H. Schaeffer, A. Friedman. Department of Pediatrics, Interfaith. Medical Center and Downstate Medical Center, Brooklyn, New York. The effectiveness of bovine ...
DEVELOPMENTAL PHARMACOLOGY PREVENTION
OF BRONCHOPULMONARY DYSPLASIA
(BPD) BY
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ADMINISTRATION OF BOVINE SUPEROXIDE DISMUTASE (SOD) W. m e n f e l d , . Evans, Concepcion, R. J h a v e r i , H . S c h a e f f e r , A . Friedman. Department of P e d i a t r i c s , I n t e r f a i t h Medical Center and Downstate Medical Center, Brooklyn, New York. The e f f e c t i v e n e s s of bovine SOD i n t h e prevention of BPD was evaluated i n a p r o s p e c t i v e double b l i n d c o n t r o l l e d study of 45 neonates (5 GA 28.7wks; ii b.wt. 1154gms) with severe IRDS. A l l were v e n t i l a t o r dependent with F i 0 2 2 0 . 7 a t 24 hours of age. E i t h e r bovine SOD (0.25mg/kg) o r placebo ( s a l i n e ) was administere d SC q12h according t o random s e l e c t i o n u n t i l p a t i e n t s could be maintained i n room a i r without v e n t i l a t o r y o r CPAP support. Twenty-one p a t i e n t s (15GA 28.8wks; 1b.wt. 1156gms) received SOD and 24 (1GA 28.5wks; i b.wt. 1153gms) received placebo. 14/21 SOD and 17/24 placebo p a t i e n t s survived (p=NS). SOD l e v e l s were d e t e c t e d i n a l l t r e a t e d c a s e s . Mean peak values a t 4 h r s . 6 dose ranged from O.lSugm/ml (dose # l ) t o 0,45ugm/ml (dose # l o ) . Among s u r v i v o r s evidence of BPD on xray (hyperaeration and/or a t e l e c t a s i s ) was s i g n i f i c a n t l y l e s s i n SOD p a t i e n t s (3/14 vs 12/17; p < 0 . 0 2 ) . C l i n i c a l s i g n s of BPD (wheezing, pneumonia) were l e s s i n SOD p a t i e n t s (3/14 vs 12/17; p L 0 . 0 2 ) . SOD p a t i e n t s r e q u i r e d fewer days of CPAP ( p C 0 . 0 3 ) . There were no d i f f e r e n c e s i n days of 02, IPPB, incidence and s e v e r i t y of PDA and I V H . SOD a d m i n i s t r a t i o n was s a f e and well t o l e r a t e d . SOD reduced t h e s e v e r i t y of BPD using c l i n i c a l and r a d i o l o g i c c r i t e r i a . This extends our e a r l i e r observations (SPR 407A, 1983) and s u g g e s t s t h e need t o i n v e s t i g a t e v a r i a t i o n i n dosage sched u l e , and combined t r e a t m e n t with o t h e r a n t i o x i d a n t a g e n t s .
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EFFECT OF BENZYL ALCOHOL (BA) ON RAT PLASMA LACTATE
PLASMA BETA ENDORPHIN CONCENTRATION IN INFANTS WITH APNEIC SPELLS. Koravangattu Sankaran, K . Wayne Hindmarsh and V a l e r i e G . Watson, P e r i n a t a l Research Laboratory, Department of P e d i a t r i c s and College of Pharmacy, University of Saskatchewan, Saskatoon. I n an attempt t o determine whether plasma b e t a endorphin (6-ED) c o n c e n t r a t i o n s c o r r e l a t e with occurrence of apnea i n preterm i n f a n t s , measurements were made i n t h r e e groups of i n f a n t s . Group 1 c o n s i s t e d of 11 c o n t r o l i n f a n t s with a mean g e s t a t i o n a l age of 30.5 2 0.8 weeks, a mean birthweight of 1650 180 g , and a mean p o s t n a t a l age of 1 . 3 + 0.5 days. Group 2 c o n s i s t e d of 8 i n f a n t s with a mean g e s t a t i o n a l age, birthweight and p o s t n a t a l age of 90 g and 7 . 8 + 1 . 9 days, r e s p e c t i v e l y . 0 . 9 weeks, 1165 30 Group 3 consisted of 8 i n f a n t s with a mean g e s t a t i o n a l a g e , b i r t h 0.8 weeks, 1380 125 g and weight and p o s t n a t a l age of 31 2.6 i 0.9 days, r e s p e c t i v e l y . Group 2 and Group 3 i n f a n t s s u f f e r e d varying degrees of apnea. Group 2 i n f a n t s s u f f e r e d c l i n i c a l l y severe apneic s p e l l s with bradycardia and hypotension whereas Group 3 d i d n o t . 6-ED was measured by a methodpreviously published (Hindmarsh) involving Sephadex G-50 column chromatography and subsequent radioimmunoassay. The plasma endorphin c o n c e n t r a t i o n s were 26.9 + 2 , 68.0 + 9 . 0 and 39.6 5 2.0 pg/ml i n Groups 1 , 2 and 3 , r e s p e c t i v e l y . S i g n i f i c a n t e l e v a t i o n i n 5-ED c o n c e n t r a t i o n was observed i n Group 2 when compared t o c o n t r o l (Group 1) and Group 3. Elevation of plasma 6-ED i s observed i n i n f a n t s with s e v e r e apneic s p e l l s . The a s s o c i a t i o n of increased plasma 8-ED r e l e a s e with severe apneic s p e l l s may suggest t h a t t h e s e endogenous opioids play a r o l e i n the pathophysiology of apnea of prematurity.
