ANNUAL REV IEW OF CHRONOPHARMACOLOGY

Volume 5

B I O L O G I C A L RHYTHMS AND M E D I C A T I O N S Proceedings of the Third Conference of Chronopharmacology, Nice, 14-17 March 1988

E d i t o r s :

A. R E I N B E R G Fondation A. de Rothschild, Paris, France

M. S M O L E N S K Y University of Texas, Houston, U.S.A.

G. L A B R E C Q U E Universite de Laval, Quebec, Canada

PERGAMON PRESS OXFORD • NEW YORK · BEIJING • FRANKFURT SAO PAULO · SYDNEY · TOKYO · TORONTO

CONTENTS

Section 1 — Laboratory and Clinical Immunology and Inflammation

C o - c h a i r m e n : J.-P. B U R E A U (N imes , France ) Ε. H A E N ( M u n i c h , W . G e r m a n y ) F. L E V I (Paris, F rance )

C i r c a n n u a l m o d u l a t i o n o f t h e c i r c a d i a n r h y t h m o f p o l y m o r p h o n u c l e a r ce l ls

J.-P. B U R E A U , G. L A B R E C Q U E , a n d M . COUPE

I n c r e a s e d e v e n i n g e x p o s u r e t o c y c l o spo r ine a n d m e t a b o l i t e s D. M . C A N A F A X , R. J . C IPOLLE , W . J . M . HRUSHESKY, J . T. R A B A T I N , D. I . M I N , Ν. Μ. GRAVES, D. Ε. R. S U T H E R L A N D a n d L. D. BOWERS

E v a l u a t i o n o f v a r i o u s fac to rs i n f l u e n c i n g t h e a c t i o n o f m o u s e α, β i n t e r f e r o n o n t h e c h e m i l u m i n e s c e n c e of m o u s e p e r i t o n e a l m a c r o p h a g e s

V. CARRIERE, P. D O R F M A N a n d M . B A S T I D E

T w o - d o s e c h r o n o p h a r m a c o k i n e t i c o p t i m i z a t i o n of c y c l o spo r ine i n panc r eas t r a n s p l a n t p a t i e n t s

R. J . C IPOLLE , D. M . C A N A F A X , J . T. R A B A T I N , L. D. BOWERS, D. E. R. S U T H E R L A N D a n d W . J . M . HRUSHESKY

C h r o n o b i o l o g i c a l aspec ts o f s p o n d y l a r t h r i t i s C. F O C A N , M . A L V I N , V. M A Z Y , D. F O C A N - H E N R A R D , F. L E V I a n d P. F R A N C H I M O N T

A l t e r a t i o n o f c i r c a d i a n t i m e s t r u c t u r e of p l a s m a p r o t e i n s i n p a t i e n t s w i t h i n f l a m m a t i o n

C. F O C A N , B. B R U G U E R O L L E , C, A R N A U D , F. L E V I , V. M A Z Y , D. F O C A N - H E N R A R D a n d G. B O U V E N O T

xi

xii Contents

C i r cad i an - s t age - spec i f i ed e f fects of m e l a t o n i n o n h u m a n n a t u r a l k i l l e r (NK) c e l l a c t i v i t y : In vitro a n d in vivo s tud i e s 25

G. G A T T I , R. C A R I G N O L A , R. M A S E R A , M . LUIS A SARTORI , A . S A L V A D O R I , E. M A G R O a n d A . A N G E L I

C i r c a d i a n - s h a p e d i n t r a r e n a l c y c l o spo r ine d e l i v e r y 29 S. A . GRUBER, R. J . C IPOLLE , D. M . C A N A F A X , J . T . R A B A T I N , G. R. E R D M A N N , P. E. HYNES , J . A . R ITZ, F. Η. G O U L D a n d W . J . M . HRUSHESKY

I n f l u e n c e o f c i r c a d i a n changes i n t r i g l y c e r i d e c o n c e n t r a t i o n s o n t h e p h a r m a c o k i n e t i c s a n d e x p e r i m e n t a l t o x i c i t y of c y c l o spo r ine 31

D. R. L U K E , K. V A D I E I a n d L. J . B R U N N E R

C i r c a d i a n dos ing - s t a g e d e p e n d e n c e i n m e t a b o l i c ef fects o f C ic lospor ine i n t h e r a t 35

M.-F. M A L M A R Y , Κ. K A B B A J a n d J . O U S T R I N

Pa in t i m e pro f i l e u n d e r t r e a t m e n t w i t h I b u p r o f e n i n p a t i e n t s s u f f e r i n g f r o m o s t e o a r t h r i t i s ( m u l t i c e n t e r s t u d y ) 39

J . M O E R C H E L

C h r o n o p h a r m a c o l o g i c o p t i m i z a t i o n o f o r a l C ic lospor in A (C IA ) i n m i c e : A s ea r ch for a c o m p r o m i s e b e t w e e n l eas t r e n a l t o x i c i t y a n d h i g h e s t i m m u n o s u p p r e s s i v e e f fects 43

A . P A T I , I . F L O R E N T I N , G. L E M A I G R E , M . M E C H K O U R I a n d F. L E V I

C i r c a d i a n v a r i a t i o n s o f t h e e f f i c i ency o f h e p a t i t i s Β v a c c i n a t i o n 45

L. P Ö L L M A N N a n d B. P Ö L L M A N N

Seasona l v a r i a t i o n s o f h o s t r e s i s t ance a n d in vitro a n t i b o d y f o r m a t i o n o f s p l e e n ce l ls f r o m t h e B 6 C 3 F 1 m o u s e 49

H . R A T A J C Z A K , P. T H O M A S , T . V O L L M U T H , D. HECK, R. S O T H E R N a n d W . HRUSHESKY

Section 2A — Neurobiology and Endocrinology

C o - c h a i r m e n : G. D A R C O U R T (Nice, France ) R. RE ITER (San A n t o n i o , Texas ) W . R I E T V E L D (Le iden , N e t h e r l a n d s ) Y. T O U I T O U (Paris, France )

F u r t h e r e v a l u a t i o n o f t h e t r e a t m e n t of j e t - l a g b y m e l a t o n i n : A d o u b l e - b l i n d c rossover s t u d y 53

J . A R E N D T a n d M . A L D H O U S

Contents

The p h a s e r e l a t i o n o f c o r t i c o s t e r one a n d p r o l a c t i n in j e c t i ons as a f a c t o r i n t h e i n h i b i t i o n of h i b e r n a t i o n i n t h e t h i r t e e n - l i n e d g r o u n d s q u i r r e l , Citellus tridecemlineatus

J . T . BURNS a n d A . H . M E I E R

C i r c a d i a n a n d c i r c a n n u a l v a r i a t i o n s o f p l a s m a c a l c i t o n i n l e v e l i n t h e r a t : I n f l u e n c e o f sex

F. DUCHÄTEL , M.-F . M A L M A R Y a n d J . OUSTRIN

T h e c i r c a d i a n p a t t e r n o f p l a s m a m e l a t o n i n i n ano r ex i a ne r vosa : I t s p o s s i b l e r e l a t i o n s h i p s w i t h t h e p i t u i t a r y — g o n a d a l i m p a i r m e n t

E. F E R R A R I , P. A . BOSSOLO, S. FOPPA, S. COMIS , P. Μ A G N I , F. F R A S C H I N I a n d F. B R A M B I L L A

T h e c i r c a d i a n r h y t h m of p r o o p i o m e l a n o c o r t i n - r e l a t e d p e p t i d e s i n a g i n g

E. F E R R A R I , P. A . BOSSOLO, S. FOPPA, M . F I O R A V A N T I , M . D A L Z A N O , A . C O S T A B A R B E a n d F. F A C C H I N E T T I

R e g u l a t i o n o f t h e t y p e I I t h y r o x i n e - 5 ' - d e i o d m a s e c i r c a d i a n r h y t h m i n t h e r a t f r o n t a l c e r eb ra l c o r t e x

