Archlvu of
Arch. Toxicol. 36, 327-339 (1976)
TOXICOLOGY 9 by Springer-Verlag 1976
New Aspects of Human Chronopharmacology* Alain Reinberg Equipe de Recherches de ChronobiologieHumaine (C.N.R.S. No. 105), Laboratoire de Physiologie,Fondation A. de Rothschild, 29, rue Manin, F-75019 Paris, France Abstract. Regular and thus predictable changes in biologic susceptibility and response to a large variety of physical as well as chemical agents can now be viewed as a rather common phenomenon. Chronopharmacology involves both the investigation of drug effects as a function of biologic timing and the investigation of drug effects upon rhythm characteristics. Illustrative examples of circadian chronopharmacology in man are discussed, keeping in mind that the objective demonstration of chronopharmacologic facts needs the use of an appropriate methodology. Circadian changes in the effects of various chemical agents have been documented: histamine, sodium salicylate, acetylcholine, halothane, prostaglandine F, reserpine, cyproheptadine, ethanol, insulin, chlorothiazide, oxymetholone, orciprenalin and SCH 1000 (bronchodilators), indomethacin, ACTH, cortisol and various synthetic corticosteroids. Three new concepts have to be considered: a. The Chronokinetic of a Drug. This term includes both rhythmic changes in the drug bioavailability, pharmacokinetic and its excretion. b. The Chronesthesy of a Biosystem to a Drug. i.e. circadian changes in the susceptibility of any biosystem to a drug. c. The Chronergy of a Drug, taking into consideration its chronokinetic and the chronesthesies of the involved organismic biosystems. Chronopharmacology is useful to solve problems of drug optimization, i.e. to enhance the desired efficiency or to reduce its undesired effects. In the human organism (among other animal species) the metabolic fate of a pharmacologic agent (as well as that of a nutrient) is not constant as a function of time. * Read at the Symposium"Relevanceof Chronobiologyfor Toxicologyand Pharmacology"held at the 16th Spring Meeting of the Deutsche PharmakologischeGesellschaft,Section: Toxicology,March 6, 1975, Mainz
328
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Thus, the chronobiologic approach of pharmacologic phenomena involves a lesser risk of errors and/or false information than the conventional homeostatic approach. Key words" Drugs - Chronokinetic - Chronesthesia - Chronergy - Optimization. Zusammenfassung. Regelm~iBig auftretende und daher vorhersehbare Ver~inderungen der biologischen Empfindlichkeit und Reaktion gegeniJber einer groBen Anzahl physikalischer und chemischer Agentien k6nnen heute als ein recht allgemeines Ph~inomen betrachtet werden. Die Chronopharmakologie umfaBt die Untersuchung der Effekte von Arzneimitteln als Funktion der Zeit und die Auswirkung von Arzneimitteln auf die Charakteristika biologischer Rhythmen. Beispiele fiir circadiane Chronopharmakologie beim Menschen werden unter Hinweis auf den Einsatz hierfiir geeigneter Methoden geschildert. Circadian bedingte Ver~inderungen von Substanzeffekten sind inzwischen ffir verschiedene chemische Agentien bekannt geworden. Sie wurden f'tir Histamin, Natriumsalicylat, Acetylcholin, Halothan, Prostaglandin F, Reserpin, Cyproheptadin, Athanol, Insulin, Chlorothiazid, Oxymetholon, Bronchodilatatoren wie Orciprenalin und SCH 1000, Indomethacin, ACTH, Cortisol und verschiedene andere synthetische Corticosteroide nachgewiesen. Drei neue Konzepte mfissen berficksichtigt werden: a. Die ,,Chronokinetik" eines Arzneimittels. Dieser Begriff beinhaltet die rhythmischen Ver~inderungen der biologischen VerfiJgbarkeit, der Pharmakokinetik und der Ausscheidung eines Arzneimittels. b. Die ,,Chronaesthesie" eines biologischen Systems gegeniiber einem Arzneimittel. Diese umfai3t circadiane Ver~inderungen der Empfindlichkeit eines Biosystems gegeniiber einem Arzneimittel. c. Die ,,Chronergie" eines Arzneimittels. Hierbei werden die ,,Chronokinetik" und die ,,Chronaesthesie" der betroffenen versehiedenen Biosysteme beriicksichtigt. Die Chronopharmakologie ist niitzlich zur Optimierung der Wirkung yon Arzneimitteln durch Verst~irkung erw~nschter Effekte oder durch Reduktion unerwiinschter Effekte. Wie bei allen Tierarten, ist auch beim Menschen der Metabofismus eines Pharmakons oder eines Nahrungsmittels nicht konstant, sondern unterliegt zeitabh/ingigen Schwankungen. Daher kommt es bei der Untersuchung pharmakologischer Ph~inomene unter Beriicksichtigung der chronobiologischen Erkenntnisse weniger zu Fehlern und/oder falschen Informationen als bei konventioneller homfostatischer Testung.
