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Ultra-short acting beta-blockers: A proposal for the treatment of the critically ill patient
Life Sciences, Vol. 31, pp. 899-907 Printed in the U.S.A.
Pergamon Press
ULTRA-SHORT ACTING BETA-BLOCKERS: A PROPOSAL FOR THE TREATMENT OF THE CRITICALLY ILL PATIENT John Zaroslinski, R o b e r t ~. Borgman, J o h n P. O ' D o n n e l l , W i l l i a m G. A n d e r s o n P a u l W. E r h a r d t , S h e u n g - T s a m Kam, R o b e r t D. R e y n o l d s , R o b e r t ~. L e e , and R i c h a r d ~. G o r c z y n s k i Department of Pharmaceutical Research American Critical Care McGaw P a r k , I l l i n o i s 60085
(Received in final form June 18, 1982) Summary Bet___.aa-blockade i s o f p r o v e n v a l u e i n t h e t h e r a p y o f a c u t e myocardlal infarction but, unfortunately, may p r o d u c e c a r d i a c f a i l u r e by removal of needed sympathetic support. The l o n g d u r a t i o n o f a c t i o n o f available blockers ( h o u r s ) makes r e v e r s a l of failure a complicated p r o b l e m and p r e c l u d e s r a p i d m o d i f i c a t i o n o f t h e r a p y t o m a t c h c h a n g i n g autonomic conditions. To i m p r o v e t h e s a f e t y and e f f i c a c y of betab l o c k a d e i n t h i s s e t t i n g we h a v e d e v e l o p e d t h e c o n c e p t o f u l t r a - s h o r t b e t a - b l o c k a d e and h a v e i d e n t i f i e d a novel beta-blocker (ASL-8052) w h i c h p o s s e s s e s a d u r a t i o n o f a c t i o n l e s s t h a n 15 m i n u t e s . T h i s compound i s cardioselectlve and p o s s e s s e s efficacy i n an a n i m a l model o f a c u t e myocardial infarction. It, therefore, a p p e a r s t o be s u l t a b l e f o r r a p i d attainment of controlled levels of beta-blockade via intravenous infus i o n and r a p i d r e c o v e r y f r o m b e t a - b l o c k a d e i f r e q u i r e d by t h e c l l n i c a l situation. The compound s h o u l d , t h e r e f o r e , be u s e f u l f o r s a f e t h e r a p y in crltically ill cardiac patients. The u s e o f b e t a - a d r e n e r g i c blocking agents in the therapy of ischemic heart d i s e a s e h a s l a r g e l y b e e n l i m i t e d t o t h e t r e a t m e n t o f a n g i n a p e c t o r i s and v a r i ous t y p e s o f v e n t r i c u l a r and s u p r a v e n t r i c u l a z dyarhythmlas.(l,2,3,4) More recent interest h a s f o c u s e d on t h e u s e o f b e t a - b l o c k e r s to limlt infarct size and t h e r e b y m o r t a l i t y i n t h e a c u t e p h a s e o f m y o c a r d l a l I n f a r c t l o n . ( $ , 6 ) The m o s t d a n g e r o u s s i d e e f f e c t o f b e t a - b l o c k a d e i n t h e s e t t i n g o f i s c h e m i c heart disease is the induction of cardiac failure.(1,2,3,5) T h i s may r e s u l t from removal of intrinsic sympathetic tone or direct myocardial depression.(3,7) At t h e t i m e o f t h e r a p y , however, the degree to which cardiac f u n c t i o n i s d e p e n d e n t upon s y m p a t h e t i c i n p u t i s n o t g e n e r a l l y known and t h e effect of b e t a - b l o c k a d e on c a r d i a c function is, therefore, difficult to predict.(3,7,8,9,10) To e x t e n d t h e u s e f u l n e s s , s a f e t y and e f f i c a c y o f b e t a - b l o c k e r s in critical c a r d i a c t h e r a p y , we h a v e d e v e l o p e d t h e c o n c e p t o f c o n t r o l l e d and t i t r a t a b l e intravenous therapy utilizing an u l t r a - s h o r t acting bet#-zeceptor antagonist. The u n i q u e a d v a n t a g e o f t h i s p r o p o s a l i s t h e a b i l i t y to rapidly alter the intensity of beta-blockade w i t h s u c h an a g e n t t o a d j u s t for changes in therapeutic requirements or the possible development of undesirable effects. The p r e s e n t study is the initial phax~macological d e s c r i p t i o n o f ASL-8052, a novel beta-adrenergic receptor antagonist which possesses an u l t r a - s h o r t duration of action.
0024-3205/82/090899-09503.00/0 Copyright (c) 1982 Pergamon Press Ltd.
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Methods In Vitro
Studies
B e t a - b l o c k a d e was a s s e s s e d ! ~ v i t r o u s i n g g u i n e a p i g r i g h t a t r i a b a t h e d i n an o x y g e n a t e d (95% 0 2 - 5 ~ CO~) K r e b s p h y s i o l o g l c a l s a l t s o l u t i o n a t 37°C. Atria were allowed to beat spontaneously. Cumulative concentration-rate response curves were produced with_~soproterenol b e f o r e and a f t e r 6 0 - m i n u t e i n c u b a t i o n w i t h ASL-S052 a t 5 . 0 x I 0 M. B l o c k i n g p o t e n c y was e s t i m a t e d by c o m p u t i n g KB v a l u e s by t h e m e t h o d o f F u r c h g o t t . ( l l ) Intrinsic sympathomimetic and/or cardiodepressant properties o f ASL-80$2 were d e t e r m i n e d u s i n g i s o l a t e d , electrically-paced left atrlal preparations f r o m g u i n e a p i g s p r e t r e a t e d w i t h r e s e r p i n e ( 5 . 0 mg/kg, i . p . , 24 h o u r s p r i o r t o experiment). After a 60-minute equilibration p e r i o d t h e t i s s u e s were e x p o s e d t o i n c r e s s i n 8 c o n c e n t r a t i o n s o f ASL-8052 a t 6 0 - m i n u t e i n t e r v a l s and any c h a n g e s in developed tension recorded. Canine Studies Duration of Action. Mongrel d o g s w e r e a n e s t h e t i z e d w i t h a c o m b i n a t i o n o f sodium p e n t o b a r b i t a l and sodium b a r b i t a l ( 1 5 . 0 and 300 m g / k g , r e s p e c t i v e l y ) and vagotomized. R e c t a l t e m p e r a t u r e was m o n i t o r e d and m a i n t a i n e d a t 3 6 - 3 8 ° C w i t h a heating pad. H e a r t r a t e was m e a s u r e d f r o m an a r t e r i a l blood pressure signal w i t h a Beckman c a r d i o t a c h o m e t e r . The d e g r e e o f b e t a - b l o c k a d e was a s s e s s e d by i n t r a v e n o u s ( i . v . ) administration of Isoproterenol ( 0 . 5 ~ g / k g ) a t t e n - m l n u t e i n t e r v a l s p r i o r t o , d u r i n g and f o l l o w i n g t e r m i n a t i o n o f a 3 - h o u r i . v . i n f u s i o n o f ASL-8052 ( 5 0 . 0 ~ g / k g / m l n ) o r propranolol hydrochloride (1.125 ~g/kg/min). Control experiments were performed using saline infusion instead of blocker. Percent inhibition of isoproterenol-induced tachycardla and h y p o t e n s i o n was c a l c u l a t e d d u r i n g and following infusion of blockers. Bose R e s p o n s e C h a r a c t e r i s t i c s . Pentobarbital anesthetized (30 ms/ks, i.v.), v a g o t o m i z e d d o g s w e r e p r e p a r e d a s d e s c r i b e d a b o v e . H e a r t r a t e and b l o o d pressure responses to increasing i.v. doses of isoproterenol were d e t e r m i n e d b e f o r e and t e n m i n u t e s f o l l o w i n g i n i t i a t i o n o f i . v . i n f u s i o n o f ASL-8052 a t r a t e s o f 2 5 . 