J . M . GUERRERO, C. S A N T A N A , M . P U I G - D O M I N G O , A . G O N Z A L E Z - B R I T O a n d R. J . REITER

C i r c a d i a n r h y t h m p a r a m e t e r s of c l i n i ca l a n d endoc r in e f u n c t i o n s i n e l d e r l y sub j e c t s u n d e r t r e a t m e n t w i t h v a r i o u s c o m m o n l y u s e d d r u g s

E. H A U S , G. Y. N I C O L A U , D. J . L A K A T U A , C. B O G D A N , Μ. POPESCU, L. S A C K E T T - L U N D E E N , A . F R A B O N I a n d E. PETRESCU

C i r c a d i a n a n d u l t r a d i a n cha rac t e r i s t i c s of p l a s m a g r o w t h h o r m o n e i n c h i l d r e n o f s h o r t s t a t u r e

R. C. H E R M I D A , L. G A R C I A , C. LODEIRO a n d T. IGLES IAS

B i o r h y t h m i c i t y a n d E E G p a r o x y s m a l a b n o r m a l i t i e s i n v a r i ous f o rms o f e p i l e p t i c se i zures

M . F. M O N G E - S T R A U S S a n d F. M I K O L

T h e ro le of t h e l a t e r a l g e n i c u l a t e n u c l e i i n phas ic r e sponse t o p h o t i c a n d p h a r m a c o l o g i c s t i m u l i

L. P. M O R I N , R. F. J O H N S O N , L. S M A L E , K. M I C H E L S a n d R. Y. M O O R E

T e s t o s t e r o n e r e p l a c e m e n t w i t h a c i r cad i an p a t t e r m V . A . P L A C E

C i r c a d i a n r h y t h m of t y p e I I thyroxine-5 ' -deiodinas5e a c t i v i t y i n t h e p i n e a l g l a n d : C o n t r o l l i n g fac tors

R. J . REITER, J . M . GUERRERO, C. S A N T A N A a n d M . P U I G - D O M I N G O

xiv Contents

T h e r o l e o f t h e h y p o t h a l a m i c s u p r a c h i a s m a t i c n u c l e u s i n m e t h a m p h e t a m i n e i n d u c e d r h y t h m s i n b e h a v i o r 99

W . J . R I E T V E L D , J . RUIS a n d P. BUIJS

S i m u l t a n e o u s s t u d y o f L H , Cort iso l , T S H a n d m e l a t o n i n i n n o r m a l s u b j e c t s 103

P. S C H U L Z , J . R E N A R D , J . W I D M E R , R. RIVEST, P. D I C K a n d R. T ISSOT

S t i m u l a t i n g e f f ec t o f 5 - m e t h o x y p s o r a l e n o n t h e s e c r e t i on o f m e l a t o n i n 107

E. SOUETRE , L. T A M A R K I N , E. S A L V A T I , G. P A C I O T T I , B. KREBS a n d G. D A R C O U R T

T h e c i r c a d i a n b o d y t e m p e r a t u r e r h y t h m i n e s t r ous r a t s : E f f ec ts o f e n v i r o n m e n t a l a n d e n d o c r i n e m a n i p u l a t i o n s 111

F. SPENCER, H . B. J O H N S O N , J . G A N E S a n d B. P. H S I

T i m e - d e p e n d e n t e f fec ts A C T H 1-17 o n p l a s m a G H a n d G H -R H i n m a n 113

Y. T O U I T O U , A . R E I N B E R G , P. GARNIER , A . B I C A K O V A -R O C H E R , Y. M O T O H A S H I , A . B O G D A N a n d A . A U Z E B Y

Section 2B — Neurobiology and Psychiatry C o - c h a i r m e n : G. D A R C O U R T (Nice, France )

P. R E D F E R N (Ba th , E n g l a n d ) R. RE ITER (San A n t o n i o , Texas ) W . R I E T V E L D (Le iden , N e t h e r l a n d s ) Y. T O U I T O U (Paris, France )

C h a n g e s f r o m c i r c a d i a n t o u l t r a d i a n p e r i od i c i t i e s o f t h e a x i l l a r y t e m p e r a t u r e i n t h r e e dep ress i v e p a t i e n t s 115

A . B I C A K O V A - R O C H E R , A . RE INBERG, A . GORCEIX , Y. M O T O H A S H I a n d J . N O U G U I E R

C h r o n o p h a r m a c o l o g i c e v a l u a t i o n o f a n " a n t i f a t i g u e " p r e p a r a t i o n . A d o u b l e - b l i n d , p l a c ebo c o n t r o l a n d cross-over s t u d y 119

A . B I C A K O V A - R O C H E R , A . RE INBERG, F. L E V I , A . G O R C E I X , Y. T O U I T O U a n d G. M E T Z G E R

C h r o n i c c l o r g y l i n e a l t e r s t h e w h e e l - r u n n i n g r e sponse o f Sy r i an h a m s t e r s t o c o n t i n u o u s b r i g h t l i g h t 123

W . C. D U N C A N , P. G. S O K O L O V E a n d T. A . W E H R

C h r o n o p h a r m a c o k i n e t i c s o f I m i p r a m i n e a n d i t s m e t a b o l i t e d e s i p r a m i n e i n b r a i n a n d p l a s m a a f te r s ing l e a n d ch ron i c a p p l i c a t i o n o f I m i p r a m i n e i n r a t s 127

L. H O L L E , Ζ. G O R K A , Β. L A N G N E R a n d B. L E M M E R

Contents xv

D e s t r u c t i o n o f s u p r a c h i a s m a t i c n u c l e i s e r o t one rg i c f i b e r s a l t e r s r e sponse o f h a m s t e r a c t i v i t y r h y t h m s t o a m o n o a m i n e ox idase i n h i b i t o r 131

J . S. KRUSE

T i m e - d e p e n d e n t v a r i a t i o n s i n m o r p h i n e - i n d u c e d a n a l g e s i a 135 G. L A B R E C Q U E , D. L E P A G E - S A V A R Y a n d E. P O U L I N

C h r o n i c a n t i d e p r e s s a n t s ( I m i p r a m i n e , C i ta lopram, m i a n s e r i n ) d i f f e r e n t l y a f f ec t b e t a - r e c ep to r - e f f e c t o r - s ys t em i n r a t f o r e b r a i n a t d i f f e r e n t t i m e s o f d a y 139

B. L E M M E R a n d H . G O T T H E I N E R

Ef fec ts o f t h e a n t i d e p r e s s a n t d r u g s c l o m i p r a m i n e , f l u o x e t i n e a n d m i a n s e r i n o n f r e e - r u n n i n g a c t i v i t y r h y t h m s i n t h e r a t 143

P. J . M I T C H E L L , P. H . R E D F E R N a n d J . STOLZ

Section 3 — Theophylline, Bronchodilators and Chest

C o - c h a i r m e n : G. D ' A L O N Z O (Hous t on , Texas ) E. H A U S (St. Paul , M i n n e s o t a ) G. K U N K E L (W. Ber l in ) J . J O N K M A N (Gron ingen , N e t h e r l a n d s )

I n c r e a s e d n o c t u r n a l b r o n c h i a l h y p e r r e a c t i v i t y w i t h o u t i n c r e a s e d a i r f l o w o b s t r u c t i o n 147

W. M . C. V A N A A L D E R E N , D. S. POSTMA, G. H . K O E T E R , J . G E R R I T S E N a n d K. K N O L

A s t u d y o f t h e c i r c a d i a n r h y t h m of s e r u m t h e o p h y l l i n e l e v e l s (STLs) i n a s t h m a t i c c h i l d r e n t r e a t e d w i t h t h r e e sus t a ined - r e l e a s e t h e o p h y l l i n e (SRT) f o r m u l a t i o n s 151

A . B A C U L A R D , P. A Y M A R D a n d G. TOURNIER

A p r e l i m i n a r y s t u d y o f t h e c i r c a d i a n r h y t h m of s e r u m t h e o p h y l l i n e l eve l s (STLs) i n a s t h m a t i c i n f an t s t r e a t e d w i t h sus t a ined - r e l e a s e t h e o p h y l l i n e (SRT) f o r m u l a t i o n 153