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DEVELOPMfDTI OF HEPATIC N-DEMFPHYLPSE ACPIVI'IY ?4S
~ U R IN D v n r ~BY THE AMINOPYRINF. BRFATH TEST. Robert J. Shulman, Charles S. I r v i n g , T h m s W. Boutton, William W. Wong, Buford L. Nichols, and P e t e r D. Klein.
Departments of P e d i a t r i c s and Patholoav. Lubbock. Texas. ' There a r e i n c r e a s i n g numbers o f c l 6 i c a l r e p o r t s on the t o x i c i t y of BA. This deserves more a t t e n t i o n s i n c e BA i s a preservat i v e agent being used i n various i n j e c t a b l e drugs in the neonatal u n i t . One experimental approach may r e s i d e i n studying t h e e f f e c t o f BA on c e r t a i n plasma enzymes known f o r t h e i r r a p i d changes during development and growth, which may be a l s o implicated i n some of BA t o x i c i t y on t h e h e a r t , i . e . , LOH. This study u t i l i z e d r a t blood plasma a s t h e source f o r LOH and evaluated t h e i n v i t r o e f f e c t of BA on t h e a c t i v i t y o f i t s "H" and "Mu i s o e n z y m e ? i n young (30 t o 45 days o l d ) and i n a d u l t male r a t s (90 t o 110 days o l d ) . Enzymatic a c t i v i t y was determined spectrophotometrical l y and expressed a s s p e c i f i c a c t i v i t y measured a t 300C. The young r a t s showed 1.67 and 4 . 5 u n i t s o f plasma H and M LDH isoenzyme, r e s p e c t i v e l y . The presence of 90 mMol o f BA i n t h e r e a c t i o n mixt u r e r e s u l t e d i n 48% i n h i b i t i o n o f t h e "H" isoenzyme compared t o 14% o f t h e "Mu s u b u n i t . The LDH a c t i v i t y assayed i n plasma of a d u l t r a t s was 0.8 u n i t s f o r t h e "H" isoenzyme and 2.9 u n i t s f o r t h e "M" LDH isoenzyme. There was a 51% i n h i b i t i o n of t h e former and a 19% i n h i b i t i o n of t h e l a t t e r LDH subunits by equimolar conc e n t r a t i o n of BA, i . e . , 90 mMol. The r e s u l t s i n d i c a t e t h a t t h e "H" isoenzyme, which predominates i n t h e h e a r t , i s more s e n s i t i v e towards t h e BA-effect noted than t h e "M" isoenzyme of LOH. This implies t h a t measurement of "H" LDH may be useful in monitoring some o f t h e c a r d i a c t o x i c i t y of BA.
Baylor College o f Medicine, Texas C h i l d r e n ' s H o s p i t a l , USDn/ARS C h i l d r e n ' s N u t r i t i o n Research Center, Department o f P e d i a t r i c s , Houston, TX. The aminopyrine (AP) b r e a t h test (KT) has keen used i n a d u l t s as a measure of h e p a t i c N-demethylase a c t i v i t y . I n o r d e r to study m a t u r a t i o n a l changes i n enzyme f u n c t i o n , 13c AP ( 2 mg/kg) was administered o r a l l y to i n f a n t s (n=13) between the ages of 1 and 38 &. Breath samples f o r m z i s u r m n t of 3 ~ enrichment ~ 2 were c o l l e c t e d f o r s i x hours a f t e r a a n i s t r a t i o n . Nine o f 10 t e r n i n f a n t s < 6 wk o f age shcwed no d e t e c t a b l e o x i d a t i o n (peak 13c0? o u t p u t < 0.05% dose/min). Three of 3 i n f a n t s o v e r 14 wk of age showed o x i d a t i o n (0.221, 0.196, and 0.261% dose/min a t 15, 18, and 38 wk, r e s p e c t i v e l y ) . Absorption was excluded a s a l i m i t i n g v a r i a b l e s i n c e no i q x o v e m e n t i n o x i d a t i o n r a t e s was found when t h e AP was administered a g a i n a s a n IV bolus i n 9 of t h e o r i @ n a l 2 a limiting 10 i n f a n t s < 6 wk. Elimination of l a b e l e d ' 3 ~ as v a r i a b l e was excluded s i n c e t h e 9 i n f a n t s d i s p l a y e d normal b i a r bnate k i n e t i c s measured by a 6-h 13c b i c a r b o n a t e BT u s i n g a n IV dose of 50 p m l / k g . Conclusions: 1 ) Maturational d i f f e r e n c e s a r e s e e n i n the metabolism of AP; 2) These d i f f e r e n c e s may r e f l e c t i m m t u r i t y o f N-demethylase a c t i v i t y o r d i v e r s i o n o f t h e l i b e r a t e d formaldehyde i n t o b i o s y n t h e t i c r a t h e r than o x i d a t i v e pathways.