0 , 5 0 . 0 and 1 0 0 . 0 ~g/kg/min. Cardloselectlvltv. Pentobarbltal anesthetized, v a g o t o m i z e d dogs were surgically prepared for perfusion of the left hindlimb at constant blood flow asprevlously described (12). Body t e m p e r a t u r e was m a i n t a i n e d b e t w e e n 3 6 . 5 38°C w i t h a h e a t i n g p a d . H e a r t r a t e was m e a s u r e d w i t h a Beckman c a r d i o t a c h o m e t e r f r o m an a r t e r i a l blood pressure signal. T h i r t y m i n u t e s p r i o r t o e x p e r i m e n t a t i o n h e x a m e t h o n i u m b r o m i d e (20 m g / k g , i . v . ) was a d m l n i s t e r e d o v e r a f i v e - m l n u t e p e r i o d . Flow was a d j u s t e d t o p r o v i d e a hindlimb p e r f u s i o n p r e s s u r e (PP) o f 1 1 0 - 1 3 0 mmHg. H e a r t r a t e and p e r f u s i o n p r e s s u r e r e s p o n s e s t o a submaximal i . v . d o s e o f I s o p r o t e r e n o l (0.27 pg/kg) were r e c o r d e d b e f o r e and t e n m i n u t e s f o l l o w i n g i n i t i a t i o n o f i n f u s i o n o f ASL-8052 (160.0 ~g/kg/min), propranolol (16.0 pg/kg/mlu) or saline. Limitation of Infarct Size. Dogs w e r e a n e s t h e t i z e d w i t h p e n t o b a r b i t a l (30 ms/k s , l.v.) and r e s p i r a t i o n was m a i n t a i n e d by means o f a c u f f e d e n d o t r a c h e a l t u b e and a H a r v a r d r e s p i r a t o r . Body t e m p e r a t u r e was m a i n t a i n e d a t 37 t o 3 9 ° C . Using sterile t e c h n i q u e s , a j u g u l a r v e i n and c a r o t i d a r t e r y w e r e c a n n u l a t e d for injection o f d r u g and f o r r e c o r d i n g mean a r t e r i a l pressure, respectively. The c h e s t was o p e n e d a t t h e l e f t f i f t h i n t e r c o s t a l s p a c e and t h e l e f t c i r c u m -
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f l e x c o r o n a r y a r t e r y (LCX) was i s o l a t e d a p p r o x i m a t e l y I 0 mm from i t s o r i g i n . LCX f l o w was m e a s u r e d e l e c t r o m a g n e t l c a l l y and a s c r e w c l a m p was u s e d t o p r o d u c e a crltlcal s t e n o s i s o f t h e LCX. C r l t i c a l s t e n o s l s was d e f i n e d a s one i n w h i c h little o r no r e d u c t i o n i n b a s a l LCX f l o w o c c u r r e d and m i n i m a l h y p e r e m i c r e s p o n s e o c c u r r e d a f t e r r e l e a s e o f a 1 0 - s e c o n d c o m p l e t e o c c l u s i o n o f t h e LCX. Once a c r i t l c a l s t e n o s l s was p r o d u c e d , an i n f u s i o n o f ASL-8052 ( 5 0 . 0 u g / k g / m l n ) o r s a l l n e was b e g u n . Twenty m i n u t e s a f t e r i n i t i a t i o n o f t h e i n f u s i o n , t h e LCX was c o m p l e t e l y o c c l u d e d . The c o m p l e t e o c c l u s i o n was m a i n t a i n e d f o r 60 m i n u t e s and t h e n r e l e a s e d so r e p e r f u s i o n c o u l d o c c u r t h r o u g h t h e c r i t i c a l s t e n o s i s . The c h e s t was c l o s e d and 4 h o u r s a f t e r i n i t i a t i o n o f r e p e r f u s i o n t h e i n f u s i o n was stopped. H e a r t r a t e and b l o o d p r e s s u r e w e r e m o n i t o r e d f o r an a d d i t i o n a l h o u r . Twenty-four hours after surgery dogs were re-anesthetlzed and t h e h e a r t s w e r e r e m o v e d . The LCX was e x a m i n e d a t t h e s i t e o f s t e n o s l s f o r t h e p r e s e n c e o f blood clots. The l e f t v e n t r l c l e (including the Interventricular aeptum) was sliced transversely i n t o s e c t i o n s 8 t o i 0 mm t h i c k and i n c u b a t e d f o r 15 m i n u t e s in a solutlon containing nitrobluetetrazollum w h i c h s t a i n s undamaged t i s s u e containing intracellular dehydrogenases dark blue. Infarcted tissue ( u n s t a i n e d ) was s e c t i o n e d f r o m n o r m a l ( s t a i n e d ) t i s s u e and t h e p e r c e n t o f l e f t ventricle infarcted was c a l c u l a t e d from the w e i g h t s of i n f a r c t e d and n o r m a l tissue.(13,14) Statistics Student's t-test (two-tailed) f o r u n p a i r e d data (and p a i r e d d a t a , where appropriate) was u s e d t o compare v a l u e s b e t w e e n g r o u p s . A p-value less than 0 . 0 5 was i n t e r p r e t e d as defining statistical significance. Drugs ASL-8052 ( m e t h y l 3 - [ 4 - [ 2 - h y d r o x y - 3 - ( i s o p r o p y l a m i n o ) p r o p o x y ] p h e n y l ] p r o p i o n a t e h y d r o c h l o r l d e ) was s y n t h e s i z e d a t A m e r i c a n C r i t i c a l Care. Racemic p r o p r a n olol hydrochlorlde and I s o p r o t e r e n o l h y d r o c h l o r l d e w e r e o b t a i n e d f r o m Sigma C h e m i c a l C o . , S t . L o u i s , MO. Results
In Vitro
Studies
ASL-8052 c a u s e d a p a r a l l e l shift of isoproterenol concentration-rate response curves in Isolated guinea pig right atria. The pA~ ( a n d 95~ c o n f i d e n c e interval) o f t h e compound was 7 . 0 1 ( 6 . 9 2 - 7 . 1 2 , N = 29);~ropranolol h a d a pA2 of 8.6 (8.48-8.73, N = 23). T h u s , ASL-80$2 was a b o u t 3 8 - f o l d l e s s p o t e n t t h a n propranolol. ASL-8052 was w i t h o u t i n t r i n s i c sympathomimetic activity; depression of ~eft atrial developed tension occurred only at concentrations greater t h a n 10-~M. Canine Studies Duration of Action. In sallne-infusion experiments, t h e h e a r t r a t e and blood pressure responses to isoproterenol given at 10-mlnute intervals were quantitatively reproducible for a five-hour period. The o n s e t o f b e t a - b l o c k a d e upon i n i t i a t i o n o f i n f u s i o n and t h e d e c a y o f b e t a - b l o c k a d e f o l l o w i n g t e r m i n a t i o n o f i n f u s i o n w e r e much f a s t e r w i t h ASL-8052 (N = 12) t h a n w i t h p r o p r a n o l o l (N = 5) ( F i g . I ) . S t e a d y - s t a t e b l o c k a d e w i t h ASL-8052 was a t t a i n e d i n 10-15 minutes, whereas, the degree of blockade observed with propranolol continued to increase for at least two h o u r s d u r i n g i n f u s i o n . Heart rate responses to Isoproterenol a t t h e end o f t h r e e h o u r s o f i n t r a v e n o u s i n f u s i o n o f p r o p r a n o l o l and ACC-8052 w e r e d e c r e a s e d by an a v e r a g e o f 66 ± 65 and 52 ± 4 ~ , r e s p e c t i v e l y . With ASL-8052 t h e t i m e r e q u i r e d f o r 80q. r e c o v e r y from b e t a - b l o c k a d e was 12 ± 3 m i n u t e s ; t w e n t y m i n u t e s a f t e r t e x ~ u l n a t l o n o f i n f u s i o n t h e r e was no d e t e c t a b l e
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Ultra-short Acting Beta-blockers
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Vol. 31, No. 9, 1982
BLOCKER
"1 ,o[
i
N-'5
N=12
MINUTQ
Fig.