A . B A C U L A R D , J . COUVREUR, B. DUBOIS, P. A Y M A R D a n d G. T O U R N I E R

T h e u t i l i t y o f t h e e s t i m a t e d T w / T t o t i n e v a l u a t i n g a l o n g a c t i n g s y m p a t h o m i m e t i c a g e n t u s e d for noc tu rna l l a s t h m a 157

R. P. B A U G H M A N a n d R. G. L O U D O N

C h r o n o p h a r m a c o k i n e t i c s o f t h e o p h y l l i n e f r o m a o ince-a-day t a b l e t d o s e d i n t h e m o r n i n g a n d a t n i g h t 161

C. J . B E T L A C H , A . B. S T R A U G H N , E. J . J A R V I , C . F. R Y A N , J . C. K I S I C K I a n d M . A . G O N Z A L E Z

xvi Contents

C i r c a d i a n c h r o n e s t h e s y o f t h e a i r w a y s o f h e a l t h y a d u l t s t o t h e ß-agonist b r o n c h o d i l a t o r i s o p r o t e r e n o l 163

A . B R O W N , M . SMOLENSKY , G. D ' A L O N Z O , H . F R A N K O F F , L. G I A N O T T I a n d J . N I L S E S T U E N

C o m p a r i s o n o f t h e k i n e t i c s a n d e f fects o f sus ta ined - r e l ease t h e o p h y l l i n e s c h e d u l e d c o n v e n t i o n a l l y a n d once -da i l y m o r n i n g s or e v e n i n g s i n a d u l t a s t h m a t i c s 167

H . F R A N K O F F , M . SMOLENSKY , G. D ' A L O N Z O a n d J . T O M L I N S O N

Ef fec t o f u n e q u a l t w i c e d a i l y t h e o p h y l l i n e o n t h e c i r c a d i a n v a r i a t i o n i n t h e e x p r e s s i o n o f ß 2 -adrenoceptor s i tes o n p e r i p h e r a l m o n o n u c l e a r l eucocy t e s ( M N L ) 171

Ε. H A E N , I . L A N G E N M A Y E R , H . E M S L A N D E R , Η. HEUS INGER, Μ. H A L L E K a n d J . R E M I E N

C i r c a d i a n v a r i a t i o n i n t h e e x p r e s s i o n o f ß 2-adrenoceptor s i tes i n m a l e a s t h m a t i c p a t i e n t s 175

E. H A E N , I . L A N G E N M A Y E R , H . E M S L A N D E R , Ν. W E B E R a n d J . R E M I E N

A p p e a r a n c e o f c i r c a n n u a l v a r i a t i o n s o f d i f f e r en t i m m u n e p a r a m e t e r s i n t h e b r o n c h o a l v e o l a r l a vage (BAL ) f l u i d i n p a t i e n t s w i t h c h r o n i c b r o n c h i t i s a f t e r t r e a t m e n t w i t h a b a c t e r i a l l y sa t e 179

M . H A L L E K , B. E M M E R I C H , R. BUSCH, Ε. H A E N a n d H . P. E M S L A N D E R

A p h a r m a c o k i n e t i c m o d e l o f sus ta ined - r e l ease t h e o p h y l l i n e w i t h c i r c a d i a n r h y t h m i c i n p u t a n d c o r r e l a t e d w i t h p u l m o n a r y f u n c t i o n r e sponse 183

A . S. K A P A D I A a n d B. P. H S I

C i r c a d i a n v a r i a t i o n s o f l y m p h o c y t e s u b p o p u l a t i o n s w i t h o u t a n d w i t h t h e o p h y l l i n e 187

G. K U N K E L , C. RAUFFUS, R. K U N Z E , Β. S IEBERT a n d D. A L B R I G H T

C i r c a d i a n v a r i a t i o n s o f ß 2 -adrenoceptors w i t h a n d w i t h o u t t h e o p h y l l i n e 189

G. K U N K E L , Β. SIEBERT, Μ. S U E R M O N D T , R. SPIERER a n d D. A L B R I G H T

C i r c a d i a n r h y t h m i n f o r c ed e x p i r a t o r y f l o w s i n a s t h m a t i c c h i l d r e n : M o d i f i c a t i o n a f t e r b r o n c h o d i l a t o r s ( i p r a t r o p i u m a n d f enotero l ) 191

R. L A M Y , J . JUST, M . B O U L E , A . B A C U L A R D , A . SARDET, A . G R I M F E L D , G. T O U R N I E R a n d F. G IRARD

Contents

Ef fec t o f a m u c o l y t i c a g e n t o n b io l og i c r h y t h m s of c o u g h a n d s p u t u m p r o d u c t i o n

R. G. L O U D O N a n d R. P. B A U G H M A N

C o m p a r i s o n o f t h e r e l a t i o n s h i p b e t w e e n t w o measure s o f b r o n c h i a l p a t e n c y , p e a k e x p i r a t o r y f l o w (PEF) a n d f o r ced e x p i r a t o r y v o l u m e (FEV a ) , over 24 h r u n d e r s t eady - s ta t e t h e o p h y l l i n e t r e a t m e n t

A . A . M E L T Z E R , Μ. H . SMOLENSKY, G. E. D ' A L O N Z O , R. B. H A R R I S T a n d P. H . SCOTT

Pe r i od i c i t i e s o f p a t i e n t adm i s s i ons t o a n e m e r g e n c y d e p a r t m e n t for a s t h m a , ch ron i c o b s t r u c t i v e p u l m o n a r y d i sease and/or t h e o p h y l l i n e t o x i c i t y

R. W . MORRIS , J . B. L E I K I N , Μ. K. P A T E L a n d M . Z E L L

C h r o n o p h a r m a c o k i n e t i c s i m u l a t i o n of a c i r c a d i a n r h y t h m i n t h e o p h y l l i n e d i s p o s i t i o n d u r i n g a c o n s t a n t - r a t e i n t r a v e n o u s i n f u s i o n o f a m i n o p h y l l i n e i n t h e d o g

R. J . R A C K L E Y , M . C. M E Y E R a n d A . B. S T R A U G H N

O r a l m o r n i n g d o s i n g o f c o r t i c os t e ro ids i n l o n g t e r m t r e a t e d c o r t i c o - d e p e n d e n t a s t h m a t i c s : I n c r e a s e d t o l e rance a n d p r e s e r v a t i o n o f t h e a d r e n o c o r t i c a l f u n c t i o n

A . R E I N B E R G , Y. T O U I T O U , M . B O T B O L , P. GERVAIS , D. C H A O U A T , F. L E V I a n d A . B I C A K O V A - R O C H E R

I n f l u e n c e o f d i f f e r e n t e v e n i n g i n t a k e t i m e s of s u s t a i n e d -re lease t h e o p h y l l i n e f o r m u l a t i o n E u p h y l o n g 0 (BY158) o n p h a r m a c o k i n e t i c s a n d p e a k e x p i r a t o r y f l o w va lues a f t e r i n d i v i d u a l dose t i t r a t i o n

B. S IEBERT, G. K U N K E L , Κ. BORNER, Η. W. S T A U D I N G E R a n d V . W . S T E I N I J A N S

Section 4 — General Chronopharmacology C o - c h a i r m e n : P. B E L A N G E R (Quebec, Canada)

Β. B R U G U E R O L L E (Marse i l l e , France ) S. N A K A N O (Eh ime , Japan) R. S T U R T E V A N T ( M a y w o o d , I l l ino i s )

C i r c a d i a n p e r i o d i c i t y i n t h e g l u t a t h i o n e c o n c e n t r a t i o n of r a t l i v e r

P. Μ. B E L A N G E R , Μ. D E S G A G N E a n d Β. B R U G U E R O L L E

D a y - n i g h t v a r i a t i o n s i n t h e a c t i v i t y a n d c o m p o s i t i o n o f t h e m i c r o s o m a l m i x e d f u n c t i o n ox idase of r a t l i ver

