1 hour p r i o r t o exposure t o papain i n hamsters d i d n o t p r e v e n i emphysemal i k e changes, b u t t h a t i n t r a t r a c h e a l i n s t i l l a t i o n of a j a n t i t r y p s i n 1 hour b e f o r e exposure s i g n i f i c a n t l y prevented t h e development of t h e l e s i o n . T h i s f i n d i n g g i v e s f u r t h e r support t o t h e concept of an i n t r a a l v e o l a r ( r a t h e r than c i r c u l a t i n g ) a n t i p r o t e a s e as a f a c t o r i n t h e pathog e n e s i s of emphysema. A lung a n t i p r o t e i n a s e , p r e s e n t a t t h e a i r - l u n g i n t e r f a c e , h a s been i s o l a t e d by s a l i n e lavage of f r e s h l y e x c i s e d dog lungs. Immunologic techniques demonstrated t h a t t h e r e were d i f f e r e n c e s between t h i s l u n g a n t i p r o t e i n a s e and serum a n t i p r o t e i n a s e . The serum and lung a n t i p r o t e i n a s e showed d i f f e r e n t i a l i n h i b i t i o n s of e l a s t a s e and t r y p s i n . 63
--
References
1. W.B. Sherman I n Cecil-Loeb Textbook of Medicine, P.B. Beeson and W. McDermott, Eds., W.B. Saunders Co., P h i l a d e l p h i a , 1973, pp. 538-539. 2 . A.W. Frankland I n C l i n i c a l Aspects of Immunology, P.G.H. Gel1 and R.A.
Chap. 9
3. 4. 5. 6. 7. 8. 9.
10. 11. 12. 13.
14. 15. 16.
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
32. 33.
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