1
Time c o u r s e o f b e t a b l o c k a d e d u r i n g and f o l l o w i n g c o n s t a n t i n f u s i o n o f ASL-8052 and p r o p r a n o l o l . Ordinate: percent inhibition ( ~ l ) o f h e a r t r a t e (HR) r e s p o n s e t o i s o p r o t e r e n o l . Abscissa: time after initiation of infusion of blockers. Inf u s i o n s t e r m i n a t e d a t 180 m i n u t e s . Means + SEM. blockade. In contrast, t h e r e was v e r y l i t t l e decay of beta-blockade following t e r m i n a t i o n o f p r o p r a n o l o l i n f u s i o n ; a t one h o u r p o s t - l n f u s l o n the heart rate r e s p o n s e t o i s o p r o t a r e n o l was s t i l l r e d u c e d b y 51 ± 4 ~ . P r o p r s n o l o l p r o d u c e d 63 ± 6~ i n h i b i t i o n of the diastolic blood pressure response to isoproterenol and, f o l l o w l n g t e r m i n a t i o n of infusion, decay of b e t a - b l o c k a d e was s l i g h t ( F i g . 2 ) . ASL-$052, h o w e v e r , p r o d u c e d o n l y a s m a l l , transient blockade of the Isoproterenol-induced decline in diastolic blood pressure (Fig. 2). Dose-resoonse Characteristics. ASL-8052 a t i n c r e a s i n g d o s e r a t e s s h i f t e d the heart rate dose response curve to Isoproterenol to the right (Fig. 3); blood pressure dose response curves to isoproterenol ( n o t shown) w e r e n o t altered. C~rdloselec~lylty. Figure 4 illustrates min) and p r o p r a n o l o l ( 0 . 1 6 m g / k g , c u m u l a t i v e ) of the heart rate response to isoproterenol.
t h a t b o t h ASL-8052 ( 1 6 0 . 0 p g / k g / produced nearly complete blockade Propranolol also nearly eltmin-
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BLOCKER INFUSION OFF
"t
I !
50-
40-
N=S
30: 204
ASL'8052
- PROPflANOLOL
10.
N=12
,;o MINUTES
Fig.
2
Time c o u r s e o f b e t a b l o c k a d e d u r i n g and f o l l o w i n g c o n s t a n t i n f u s i o n o f ASL-8052 and p r o p r a n o l o l . Ordinate: percent inhibition (~I) of dlastolic b l o o d p r e s s u r e (BP) r e s p o n s e to Isoproterenol. Abscissa: time after initiation of infusion of blockers. ~ n f u s i o n s t e r m i n a t e d a t 180 m i n u t e s . Means + SEM. ated the perfusion pressure response to isoproterenol. produced only slight blockade of this response.
In
contrast,
ASL-8052
Limitation of Infarct S~e. One dog ( s a l l n e - t r e a t e d ) fibrillated during t h e 6 0 - m l u u t e LCX o c c l u s i o n and was e x c l u d e d f r o m a n a l y s i s . None o f t h e d o g s had v i s i b l e c l o t f o r m a t i o n in the area of the s t e n o s i s a t a u t o p s y . Left ventricular w e i g h t , LCX f l o w and h y p e r e m l c r e s p o n s e w e r e s i m i l a r i n t h e two g r o u p s o f d o g s p r i o r t o and a f t e r p r o d u c t i o n o f t h e c r i t i c a l stenosls S t e n o s i s r e s u l t e d i n a s i m i l a r marked a t t e n u a t i o n of the hyparemlc response to I 0 s a c LCX o c c l u s l o n b u t had no e f f e c t on b a s a l LCX f l o w i n t h e two g r o u p s . Infarct s i z e was s i g n l f l c a n t l y l e s s i n ASL-80 2 - t r e a t e d dogs (7.5 ± 2.4~ of left ventricle) than in sallne-trcstcd dogs (24.0 ± 4.$~ of left ventrlcle) (Fig, 5). H e a r t r a t e and mean a r t e r i a l t h e two g r o u p s a t any t i m e .
pressure
were not
significantly
different
in
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Ultra-short Acting Beta-blockers
AHR
-
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: CONTROL
bpm
A S L - 8 0 5 2 , 2 5 . 0 u g kg rnin A S L - 8 0 5 2 , 5 0 . O o g kg rain
70.
60. 50.
40-
30-
20-
10-
i
s
e
ODllli
0.031
(1063
!
s
0.125 0.25 ISOPROTERENOL ug/kg, IV
Fig.
e
0.5 0
!
s
1.00
2.00
3
Modification of Isoproterenol-lndu©ed i n c r e a s e s i n HR b y i n c r e a s i n g i n f u s i o n r a t e s o f ASL-8052. O r d i n a t e : i n c r e a s e i n HR (AHR, BPM). A b s c i s s a : i s o p r o t e r e n o l dose (pg/kg, i.v.). Means + SEM. Discussion Beta-adrenergic blockade is of proven value in the treatment of classical angina pectoris and ventricular and s u p r a v e n t r t c u l a r dyarhythmias, particularly when t h e s e a r e o f a d r e n e r g i c origin (1,2,3,4). More r e c e n t w e l l - c o n t r o l l e d studies have also demonstrated the ability of long-tex~ beta-blockade to reduce mortality and the incidence of reinfarction in patients s u r v i v i n g a c u t e myocardial infarction.(15,16) The v a l u e o f b e t a - b l o c k a d e in the treatment of angina pectoris and in reducing mortality and reinfarotion is presumably attributable, in large part, to improvement of myocardial o x y g e n s u p p l y t o demand r a t i o . The p o t e n t i a l ability of beta-blockade to limit infarct size following an acute ischemic i n s u l t was, t h e r e f o r e , a logical extension.(17,18) While results obtained in early clinical studies have been conflicting (5,6,19,20), more r e c e n t s t u d i e s have indicated that administration of beta-blockers early in the course of acute myocardial infarction produced salutory h e m o d y n a m i c and e l e c t r o c a r d i o graphic effects and enzymatic changes indicative of a decrease in extent of infarction.(21,22,23,24)
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IHEART NCREASE IN RATE bpm
905
RESPONSES TOISOPROTERENOL
• - PIlE - DRUG 10
• - POST - DRUG
DECREASE PERFUSIOIN PRESSURE NHINDLIMB "3~
il
/
mmHg
N:7 ASL'8052
N:6 N:~ PflOPRANOLOL SALINE
FiS. 4 Modification of isoproterenol (0.27 pg/kg, i.v.) induced increase i n HR and d e c r e a s e i n PP i n i s o l a t e d , perfused canine hindlimb p r e p a r a t i o n by ASL-8052 ( 1 6 0 . 0 p g / k g / m t n ) , p r o p r a n o l o l ( 0 . 1 6 m$/kg, c u m u l a t i v e ) and s a l i n e ( 0 . 0 5 m l / k g / m i n ) . Split ordinate: upper i n c r e a s e i n HR (AHR, BPM); l o w e r - d e c r e a s e i n h i n d l i m b p e r f u s i o n p r e s s u r e (APP, n H g ) . Means ± SEM.