EFFECT OF BENZYL ALCOHOL ON SUBCELLULAR LACTATE DEHYOROGENASE IN THE MALE RAT. Philippe Samson, Edwin A. Contreras, Robert M. Bidwell, and Fathy S. m s i h a , ( S p d y y S u r e n d r a K. V TT -ehVniversityH e a l t h s c i e n c e s Center, Departments o f P e d i a t r i c s and Pathology, Lubbock, Texas. Benzyl alcohol (BA) can evoke c a r d i a c t o x i c i t y on t h e premature newborn when given in conjunction with various i n j e c t a b l e medications and/or I.V. f l u s h s o l u t i o n s . L i t t l e i s known on t h e underlying mechanism involved. This study e v a l u a t e s t h e i n v i t r o e f f e c t of BA on r a t h e a r t l a c t a t e dehydrogenase (LDV i s o =s in d i s t i n c t subcellular fractions as a possible reflect i o n of such t o x i c i t y . Both h e a r t H and M s u b u n i t s were measura b l e i n t h e nuclear (NC), mitochondria1 (MT) and cytoplasmic (CT) f r a c t i o n s of j u v e n i l e and a d u l t r a t s . Presence o f 90 mM BA exe r t e d i n h i b i t o r y a c t i o n on M T LDH which was age-dependent, i . e . , 67% and 59% i n h i b i t i o n of t h e H subunits occurred i n t h e young and o l d r a t s , r e s p e c t i v e l y . The'MT M isoenzyme was not i n h i b i t e d by 90 mMol BA in t h e young but a 29% i n h i b i t i o n occurred in t h e o l d animals. Changes determined i n t h e H s u b u n i t of NC-LDH were l e s s profound than those of t h e MT isoenzyme using t h e same conc e n t r a t i o n o f BA. The l a t t e r concentration exerted only minimal a c t i o n on t h e H s u b u n i t of t h e CT f r a c t i o n of o l d but not of young r a t s . The r e s u l t s demonstrate BA t o x i c i t y on h e a r t LDH in general and on i t s H subunit i n p a r t i c u l a r . Also, a d i f f e r e n t i a l s u b c e l l u l a r LDH s e n s i t i v i t y t o BA t o x i c i t y was noted. The data suggest t h a t BA adverse c a r d i a c r e a c t i o n may be a s s o c i a t e d with a1 t e r e d LOH a c t i v i t y .
PHENYL-ISOPROPYL ADENOSINE (PIA) CAUSES ALTERATION I N FETAL ELECTROCORTICOGRAM (ECOG) PATTERNS AND CESSATION OF FETAL BREATHING MOVEVENTS (FBM) IN THE FETAL SHEEP. Kim G. Smith, Paul L. Toubas, Roger E. Sheldon, Thomas W. Seale. (@=by OW R G e r i ) FM. Dept. of Pediatrics, Univ. of Okla. Health Sci. Ctr., Okla. City. In studying the control of ECoG and FBM, we equipped 4 fetal lambs with intratracheal, amniotic, vascular catheters and ECoG electrodes. 2 of these were equipped with EKG electrodes. After 48 hours recovery, a t 0.9 gestation, continuous recordings of tracheal and amniotic pressures, ECoG and EKG were begun. During 1000 minute control periods, low voltage high frequency (LVHF) ECoG predominated 61.5% of the total time. FBM occurred 35.6% of the total time and only during the LVHF ECoG. PIA, a known agonist for both A1 and A2 receptors, 0.125mg (0.050mg/kg estimated fetal weight) was given intravenously to each fetus during established LVHF ECoG and FBM. LVHF ECoG converted in 45 GO seconds (mean rS.E.N.) t o high voltage low frequency (HVLF) ECoG which persisted for 12 t 2 minutes. These were followed by an intermediate ECoG pattern, neither LVHF or HVLF, that persisted for 125 +15 minutes. FBM ceased within 2 r 1 minutes and did not recur over the subsequent 143 +22 minutes. A rebound increase in FBM (51.0% of the total time) occurred over the subsequent 500 minutes (control 35.6%) without a significant increase in the LVHF ECoG. No significant changes in blood gases were observed. By inspection, EYG tracings in 2 fetal sheep showed a several second decrease in fetal heart r a t e (175 t 7 BPM t o 95 i 7 BPM) and a several minute loss of beat-to-beat variability. Similar subtle changes have been seen with doses between 0.001 and O.Olmg/kg. We conclude that fetal ECoG, FRM, HR and beat-to-beat variability are influenced by adenosine and its receptors.
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