P. M . B E L A N G E R a n d M . L A L A N D E

xviii Contents

B u p i v a c a i n e c h r o n o k i n e t i c s i n m a n a f t e r a p e r i d u r a l c o n s t a n t r a t e i n f u s i o n 223

Β. B R U G U E R O L L E , Μ. D U P O N T , P. L E B R E a n d G. L E G R E

T e m p o r a l v a r i a t i o n s o f m e m b r a n e p e r m e a b i l i t y t o l o ca l a n a e s t h e t i c a gen t s , b u p i v a c a i n e a n d m e p i v a c a i n e , d o c u m e n t e d b y t h e i r e r y t h r o c y t i c passage 227

B. B R U G U E R O L L E a n d M . P R A T

C i r c a d i a n r h y t h m i n s e r u m z inc c o n c e n t r a t i o n s i n h e a l t h y h u m a n s 2 3 1

J . C. C A L , F. D U M A S , F. P E L E N , J . M . R A Y M O N D , J . C A M B A R a n d M . A M O U R E T T I

T h e m e c h a n i s m of t h e c h r o n o h e p a t o t o x i c i t y o f c h l o r o f o r m i n r a t : C o r r e l a t i o n b e t w e e n b i n d i n g t o h e p a t i c subce l l u l a r f r a c t i ons a n d h i s t o l o g i c c h a n g e s 235

M . D E S G A G N E , M . B O U T E T a n d P. M . B E L A N G E R

C i r c a d i a n v a r i a t i o n s i n m i c e e r y t h r o c y t e m e m b r a n e p e r m e a b i l i t y t o s o d i u m a n d p o t a s s i u m 239

C. D O R I A N , P. C A T R O U X , B. B R U G U E R O L L E a n d J . C A M B A R

Ins e c t s as a n i m a l m o d e l s for c h r o n o p h a r m a c o l o g i c a l r e s e a r c h 243 D. K. H A Y E S a n d N . O. M O R G A N

D o s i n g - t i m e a n d sex r e l a t e d d i f f e rences i n t h e p h a r m a c o k i n e t i c s o f c e f od i z ime as w e l l as i n Cort iso l c i r c a d i a n r h y t h m 247

J . H . G. J O N K M A N , A . RE INBERG, Β. OOSTERHUIS, Ο. Ε. D E N O O D , F. A . K E R K H O F , Y. M O T O H A S H I , F. L E V I a n d F. C A R A N D E N T E

C i r c a d i a n v a r i a t i o n s o f n i c o t i n e - i n d u c e d s t i m u l a n t e f fects o n a m b u l a t o r y a c t i v i t y a n d d r i n k i n g p r o d u c e d b y d a i l y a d m i n i s t r a t i o n i n r a t s 249

T. K I T A , Μ. SHIRASE, Η. K O N D O H , Τ. N A K A S H I M A a n d Y. K U R O G O C H I

D i u r n a l v a r i a t i o n s i n t h e l o ca l a n e s t h e t i c e f fect of c a r t i c a in e p l u s e p i n e p h r i n e ( u l t r a c a i n D-S R ) i n p a t i e n t s w i t h car ies — s t u d i e s w i t h a n e l e c t r on i c p u l p t e s t e r 253

B. L E M M E R a n d R. W I E M E R S

Is a c e t y l a t o r p h e n o t y p e d i s t r i b u t i o n d e p e n d e n t o f c i r c a d i a n r h y t h m s ? 257

M . O L L A G N I E R , J . P. GAY , Y. C H E R R A H , H . DECOUSUS a n d A . R E I N B E R G

Contents xix

R e t r o s p e c t i v e ana l ys i s o f n o n - e q u i d i s t a n t p h a r m a c o l o g i c a l d a t a 259

R. PIERRE, J . DE PRINS, E. M A L H E R B E , P. M A N C H O N a n d S. M O R E

C h r o n o t o x i c i t y a n d c h r o n o k i n e t i c s o f t w o l o ca l a n a e s t h e t i c a gen t s , b u p i v a c a i n e a n d mep i va ca ine , i n m i c e 263

M . P R A T a n d B. B R U G U E R O L L E

D i u r n a l o sc i l l a t i ons i n sa l i va r y leve ls of q u i n i n e f o l l o w i n g a s ing l e dose a d m i n i s t r a t i o n t o h u m a n v o l u n t e e r s 267

B. R A M E S H R A O a n d D. R A M B H A U

C i r c a d i a n e t h a n o l e x p o s u r e r e l a t e d t o f e t a l g r o w t h a n d d e v e l o p m e n t i n m i c e 2 7 1

I . SAUERBIER

M a t u r a t i o n of c i r c a d i a n b e h a v i o r r h y t h m s i n t h e f i r s t y ear of h u m a n l i fe 273

U. S C H M I D , R. L A N G , M . H A L L E K , D. H E I M E R - L A N G , M . WERRES, R. S C H M I D a n d T. HELLBRÜGGE

A m e t h o d for t h e r e p e t i t i v e c o l l e c t i on o f s m a l l b l o o d samp les f r o m u n a n e s t h e t i z e d r a t s 277

K. S C H Ü M A N N , Ε. R I C H T E R a n d Ε. H A E N

A n a l y s i s o f v a r i ance i n h u m a n c h r o n o p h a r m a c o l o g y . A n o l d m e t h o d i n a n e w area o f r e s ea r ch 2 8 1

K. S T E P H A N , R. D O R O W , K. W E G S C H E I D E R a n d B. STRE ITBERG

Section 5 — Ulcerogenesis, H2-Antagonists, Diabetes and Nutrition

C o - c h a i r m e n : A . M A R K I E W I C Z (Ka tow ice , Pola:nd) J . M O O R E (Salt L a k e C i ty , U tah ) S. SZABO (Boston , M a s s a c h u s e t t s )

U l t r a n n u a l r h y t h m of s t i m u l a t e d gas t r i c ac id s e c r e t i o n i n d u o d e n a l u l c e r (DU) 283

J . P. A C C A R Y , M . M E R R O U C H E , D. R IGAUD, J . V A T I E R a n d M . M I G N O N

N i z a t i d i n e 3 0 0 m g H.S. c o m p a r e d w i t h C ime t id ine 800 m g H.S. i n t h e t r e a t m e n t o f a cu t e d u o d e n a l u lcer 285

M . C L O U D a n d W . O F F E N

T h e c i r c a d i a n ef fect o f a l l oxan -d i abe t e s o n t h e t i nned r e g u l a t i o n of h e p a t i c p y r u v a t e k inase f r o m mice 287

R. J . FEUERS, R. A . M I T T E L S T A E D T , L. E. S C H E V I N G , Τ. H . T S A I a n d J . H U N T E R

XX Contents

T h e s u p p r e s s i o n o f n o c t u r n a l a c i d s e c r e t i on b y H.S. f a m o t i d i n e t h e r a p y is su f f i c i en t t o h e a l b e n i g n g a s t r i c u l c e r s 2 9 1

T. J . H U M P H R I E S a n d R. G. B E R L I N

C i r c a d i a n v a r i a t i o n s i n i n s u l i n a n d a l l o x a n s e n s i t i v i t y n o t e d i n b l o o d g lucose a l t e r a t i o n s i n n o r m a l a n d d i a b e t i c m i c e 295

J . D. H U N T E R , J . P. M c G E E , J . S A L D I V A R , T . T S A I , R. FEUERS a n d L. E. S C H E V I N G

C i r c a d i a n v a r i a t i o n o f c a t e c h o l a m i n e s e x c r e t i o n a n d s k i n bas ic r e s i s t ance i n c h i l d r e n w i t h i n s u l i n d e p e n d e n t d i a b e t e s 299

D. K I E L C Z E W S K A - M R O Z I K I E W I C Z , A . M R O Z I K I E W I C Z a n d E. C H M A R A

D i e t a n d m e a l t i m i n g as c i r c a d i a n s y n c h r o n i z e r s 303 D. J . L A K A T U A , M . H A U S , C. BERGE, L. S A C K E T T - L U N D E E N a n d E. H A U S