Available beta-blockers are relatively l o n g - a c t i n g and a r e c h a r a c t e r i z e d by erratic oral bioavailabiltty (8) w h i c h n e c e s s i t a t e s intravenous administration if therapeutic plasma concentrations n e e d t o be e s t a b l i s h e d rapidly. In order to safeguard against the possible induction of acute failure, however, i n t r a v e n o u s t h e r a p y must b e g i n a t v e r y low d o s e s w h i c h a r e g r a d u a l l y i n c r e a s e d until a given therapeutic effect is obtained or until side-effects occur.(3) R e c o v e r y from f a i l u r e i s slow and t h e u s e o f i n o t r o p i c a g e n t s may be r e q u i r e d (6,9). Additionally, t h e l o n g d u r a t i o n o f b e t a - b l o c k a d e makes i t i m p o s s i b l e t o match pharmacological input to changing autonomic conditions. Thus, the persistent activity o f a v a i l a b l e b e t a - b l o c k i n g a g e n t s c a n be c o u n t e r - p r o d u c t i v e and may g r e a t l y c o m p l i c a t e t h e t h e r a p e u t i c decisions required during critical care of cardiac patients. The c o n c e p t o f u l t r a - s h o r t acting beta-blockers stems from t h e need t o rapidly alter the level of blockade to enhance therapeutic effects or to minimize side-effects. Our a p p r o a c h t o t h e d e v e l o p m e n t o f ASL-8052 a s a s h o r t acting agent consisted of incorporation of enzymatic lability into the beta-
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> 25" I-. U. UJ -i
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ASL-8052
SALINE
Fig.
5
Reduction of infarct s i z e d e t e r m i n e d 24 h o u r s a f t e r one h o u r comp l e t e LCX o c c l u s i o n f o l l o w e d b y ~ e p e r f u s i o n i n t o c r i t i c a l stenosis b y ASL-8052. O r d i n a t e : % o f LV i n f a r c t e d . Left, saline-treated animals; Right, ASL-8052-treated animals. Means ± SEM. blocker pharmacophore such that rapid inactivation of the drug would occur via drug metabolism. R e s u l t s o f t h i s s t u d y show t h a t ASL-8052 h a s a d u r a t i o n o f action of less t h a n 15 m i n u t e s . This drug produces cardioselectivc betab l o c k a d e and l a c k s s y m p a t h o m i m e t i c a n d s i g n i f i c a n t direct depressant activity. The p r e s e n t s t u d y a l s o d e m o n s t r a t e s t h a t ASL-8052 p o s s e s s e s e f f i c a c y i n t h e acute myocardial infarction setting. Since it has been previously reported that single doses of long-acting bet_._.!-blockers ( p r o p r a n o l o l , nadolol and 8tenolol) also limit infarct size in this model (13,14), it is reasonable to assume that the mechanism of the beneficial action o f ASL-8052 i s b e t a blockade. The o b s e r v a t i o n t h a t ASL-80$2 h a d no e f f e c t on h e a r t r a t e o r b l o o d pressure in this study is in agreement with previous studies concerned with the a c t i o n s o f bet_._..Aa-adrenergic b l o c k e r s i n t h i s m o d e l . ( 1 3 , 1 4 ) The u l t r a - s h o r t activity o f ASL-8052 s h o u l d i n c r e a s e t h e c o n v e n i e n c e and safety of inducing beta-blockade in hospitalized patients with ischemic heart disease where the level of sympathetic activity a t t h e m y o c a r d l u m i s unknown and rapid modification of pharmacological effect may b e n e e d e d t o m a t c h changing autonomic conditions. Acknow,lcdsements Excellent technical assistance b y L, C. P r c u s s c r , A. L e v a n h o , W. B u r m c l s t e r a n d D. ~ . E l l i s i s g r e a t l y a p p r e c i a t e d . We t h a n k M~s. C. M a l e r f o r t y p i n g and processing this manuscript.
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References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
D.B. MCDEVITT, Drugs 17, 267-288 ( 1 9 7 9) . W. FRISHMAN, R. SILVERMAN, Am. Heart I . 98, 119-131 ( 1 9 7 9 ) . R. ALRQUIST, Am. B e a r t J . 93, 117-120 ( 1 9 7 7 ) . L. SZEKERES, P r o c e e d i n g s of t h e V I I I World Congress of C ~ r d i o l o g y , p 933, N o r t h - H o l l a n d , Amsterdam ( 1 9 7 8 ) . R . J . LEE, L i f e S c i . 23, 2539-2542 ( 1 9 7 8 ) . ~.D. FITZGERALD, P o s t g r a d . Med. 3. 52, 770-781 ( 1 9 7 6 ) . J . D . FITZGERALD, C l i n . Pharm. Therap. 10, 292-306 ( 1 9 6 9 ) . A.S. NIES and D.G. SBAND, C i r c u l a t i o n 52, 6-15 ( 1 9 7 5 ) . F. HAGE~IJER, B e t a - a d r e n o c e p t o r B l o c k i n g Agents, P.R. Saxena and R.P. F o r s y t h , e d i t o r s , p. 273, N o r t h - H o l l a n d , Amsterdam ( 1 9 7 6 ) . W. FRISBMAN, R. SILVERI~N, J . STROM, O. ELKAYAM and E. SONNENBLICK, Am. R e a r t ~ . , 98, 256-262 ( 1 9 7 9 ) . R.F. FURCHGOIT, Ann. N.Y. Aesd. S o l . , 139, 553-570 ( 1 9 6 7 ) . R.D. REYNOLDS and R . J . GORCZYNSKI, 7. Pharmaeol. Exp. T h e r p . , 212, 579-583 (1 9 8 0 ) . W.E. BURMEISTER, R.D. REYNOLDS and R . J . LEE, Eur. J . P h e r m a e o l . 75, 7-10 (1981). R.D. REYNOLDS, W.E. BURMEISTER, R.J. GORCZYNSKI, D.D. DICKERSON, M.P. MAT~EWS and R.J. LEE, Cardiovas. Res. 15, 411-420 (1981). THE NORWF~IAN MULTICENTER STUDY GROUP, N. E n g l . J . Med., 304, 801-813 (1981). g.G. GREEN, D.A. CBA~ERLAIN, R.M. FULTON, N.A. RAMER, M.F. OLIVER, B.L. PENTOCOST, ~.A. LEWIS and R. TUSON, B r i t . Med. J . 2, 419-421 ( 1 9 7 7 ) . J.W. BLACK, Drug Responses i n Man, p. 121, L i t t l e , Brown and Company, London (1 9 6 7 ) . S. EPSTEIN, R. GOLDSTEIN, D.R. REDWOOD, K.~. KENT and E.R. S M I ~ , Ann. I n t e r n a l Med. 78, 918-936 ( 1 9 7 3 ) . W.H. FRISHMAN, Am. R e a r t 7. 99, 528-536, ( 1 9 8 0 ) . R.M. NORRIS, Am. B e a r t 7. 99, 683-685, ( 1 9 8 0 ) . L . 3 . PELIDES, D.S. REID, M. THOMAS and S . F . SRILLINGFORD, C a r d i o v a s . R e s . , 6, 295-301 ( 1 9 7 2 ) . R.K. GOLD, R.C. LEINBACH, and F.R. MAROKO, Am. 7. Card. 38, 689-695 ( 1 9 7 6 ) . J . S . CAIRNS and G. KLASSEN, C i r c u l a t i o n , 52 (Suppl 2 ) , 107 ( 1 9 7 5 ) . B. PITT, J . L . WEISS, R.A. SCRULZE, D.R. TAYLOR, R.L. KENNEDY IlL, and D. CARALIS, C i r c u l a t i o n , 54 (Suppl 2 ) , 29 ( 1 9 7 6 ) .
