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. RE INBERG Fondation A. de Rothschild, Paris, France

M . SMOLENSKY University of Texas, Houston, U.S.A.

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

P E R G A M O N PRESS OXFORD · NEW YORK - BEIJING · FRANKFURT SAO PAULO · SYDNEY · TOKYO TORONTO

CONTENTS

Section 1 — Laboratory and C l in i ca l Immunology and In f lammat ion

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, France )

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 of 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 yc 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 of 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 of 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 of 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 . OUSTR IN

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 of 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 of 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 Endocr ino logy

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 of 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 of p l a s m a c a l c i t o n i n l e ve 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 of 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. M 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 i n 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 ex

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 n n 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 thy rox ine -5 ' -de i od inas i e 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 isol , 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 ICK 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, Η. 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 -ROCHER , 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

Sect ion 2B — Neurobiology and Psych ia t ry 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 depress 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 esponse of 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 ta - r e cep 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

Sect ion 3 — Theophyl l ine , Bronchodilators a n d Ches t

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 ve 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 iace-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 of 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. HEUSINGER, 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 log 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 measures of 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 rced e x p i r a t o r y v o l u m e (FEV! ) , 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 ad i an 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 of 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 of 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 eased 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 TB 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 en 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 (BY 158) 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

Sect ion 4 — Gene ra l 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 of 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. DUPONT , P. LEBRE 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 changes 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. DE 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 of 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 of 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 of sma 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 281

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

Sect ion 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 , Po land ) 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 in 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 and M . M I G N O N

N i z a t i d i n e 3 0 0 m g H.S. compared w i t h Cimetidine* 800 mg H.S. in t h e treatment o f a cu t e d u o d e n a l ulcer 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 on the t inned 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. SCHIEVING, 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 of 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 tance 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 ynch ron 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 of 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 of 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 of 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

Sect ion 6 — C a n c e r 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, Be l g ium ) 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 cance 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 ta 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 so 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

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 of 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

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 en 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

L. A . S C H E V I N G , T. H . TSA 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

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

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 of 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 syn thes 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 ! 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

373

377

381

383

385

Contents

Sources of 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 De l ive ry Sys tems and Pumps for T im ing 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 po 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 enous i n f u s i o n of 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 ra 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 of 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 — Card iovascu la r and R e n a l Sy s t ems 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 ra 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 of 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 ef 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 INTERS , 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

EFFECT OF UNEQUAL TWICE DAILY THEOPHYLLINE ON THE CIRCADIAN VARIATION IN THE EXPRESSION OF ß 2-ADRENOCEPTOR SITES ON PERIPHERAL MONONUCLEAR LEUCOCYTES (MNL) E . Haen, ' I. Langenmayer, " H. Emslander,* *H. Heus inger , * " Μ. H a l l e k " and J . Remien*

'Walther-Straub-Institute of Pharmacology and Toxicology, Nussbaumstr. 26, D-8000 München 2, F.R.G. **I. 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 thma , theophyl l ine

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

The react ion of hormone receptors to s y s t e m i c a l i y admin is te red drugs may be studied on i n -t a c t mononuclear l eucocytes (MNL ) . ß2-adrenoceptors respond to ß-sympathomimetics w i th a so ca l l ed "down-regu lat ion" , i .e. a dec rease of the number of expressed receptor s i tes (Aarons e t a l 1983). The opposite e f f e c t , receptor "up - regu la t ion" may be ach ieved wi th ß-blockers such as propranolol (Aarons et a l 1980). Theophyl l ine may i n t e r a c t w i th the i n -t r a ce l l u l a r c A M P sys tem which in M N L is coupled among others to ß2~adrenoceptors. This d r u g i s cu r r en t l y being r ecommended for the prevention of nocturna l a s t h m a t i c a t t a c k s ( B a r n e s 1984) . It is of in te res t , there fore , to study the e f f ec t of the rapeut i c theophy l -l i n e c o n c e n t r a t i o n s on t h e c i r c a d i a n var ia t ion in the express ion and funct ion of ß2~adrenoceptor s i tes (Panger l et a l 1986, Haen 1987) in male a s t h m a t i c pat ients suf -fering from nocturnal asthma (Haen et a l 1988).