Seasona l v a r i a t i o n i n t h e i n c i d e n c e o f b l e e d i n g u l c e r 307 A . M A R B E L L A , D. G R A H A M a n d M . S M O L E N S K Y

C h r o n o s u p p l e m e n t a t i o n a f t e r g a s t r e c t o m y 311 A . M A R K I E W I C Z , Η. Β O L D YS, D. SKRZYPEK a n d J . K A L A C I N S K I

C o n t i n u o u s i n f u s i o n o f f a m o t i d i n e m a i n t a i n s h i g h g a s t r i c p H i n d u o d e n a l u l c e r (DU) 315

Η. M E R K I , L. W I T Z E L , M . L A N G M A N , D. K A U F M A N N , J . N E U M A N N , J . RÖHMEL a n d R. W A L T

M a n i p u l a t i o n o f f e e d i n g s c h e d u l e c a n m o d i f y t h e c i r c a d i a n r h y t h m s of t o x i c i t y a n d k i n e t i c s o f t h e o p h y l l i n e i n m i c e 317

S. N A K A N O , S. O H D O a n d N . O G A W A

T i m i n g o f e v e n i n g m e a l a n d r a n i t i d i n e a d m i n i s t r a t i o n o n p a t t e r n s of 24hr i n t r a g a s t r i c p H 321

W . C. ORR, Μ. A L L E N , A . F I N N a n d M . G. R O B I N S O N

C i r c a d i a n r h y t h m s o f g a s t r o i n t e s t i n a l p e p t i d e s i n o v a r i e c t o m i z e d r a t s : E f f ec ts o f e s t r a d i o l a n d p r o g e s t e r o n e t r e a t m e n t 323

J . N . PASLEY a n d P. L. R A Y F O R D

Ef fec t o f seasona l v a r i a t i o n s o n s e r u m n e u t r a l a m i n o a c i d s i n r e sponse t o s t ress i n r a t 327

A . G. ROBERGE

Ef fec t o f seasona l v a r i a t i o n s o n b l o o d p a r a m e t e r s i n r e s p o n s e t o s t ress i n ca t 331

A . G. ROBERGE a n d L. T H I B A U L T

Contents xxi

C i r c a d i a n v a r i a t i o n i n t h e p h a r m a c o d y n a m i c effect o f i n t r a v e n o u s r a n i t i d i n e 335

S. W . SANDERS, J . G. M O O R E , K. N . B U C H I a n d A . L. B ISHOP

C i r c a d i a n d i s s o c i a t i o n b e t w e e n d r u g - i n d u c e d gas t r i c m u c o s a l l e s i ons a n d g a s t r i c s e c r e t i on i n t h e r a t 339

S. SZABO, C. ROGERS a n d K. J . V E N E R

R e l a t i o n s h i p b e t w e e n a c t i v i t y — r h y t h m sh i f t b y d a y t i m e r e s t r i c t e d f e e d i n g a n d u l c e r - d e v e l o p m e n t i n ac t i v i t y—s t r ess p r o c e d u r e 341

K. W A T A N A B E , C. H A R A a n d N. O G A W A

Section 6 — Cancer C o - c h a i r m e n : I . A S H K E N A Z I (Tel A v i v , Israel )

C. F O C A N (Liege, B e l g i u m ) R. V O N R O E M E L I N G (Lubbock , Texas ) L. S C H E V I N G (L i t t l e Rock, A r k a n s a s )

T w e n t y - f o u r h o u r v a r i a t i o n i n s e l f - a d m i n i s t r a t i o n o f m o r p h i n e su l f a t e (MS) a n d h y d r o m o r p h o n e (H) b y p o s t - s u r g i c a l g yneco l o g i c c ance r p a t i e n t s 343

S. E. A U V I L - N O V A K , R. D. N O V A K , Μ. H . SMOLENSKY, J . J . K A V A N A G H , J . W . K W A N a n d J . T. W H A R T O N

T h e ro l e of c i r c a d i a n m i t o t i c c o n t r o l for t h e p r o m o t i o n o f p r e n e o p l a s t i c l e s i o n s i n i t i a t e d b y d i e t h y l n i t r o s a m i n e (DEN) 347

H . B A R B A S O N , B. B O U Z A H Z A H a n d M.-C. M O R M O N T

T o x i c i t i e s a n d t i s s u e p h a r m a c o k i n e t i c s of o x a l i p l a t i n a n d c a r b o p l a t i n d e p e n d u p o n t h e i r d o s i n g t i m e i n m i c e 351

N . A . B O U G H A T T A S , F. L E V I , B. H E C Q U E T , G. L E M A I G R E , A . R O U L O N , C. F O U R N I E R a n d A . RE INBERG

C i r c a d i a n c e l l u l a r p r o l i f e r a t i o n i n h u m a n r e c t a l m u c o s a 355 Κ. N . B U C H I , Ν. H . R U B I N a n d J . G. M O O R E

C h r o n o t o x i c i t y o f a n t i - c a n c e r d r u g s : I I . Recovery p a t t e r n 357 R. C A R L E B A C H , Μ. R A V I D , L. PELEG, I . A S H K E N A Z I a n d Y. K I T A Y - C O H E N

M o d u l a t i o n of t h e c i r c a d i a n r h y t h m i n m e t h o t r e x a t e t o x i c i t y i n t h e r a t b y m e l a t o n i n a n d p h o t o p e r i o d 359

J . E N G L I S H , G. W . A H E R N E a n d J . A R E N D T

O b s e r v a t i o n o f c i r c a d i a n v a r i a t i o n s of s e r u m t h y m i d i n e k i n a s e l eve l s i n c o n t r o l a n d t u m o r p a t i e n t s 361

M . H A L L E K , B. E M M E R I C H , A . RE ICHLE, H . D. SCHICK, R. S E N E K O W I T S C H a n d A . RE INBERG

xx i i Contents

C h r o n o t o x i c i t y o f an t i - cance r d r u g s : I . I m m e d i a t e e f fects 365 Y. K I T A Y - C O H E N , I . A S H K E N A Z I , M . R A V I D , L. P E L E G a n d R. C A R L E B A C H

C i r c a d i a n r h y t h m i n m u r i n e t o l e r a n c e for t h e a n t i c a n c e r a g e n t m i t o m y c i n - C (MIT-C ) 367

F. K L E I N , L. D A N O B E R , A . R O U L O N , G. L E M A I G R E , M . M E C H K O U R I a n d F. L E V I

C i r c a d i a n g a t i n g o f D N A s y n t h e s i s a n d i t s r e l a t i o n s h i p t o s u r g i c a l d e b u l k i n g i n h u m a n o v a r i a n cancer 371

R. R. K L E V E C Z a n d P. S. B R A L Y

E t o p o s i d e a n d c i s p l a t i n i n a d v a n c e d s o l i d t u m o r s : Resu l t s o f a s t u d y o f c h r o n o t o l e r a n c e 373

I . K R A K O W S K I , F. L E V I , Μ. M E C H K O U R I , Τ. CONROY, Ε. LUPORSI , Β. W E B E R a n d R. M E T Z

T r e a t m e n t o f c h i l d h o o d a cu t e l y m p h o b l a s t i c l e u k e m i a w i t h 6 - m e r c a p t o p u r i n e : C i r c a d i a n v a r i a b i l i t y o f ef f icacy, b i o a v a i l a b i l i t y a n d p h a r m a c o k i n e t i c s 377

G. E. R I V A R D , K.-T. L I N , C. I N F A N T E - R I V A R D , J . M . L E C L E R C a n d F. V A R I N

D i f f e r e n t i a l e f fect o f i n t e r l e u k i n - 2 o n [ 3 H ] T d R i n c o r p o r a t i o n i n t o D N A i n t h e t h y m u s , s p l e e n a n d b o n e m a r r o w o f C D 2 F a

m a l e m i c e 381 L. A . S C H E V I N G , T . H . T S A I , R. J . FEUERS, Μ. Η. SMOLENSKY , J . D. Y O U N G a n d L. E. S C H E V I N G