Pergamon Press
ULTRA-SHORT ACTING BETA-BLOCKERS: A PROPOSAL FOR THE TREATMENT OF THE CRITICALLY ILL PATIENT John Zaroslinski, R o b e r t ~. Borgman, J o h n P. O ' D o n n e l l , W i l l i a m G. A n d e r s o n P a u l W. E r h a r d t , S h e u n g - T s a m Kam, R o b e r t D. R e y n o l d s , R o b e r t ~. L e e , and R i c h a r d ~. G o r c z y n s k i Department of Pharmaceutical Research American Critical Care McGaw P a r k , I l l i n o i s 60085
(Received in final form June 18, 1982) Summary Bet___.aa-blockade i s o f p r o v e n v a l u e i n t h e t h e r a p y o f a c u t e myocardlal infarction but, unfortunately, may p r o d u c e c a r d i a c f a i l u r e by removal of needed sympathetic support. The l o n g d u r a t i o n o f a c t i o n o f available blockers ( h o u r s ) makes r e v e r s a l of failure a complicated p r o b l e m and p r e c l u d e s r a p i d m o d i f i c a t i o n o f t h e r a p y t o m a t c h c h a n g i n g autonomic conditions. To i m p r o v e t h e s a f e t y and e f f i c a c y of betab l o c k a d e i n t h i s s e t t i n g we h a v e d e v e l o p e d t h e c o n c e p t o f u l t r a - s h o r t b e t a - b l o c k a d e and h a v e i d e n t i f i e d a novel beta-blocker (ASL-8052) w h i c h p o s s e s s e s a d u r a t i o n o f a c t i o n l e s s t h a n 15 m i n u t e s . T h i s compound i s cardioselectlve and p o s s e s s e s efficacy i n an a n i m a l model o f a c u t e myocardial infarction. It, therefore, a p p e a r s t o be s u l t a b l e f o r r a p i d attainment of controlled levels of beta-blockade via intravenous infus i o n and r a p i d r e c o v e r y f r o m b e t a - b l o c k a d e i f r e q u i r e d by t h e c l l n i c a l situation. The compound s h o u l d , t h e r e f o r e , be u s e f u l f o r s a f e t h e r a p y in crltically ill cardiac patients. The u s e o f b e t a - a d r e n e r g i c blocking agents in the therapy of ischemic heart d i s e a s e h a s l a r g e l y b e e n l i m i t e d t o t h e t r e a t m e n t o f a n g i n a p e c t o r i s and v a r i ous t y p e s o f v e n t r i c u l a r and s u p r a v e n t r i c u l a z dyarhythmlas.(l,2,3,4) More recent interest h a s f o c u s e d on t h e u s e o f b e t a - b l o c k e r s to limlt infarct size and t h e r e b y m o r t a l i t y i n t h e a c u t e p h a s e o f m y o c a r d l a l I n f a r c t l o n . ( $ , 6 ) The m o s t d a n g e r o u s s i d e e f f e c t o f b e t a - b l o c k a d e i n t h e s e t t i n g o f i s c h e m i c heart disease is the induction of cardiac failure.(1,2,3,5) T h i s may r e s u l t from removal of intrinsic sympathetic tone or direct myocardial depression.(3,7) At t h e t i m e o f t h e r a p y , however, the degree to which cardiac f u n c t i o n i s d e p e n d e n t upon s y m p a t h e t i c i n p u t i s n o t g e n e r a l l y known and t h e effect of b e t a - b l o c k a d e on c a r d i a c function is, therefore, difficult to predict.(3,7,8,9,10) To e x t e n d t h e u s e f u l n e s s , s a f e t y and e f f i c a c y o f b e t a - b l o c k e r s in critical c a r d i a c t h e r a p y , we h a v e d e v e l o p e d t h e c o n c e p t o f c o n t r o l l e d and t i t r a t a b l e intravenous therapy utilizing an u l t r a - s h o r t acting bet#-zeceptor antagonist. The u n i q u e a d v a n t a g e o f t h i s p r o p o s a l i s t h e a b i l i t y to rapidly alter the intensity of beta-blockade w i t h s u c h an a g e n t t o a d j u s t for changes in therapeutic requirements or the possible development of undesirable effects. The p r e s e n t study is the initial phax~macological d e s c r i p t i o n o f ASL-8052, a novel beta-adrenergic receptor antagonist which possesses an u l t r a - s h o r t duration of action.
0024-3205/82/090899-09503.00/0 Copyright (c) 1982 Pergamon Press Ltd.
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B e t a - b l o c k a d e was a s s e s s e d ! ~ v i t r o u s i n g g u i n e a p i g r i g h t a t r i a b a t h e d i n an o x y g e n a t e d (95% 0 2 - 5 ~ CO~) K r e b s p h y s i o l o g l c a l s a l t s o l u t i o n a t 37°C. Atria were allowed to beat spontaneously. Cumulative concentration-rate response curves were produced with_~soproterenol b e f o r e and a f t e r 6 0 - m i n u t e i n c u b a t i o n w i t h ASL-S052 a t 5 . 0 x I 0 M. B l o c k i n g p o t e n c y was e s t i m a t e d by c o m p u t i n g KB v a l u e s by t h e m e t h o d o f F u r c h g o t t . ( l l ) Intrinsic sympathomimetic and/or cardiodepressant properties o f ASL-80$2 were d e t e r m i n e d u s i n g i s o l a t e d , electrically-paced left atrlal preparations f r o m g u i n e a p i g s p r e t r e a t e d w i t h r e s e r p i n e ( 5 . 0 mg/kg, i . p . , 24 h o u r s p r i o r t o experiment). After a 60-minute equilibration p e r i o d t h e t i s s u e s were e x p o s e d t o i n c r e s s i n 8 c o n c e n t r a t i o n s o f ASL-8052 a t 6 0 - m i n u t e i n t e r v a l s and any c h a n g e s in developed tension recorded. Canine Studies Duration of Action. Mongrel d o g s w e r e a n e s t h e t i z e d w i t h a c o m b i n a t i o n o f sodium p e n t o b a r b i t a l and sodium b a r b i t a l ( 1 5 . 0 and 300 m g / k g , r e s p e c t i v e l y ) and vagotomized. R e c t a l t e m p e r a t u r e was m o n i t o r e d and m a i n t a i n e d a t 3 6 - 3 8 ° C w i t h a heating pad. H e a r t r a t e was m e a s u r e d f r o m an a r t e r i a l blood pressure signal w i t h a Beckman c a r d i o t a c h o m e t e r . The d e g r e e o f b e t a - b l o c k a d e was a s s e s s e d by i n t r a v e n o u s ( i . v . ) administration of Isoproterenol ( 0 . 5 ~ g / k g ) a t t e n - m l n u t e i n t e r v a l s p r i o r t o , d u r i n g and f o l l o w i n g t e r m i n a t i o n o f a 3 - h o u r i . v . i n f u s i o n o f ASL-8052 ( 5 0 . 0 ~ g / k g / m l n ) o r propranolol hydrochloride (1.125 ~g/kg/min). Control experiments were performed using saline infusion instead of blocker. Percent inhibition of isoproterenol-induced tachycardla and h y p o t e n s i o n was c a l c u l a t e d d u r i n g and following infusion of blockers. Bose R e s p o n s e C h a r a c t e r i s t i c s . Pentobarbital anesthetized (30 ms/ks, i.v.), v a g o t o m i z e d d o g s w e r e p r e p a r e d a s d e s c r i b e d a b o v e . H e a r t r a t e and b l o o d pressure responses to increasing i.v. doses of isoproterenol were d e t e r m i n e d b e f o r e and t e n m i n u t e s f o l l o w i n g i n i t i a t i o n o f i . v . i n f u s i o n o f ASL-8052 a t r a t e s o f 2 5 . 