ANNUAL REVIEW OF CHRONOPHARMACOLOGY

Vo lume 1

BIOLOGICAL RHYTHMS AND MEDICATIONS P r o c e e d i n g s of t h e F i r s t M o n t r e u x C o n f e r e n c e of C h r o n o p h a r m a c o l o g y , M o n t r e u x , 2 6 - 3 0 M a r c h 1984

Edi tors :

A. R E I N B E R G F o n d a t i o n A . d e R o t h s c h i l d , P a r i s , F r a n c e

M . S M O L E N S K Y U n i v e r s i t y of T e x a s , H o u s t o n , U . S . A .

G. L A B R E C Q U E U n i v e r s i t e d e L a v a l , Q u e b e c , C a n a d a

PERGAMON PRESS OXFORD • NEW YORK TORONTO • SYDNEY • PARIS • FRANKFURT

C O N T E N T S

Section 1 — Neurobiology Cha i rmen : A . WIRZ-JUSTICE (Basel, Switzerland)

W. R IETVELD (Leiden, Netherland)

The effect of part ia l lesions of the hypothalamic suprachiasmatic nucleus on the circadian control of behaviour

W. J . R I E T V E L D

In v i v o vol tammetry: monitoring drug induced changes in 5HT at the suprachiasmatic nucleus level

K. F. M A R T I N and C. A . M A R S D E N

Effect of prolonged administrat ion of clomipramine on 24-hour Variation in 5HT metabol ism in the rat brain

K. F. M A R T I N and P. H. R E D F E R N

Chronopharmacological alterations in pentobarbital induced hypnosis and body temperature produced by drugs inf luencing brain monoamines

S. G. S P E C I A L E and A. H. F R I E D M A N

Circadian dysrhythmias in the E E G of chi ldren w i th clonazepam treatment

B. A R B O G A S T , M . H A L L E K , H. A R B O G A S T , T. HELLBRÜGGE and R. SCHMID

Temporal and sex related variations of lorazepam kinetics B. B R U G U E R O L L E , G. B O U V E N O T and R. B A R T O L I N

Effects of different treatments on the circadian rhythm of plasma prolactin in Parkinson's disease

E. FERRARI , G. MICIELI , P. A . BOSSOLO, E. MARTIGNONI , L. M A G N A N I and G. NAPP I

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xiv Contents

Circad ian rhythms in the w a k i n g E E G 29 A . G U N D E L

Circad ian patterns of p l asma 3-methoxy-4-hydroxyphenylg lyco l (MHPG) i n normal and depressed subjects 33

A . H A L A R I S

Ci rcad ian dysrhy thmia i n the behavior of epi leptic chi ldren w i t h c lonazepam and/or phenobarb i ta l treatment 37

M . H A L L E K , B. A R B O G A S T , T. HELLBRÜGGE, R. SCHMID , H . A R B O G A S T and B. KLE ISER

Quanti tat ive chronopharmacodynamic endpoint in hea l th and schizophrenia : t im ing of p lasma dehydroepiandrosterone (DHEA) versus DHEA-su l fa te 41

B. KLEISER, F. H A L B E R G , G. C O R N E L I S S E N and C. V A N V A L K E N B U R G

Effect of benztropine on p lasma haloper idol chronopharmacology and blood chol ine levels i n man 45

R. S. N A T H A N , J . M . P E R E L , I. H A N I N , U. KOPP, T. M C C A R T H Y and R. ST ILLER

A comparison of three-t ime-dai ly and Single dose regime of haloperidol 49

R. L U N D and E. RÜTHER

Gamma-aminobutyr ic ac id and the neura l basis of c ircadian t imekeeping: impl icat ions for pathophysio logy and psychopharmacotherapy of c i rcadian based disorders 53

D. BORSOOK, M . C. M O O R E - E D E , T. H E D B E R G , G. R I C H A R D S O N and M . J . W. B R E N N A N

Section 2 — Antihistamines & Bronchodilators

C h a i r m e n : M . S M O L E N S K Y (Houston, Texas, U.S.A.) A . R E I N B E R G (Paris, France)

Ant ih is tamine and other effects of 5 m g mequitaz ine vary be tween morn ing and evening acute administrat ion 57

A . R E I N B E R G , F. LEV I , J . P. F O U R T I L L A N , C. PEIFFER, A . B I C A K O V A - R O C H E R and A . N I C O L A I