According to Aschoff [1] the first doctorial thesis on "biological clocks" was written by Julien-Joseph Virey in 1814 [2]. From (unquantified) examples, Virey concludes
New Aspects of Human Chronopharmacology
329
that any given drug (or food) is not indicated equally 1 at all hours (within the 24 h scale) and that we need urgently to learn more about this problem. As a matter of fact what is called now chronopharmacology has been simply ignored, from a scientific point of view, during more than 120 years. Credit has to be given to Jores [3], M t l l e r s t r t m [4] and Menzel [5] since the publication of their pioneer works shows the beginning of modern investigations in this field. Regular and thus predictable changes in biologic susceptibility and response to a large variety of physical as well as chemical agents (including foods and drugs) can now be viewed as a rather, c o m m o n phenomenon. This is true for both plants and animals [6, 7] including man. Experimental evidence of circadian ( ~ 24 h) circatrigentan ( ~ 30 days) and circannual ( ~ 1 year) changes in human biologic response to various agents, including drugs, has been presented in review papers by Reinberg et al. [6, 8 - 1 2 ] and/or Halberg et al. [ 13-20]. This rapidly growing number of chronobiologic facts leads to concepts such as: the hours of changing responsiveness (Halberg , [13, 14]; Reinberg [8, 9] circadian chronopharmacology [6], chronosusceptibility [9] etc. It has to be added that chronopharmacology involves both the investigation of drug effects as a function of biologic timing and the investigation of drug effects upon rhythm characteristics: the period, z, and/or the acrophase, ~, the amplitude, A, and the rhythm adjusted mean or mesor, M s. Taking into consideration that review papers have been published recently [6, 7, 12, 21, 22], aims of this presentation are mainly: 1. to give up-to-dated tables summarizing illustrative examples of circadian chronopharmacology in man; 2. to propose new concepts in chronopharmacology" mainly the biosystem chronesthesy, the chronopharmacokinetics and the chronergy of a drug (or a nutrient as well); 3. to show that chronopharmacology is useful to solve problems of drug optimization.