0 , 5 0 . 0 and 1 0 0 . 0 ~g/kg/min. Cardloselectlvltv. Pentobarbltal anesthetized, v a g o t o m i z e d dogs were surgically prepared for perfusion of the left hindlimb at constant blood flow asprevlously described (12). Body t e m p e r a t u r e was m a i n t a i n e d b e t w e e n 3 6 . 5 38°C w i t h a h e a t i n g p a d . H e a r t r a t e was m e a s u r e d w i t h a Beckman c a r d i o t a c h o m e t e r f r o m an a r t e r i a l blood pressure signal. T h i r t y m i n u t e s p r i o r t o e x p e r i m e n t a t i o n h e x a m e t h o n i u m b r o m i d e (20 m g / k g , i . v . ) was a d m l n i s t e r e d o v e r a f i v e - m l n u t e p e r i o d . Flow was a d j u s t e d t o p r o v i d e a hindlimb p e r f u s i o n p r e s s u r e (PP) o f 1 1 0 - 1 3 0 mmHg. H e a r t r a t e and p e r f u s i o n p r e s s u r e r e s p o n s e s t o a submaximal i . v . d o s e o f I s o p r o t e r e n o l (0.27 pg/kg) were r e c o r d e d b e f o r e and t e n m i n u t e s f o l l o w i n g i n i t i a t i o n o f i n f u s i o n o f ASL-8052 (160.0 ~g/kg/min), propranolol (16.0 pg/kg/mlu) or saline. Limitation of Infarct Size. Dogs w e r e a n e s t h e t i z e d w i t h p e n t o b a r b i t a l (30 ms/k s , l.v.) and r e s p i r a t i o n was m a i n t a i n e d by means o f a c u f f e d e n d o t r a c h e a l t u b e and a H a r v a r d r e s p i r a t o r . Body t e m p e r a t u r e was m a i n t a i n e d a t 37 t o 3 9 ° C . Using sterile t e c h n i q u e s , a j u g u l a r v e i n and c a r o t i d a r t e r y w e r e c a n n u l a t e d for injection o f d r u g and f o r r e c o r d i n g mean a r t e r i a l pressure, respectively. The c h e s t was o p e n e d a t t h e l e f t f i f t h i n t e r c o s t a l s p a c e and t h e l e f t c i r c u m -
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f l e x c o r o n a r y a r t e r y (LCX) was i s o l a t e d a p p r o x i m a t e l y I 0 mm from i t s o r i g i n . LCX f l o w was m e a s u r e d e l e c t r o m a g n e t l c a l l y and a s c r e w c l a m p was u s e d t o p r o d u c e a crltlcal s t e n o s i s o f t h e LCX. C r l t i c a l s t e n o s l s was d e f i n e d a s one i n w h i c h little o r no r e d u c t i o n i n b a s a l LCX f l o w o c c u r r e d and m i n i m a l h y p e r e m i c r e s p o n s e o c c u r r e d a f t e r r e l e a s e o f a 1 0 - s e c o n d c o m p l e t e o c c l u s i o n o f t h e LCX. Once a c r i t l c a l s t e n o s l s was p r o d u c e d , an i n f u s i o n o f ASL-8052 ( 5 0 . 0 u g / k g / m l n ) o r s a l l n e was b e g u n . Twenty m i n u t e s a f t e r i n i t i a t i o n o f t h e i n f u s i o n , t h e LCX was c o m p l e t e l y o c c l u d e d . The c o m p l e t e o c c l u s i o n was m a i n t a i n e d f o r 60 m i n u t e s and t h e n r e l e a s e d so r e p e r f u s i o n c o u l d o c c u r t h r o u g h t h e c r i t i c a l s t e n o s i s . The c h e s t was c l o s e d and 4 h o u r s a f t e r i n i t i a t i o n o f r e p e r f u s i o n t h e i n f u s i o n was stopped. H e a r t r a t e and b l o o d p r e s s u r e w e r e m o n i t o r e d f o r an a d d i t i o n a l h o u r . Twenty-four hours after surgery dogs were re-anesthetlzed and t h e h e a r t s w e r e r e m o v e d . The LCX was e x a m i n e d a t t h e s i t e o f s t e n o s l s f o r t h e p r e s e n c e o f blood clots. The l e f t v e n t r l c l e (including the Interventricular aeptum) was sliced transversely i n t o s e c t i o n s 8 t o i 0 mm t h i c k and i n c u b a t e d f o r 15 m i n u t e s in a solutlon containing nitrobluetetrazollum w h i c h s t a i n s undamaged t i s s u e containing intracellular dehydrogenases dark blue. Infarcted tissue ( u n s t a i n e d ) was s e c t i o n e d f r o m n o r m a l ( s t a i n e d ) t i s s u e and t h e p e r c e n t o f l e f t ventricle infarcted was c a l c u l a t e d from the w e i g h t s of i n f a r c t e d and n o r m a l tissue.(13,14) Statistics Student's t-test (two-tailed) f o r u n p a i r e d data (and p a i r e d d a t a , where appropriate) was u s e d t o compare v a l u e s b e t w e e n g r o u p s . A p-value less than 0 . 0 5 was i n t e r p r e t e d as defining statistical significance. Drugs ASL-8052 ( m e t h y l 3 - [ 4 - [ 2 - h y d r o x y - 3 - ( i s o p r o p y l a m i n o ) p r o p o x y ] p h e n y l ] p r o p i o n a t e h y d r o c h l o r l d e ) was s y n t h e s i z e d a t A m e r i c a n C r i t i c a l Care. Racemic p r o p r a n olol hydrochlorlde and I s o p r o t e r e n o l h y d r o c h l o r l d e w e r e o b t a i n e d f r o m Sigma C h e m i c a l C o . , S t . L o u i s , MO. Results
In Vitro
Studies
ASL-8052 c a u s e d a p a r a l l e l shift of isoproterenol concentration-rate response curves in Isolated guinea pig right atria. The pA~ ( a n d 95~ c o n f i d e n c e interval) o f t h e compound was 7 . 0 1 ( 6 . 9 2 - 7 . 1 2 , N = 29);~ropranolol h a d a pA2 of 8.6 (8.48-8.73, N = 23). T h u s , ASL-80$2 was a b o u t 3 8 - f o l d l e s s p o t e n t t h a n propranolol. ASL-8052 was w i t h o u t i n t r i n s i c sympathomimetic activity; depression of ~eft atrial developed tension occurred only at concentrations greater t h a n 10-~M. Canine Studies Duration of Action. In sallne-infusion experiments, t h e h e a r t r a t e and blood pressure responses to isoproterenol given at 10-mlnute intervals were quantitatively reproducible for a five-hour period. The o n s e t o f b e t a - b l o c k a d e upon i n i t i a t i o n o f i n f u s i o n and t h e d e c a y o f b e t a - b l o c k a d e f o l l o w i n g t e r m i n a t i o n o f i n f u s i o n w e r e much f a s t e r w i t h ASL-8052 (N = 12) t h a n w i t h p r o p r a n o l o l (N = 5) ( F i g . I ) . S t e a d y - s t a t e b l o c k a d e w i t h ASL-8052 was a t t a i n e d i n 10-15 minutes, whereas, the degree of blockade observed with propranolol continued to increase for at least two h o u r s d u r i n g i n f u s i o n . Heart rate responses to Isoproterenol a t t h e end o f t h r e e h o u r s o f i n t r a v e n o u s i n f u s i o n o f p r o p r a n o l o l and ACC-8052 w e r e d e c r e a s e d by an a v e r a g e o f 66 ± 65 and 52 ± 4 ~ , r e s p e c t i v e l y . With ASL-8052 t h e t i m e r e q u i r e d f o r 80q. r e c o v e r y from b e t a - b l o c k a d e was 12 ± 3 m i n u t e s ; t w e n t y m i n u t e s a f t e r t e x ~ u l n a t l o n o f i n f u s i o n t h e r e was no d e t e c t a b l e
902
Ultra-short Acting Beta-blockers
|
Vol. 31, No. 9, 1982
BLOCKER
"1 ,o[
i
N-'5
N=12
MINUTQ
Fig.