Contents x v

Biologie t ime re lated changes in ant i -histamine and other effects of chronic administrat ion of mequi taz ine in healthy adul ts 61

A . R E I N B E R G , F. LEV I , A . B I C A K O V A - R O C H E R , J . P. B L U M , M . M . O U E C H N I and A . N I C O L A I

Mu l t i c en t r i c chronotherapeut ic s tudy of mequi taz ine in pat ients w i t h allergic rhini t is 65

P. G E R V A I S

Compar i son of nocturnal a n d d iurna l theophyl l ine levels at steady-state 69

S. S A M A A N , R. F O X , S. B U K A N T Z and R. L O C K E Y

Chronopharmaco logy of theophyl l ine, w i t h specia l reference to age 73

J . H . G. J O N K M A N and M . H . S M O L E N S K Y

Circad ian rhythms in steady-state theophyl l ine pharmaeokinet ics i n ch i ldren 77

W. G. K R A M E R , P. H . SCOTT , M . H . S M O L E N S K Y , R. HARRIST , P. H IATT , J . B A E N Z I G E R , B. K L A N K and H . E I G E N

Circadian Variat ion in theophyl l ine absorpt ion 81 M . St. PEIRRE, S. L E E D E R , M . SPINO, A . ISLES and S. M a c L E O D

Variat ion i n theophyl l ine levels fo l lowing morn ing or evening administrat ion 85

W. R. P R I M R O S E

The effect of sustained-release theophyl l ine on the c ircadian Variation of pulmonary funetion in pediatr ic asthmat ic patients 89

P. SCOTT, R. HARRIST, M . S M O L E N S K Y , W. K R A M E R , P. HIATT, J . B A E N Z I G E R , B. K L A N K and H . E I G E N

A chronopharmaeokinetie mode l for controlled-release formulations 93

A . S T R A U G H N , M . M E Y E R , A . G O L U B and M . G O N Z A L E Z

Chronopharmacokinet ics of caffeine in heal thy volunteers 97 M . LEVY , L. G R A N I T and E. Z Y L B E R - K A T Z

Slow release terbutal ine i n nocturna l bronchia l obstruetion: relation of terbutal ine dosage and b lood levels w i t h c ircadian changes in peak f low values 101

D. S. P O S T M A , G. H . K O E T E R , H . M E U R S and J . J . K E Y Z E R

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Nocturna l bronchia l obstruct ion: influence of s low release terbutal ine on c ircadian rhy thm of spirometry, histamine and catecholamines 105

D. S. P O S T M A , G. H . K O E T E R , H . M E U R S and J . J . K E Y Z E R

Section 3 — Anticancerous Medications & Cancer C h a i r m e n : L. E. S C H E V I N G (Little Rock, Arkansas ,

U.S.A.) E. H A U S (Saint-Paul, M inn . , U.S.A.)

M e a l schedul ing, fasting, cel lular rhythms and chronoptherapy of Cancer 109

L. A . S C H E V I N G , T. H . TSAI , L. E. S C H E V I N G and J . E. P A U L Y

Circadian Variation in serum concentrat ion of carcinoembryonic ant igen (CEA) is altered in Cancer patients 111

C. F O C A N , V . C A S T R O N O V O , J . C O L L E T T E , D. F O C A N -H E N R A R D , M . H . F R E R E , S. L E H U N G , Y. TOUITOU and P. F R A N C H I M O N T

Circadian rhy thm in c isp lat in b ind ing on p lasma proteins 115 B. H E C Q U E T , J . M E Y N A D I E R , J . B O N N E T E R R E and L. ADENIS

Circadian chronopharmacokinet ics and chronotoxicology of doxorubic in and c isp lat in in h u m a n beings w i t h Cancer 119

W. J . M . H R U S H E S K Y

Prote in synthesis in human tumor cel l populat ions — governed by per iodical ly transferred Signals 123

T. L E D E R E R , A . L E H M E R and K. ZÄNKER

Chronopharmacology: a cr i t ical stage in the development of anticancer drugs? T H P adr iamyc in as an example 127

F. LEVI , J . P. B L U M , G. L E M A I G R E , M . M E C H K O U R I , A . R O U L O N , A . R E I N B E R G and G. M A T H E

Circadian rhythms in 6 c i rculat ing lymphocyte Subtypes in healthy men: a 100-fold Variat ion may be Physiologie 131