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

Four so far untreated male a s t h m a t i c pat ients , 19-27 years of age, were given 1050 mg/day theophylline (Bronchoretard^- , K l inge P h a r m a M u n i c h / F R G ) . The dosage was divided in 1/3 (350 mg) at 08h00 and 2/3 (700 mg) a t 22h00 because of the c i r c a d i a n var ia t ion in the s e -rum concent ra t ion/t ime profile of this drug (Scott et a l 1981). Be fore t r e a t m e n t and on day 7 venous blood was drawn at l^hOO, 18h00, 22h00, 02h00, 06h00, lOhOO, and again at l^hOO. T h e blood spec imen were immed i a t e l y assayed for the number of high a f f in i ty ß-adre-n e r g i c binding s i tes (B -max ) on i n t a c t l ymphocytes , using a receptor binding assay ( A n -n a up l e t a l 1988) with ^ I - c y a n o p i n d o l o l , a ß-antagonist. ß2~adrenoceptor coupled a d e n y l a t e c y c l a s e was s t imu la ted by incubat ing the in tac t ce l l s with 10~7 mol/1 i s o -p rena l ine for 5 minutes at 37°C; the inc rease of in t race l lu l a r c A M P above basal va lues was determined by rad io - immunoassay a f ter c e l l d isruption.

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

171

172 Ε. Haen et al.

The subjects were asked to follow a regular l i f e - s t y l e for the two weeks preceed ing the study wi th bed rest between 23h00 and 07h00. On the day of the study the sub jects s t ayed i n the c l i n i c a l pharmaco log ica l r e s e a r c h unit of the hospita l . They continued to follow their normal dai ly rout ine. Subjects we re asked to record m e a l t i m e s , the consumption of a l c o h o l and Coffein. A l l were non-smokers .

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 s ingle cosinor method (Ha lberg et a l 1967 ) a n d by ana l y s i s of v a r i ance (anova) . S i gn i f i cance l im i t was p < 0 . 0 5 .

R E S U L T S

The theophyl l ine dosing s c h e m e resulted in p l a sma drug concent ra t i ons of 8 -13 ug/ml on day 7 ( F i g . 1). Resp i r a to ry funct ion markedly improved , wh ich matched the sub ject ive r e l i e f of complaints. E spec i a l l y the "noc tu rna l dip" in peak exp i ratory flow was much less p ro n o u n c e d (F i g . 2) ind icat ing that theophyl l ine was most e f f e c t i v e between 02h00 and 0 6 h 0 0 w h e n p l a s m a drug concent ra t ions were in the upper range (F i g . 1).

Fig . 1. Theophyl l ine p lasma concent ra t ion in male a s t h m a t i c pat ients on day 7 of 1050 mg/d t h e o p h y l l i n e ( x + S E ) .

ο — ο untreated I /min — — on day 7 of 1050 mg/d theophylline

U 18°° 22°° 02°° 06°° 10 0 0 H°° time of day (h)

Fig . 2. Peak exp i ratory flow of male a s t h m a t i c pat ients before and on day 7 of 1050 mg/d t h e o p h y l l i n e ( x + S E ) .

Unequal twice daily theophylline 173

T h e c i r c ad i an va r i a t i on in the express ion of ß2~adrenoceptor s i t e s was preserved a f te r treatment with theophyl l ine ( F i g . 3). Peak dayt ime values , however , we re reduced r e s u l -ting in a sma l l e r c i r c ad i an range of 63 .1 -139.0 % of 24h -mean (compared to 59 .1 -155 .2 % of 2 4 h - m e a n before t r e a tment ) . The 24h -mean i tse l f was lowered from 1014+119 s i tes/ c e l l to 853+87 s i tes c e l l (x+SE) equiva lent to a receptor down-regulat ion of 15.9 % (not s i g n i f i c a n t ) .

sites/cell

- o untreated on day 7 of 1050 mg/d theophyllir

>. 1800

I uoo-I 1000-I 600 "8 200·

Fig. 3. ß2~Adrenoceptor density on per iphera l mononuclear l eucocy te s of ma le a s t h m a t i c p a t i e n t s before and on day 7 of 1050 mg/d theophyl l ine (x+SE) .

Inspite of the reduced ß2~adrenoceptor density during the day basal c A M P contents of the cells were equal ly e l evated throughout the 24 hours (F i g . 4). The c i r c a d i a n va r i a t ion w a s p r e s e r v e d with a 24h -mean increased from 4.8+0.4 pmol/10^ c e l l s to 8.3+0.6 p m o l / 1 0 ^ c e l l s (x + S E , n o t s i g n i f i c a n t ) . ß2~adrenoceptor c o u p l e d a d e n y l a t e c y c l a s e c o u l d s t i l l be s t i m u l a t e d by 1 0 " ^ mol/1 i soprena l ine to 9.6+0.6 pmol/ 1 0 6 ( 2 4 h - m e a n + S E ) c e l l s ( i n c r e a s e of 1.3 p m o l / 1 0 6 c e l l s c o m p a r e d to 2.0 p m o l / 1 0 6 c e l l s b e f o r e t r ea tment , F i g . 4, Haen et a l 1988).

timt of day (h)

Fig. 4. C y c l i c AMP content of per iphera l mononuclear l eucocy t e s from male a s t h m a t i c pa -tients on day 7 of 1050 mg/d theophyl l ine before and a f ter in v i t ro s t imula t ion by 1 0 - 7 rriol/1 isoprenal ine (x+SE).