A c i r c a d i a n s t u d y o f ce l l cyc l e d i s t r i b u t i o n i n n o n - H o d g k i n l y m p h o m a s 383

R. S M A A L A N D , K. L O T E , Ο. D. L A E R U M a n d Z. V O K A C

C i r c a d i a n s tage n o t t i m e o f d a y charac t e r i z es d o x o r u b i c i n s u s c e p t i b i l i t y r h y t h m o f m i c e i n c o n t i n u o u s l i g h t 385

R. B. SOTHERN, F. H A L B E R G a n d W. J . M . HRUSHESKY

P r o f o u n d c i r c a d i a n s t age d e p e n d e n c e o f m i t o m y c i n - C t o x i c i t y 389 R. B. SOTHERN, R. H A U S , Τ. R. L A N G E V I N , J . A . POPOVICH , M . W I C K , R. v . R O E M E L I N G a n d W . J . M . HRUSHESKY

C l in i ca l c h r o n o p h a r m a c o k i n e t i c s of d o x o r u b i c i n (DXR) 393 A . S Q A L L I , J . OUSTRIN , G. H O U I N , R. B U G A T , P. C A N A L a n d M . C A R T O N

C i r c a d i a n i n f l u ence of i n t e r l e u k i n - 2 i n s t i m u l a t i n g D N A s y n t h e s i s i n t h e l u n g , l i v e r a n d pancreas o f C D 2 F a m a l e m i c e 397

Τ. H . TSA I , L. A . S C H E V I N G , R. J . FEUERS, J . D. Y O U N G a n d L . E . S C H E V I N G

Contents

Sources o f v a r i a b i l i t y o f d i h y d r o p y r i m i d i n e d e h y d r o g e n a s e a c t i v i t y i n h u m a n b l o o d m o n o n u c l e a r cel ls

M . T U C H M A N , R. v . R O E M E L I N G , R. M . L A N N I N G , R. B. S O T H E R N a n d W . J . M . HRUSHESKY

Round Table — Drug Delivery Systems and Pumps for Timing Medications

C h a i r m a n : W. J . M . HRUSHESKY (M inneapo l i s , M i n n e s o t a )

C h r o n o t h e r a p y o f p a t i e n t s w i t h m e t a s t a t i c co l o rec ta l cancer w i t h 5 - f luo rourac i l (5-FU) a n d o x a l i p l a t i n (1-OHP), a u t o m a t i c a l l y d e l i v e r e d v i a a p r o g r a m m a b l e e x t e r n a l p u m p . P r e l i m i n a r y r e su l t s

J . P. C A U S S A N E L , F. L E V I , J . L. MISSET, Α . DESCORPS DECLERE , R. A D A M , H . B I S M U T H , A . R E I N B E R G a n d G. M A T H E

T i m e - m o d u l a t i n g c o n t r o l l e d d e l i v e r y of p e p t i d e / p r o t e i n d r u g s for p o s s i b l e a p p l i c a t i o n s i n c h r o n o t h e r a p y

Y. W . C H I E N

C i r c a d i a n v a r i a t i o n s o f v i n d e s i n e s e r u m c o n c e n t r a t i o n s d u r i n g c o n t i n u o u s i n f u s i o n

C. F O C A N , V. M A Z Y , J . Z H O U , R. R A H M A N I a n d J . P. C A N O

I m p l a n t a b l e t h e r a p e u t i c s y s t e m s J . KOST

A m b u l a t o r y 5-day c h r o n o t h e r a p y of co lo rec ta l cancer w i t h c o n t i n u o u s v e n o u s i n f u s i o n o f 5 - f luorourac i l (5-FU) at c i r c a d i a n - m o d u l a t e d r a t e . P r e l i m i n a r y r e su l t s

F. L E V I , R. A D A M , A . SOUSSAN, J . P. CAUSSANEL , M . B E N A V I D E S , J . L. MISSET, F. BURKI , Α . RE INBERG, Μ. SMOLENSKY , Η. B I S M U T H a n d G. M A T H E

P u m p d e l i v e r e d i n s u l i n a n d h o m e m o n i t o r e d b l o o d g lucose i n a d i a b e t i c p a t i e n t : Re t r o spec t i v e a n d ch ronophys i o l o g i c e v a l u a t i o n o f 3-year t i m e ser ies

A . RE INBERG, P. D R O U I N , M . KOLOPP ? L. M E J E A N , F. L E V I , G. DEBRY, M . M E C H K O U R I , G. D I C O S T A N Z O a n d A . B I C A K O V A - R O C H E R

C i r c a d i a n t i m i n g a n d m o d e o f f l u o r o p y r i m i d i n e a d m i n i s t r a t i o n m a r k e d l y i m p a c t organ-spec i f i c t o x i c i t y a n d m a x i m a l dose i n t e n s i t y

R. v . R O E M E L I N G , J . R A B A T I N , Μ. T U C H M A N a n d W . J . M . HRUSHESKY

xxiv Contents

Feas ib i l i t y , sa f e ty a n d accuracy o f a n a u t o m a t e d d r u g d e l i v e r y s y s t e m s u i t a b l e for c h r o n o c h e m o t h e r a p y i n p e d i a t r i c p a t i e n t s 4 3 1

J . M . A . V A N T U R N O U T , M . E. NESBIT , Jr. , B. B O S T R O M , Ν. K. C. R A M S A Y , S. S O M A N I , T . L A N G E V I N , R. L A N N I N G , R. V O N R O E M E L I N G a n d W . J . M . HRUSHESKY

Section 7 — Cardiovascular and Renal Systems C o - c h a i r m e n : J . C A M B A R (Bordeaux , France )

H . DECOUSUS (St. E t i e n n e , France ) B. L E M M E R ( F r a n k f u r t , W . G e r m a n y )

C i r c a d i a n v a r i a t i o n s i n p o s t i s c h e m i c a cu t e r e n a l f a i lu r e i n r a t s 433

P. C A T R O U X , C. D O R I A N a n d J . C A M B A R

Role o f r e n i n a n g i o t e n s i n s y s t e m i n a m i k a c i n c h r o n o n e p h r o t o x i c i t y 437

C. D O R I A N , P. C A T R O U X a n d J . C A M B A R

Does t h e c i r c a d i a n v a r i a t i o n o f ß 2 -adrenoceptor s i tes o n p e r i p h e r a l m o n o n u c l e a r l eucocy t e s (MNL) re f l ec t t h e c i r c a d i a n v a r i a t i o n of d i f f e r e n t M N L subse t s? 4 4 1

Ε. H A E N , T . LEDERER, P. R IEBER, P. SCHLEICHER, I . L A N G E N M A Y E R , M . H A L L E K a n d J . R E M I E N

24 -hour v a r i a t i o n s i n t h e d i s t r i b u t i o n of l a b e l e d m i c r o s p h e r e s t o t h e i n t e s t i n e , l i v e r a n d k i d n e y s 445

G. L A B R E C Q U E , P. M . B E L A N G E R , F. DORE a n d M . L A L A N D E

N o c t u r n a l b l o o d p r e s s u r e i n s l eep apnea , e f fect o f n a s a l c o n t i n u o u s p o s i t i v e a i r w a y p r e s s u r e (nCPAP) 449

J . M A Y E R , H . BECKER, U . B R A N D E N B U R G , T. PENZEL , J . H . PETER, R. STOOHS, M . W E I N E R a n d P. v . W I C H E R T

A l t e r a t i o n o f c i r c a d i a n r h y t h m s o f b l o o d p r e s s u r e b y d e l a y e d b e d - t i m e s leep s c h e d u l e 453

Y. M O T O H A S H I a n d Τ. T A K A N O

C i r c a d i a n v a r i a t i o n i n d i g o x i n p h a r m a c o k i n e t i c s 457 A . M R O Z I K I E W I C Z , A . J A B L E C K A , Z. L O W I C K I a n d E. C H M A R A

Seasonal v a r i a t i o n s i n g e n t a m i c i n n e p h r o t o x i c i t y i n r a t s 461 C. P A R I A T , P. COURTOIS , J . C A M B A R , A . P IR IOU a n d S. B O U Q U E T