F. LEVI , C. C A N O N , J . P. B L U M , J . L. MISSET, M . M E C H K O U R I , M . B E N N A C E U R and G. M A T H E

Mult i f requency chronotherapy w i t h c ircaseptan and eventually c i rcannual opt imizat ion may fol low early c ircadian-sinusoidal pump- implemented infusions of cyclosporine 133

T. LIU, M . C A V A L L I N I , F. H A L B E R G , G. C O R N E L I S S E N , J . F IELD and D. E. R. S U T H E R L A N D

Contents x v i i

Chronobio logy of urate excret ion after cytostat ic treatment 137 M . H . R O B I N S O N , M . S. K N A P P and R. P O W N A L L

P lasma carc inoembryonic ant igen rhy thm in pat ients w i t h ovar ian cancer : effects of chemotherapy 141

Y. TOUITOU, W. H R U S H E S K Y , C. F O C A N , A . A U Z E B Y and A . B O G D A N

Effect of cort icosteroids and melatonin on the c i radian rhy thm of methotrexate toxic i ty i n the rat 145

J . E N G L I S H , G. W. A H E R N E and J . A R E N D T

The effect of c i rcadian rhy thm on immune function and splenic l ymphocyte subset ratios in mice 149

G. F E R N A N D E S , N . T A L A L and J . D E HÄVEN

Section 4 — Statistics, Methods and Instrumentation (Including Pumps)

C h a i r m e n : J . De PRINS (Brüssels, Belgium) W. H R U S H E S K Y (Minneapol is , M i n n . . U.S.A.)

Serial sect ion w i t h flexible per iod correction and an appl icat ion in longterm E E G analysis 153

B. A R B O G A S T and T H . HELLBRÜGGE

Automat ic detect ion of mult ip le outl iers i n Physiologie t ime series: notably temperature 157

G. C O R N E L I S S E N

The development of n e w Statist ical methods for event detection in t ime series 161

R. P O W N A L L , K. G O R D O N , M . S. K N A P P and A . F. M . S M I T H

Cortisol marker rhythmometry in pediatr ics and cl inical pharmacology 165

E. H A E N , F. H A L B E R G and G. C O R N E L I S S E N

Circadian and u l t rad ian rhy thm per iod alterations in apparently healthy subjects w i t h and w i thout placebo 169

A . B I C A K O V A - R O C H E R , A . G O R C E I X and A . N I C O L A I

A chronopharmacological mode l of psychotropic drug act ion and its pract ical inc idence on phases I and II methodology 173

J . D O U C H A M P S , J . L. GUISSET, J . P. B I N O N , J . M . B A R R E , B. GHISTE and P. T U B E L L O

A n experimental des ign for eva luat ing treatment effects and circadian rhythm in respiratory function 177

R. B. HARRIST, M . H . S M O L E N S K Y and P. H . SCOTT

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Rhythmometry analysis on personal Computers for applications to chronopharmacology studies 181

B. P. HSI

Microprocessor-based ambulatory temperature and activity recorder 183

J . N O U G U I E R - S O U L E and J . N O U G U I E R

Diurnal Variation in glucose levels can impede Single rate continuous intravenous insu l in therapy 185

E. P. C H U T E , T. D. R O H D E , W. M . RUPP, F. J . G O L D E N B E R G , W. J . M . H R U S H E S K Y and H. B U C H W A L D

A new technique to s tudy the effect of dynamic administrat ion of b iochemica l agents in v i t r o and in v i v o 189

M . L. G R U E N B E R G and J . J . P E L U S O

Implantable and extracorporeal programmable d rug delivery Systems: wha t to program 193

B. J . K E N N E D Y , D. C O V E L L and W. J . M . HRUSHESKY

A phase I tr ia l of an implanted l i th ium battery-powered drug administrat ion device System (DADS, Medtronic , inc.) for continuous doxorubic in infusion (CDI) 197

N. J . V O G E L Z A N G

Microcomputer-re lated modules for exper imental standardizat ion and temperature-act iv i ty-rhythmometry in pharmacology, toxicology and biology 201

E. H A L B E R G , B. B R O C K W A Y , D. OSGOOD, W. NELSON, J . H A L B E R G , S. S A N C H E Z De L a P E N A and F. H A L B E R G

Section 5 — Endocrinology & Reproduction

C h a i r m e n : I. A S S E N M A C H E R (Montpell ier, France) Y. T O U I T O U (Paris, France)

Regulat ion and drug effect on the l ight-dependent circadian prolact in rhythms in estrogen pr imed female rats 205