I. A Large Number of Illustrative Examples of Circadian Chronopharmaeology in Man has been Published and Reviewed
The objective demonstration of chronopharmacologic facts needs the use of an appropriate methodology [6, 19, 23, 24]. The chronobiologic study of any bioperiodic phenomenon, as to whether or not it can be called evident, must follow a set of elementary r u l e s , [16, 23] regarding 1 "... les hypnotiques, les narcotiques, ropium, hors les conjonctures extremes, ne seraient pas bien plac+s dans la matinte, lorsque routes les facultts tendent au r+veil; mais ces remtdes ont une action plus intense et plus salutaire, dans la soir+e, parce que les forces de la nature aspirent au sommeil et au repos" 2 The circadian period, T, is as a mean equal to 24 h when the period of synchronizer is also equal to 24 h. In man, the most powerful synchronizer for circadian rhythms is the alternation of the activityrest cycle related to our societal life [16, 19, 23]. Synchronizers may influence T, #, and A but they do not cause rhythms. The acrophase, # (for a given T) is the peak time of the best fitting sine function least squares method -- used to approximate all data. The amplitude A is equal to 1/2 the within-zrhythmic variability. The mesor, M, is the rhythm adjusted mean for the considered T
1 (4)
1 (4)
1 (4)
1 (4)
1 (4)
4 (6)
1 (6)
(6)
(~ 6)
12
06
11a
5
6
6
7
165 b
60 b
Prostaglandine b
Halothane b
Acetylcholine
Sodium salicylate
House dust extract
Penicillin
Histamine
48/80 (Histamine liberator)
Histamine
Chemical agent (fixed doses and multiple test times)
shorter induced abortion interval after injection
Lower amount of halothane used for anaesthesia
Bronchial reaction
Total duration of salicylate excretion in urines (oral administration)
Immediate skin reaction (erythema) to the antigen
Immediate skin reaction (erythema) to the antigen
Airways reactivity
Skin reactions (erythema and wheal) to intradermal injection
Skin reactions (erythema and wheal) to intradermal injection
Variable investigated
Nocturnal rest
Nocturnal rest
L (07.00--23.00) D (23.00--07.00)
L (07.00--23.00) D (23.00--07.00)
L (07.00--23.00) D (23.00--07.00)
L (07.00--23.00) D (23.00--07.00)
Nocturnal rest
L (07.30--23.30) D (23.30-07.30)
L (07.30--23.30) D (23.30--07.30)
Synchronizer schedule
--
--
29% (4--53)
12.3% (7.5--16.8)
38% (5--72)
41% (10--71)
--
38%
24% (19--29)
Amplitude C as per cent of 24 h mean (95% confidence
Reinberg et al. [29]
De Vries et al. [31], De Vries and Tammeling [32]
23.00
Midnight to 04.00
18.00
Between midnight and 06.00
14.2Z (11.01--17.53)
06.41 01.45--10.52
21.52 (16.32--01.08)
D. Smith et al. [37]
Fukani et al. [36]
Reinberg et al. [34, 35]
Reinberg et al. [33]
Reinberg et al. [30]
Reinberg et al. [30]
Reinberg et al. [29, 30] Smolensky et al. [24]
23.08 (21.44--00.48)
20.32 (18.48--04.00)
References
Acrophase c ~ in hour O origin: 00.00 h interval)
a Allergic patients b Presumably similar time groups; only one datum obtained from each patient c The acrophase (peak of the cosine function used to approximate the rhythm) is expressed in hours, minutes, with its 95% confidence interval when time series were analysed by cosinor method. Chronogram peak time for airway reactivity to histamine, and reactions to halothane and prostaglandine
No. of days (At, h)
No. of subjects
Table 1. Effects of chemical agents, including drugs, as a function of circadian system stage in human beings
o
7~
.>
New Aspects of Human Chronopharmacology
331
Table 2. Chemical agent effects upon circadian rhythms of human beings as a function of circadian state Group
Chemical agent Effect on circadian (fixed dose, rhythm multiple test times)
References
Mentally deficient adults
Reserpine
Alteration of body temperature circadian rhythm
Halberg [38]
Healthy adults
Cyproheptadine (per os) (antihistaminic drug)
Circadian changes in the duration of the inhibitory effect on skin reaction to histamine
Reinberg and Sidi [39]
Healthy adults
Ethanol (per os)
Circadian changes in blood ethanol concentration. Alteration in psychologic test circadian rhythms
Rutenfranz [40] Haus et al. [41] Reinberg et al. [42]