1
Time c o u r s e o f b e t a b l o c k a d e d u r i n g and f o l l o w i n g c o n s t a n t i n f u s i o n o f ASL-8052 and p r o p r a n o l o l . Ordinate: percent inhibition ( ~ l ) o f h e a r t r a t e (HR) r e s p o n s e t o i s o p r o t e r e n o l . Abscissa: time after initiation of infusion of blockers. Inf u s i o n s t e r m i n a t e d a t 180 m i n u t e s . Means + SEM. blockade. In contrast, t h e r e was v e r y l i t t l e decay of beta-blockade following t e r m i n a t i o n o f p r o p r a n o l o l i n f u s i o n ; a t one h o u r p o s t - l n f u s l o n the heart rate r e s p o n s e t o i s o p r o t a r e n o l was s t i l l r e d u c e d b y 51 ± 4 ~ . P r o p r s n o l o l p r o d u c e d 63 ± 6~ i n h i b i t i o n of the diastolic blood pressure response to isoproterenol and, f o l l o w l n g t e r m i n a t i o n of infusion, decay of b e t a - b l o c k a d e was s l i g h t ( F i g . 2 ) . ASL-$052, h o w e v e r , p r o d u c e d o n l y a s m a l l , transient blockade of the Isoproterenol-induced decline in diastolic blood pressure (Fig. 2). Dose-resoonse Characteristics. ASL-8052 a t i n c r e a s i n g d o s e r a t e s s h i f t e d the heart rate dose response curve to Isoproterenol to the right (Fig. 3); blood pressure dose response curves to isoproterenol ( n o t shown) w e r e n o t altered. C~rdloselec~lylty. Figure 4 illustrates min) and p r o p r a n o l o l ( 0 . 1 6 m g / k g , c u m u l a t i v e ) of the heart rate response to isoproterenol.
t h a t b o t h ASL-8052 ( 1 6 0 . 0 p g / k g / produced nearly complete blockade Propranolol also nearly eltmin-
Vol. 31, No. 9, 1982
Ultra-short Acting Beta-blockers
903
BLOCKER INFUSION OFF
"t
I !
50-
40-
N=S
30: 204
ASL'8052
- PROPflANOLOL
10.
N=12
,;o MINUTES
Fig.
2
Time c o u r s e o f b e t a b l o c k a d e d u r i n g and f o l l o w i n g c o n s t a n t i n f u s i o n o f ASL-8052 and p r o p r a n o l o l . Ordinate: percent inhibition (~I) of dlastolic b l o o d p r e s s u r e (BP) r e s p o n s e to Isoproterenol. Abscissa: time after initiation of infusion of blockers. ~ n f u s i o n s t e r m i n a t e d a t 180 m i n u t e s . Means + SEM. ated the perfusion pressure response to isoproterenol. produced only slight blockade of this response.
In
contrast,
ASL-8052
Limitation of Infarct S~e. One dog ( s a l l n e - t r e a t e d ) fibrillated during t h e 6 0 - m l u u t e LCX o c c l u s i o n and was e x c l u d e d f r o m a n a l y s i s . None o f t h e d o g s had v i s i b l e c l o t f o r m a t i o n in the area of the s t e n o s i s a t a u t o p s y . Left ventricular w e i g h t , LCX f l o w and h y p e r e m l c r e s p o n s e w e r e s i m i l a r i n t h e two g r o u p s o f d o g s p r i o r t o and a f t e r p r o d u c t i o n o f t h e c r i t i c a l stenosls S t e n o s i s r e s u l t e d i n a s i m i l a r marked a t t e n u a t i o n of the hyparemlc response to I 0 s a c LCX o c c l u s l o n b u t had no e f f e c t on b a s a l LCX f l o w i n t h e two g r o u p s . Infarct s i z e was s i g n l f l c a n t l y l e s s i n ASL-80 2 - t r e a t e d dogs (7.5 ± 2.4~ of left ventricle) than in sallne-trcstcd dogs (24.0 ± 4.$~ of left ventrlcle) (Fig, 5). H e a r t r a t e and mean a r t e r i a l t h e two g r o u p s a t any t i m e .
pressure
were not
significantly
different
in
904
Ultra-short Acting Beta-blockers
AHR
-
Vol. 31, No. 9, 1982
: CONTROL
bpm
A S L - 8 0 5 2 , 2 5 . 0 u g kg rnin A S L - 8 0 5 2 , 5 0 . O o g kg rain
70.
60. 50.
40-
30-
20-
10-
i
s
e
ODllli
0.031
(1063
!
s
0.125 0.25 ISOPROTERENOL ug/kg, IV
Fig.
e
0.5 0
!
s
1.00
2.00
3
Modification of Isoproterenol-lndu©ed i n c r e a s e s i n HR b y i n c r e a s i n g i n f u s i o n r a t e s o f ASL-8052. O r d i n a t e : i n c r e a s e i n HR (AHR, BPM). A b s c i s s a : i s o p r o t e r e n o l dose (pg/kg, i.v.). Means + SEM. Discussion Beta-adrenergic blockade is of proven value in the treatment of classical angina pectoris and ventricular and s u p r a v e n t r t c u l a r dyarhythmias, particularly when t h e s e a r e o f a d r e n e r g i c origin (1,2,3,4). More r e c e n t w e l l - c o n t r o l l e d studies have also demonstrated the ability of long-tex~ beta-blockade to reduce mortality and the incidence of reinfarction in patients s u r v i v i n g a c u t e myocardial infarction.(15,16) The v a l u e o f b e t a - b l o c k a d e in the treatment of angina pectoris and in reducing mortality and reinfarotion is presumably attributable, in large part, to improvement of myocardial o x y g e n s u p p l y t o demand r a t i o . The p o t e n t i a l ability of beta-blockade to limit infarct size following an acute ischemic i n s u l t was, t h e r e f o r e , a logical extension.(17,18) While results obtained in early clinical studies have been conflicting (5,6,19,20), more r e c e n t s t u d i e s have indicated that administration of beta-blockers early in the course of acute myocardial infarction produced salutory h e m o d y n a m i c and e l e c t r o c a r d i o graphic effects and enzymatic changes indicative of a decrease in extent of infarction.(21,22,23,24)
Vol. 31, No. 9, 1982
Ultra-short Acting Beta-blockers
IHEART NCREASE IN RATE bpm
905
RESPONSES TOISOPROTERENOL
• - PIlE - DRUG 10
• - POST - DRUG
DECREASE PERFUSIOIN PRESSURE NHINDLIMB "3~
il
/
mmHg
N:7 ASL'8052
N:6 N:~ PflOPRANOLOL SALINE
FiS. 4 Modification of isoproterenol (0.27 pg/kg, i.v.) induced increase i n HR and d e c r e a s e i n PP i n i s o l a t e d , perfused canine hindlimb p r e p a r a t i o n by ASL-8052 ( 1 6 0 . 0 p g / k g / m t n ) , p r o p r a n o l o l ( 0 . 1 6 m$/kg, c u m u l a t i v e ) and s a l i n e ( 0 . 0 5 m l / k g / m i n ) . Split ordinate: upper i n c r e a s e i n HR (AHR, BPM); l o w e r - d e c r e a s e i n h i n d l i m b p e r f u s i o n p r e s s u r e (APP, n H g ) . Means ± SEM.