R. DOROW, H . W A C H T E L , K. J . RETTIG, S. H A S A N and R. H O R O W S K I

Pineal rhythms: modi f icat ion by drugs and l ight 207 R. J . REITER

Contents xix

The use of two different l i gh t ing reg imens al lows the dissociat ion of the mechan isms responsible for the act ion of melaton in on estrous cycles and those provoking the proestrous surge of gonadotropins 211

R. W. RIVEST, U . L A N G , M . L. ÄUßERT, M . F. N A W R A T I L , A . S C H E R R E R and P. C. S I Z O N E N K O

Apparent absence of inf luence of melatonin on the c ircadian rhy thm i n cel l d i v i s ion 215

N . H . RUBIN, R. J . RE ITER and J . A . H O K A N S O N

Circadian rhy thm in c A M P content and in the activit ies of basal adenylate cyclase and Phosphodiesterase i n rat heart ventncles 219

P.-H. L A N G , H . BISSINGER and B. L E M M E R

Circannual peak-shift in c i rcadian rhy thm in basa l c A M P content in rat heart ventr ic les 223

B. L E M M E R , P. -H. L A N G and H . BISSINGER

Interference w i t h c i rcadian rhythms of hemopoies is by a synthetic hemoregulatory pept ide 227

0. D. L A E R U M and W. R. P A U K O V I T S

Seasonal variations i n the humora l immune response i n mice fol lowing administrat ion of thymic hormones 231

M . D O U C E T - J A B O E U F , A . P E L E G R I N , M . C. COT , J . G U I L L E M A I N and M . B A S T I D E

Circadian dependent effect of ep idermal g r ow th factor, insul in and g lucagon on hepat ic pyruvate k inase and malic enzyme of mice 235

R. J . FEUERS, R. R. D E L O N G C H A M P , L. A . S C H E V I N G , T. H. TSAI, D. A . C A S C I A N O , J . E . P A U L Y and L. E. S C H E V I N G

Responses of nymphs of the large m i l kweed b u g and pupae of the yel low mea lworm to three Compounds affecting insect growth 239

R. E. R E D F E R N , D. K. H A Y E S , J . D. W A R T H E N , JR., A. B. DeMILO and T. P. M c G O V E R N

Loss of circadian rhythmic i ty in p lasma testosterone levels in adult men w i th Cush ing ' s Syndrome or under long-term treatment w i th glucocort icoids 243

A. ANGEL I , G. B E L L O T T I , C. D E M I C H E L I , G. GATTI , R. C A V A L L O , V. G A L L O and F. A G R I M O N T I

X X Contents

Circadian patterns of cort isol and aldosterone in p lasma, urine and per i toneal f luid of chronic uremic pat ients under continuous ambulatory per i toneal dialysis 247

F. A G R I M O N T I , G. TRIOLO, M . S A L O M O N E , D. BISBOCCI , G. P INNA, C. M A R I N O N E and A . A N G E L I

Circadian-effect of somatostat in, g lucagon, insul in , epidermal g rowth factor, pentagastr in and A C T H 1—17 on cel l proliferation in mice 251

L. E. S C H E V I N G , T. H . TSAI , L. A . S C H E V I N G and J . E. P A U L Y

Section 6 — Metabolism & Nutrition C h a i r m e n : H . N A K A G A W A (Osaka, Japan)

A . A N G E L I (Torino, Italy)

Circadian rhythms of food intake and prote in select ion in young and old rats 255

P. D. L E A T H W O O D and L. A R I M A N A N A

Chronopharmacological studies on central regulat ion of blood sugar homeostasis 259

H . N A K A G A W A , K. N A G AI, T. M O R I and H. Y A M A M O T O

Role of feeding schedule and pharmacokinet ics in chronopharmacology of drugs act ing on the central nervous System 263

S. N A K A N O , K. N A G A I and N . O G A W A

Circadian and c i rcahemid ian variat ions of the active ca lc ium absorption: effects of dietry and environmental changes 267

D. PANSU , C. R O C H E , C. B E L L A T O N , M . M E C H K O U R I and TH. T E U V E N Y

Cosinor and spectral analysis of c ircannual rhythms of mucous, acid and pept ic gastr ic secretions in cats 271

D. PANSU, M . V A G N E , M . COLL INET , A . D E S V I G N E , A . R E I N B E R G and M . M E C H K O U R I

Circadian variat ions of p lasma histamine and c irculat ing leucocyte Subtypes in magnes ium deprived rats