B io l og i ca l r h y t h m s o f b l o o d c o a g u l a t i o n a n d of t h e e f fect o f w a r f a r i n i n r a t s 465

G. S O U L B A N a n d G. L A B R E C Q U E

Contents xxv

C i r c a d i a n v a r i a t i o n o f p r o h o r m o n e a t r i a l n a t r i u r e t i c f ac tors 1-30, 31-67 a n d 99-126 i n m a n 469

D. L. VESELY, C. J . W I N T E R S , A . L. S A L L M A N , D. M . RICO, J . M E A D O W S , B. L e M A Y , J . HARRIS , S. D. L U N N I N G H A M a n d V . M E L H O R N

Ef fec ts of d i f f e r en t s t i m u l i ( i soprena l ine , G p p ( N H ) p , f o rsko l in ) o n c i r c a d i a n r h y t h m s i n c A M P c o n t e n t a n d a d e n y l a t e cyc lase a c t i v i t y i n t h e r a t h e a r t 473

K. W I T T E a n d B. L E M M E R

A u t h o r I n d e x 477

Sub jec t I n d e x 4 8 1

CIRCADIAN VARIATION IN THE EXPRESSION OF ß2-ADRENOCEPTOR SITES IN MALE ASTHMATIC PATIENTS Ε. Haen,* l. Langenmayer , " Η. Emslander,** Ν. Weber*** and J . Remien*

*Walther-Straub-Institute of Pharmacology and Toxicology, Nussbaumstr. 26, D-8000 München 2, F.R.G.

Medical Clinic, Klinikum r.d. Isar, Ismaninger Str. 22, D-8000 München 80, F.R.G. " ' C e n t r a l Hospital Gauting, D-8035 Gauting, F.R.G.

K E Y W O R D S

c i r c a d i a n v a r i a t i o n , ß2 -adrenoceptors , p e r i p h e r a l mononuclear l eucocy te s (MNL) , noc tu rna l a s t h m a

I N T R O D U C T I O N

We r e c e n t l y descr ibed a c i r c a d i a n va r i a t i on in the express ion of ß2~adrenoceptor s i tes on peripheral mononuclear l eucocy te s (MNL ) from healthy sub jects (Panger l et a l 1986, Haen 1 9 8 7 ) . A t night ß2~adrenoceptor density was found to be m in ima l . Th i s co inc ides with the t i m e of lowest resp i ratory funct ion in both hea l thy and a s t h m a t i c persons (Re inberg et a l 1963, Barnes et a l 1980). In a s t h m a t i c s resp i ratory function dec reases so much at night t h a t p a t i e n t s a re most endangered by a t t a c k s at that t ime of day ( "nocturna l a s thma " , "nocturnal dip" , H e t z e l & C l a r k 1980). In 1968 Szen t i vany i suggested that the atopic ab ­n o r m a l i t i e s in a s t h m a t i c disease a re re l a ted to a mal funct ion of ß2~adrenoceptors, i.e either a dec reased adrenoceptor density or an impa i red sens i t i v i ty of these hormone r e c e p ­tors to ß-adrenergic s t imul i ( S zent i vany i 1968). We there fore studied the c i r c ad i an v a r i a ­t i o n of ß2~adrenoceptor density and funct ion in a s t h m a t i c pat ients with predominant ly noc tu rna l compla in t s .

M A T E R I A L S A N D M E T H O D S

At I4h00, 18h00, 22h00, 02h00, 06h00, lOhOO, and again at 14h00 venous blood was drawn from k male a s t h m a t i c pat ients , 19-27 yea rs of age. Two of them demonstrated normal or low no rma l resp i ratory function during day t ime (24h-mean of peak exp i ratory flow + S E : 597+32.6 1/min and 497+29.4 1/min) w i th a marked nocturna l dip (30.1 and 26.0 % of 24h-mean, r e spec t i ve ly ) between 02h00 and 06h00. The other two pat ients showed a s imi la r nocturnal dip (29.8 and 26.7 % of 24h-mean ) from an overa l l dec reased resp i ra tory funct ion ( 2 4 h - m e a n of p eak e x p i r a t o r y f l ow + S E : 335+21 .0 1/min and 434+45.8 1/min, Fig. 1). A l l four men were without any bronchodi lator therapy before the study. The sub­j e c t s w e r e asked to follow a regular l i f e - s ty l e for the two weeks preceeding the study with bed res t between 23h00 and 07h00. On the day of the study the subjects s t ayed in the c l i n i c a l pharmaco log ica l r e s ea r ch unit of the hospita l . They cont inued to follow thei r normal dai ly routine. Subjects were asked to record mea l t imes , the consumption of a l c o ­h o l a n d C o f f e i n . A l l w e r e non-smokers .

The blood spec imen were immed ia te ly a s sayed for the number of high a f f in i ty ß-adrenergic

175

176 Ε. Haen et al.

binding sites (B -max ) on i n t a c t l ymphocytes , using a receptor binding assay (Anhäupl e t a l 1988 ) w i t h l ^ i ^ y a n o p i n d o i o i ^ a ß-antagonist. ß2-adrenoceptor coupled adeny la te c y c l a s e was s t imu la ted by incubat ing the i n t a c t ce l l s w i th 10"^ mol/1 i soprena l ine for 5 minutes at 37°C; the inc rease of i n t r ace l l u l a r c A M P above basal va lues was d e t e r ­m i n e d by r a d i o - i m m u n o a s s a y a f t e r c e l l d isrupt ion.

D i r e c t l y a f ter venepuncture resp i ra tory funct ion was assessed using a compute r based, room-restr icted sp i rometer . Among other var iab les the best of three peak exp i r a to ry flow ( P E F ) readings was recorded .

C i r c a d i a n var ia t ions were s t a t i s t i c a l l y va l idated by the single cosinor method (Ha lberg et a l 1967 ) and by ana lys is of v a r i ance (anova). S i gn i f i cance l imi t was ρ < 0 .05.

l/min

600

400

U°° 18°° 22°° 02°° 06' time of day (h)

F i g . 1. Peak exp i ra tory flow of unt reated ma le a s t h m a t i c s (x+SE) .

R E S U L T S

When exp res sed as % of the 24h -mean the c i r c a d i a n va r i a t i on in the express ion of ß2~ adrenoceptor s i tes on per iphera l M N L from male a s t h m a t i c pat ients was s i gn i f i cant w i th a ρ < 0 .05 (anova). The max imum was seen at lOhOO (1575+462 s i t e s/ce l l , x+SE) , the minimum at 02h00 (600+101 s i t e s/ce l l , F i g . 2). The c i r c a d i a n range was 59 .1 -155 .2 % of t h e 2 4 h - m e a n . Cos inor ana lyses approx imated a c i r c a d i a n mesor of 976+51 s i t e s / c e l l , a c i r c a d i a n ampl i tude of 475+197 s i t e s/ce l l (equivalent to 4 8 . 7 % of mesor ) , and a c i r ­c a d i a n a c r o p h a s e of -198+34° e q u i v a l e n t to 1 3 h l 4 + 2 h l 7 (a l l x+SE) . The i n d i v i ­d u a l single cosinor ana lyses did not r each s t a t i s t i c a l s i gn i f i cance .

F i g . 2. ß2-Adrenoceptor density on per iphera l mononuclear l eucocy tes of hea l thy men and of untreated male asthmatic pat ients .

Expression of ß2-adrenoceptor sites 177

Basal cAMP content of the ce l l s c lose ly para l le led the c i r c ad i an var ia t ion in the e xp r e s ­s i o n of ß2-adrenoceptor s i t e s . Max ima l va lues were seen between 06h00 and lOhOO ( 6 . 0 + 1 .12 p m o l / 1 0 6 c e l l s , x + S E ) , m i n i m a l v a l u e s a t 2 2 h 0 0 ( 3 . 5+0 .95 p m o l / 1 0 6 c e l l s , x + S E ) w i t h a c i r c a d i a n range of 74 .6 -126.7 % of 24h -mean (4.8+0.36 p m o l / 1 0 6 c e l l s , F i g . 3 ) .