Available beta-blockers are relatively l o n g - a c t i n g and a r e c h a r a c t e r i z e d by erratic oral bioavailabiltty (8) w h i c h n e c e s s i t a t e s intravenous administration if therapeutic plasma concentrations n e e d t o be e s t a b l i s h e d rapidly. In order to safeguard against the possible induction of acute failure, however, i n t r a v e n o u s t h e r a p y must b e g i n a t v e r y low d o s e s w h i c h a r e g r a d u a l l y i n c r e a s e d until a given therapeutic effect is obtained or until side-effects occur.(3) R e c o v e r y from f a i l u r e i s slow and t h e u s e o f i n o t r o p i c a g e n t s may be r e q u i r e d (6,9). Additionally, t h e l o n g d u r a t i o n o f b e t a - b l o c k a d e makes i t i m p o s s i b l e t o match pharmacological input to changing autonomic conditions. Thus, the persistent activity o f a v a i l a b l e b e t a - b l o c k i n g a g e n t s c a n be c o u n t e r - p r o d u c t i v e and may g r e a t l y c o m p l i c a t e t h e t h e r a p e u t i c decisions required during critical care of cardiac patients. The c o n c e p t o f u l t r a - s h o r t acting beta-blockers stems from t h e need t o rapidly alter the level of blockade to enhance therapeutic effects or to minimize side-effects. Our a p p r o a c h t o t h e d e v e l o p m e n t o f ASL-8052 a s a s h o r t acting agent consisted of incorporation of enzymatic lability into the beta-
906
Ultra-short Acting Beta-blockers
Vol. 31, No. 9, 1982
35' .I
o_30I'Z W
> 25" I-. U. UJ -i
|
~' w
15"
i-
O10" ~r
E
5"
ASL-8052
SALINE
Fig.
5
Reduction of infarct s i z e d e t e r m i n e d 24 h o u r s a f t e r one h o u r comp l e t e LCX o c c l u s i o n f o l l o w e d b y ~ e p e r f u s i o n i n t o c r i t i c a l stenosis b y ASL-8052. O r d i n a t e : % o f LV i n f a r c t e d . Left, saline-treated animals; Right, ASL-8052-treated animals. Means ± SEM. blocker pharmacophore such that rapid inactivation of the drug would occur via drug metabolism. R e s u l t s o f t h i s s t u d y show t h a t ASL-8052 h a s a d u r a t i o n o f action of less t h a n 15 m i n u t e s . This drug produces cardioselectivc betab l o c k a d e and l a c k s s y m p a t h o m i m e t i c a n d s i g n i f i c a n t direct depressant activity. The p r e s e n t s t u d y a l s o d e m o n s t r a t e s t h a t ASL-8052 p o s s e s s e s e f f i c a c y i n t h e acute myocardial infarction setting. Since it has been previously reported that single doses of long-acting bet_._.!-blockers ( p r o p r a n o l o l , nadolol and 8tenolol) also limit infarct size in this model (13,14), it is reasonable to assume that the mechanism of the beneficial action o f ASL-8052 i s b e t a blockade. The o b s e r v a t i o n t h a t ASL-80$2 h a d no e f f e c t on h e a r t r a t e o r b l o o d pressure in this study is in agreement with previous studies concerned with the a c t i o n s o f bet_._..Aa-adrenergic b l o c k e r s i n t h i s m o d e l . ( 1 3 , 1 4 ) The u l t r a - s h o r t activity o f ASL-8052 s h o u l d i n c r e a s e t h e c o n v e n i e n c e and safety of inducing beta-blockade in hospitalized patients with ischemic heart disease where the level of sympathetic activity a t t h e m y o c a r d l u m i s unknown and rapid modification of pharmacological effect may b e n e e d e d t o m a t c h changing autonomic conditions. Acknow,lcdsements Excellent technical assistance b y L, C. P r c u s s c r , A. L e v a n h o , W. B u r m c l s t e r a n d D. ~ . E l l i s i s g r e a t l y a p p r e c i a t e d . We t h a n k M~s. C. M a l e r f o r t y p i n g and processing this manuscript.
Vol. 31, No. 9, 1982
Ultra-short Acting Beta-blockers
907
References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
D.B. MCDEVITT, Drugs 17, 267-288 ( 1 9 7 9) . W. FRISHMAN, R. SILVERMAN, Am. Heart I . 98, 119-131 ( 1 9 7 9 ) . R. ALRQUIST, Am. B e a r t J . 93, 117-120 ( 1 9 7 7 ) . L. SZEKERES, P r o c e e d i n g s of t h e V I I I World Congress of C ~ r d i o l o g y , p 933, N o r t h - H o l l a n d , Amsterdam ( 1 9 7 8 ) . R . J . LEE, L i f e S c i . 23, 2539-2542 ( 1 9 7 8 ) . ~.D. FITZGERALD, P o s t g r a d . Med. 3. 52, 770-781 ( 1 9 7 6 ) . J . D . FITZGERALD, C l i n . Pharm. Therap. 10, 292-306 ( 1 9 6 9 ) . A.S. NIES and D.G. SBAND, C i r c u l a t i o n 52, 6-15 ( 1 9 7 5 ) . F. HAGE~IJER, B e t a - a d r e n o c e p t o r B l o c k i n g Agents, P.R. Saxena and R.P. F o r s y t h , e d i t o r s , p. 273, N o r t h - H o l l a n d , Amsterdam ( 1 9 7 6 ) . W. FRISBMAN, R. SILVERI~N, J . STROM, O. ELKAYAM and E. SONNENBLICK, Am. R e a r t ~ . , 98, 256-262 ( 1 9 7 9 ) . R.F. FURCHGOIT, Ann. N.Y. Aesd. S o l . , 139, 553-570 ( 1 9 6 7 ) . R.D. REYNOLDS and R . J . GORCZYNSKI, 7. Pharmaeol. Exp. T h e r p . , 212, 579-583 (1 9 8 0 ) . W.E. BURMEISTER, R.D. REYNOLDS and R . J . LEE, Eur. J . P h e r m a e o l . 75, 7-10 (1981). R.D. REYNOLDS, W.E. BURMEISTER, R.J. GORCZYNSKI, D.D. DICKERSON, M.P. MAT~EWS and R.J. LEE, Cardiovas. Res. 15, 411-420 (1981). THE NORWF~IAN MULTICENTER STUDY GROUP, N. E n g l . J . Med., 304, 801-813 (1981). g.G. GREEN, D.A. CBA~ERLAIN, R.M. FULTON, N.A. RAMER, M.F. OLIVER, B.L. PENTOCOST, ~.A. LEWIS and R. TUSON, B r i t . Med. J . 2, 419-421 ( 1 9 7 7 ) . J.W. BLACK, Drug Responses i n Man, p. 121, L i t t l e , Brown and Company, London (1 9 6 7 ) . S. EPSTEIN, R. GOLDSTEIN, D.R. REDWOOD, K.~. KENT and E.R. S M I ~ , Ann. I n t e r n a l Med. 78, 918-936 ( 1 9 7 3 ) . W.H. FRISHMAN, Am. R e a r t 7. 99, 528-536, ( 1 9 8 0 ) . R.M. NORRIS, Am. B e a r t 7. 99, 683-685, ( 1 9 8 0 ) . L . 3 . PELIDES, D.S. REID, M. THOMAS and S . F . SRILLINGFORD, C a r d i o v a s . R e s . , 6, 295-301 ( 1 9 7 2 ) . R.K. GOLD, R.C. LEINBACH, and F.R. MAROKO, Am. 7. Card. 38, 689-695 ( 1 9 7 6 ) . J . S . CAIRNS and G. KLASSEN, C i r c u l a t i o n , 52 (Suppl 2 ) , 107 ( 1 9 7 5 ) . B. PITT, J . L . WEISS, R.A. SCRULZE, D.R. TAYLOR, R.L. KENNEDY IlL, and D. CARALIS, C i r c u l a t i o n , 54 (Suppl 2 ) , 29 ( 1 9 7 6 ) .