M . B E N N A C E U R , O. F E R M E N T , B. L E B E L and 275 F. G A U D I N - H A R D I N G

Ultradian, c i rcadian and c i rcannual rhythms of blood glucose and injected insu l in documented in self-controlled diabetics 279

M . KOLLOP , A . B I C A K O V A - R O C H E R , P. DROUIN, L. M E J E A N and G. D E B R Y

Contents xx i

Corre lat ion b e t w e e n circadian-stage dependent variat ions of oral g lucose tolerance test and al imentary patterns in young subjects w i t h diabet ic family history 283

P. M A R R I N O , G. R A V A G L I A , M . C A P E L L I , S. E . C O G L I A N D R O , F. A G R I M O N T I , D. F O R N A R O and A . LODI

C i rcad ian a n d u l t rad ian rhythms i n acute respiratory failure: effects of bo th cont inuous enteral feeding and ranit idine (H2 receptor blocker) infusion at constant rate 287

J . P. A C C A R Y , D. R I G A U D , J . C H A S T R E , F. C A N T O W I T Z , C. G I B E R T and S. B O N F I L S

Postoperative enteral feeding patterns and d iurnal temperature rhythms 291

I. T. C A M P B E L L , R. P. M O R T O N and P. M . S T E L L

Cl in ica l s tudy of cycl ic (nocturnal) total parenteral and cont inuous enteral nutr i t ion ( including lipids) on c ircadian rhythms i n serum l ip ids, l ipoproteins, apol ipoproteins and glucose 295

J . F A B R E , O. G U I L L A R D , D. REISS and C. M A T U C H A N S K Y

Observations on the pharmacokinet ics of ethanol 297 D. L A K A T U A , T. S. L E S A R , D. E. Z A S K E , W. A . W A R G I N and E. H A U S

Circadian rhythms of insul ine and H G H secret ion in heal thy and diabetic chi ldren 301

A. MROZIK IEWICZ and D. K I E L C Z E W S K A - M R O Z I K I E W I C Z

Increased stomach size and mortal i ty observed in ad l i b i t u m fed C D 2 F a adult male mice injected w i t h insul in , g lucagon, epidermal g rowth factor, saliva, or sympathomet ic submandibular g land St imulat ion 305

L. A . S C H E V I N G , T. H. TSAI, L. E. S C H E V I N G and J . E. P A U L Y

Section 7 — Cardiovascular and Antiinflammatory Agents

C h a i r m e n : B. L E M M E R (Frankfurt/M., West Germany G. L A B R E C Q U E (Quebec, Canada)

Biological rhy thm stüdies on the hypotensive act ion of Prostaglandin E 2 and arachidonic ac id in the rat 309

F. DORE, G. L A B R E C Q U E , C. D ' A U T E U I L and P. M . B E L A N G E R

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Chronopharmacolog ica l studies of diuretics in hypertensive rats 313

F. DORE, C. D ' A U T E U I L , G. L A B R E C Q U E and P. M . B E L A N G E R

Chronopharmacokinet ics of the beta-adrenoceptor-blocking drugs Propranolol, metoprolol , Sotalol and atenolol in p lasma and organs after Single and mult ip le dos ing in the rat 317

B. L E M M E R , H . W I N K L E R , M . F INK and T. O H M

Circadian-stage-dependency i n antagonist b ind ing of 3 H-dihydroalprenolo l to rat heart ventr icular membranes 321

B. L E M M E R and P.-H. L A N G

The Sine-O-Graph pulse monitor : a potent ia l quantif ier of cardiovascular Wel lness 325

W. J . M . H R U S H E S K Y

Circatr ig intan and c i rcannual ang ina crises and isosorbide dinitrate compliance rhythms 329

R. W. MORRIS

Circadian rhy thm studies on B C G - i n d u c e d migrat ion of P M N in normal and adrenalectomized mice 333

J . P. B U R E A U , L. G A R R E L L Y , M . C O U P E and G. L A B R E C Q U E

Circannual rhythms of P M N migrat ion induced by B C G in intact mice 337

J . P. B U R E A U , M . C O U P E , L. G A R R E L L Y and G L A B R E C Q U E

Chronopharmacokinet ic s tudy of indomethac in 341 G. CUISINAUD, P. GUISSOU and J . S A S S A R D