ß2~adrenoceptor coupled adeny late c y c l a s e could be s t imu la t ed by 10 "? mol/1 i s o -p r e n a l i n e to 6 . 8+0 .52 p m o l / 1 0 6 c e l l s result ing in a 44+11 % inc r ea se over ba ­s a l c A M P v a l u e s ( 2 4 h - m e a n + S E , F i g . 3).

pmol /10* cells . ο ο basal content

13- ο- ο after stimulation by 10"7mol/l isoprenaline

14" I T 2^· I B " Οβ* X T Η · 0

time of day(h)

Fig. 3. C y c l i c A M P content of per iphera l mononuclear l eucocy te s from untreated ma le a s t h ­m a t i c p a t i e n t s before and a f te r in v i t ro s t imu la t ion by 10 "? mol/1 isoprenal ine .

D I S C U S S I O N

Studies t ry ing to de tec t ß-adrenoceptor ma l funct ion in a s t h m a t i c pat ients a re c o n t r a d i c ­t o r y in the i r resu l ts (Conol ly et a l 1976, Sca r pace et a l 1982, T i t i n c h i e t a l 1984). In g e n e r a l a d i f fe rence in the express ion of ß2-adrenoceptor s i tes and in the i r response to isoprenal ine could not be c l ea r l y observed between hea l thy and a s t h m a t i c people. These studies , however , were not chronobio logica l ly designed and were hampered wi th p r e t r e a t -m e n t of the subjects or w i th in te r - ind iv idua l d i f f e rences in the pathophysiology of the d i s e a s e .

T h e four pat ients in this study were c l e a r l y unt reated . The seve r i ty of impa i rment of their resp i ratory funct ion, however , d i f fered a lot among the individuals ( F i g . 1). A c i r ­c a d i a n var ia t ion in the express ion of ß2~adrenoceptor s i t e s could be observed in these patients that co r r e l a t ed we l l w i th the c i r c a d i a n va r i a t ion in peak exp i ra tory flow. N e v e r ­the less , d i f f e rences to our hea l thy cont ro l group (Panger l et a l 1986) a re , i f a t a i l p r e ­s e n t , v e r y sha l low. Most of a l l the marked nocturna l dip in resp i ratory funct ion is not p a r a l l e l e d by an equal ly enlarged dec rease in ß2~adrenoceptor density compared to the h e a l t h y contro ls ( F i g . 2). There is just a tendency towards an inc reased c i r c a d i a n a m ­p l i t u d e in the expression of ß2-adrenoceptor s i tes among the a s thmat i c s , wh ich might stil l be obscured at that stage of our invest igat ion by the sma l l number of unt rea ted sub ­j e c t s and t h e i r large in te r - ind iv idua l d i f f e rences in resp i ratory funct ion .

T h i s s t u d y suggests that the express ion and funct ion of ß2~adrenoceptors is not c r i t i ­cally l inked to pathologica l abnormal i t i es of peak exp i ra tory flow measurements in noc tu r ­na l a s t h m a . However , the resu l ts a lso ra i se the quest ion of M N L being a useful t i ssue model for studies of receptor d is turbances in humans. It is w i th in reason to assume that data for receptors obtained from the study of M N L do represent the physio logica l s i tuat ion in t h e body; the shielding of c e r t a i n receptor populations from ove ra l l occur ing i n f l u ­e n c e s (e.g. endocr ine e f fects ) cons t i tu tes an ext raord inary and unnecessary bio logi ­c a l e x p e n d i t u r e . The same holds t rue for e f f ec t s of s y s t e m i c a l l y admin i s te red drugs. T h e r e s u l t s o f t h i s s t u d y , h o w e v e r , do not p r e c l u d e i s o l a t e d , p a t h o l o g i c a l ß2-adrenoceptor disturbances in bronchia l t i ssue of a s t h m a t i c pat ients .

178 Ε. Haen et al.

R E F E R E N C E S

1. Anhäup l Τ, L i e b l Β, R e m i e n 3 ( 1 9 8 8 ) . K i n e t i c a n d Equ i l i b r i um Stud ies of ( - ) 1 2 5 j o c j O C y a n o p i n ( j 0 i 0 i Binding to ß-Adrenoceptors in Human L y m p h o c y t e s : E v i d e n c e fo r t h e E x i s t e n c e of T w o C l a s s e s of Binding S i t e s . 3 R e e R e s 8, (in press )

2. Barnes P, F i t z g e r a l d G , Brown M, Do l l e ry C (1980). Nocturna l A s t h m a and C h a n g e s in C i r c u l a t i n g Ep inephr ine , H i s t amine , and C o r t i s o l . Ν Eng l 3 Med 303 , 263 -267

3. Cono l iy M E , G r e e n a c r e 3K (1976). The L y m p h o c y t e ß-Adrenoceptor in No rma l Sub jec t s and P a t i e n t s w i th Bronch ia l A s t h m a . 3 C l i n Invest 58, 1307-1316

4. Haen Ε (1987). The Pe r i phe ra l L y m p h o c y t e as C l i n i c a l Model for Recep to r D i s t u r b a n c e s : A s t h m a t i c D i s e a s e s . Bu l l E u r Phys iopathol R e s p 22, 539-541

5. Halberg F , Tong Y L , 3ohnson Ε A (1967). C i r c a d i a n Sys tem Phase - An A s p e c t of T e m p o r a l Mo rpho logy ; P rocedures and I l l u s t r a t i ve Examp l e s , in : The C e l l u l a r A s p e c t s of B i o -rhythms (ed Η ν Mayersbach) , Springer Ve r l ag Ber l in/Heidelberg/New Y o r k , pp 20 -48

6. Hetze l MR, C l a r k T 3 H (1980). Compar i son of No rma l and A s t h m a t i c C i r c a d i a n R h y t h m s in P e a k E x p i r a t o r y F low R a t e . Thorax 35, 732 -738

7 . P a n g e r l A , R e m i e n 3, Haen Ε (1986). The Number of ß-Adrenoceptor S i t e s on In tac t Human Lymphocytes Depends on T i m e of Day , on Season, and on Sex. Ann R e v C h r o n o -pha rmaco l 3, 331-334

8 . R e i n b e r g Α, G e r v a i s Ρ (1972). C i r c a d i a n R h y t h m s in Resp i r a to ry Func t i ons , w i t h S p e ­cial Re fe rence to Human Chronophysio logy and Chronopharmaco logy . Bu l l E u r P h y s i o -pato l R e s p 8, 663-675

9 . S c a r p a c e P 3 , L i t t n e r MR, Tashk in D P , Abrass IB (1982). L y m p h o c y t e B e t a - A d r e n e r g i c R e f r a c t o r i n e s s Induced by Theophyl l ine or Metaprotereno l in Hea l thy and A s t h m a t i c Sub jects . L i f e Se i 31, 1567-1573

10. S zen t i v any i A (1968). The B e t a Adrene rg i c Theory of the A top i c Abnorma l i ty in B r o n ­c h i a l A s t h m a . 3 A l le rgy 42 , 203 -232

11 . T i t i n c h i S, S h a m m a MA, P a t e l K R , K e r r 3W, C l a r k Β (1984). C i r c a d i a n V a r i a t i o n in N u m b e r and A f f in i ty of ß2~Adrenoceptors in L y m p h o c y t e s of A s t h m a t i c P a t i e n t s . C l i n Sei 66, 323 -238

A C K N O W L E D G E M E N T S

This study was supported by a r e s ea r ch grant from K l inge P h a r m a M u n i c h / F R G . We g ra te fu l l y acknowledge the sk i l l fu l l t e c h n i c a l a s s i s t ance of our lab t echn i c i ans U r su l a 3udenhofer , Christina Le rnmermann , Sybi l le K i r z i n g e r , and Iris R e i t h m e i e r . Without the i r ready a c c e p ­tance to work overtime this study would have been impossib le to per form.