Healthy adults males
Quiadon | (tranquilizer)
Chronobiotic effect: rapid resynchronization of temperature rhythm
Simpson et al. [43]
Diabetics adults
Regular insulin
Alteration of eortisol circadian rhythm in plasma
Serio et al. [44]
Midly hypertensive subject
Chlorothiazide
Systolic and diastolic blood pressure mesor
Levine and Halberg [45]
Paraplegic patients
Oxymetholone
Minimization of hypercalciuria and bone demineralization
Moore Ede and Burr [46]
Healthy children
Orciprenalin
Chronoeffectiveness on lung resistance and dynamic compliance
Gaultier et al. [47]
Healthy children
SCH 1 0 0 0
Chronoeffectiveness on lung resistance and dynamic compliance
Gaultier et al. (unpublished)
Healthy adults
Insulin
Changes in plasma glucose, NEFA, growth hormone circadian rhythms
Gibson et al. [48]
Healthy adults
Sodium salicylate
Circadian changes in urinary pharmacokinetic
Reinberg et al. [49]
Healthy adults
Indomethacin |
Circadian changes in rhythm detection, and side effects
Reinberg and Clench (unpublished)
a) the subjects' synchronization (timing and regularity of the socio-ecologic synchronizer; i.e. light-on and light-off hours, meal timing, [22, 25] etc.; b) the time series of each of the studied physiological a n d / o r pathological variables (accuracy of measurements or determinations, span o f time for d a t a gathering - at least 24 h sampling interval - usually A t = 4 h - etc.); c) statistical analyses o f time series thus obtained: cosinor and related methods [20]. Moreover, circadian r h y t h m s can be modulated and modified b y coexisting r h y t h m s o f ~ 1 year and ~ 30 d a y s (mainly but not exclusively documented in women for the latter). Therefore, the month of the year (and the d a y of the monthly
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Table 3. Studies demonstrating that no or small adrenal inhibition and no or small subject's temporal structure alteration (e.g. acrophase shift) occurs when the corticosteroid is given once (or twice) a day not far from the expected acrophase of plasma cortisol circadian rhythm (i.e. around 08.00 for subjects synchronized with light-on at 07.00 and light-off at 23.00) Group
Used corticosteroid or ACTH fixed dose, multiple test times, (c) chronic, (a) acute medication (Route)
Explored variables
References
Healthy adults
Dexamethazone (c) (per os)
Plasma and urinary 17-OHCS
Nichols et al. [50] D'Agata et al. [51]
Healthy adults
Flumethazone (c) (per os)
Urinary 17-OHCS
Segre et al. [52]
Healthy adults
Triamcinolone (c) (per os)
Plasma and urinary 17-OHCS
Grant et al. [53]
Healthy adults
Methylprednisolone (a) (i.v. infus.)
Urinary 17-OHCS
Ceresa et al. [54]
Healthy adults
ACTH (a) (i.v. infusion)
Urinary 17-OHCS (phase shift)
Martin et al. [55, 56]
Healthy adult males
Dutimelan| (c) (per so)
Urinary 17-OHCS (phase shift)
Montalbetti [57]
Adrenal insufficiency adults
Cortisol (c) (per os)
Acrophase shift of Reinberg et al. circadian rhythms for [58, 59] grip strength and K, Na, 17-OHCS, 17-KS urinary excretion
Asthmatic children
Prednisone (c) (per os)
Aerophase shift of circadian rhythms for PEF and urinary K
Reindl et al. [60]
Asthmatic adults
Dutimelan| (c) (per os)
PEF and plasma cortisol
Serafini et al. [61]
Symptom-free asthmatic children
Methylprednisolone (a) (s.c. injection)
Acrophase shift of Reinberg et al. PEF circadian rhythm [62]
N.B.: Results on human subjects summarized in this table are in good agreement with those obtained by Hans and Halberg [15, 68] and Ungar and Halberg [69] in mice, including adrenal in vitro experiments
cycle) m u s t be given in a n y study devoted to c h r o n o p h a r m a c o l o g i c (as well as other) c i r c a d i a n r h y t h m s [11, 2 6 - 2 8 ] . C h a n g e s in effects of chemical agents, including drugs, as a f u n c t i o n o f circadian s y s t e m stage, in h u m a n beings, are s u m m a r i z e d in T a b l e 1. This type o f effects is relatively easy to d e m o n s t r a t e a n d to describe. A n other type o f effect: drug i n d u c e d
New Aspects of Human Chronopharmacology
333