Chronotherapy of osteoarthrit ic pat ients: opt imizat ion of indomethacin susta ined release (ISR) 345

F. LEVI , C. Le L O U A R N and A . R E I N B E R G

Chronobiological considerat ions of aspir in and indomethac in 349 L. PÖLLMANN

Ketoprofen chronokinetics in human volunteers 353 P. Q U E N E A U , M . O L L A G N I E R , H . D E C O U S U S , Y. C H E R R A H and B. PERPOINT

Prel iminary observations from a double b l ind crossover study to evaluate the efficacy of f lurbiprofen g iven at different t imes of day in the treatment of rheumatoid arthrit is 357

V. R E J H O L E C , V. V I T U L O V A and J . V A C H T E N H E I M

Contents

Ci r cad ian a n d about-7-day (circaseptan) cardiovascular Var iat ion unde r treatment w i t h the ß-adrenergic blocker Penbuto lo l

F. H A L B E R G , E. H A L B E R G , F. C A R A N D E N T E and E. H A U S

Section 8 — (A) Toxicology and (B) Aspects of Chronotherapeutics

C h a i r m e n : M . K N A P P (Nott ingham, England) I. A S H K E N A Z I (Tel Av iv , Israel)

Chronotherapeut ics — the importance of the ind iv idua l and the need for an ind iv idua l approach in therapeut ic trials and in therapy

M . S. K N A P P Chronobioassay of rad iat ion injury i n mice w i t h and wi thout t ime shift

B. J . A R B O G A S T and A . L. G E R B E S Influence of t ime of exposure to carbon tetrachloride on toxic l iver injury

J . V . B R U C K N E R , R. L U T H R A , G. M . K Y L E , S. M U R A L I D H A R A , R. R A M A N A T H A N and D. A C O S T A

T ime dependent mercuric Chloride induced acute renal failure in rats and mice

J . C. C A L and J . C A M B A R Circadian variat ions i n the acute toxic i ty of three aminoglycosides: gentamic in , d ibekac in and net i lmic in in mice

C. PARIAT , J . C A M B A R and P H . COURTOIS

Effects of c ircadian rhy thm on kanamyc in induced hearing loss

J . F ISCH, A . Y O N O V I T Z and M . S M O L E N S K Y Mur ine circadian variat ions in suscept ib i l i ty to 4 a -demethyl-epipodophyllotoxin-ß-D-ethylidene glucoside (VP 16-213) as we l l as to the solvent alone i n w h i c h it was suspended

T. H. TSAI and L. E. S C H E V I N G Circadian variations i n the response to hypox ia studies in animals and man

C. H E C K M A N N and A . HARIRI

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Time-related effects of hazardous factors (hypoxia, hyperbar ism, etc.) on c ircadian rhythms of a set of Physiologie variables i n healthy young males 397

I. E. A S H K E N A Z I , J . R Y B A K and C. H A R E L Influence of sodium minera l waters on the c i rcadian Variation of urine exeretions 399

CHR. G U T E N B R U N N E R , K. F. HOLTZ , B. MÜLLER and M . PETRI

Chronobiological aspects of phys ica l eure treatment 403 G. H I L D E B R A N D T

Chronobiological approach to the treatment of Cluster headache by l i th ium carbonate 407

E. FERRAR I , P. A . BOSSOLO, G. B O N O , G. MICIELI , A . VA ILAT I , L. M A G N A N I , E. M A R T I G N O N I and G. N A P P I

Circadian and c ircaseptan aspects of malar ia l infection and cyclosporine treatment in mice 411

S. S A N C H E Z D E L A P E N A , P. WOOD, E. H A L B E R G , G. C O R N E L I S S E N , J . E A T O N and F. H A L B E R G

Author Index 415

Subject Index 419

C H R O N O B I O A S S A Y OF RADIATION INJURY IN M I C E WITH A N D WITHOUT T IME SHIFT B. J . Arbogast and A. L. Gerbes

Institute of Social Pediatrics, Lindwurmstrasse 131, and Klinikum Grosshadern, University of Munich, D-8000 Munich, F.R.G.

ABSTRACT

The relation between circadian tenperature amplitude and radioresistance was studied in three groups of male C3H mice two of V i l i c h were subjected to an 8-h time shift shortly before irradiation. In animals with unshifted schedu­le , the impact of the size of circadian temperature amplitude on radiation susceptibility showed a circadian rhythm depending on time of irradiation. Radiation injury cou]d be shown to cause circadian dyschronism of bcdy tem­perature and inhibition of resynchronization in time-shifted groups, the ex-tent of dissynchronization also depending on time of irradiation.