174 Ε. Haen et al,

D I S C U S S I O N

A 25 % down-regulat ion of ß2~adrenoceptors by theophyl l ine t r e a t m e n t was a l ready d e -s c r i b e d by S c a r p a c e et a l in 1982 in a non-chronobio logica l study. Such an e f f e c t could be m e d i a t e d v ia s t imulat ion of c a t e c h o l a m i n e sec re t i on by theophyl l ine (Hedquist et a l 1978) and/or v i a an inc reased i n t r a c e l l u l a r c A M P content , s ince a c A M P dependent protein k i n a s e has been suggested to be responsib le for receptor down-regulat ion (He lmre i ch & P feu f f e r 1985). The adrenoceptor down-regu lat ion by theophyl l ine is c l i n i c a l l y i r r e l avant in asthma therapy, s ince resp i ratory funct ion is on the cont ra ry marked ly improved. H o w -e v e r , t h e reduced response of the adeny l a te c y c l a s e sy s t em to ß-adrenergic s t imul i (as compared to p re t r ea tment , Haen et a l 1988) may be re levant to a combinat ion of theophy l -l ine w i th ß-sympathomimetic drugs. ß-Sympathomimetics may inc r ea se the e f f ec t i veness of a t h e o p h y l l i n e therapy, but both drugs a r e less than addi t ive in e f f ec t .

R E F E R E N C E S

1. Aarons R D , Nies AS , G a l 3, Hegs t rand L R , Molinoff P B (1980). E l e va t i on of ß-Adrener-gic Receptor Dens i ty in Human L y m p h o c y t e s a f ter Propranolo l Admin i s t r a t i on . 3 C l i n Invest 65, 949-957

2. Aarons R D , Nies AS , Gerber 3 G , Molinoff P B (1983). D e c r e a s e d B e t a Adrenerg ic R e c e p t o r Density on Human L y m p h o c y t e s a f t e r C h r o n i c T r e a t m e n t with Agonists . 3 P h a r m a c o l E x p Ther 224, 1-6

3 . Anhäup l Τ, L i e b l Β, R e m i e n 3 (1988) . K i n e t i c and Equi l i b r ium Studies of ( - ) 1 2 5 I o d o -cyanopindolol 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 for the E x i s t e n c e o f 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)

4 . B a r n e s P3 (1984). Nocturna l A s t h m a : Mechan isms and T r e a t m e n t . B r i t Med 3 288, 1397-1398

5. Haen Ε (1987). The Pe r iphe 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 tu rbances : A s t h m a t i c D i seases . Bu l l Eur Phys iopatho l Re sp 22, 539-541

6. Haen E , Langenmayer I, Ems lande r Η, Weber Ν, R e m i e n 3 (1988). C i r c a d i a n Var i a t ion in t h e E x p r e s s i o n of ß2~Adrenoceptor S i tes in Male A s t h m a t i c Pa t i en t s . Ann R e v Chronopharmacol 5 (this volume)

7. Halberg F , Tong Y L , 3ohnson Ε A (1967) . C i r c a d i a n Sys tem Phase - An Aspec t of T e m p o r a l Morpho 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 -r h y t h m s (ed Η ν Mayersbach ) , Spr inger Ver l ag Ber l in/Heidelberg/New Y o r k , pp 20 -48

8 . H e d q u i s t P, F redho lm BB , Ölundh S (1978). Antagon i s t i c E f f e c t s of Theophyl l ine and Adenos ine on Adrenerg i c Neuroe f fector T ransmiss ion in the Rabb i t K i d n e y . C i r c u l Res 43, 592-598

9 . H e l m r e i c h E 3 M , Pfeuf fer Τ (1985). Regu la t ion of Signal T ransduct ion by ß-Adrenergic Hormone Receptors . Trends P h a r m a c o l Se i 6, 438 -443

10 . Panger 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

11. S c a r p a c e P3 , 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

1 2 . S c o t t P H , MacLeod S, Newth C (1981). Susta ined R e l e a s e Theophyl l ine for Chi ldhood A s t h m a . E v i d e n c e for C i r c a d i a n V a r i a t i o n of Theophy l l i ne P h a r m a c o k i n e t i c s . 3 Ped i a t r i c s 99, 476 -479

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 grateful ly 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 L e m m e r m a n n , Sybi l le K i r z i nge r , and Iris R e i t h m e i e r . Without their ready a c c e p -tance to work overtime this study would have been impossible to per form.