KEYWORDS

Radiation injury; circadian temperature parameters; mice; time shift; dys­chronism.

INTRODUCTION

Numerous investigations have shown that mammalian radiation response depends upon the phase of circadian Systems at exposure tijne (Lach and Srebro,1971, Lappenbusch, 1972) It now seems generally accepted that animals such as rats (Pizzarello et a l . , 1963) and mice (Pizzarello et a l . , 1964, Haus et a l . , 1971) show lower radiation susceptibility during the daily light as compared to the daily dark span (compare Gerbes and Arbogast, 1983) .Sudden time shift of synchronizer phase is known to impose considerable internal desynchroni-zation to biological Systems (Klein und Wegmann, 1975), before the organism accepts the new schedule. It seemed worth while to investigate

1) in which manner radiation response depends not only uoon the phase but also on the amplitude of circadian rhythms and

2) inhowfar radiation injury causes dyschronisms and inhibits the process of synchronization to a new schedule after time shift .

MATERIAL AM) METHODS

Three groups of male C3H mice were subjected to L:D 15:9 schedules (light 06co - 21 co, dark 21oo - 06oo) for 3 weeks, the schedules of groups II and III being shifted by 8 hours as compared to the schedule of crroun I. Circa­dian profiles of bcdy temperature were determined provina good synchroniza-

369

370 B . J . Arbogast and A . L . Gerbes

tion. Thereafter, groups II and III were suddenly shifted to the schedule of group I, resulting in a maximal reduction of the daily light and dark span-, respectively. At seven about eouidistant times durina the following day, subgroups (10 animals each) of groups I - III were exposed to whole-body X-irradiation (X-ray unit MG 300, C.H.F. K i l l e r , Hambura, F R n . 250 kv, 12 IQA, half-value layer 1.9 mm Cu, dose rate 88 cGy/min). At a focus-mouse distance of 40 cm, the total dose was 640 cGy. Ten animals ner group remai-ned without irradiation (controls). Mortality and temperature of each animal were measured for 30 days following irradiation as indicators of radiation susceptibility. On the 10th day following irradiation, again circadian tem­perature profiles were determined for a l l animals s t i l l alive. Stat ist ical analysis was performed on a Cyber 175 Computer using our own Fortran programs for linear rhythmometry.

RESULTS

The maximal reduction of bcdy temperature during the Observation span- as compared to a reference temperature before irradiation - was taken as a measure of radiosusceptibility (variable TEMPcLLf f) • Regressions of TEMP^iff on the amplitude of circadian temperature rhythm before irradiation - com-puted for a l l subgroups separately - revealed that in group I, the sub­groups irradiated at the end of the dark or begin of the light span ( few hours after the time of ccmputed greatest radiosusceptibility, see Gerbes and Arbogast, 1983) took advantages from low circadian amplitudes, while for animals irradiated at the end of the light or begin of the dark span, high circadian amplitudes were advantageous. There were no such effects in the time shifted groups II and III, possibly due to the onset of internal desynchronization after time shift . The slopes of the regressions of TEMPdiff o n circadian temperature amplitudes ccmputed within the irradia-tion subgroups are displayed in figure 1.

Slope of TEMPdiff on circadian temperature amplitude

Time of irradiation - 1 ""I

j • * r Figure 1: % 1 Slopes of TEMPdiff (maximal reduction of body temoera-

Acrophase ture as a measure of radiosensitivity) on circadian of Rad io - temperature amplitude one day before irradiation as s e n s i t i v i t y ccmputed by linear regression within a l l irradiation

subgroups, displayed versus time of irradiation.

Chronobioassay of rad ia t ion in jury in mice 371

Figure 2 shows Single cosinor ana-lysis of the data in figure 1. Besides the aforementioned fact that in group I (not time shifted), the impact of the size of circadian tem­perature amplitude exhibits a signi-ficant (pO.05) circadian rhythm which is not the case for the time shifted groups II and III, a global deterioration of radioresistance in case of high circadian temperature amplitudes is indicated by the fact that a l l mesors are greater than zero. This effect i s , however only significant for group III, since the confidence interval of i ts mesor does not include zero.

SINGLE COSINOR

DATA: SLOPE OF T(DIFFI ON AMPI (within 7 Irradiation subgroups)

I: not time shifted;II,III time shif-CDNF I HFNHF RFK I ANS ted

AMPLITUDE-ACROPHASE MESOR

Figure 2 Cosinors

of the data in figure 1

.761 0.00. 3.271

Circadian temperature profiles de-termined 10 days after irradiation (11 days after time shift for oroups II and III)were f inal ly used to study eventual dyschronisms caused by radiation injury. From the pooled control groups of groups I - III (a to­tal of 30 unirradiated ammals) , a Population mean cosinor was computed which proved gcod synchronization of a l l control animals to the new L:D schedule. The amplitude-acrophase-pairs of a l l irradiated animals which were s t i l l alive were then compared with a 10% - Parameterdesm computed from the control an:Lmals. (see figure 3) Just 54,3 % of the irradiated animals of group I had amplitude-acrophase pairs within the control paradesm: Radi­ation injury seems to cause circadian dyschronism. For groups II and III,

Figure 3:

Predicto-cosinor computed from con­trol ani­mals of groups I - III and ampli­tude-acro­phase pairs of irradiateJ animals:

» group I

grouo II

group

III

PREDICTO-COSI CONTROL GROUPS ONLY Circadian temperature rhythm

90%~PARAMFTFRT)FSMS AMPLITUDE-ACROPHASE

0

NOR

MESOR

PERIOD 2* HOURS (CIRCADIAN) z#m DARK t=D LIEHT

DATA p [MESOR SE

30 .OSO j 37.5!

.093

AMPLITUDE

ACROPHASE

3.4< 118.6. -22.91

372 B . J . Arbogast and A . L . Gerbes

the percentages of i r r a d i a t e d animals with ampl i tude-acrophase p a i r s of the c i r c a d i a n temperature rhythm wi th in the c o n t r o l paradesm was even lower (30 r e s p . 31.4 % ) i n d i c a t i n g i n h i b i t e d s y n c h r o n i z a t i o n to the L:D schedule a f t e r time s h i f t .

F igure 4: NUMBER OF ANIMALS WITH AMPLITUDE-ACROPHASE WITHIN PARADESM

The number of animals with ampl i tude-acrophase p a i r s wi th in the c o n t r o l paradesm, for each i r r a d i a t i o r ; group s e p a r a t e l y , i s d i s p l a y e d in f i g u r e 4. It can be seen that most cases of dyschronism occur in subgroups i r r a d i a t e d around the time of greatest r a d i o s u s c e p t i b i l i t y , e s p e c i a l l y in groups II and I I I .

REFERENCES

Gerbes, A . L . and Arbogas t , B . J . (1983). The i n f l u e n c e of time s h i f t on c i r c a d i a n rhythrn of s e n s i t i v i t y to X - i r r a d i -a t i o n in mice ( a b s t r . ) Chronob io log ia X,2 (p . 127)

H a u s , E . , Ha lberg , F . , Cohen, M. , Kim, Y . S . (1971). C i r c a d i a n rhythmometry of mammalian r a d i o s e n s i t i v i t y . In: Space Rad ia t ion B i o l o g y (C . T o b i a s , E d , ) , pp 435-474

K l e i n , K . E . , Wegmann, H.M. (1975). Das Verha l ten des m e n s c h l i ­chen Organismus beim Z e i t z o n e n f l u g . T e i l 1: Die z i r k a ­diane Rhytnmik und ihre D e s y n c h r o n i s a t i o n . Fort s e h r . Med. 93 (29) , pp 1407-1414

L a c h , H . , S r e b r o , Z . (1971). Changes in the d i u r n a l rhythm of neurosecre tory a c t i v i t y in the mouse fo l lowing X - i r r a -d i a t i o n . F o l i a B i o l . 19(2) , pp 239-297

Lappenbusch, W. (1972). E f f e c t of c i r c a d i a n rhythm on the ra c i a t i o n response of the Chinese harnster. Radiat . Res . 50, pp600-610

P i z z a r e l l o , D , 3 . , W i t c o f s k i , R . L . , Lyons, E . A . (1963). V a r i a -t i o n s in s u r v i v a l time a f t e r whole body r a d i a t i o n at two times of day. Sc ience 139, 349

P i z z a r e l l o , D . U . , Isaak, D . , Chua, K. (1964). C i r c a d i a n rhy th -m i c i t y in the s e n s i t i v i t y of two s t r a i n s of mice to whole-body r a d i a t i o n . Sc ience 145, pp 286-291