changes in circadian rhythms of human being - as a function of a timed administration - needs a more elaborated experimental protocol. Circadian rhythms in a set variables must be documented both without and with drug administration, taking into account, for the latter, the timing (e.g. clock hour) apart from other conventional experimental circumstances such as route, dose, etc. The corresponding results are summarized in Table 2 and 3. The existence of two types of effects is important for both a theoretical and a practical point of view; however one must keep in mind that a drug such as ethanol [40-42] or a corticosteroid [62] involves both effects as a function of biologic timing and effects upon rhythms characteristics (mainly Cs and M s of certain circadian rhythms). Circadian changes in the effects of various drug have been documented: histamine [27, 29-32], sodium salicylate [33, 49] acetylcholine [34, 35], halothane [36], prostaglandine F2ce [37], reserpine [38], cyproheptadine [39], ethanol [40--42], quiadon | [43], insulin [44, 48], ehlorothiazide [45], oxymetholone [46], oreiprenalin and SCH 1000 (bronchodilators), indomethacin | ACTH, cortisol and corticosteroids [50-62]. Chronopharmacology is not restricted to circadian rhythms but can be extended to rhythms with period ~" > 24 h. For examples a menstrual chronopharmaeology in women has been explored with: a) days of changing responsiveness to chemical as well as to physical agents during the menstrual cycle; and b) drug induced menstrual rhythm alteration [12, 27, 28]. However, only the circadian chronopharmacology is well documented as yet.
II. New Concepts have to be Considered for a Better Understanding of Chronopharmaeologic Faets
The chronopharmacokinetics of a drug (or chronokinetics). Several parameters can be used to characterize the pharmacokinetic of a drug. When the timing of administration is manipulated (e.g. single daily dose; 4 fixed times in the 24-h scale each one being explored one week apart) statistically significant circadian rhythms can be demonstrated in the pharmacokinetic of substances such as ethanol (blood) [42] and sodium salicylate (urine) [33, 491. This means that in the human organism (among other animal species) the metabolic fate of a pharmacologic agent as well as that of a nutrient [25, 63] is not constant as a function of time. The metabolic pathways are neither open permanently nor open with a constant patency in the 24 h scale among other bioperiodic domains. The chronokinetics 3 of a drug includes both rhythmic (circadian) changes in the drug bioavailability (or phamacokinetic) and in its excretion, urinary among others. 3 "Chronobioavailability"was first proposed [12, 22, 42]. "Chronopharmacokinetic"or "chronokinetic" seems to be a better choice: a) the chronokineticof a substance can be studied in urine when it is no more biologicallyavailablefor the organism; b) two greekroots are use instead of a mixtureof greek and latin ones
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A, Reinberg
Concepts in Temporal Pharmacology Subjects' synchronization + Timing in administration of drug (or food) +
Environmental factors
Circadian cfianges in metabolic processes Biosystem chronesthesy
Organismic bioperiodicity
Chronokinetics ~ Chronergy of drug or food Fig. 1
To understand rhythmic changes in a drug pharmacokinetic, as well as in its effects, rhythmic changes in the susceptibility of solicited biosystems have to be assumed. The chronesthesy of a biosystem (rhythmic changes in its susceptibility) includes both molecular and membrane phenomena, and related metabolic processes; it involves cells, tissues, organ, organ-systems as well as parasites, bacteria, etc. The chronergy corresponds to rhythmic (e.g. circadian) change(s) either in any drug effect(s) or in biosystem response(s) to it. The acrophase, r in the chronergy of a biosystem does not necessarily coincide in time with the acrophase of the drug blood level. The ethanol chronopharmacologic study [42, 64] shows that the peak of ethanol blood level correspond to an about 11 a.m. ingestion of the substance (r = 10.40; from 06.16 to 15.02 = 95% confidence interval) while the self-rating of ebriety peaks for the ethanol intake around midnight (r = 01.15, from 21.02 to 05.28) and the shortest span of time to perform a random number addition test is found for an early morning intake (~ = 06.14; from 01.08 to 11.20). The term chronergy includes rhythmic changes in the biosystem effect(s) and in the effectiveness of any drug. This term being "neutral" one can refer easely to the circadian chronergy of ethanol rather than to its chronoeffectiveness. Concepts in temporal pharmacology are summarized in Figure 1. In any pharmacological study one must take into consideration - in addition to conventional items such as species, sex, age, dose, route and mode of the drug administration, etc. a) environmental factors, mainly: subject's synchronization and timing in administration of any drug (or food); b) organismic bioperiodicity which involves: rhythmic (e.g. circadian) changes in metabolic processes, biosystem chronesthesy, chronokinetics and chronergy of any drug (or food). This set of new concepts are deduced from pharmacologic investigations in which chronobiologic methods have been applied. Actually, the chronobiologic approach of pharmacologic phenomena involves a lesser risk of error and/or false information than the conventional homeostatic approach. -
New Aspects of Human Chronopharmacology
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III. Chronopharmaeology is Useful to Solve Problems of Drug Optimization It would be naive to think that the major aim of chronopharmacology is to give the right standardized time for any drug prescription. Such a time does not exist since, for a chronotherapeutic approach [ 10, 59, 62] we must take into consideration two types of individual requirement: the patient's synchronization and the desired (expected) effect(s) from the administration of a given medication. As illustrative example, chronopharmacology has been temptatively used to optimize corticosteroid prescription. Adverse or undesired effects resulting from corticosteroid medication are related, at least in part, to adrenal suppression and to alteration of rhythm in muscular activity, airway patency, potassium and sodium metabolism etc. [50, 51, 57, 58, 60, 62]. A conventional attempt to reduce these undesired effects consists in changing the molecular structure of the drug, its vehicle as well as its route of administration, with reference to an homeostatic point of view of pharmacologic processes. The chronopharmacologic approach to solve this problem is to give the drug, once (or twice) a day, in the 24 h scale, at clock hours selected in such a way that the endogenous secretion of cortisol is not affected e.g. the early morning hours (~ 08.00) for subjects with diurnal activities and nocturnal rest (from ~ 23.00 to ~ 07.00) (Table 3). When the corticosteroid is given far from the cortisol acrophase timing ( 8 - 1 2 h apart) or given in divided doses, with different timing, cortisol secretion is reduced and/or a set of physiological circadian rhythms are altered. But a timed administration can be used as well to enhance the activity of a corticoid. Reinberg et al. [62] demonstrated a statistically significant rise in the circadian mesor of the peak expiratory flow: PEF, induced by a 40 mg methylprednisolone s.c. injection, greater when timed at 15.00 than at other clock hours (03.00, 07.00 and 19.00), in symptom-free asthmatic children. A high PEF mesor indicates a correspondingly high airway patency, i.e. little or no airway obstruction. However, the injection at 15.00 is associated with the major acrophase-shift in PEF circadian rhythm. Thus, from a chronotherapeutic point of view it appears that corticosteroid administration can be timed with two main possibilities in mind. (1) When one wants to reduce undesired effects, administration at the time of the cortisol peak is preferred. (2) When the desired activity of the drug is to be enhanced, a different timing seems to be more pertinent. However, in so doing one, at least partially, alters the organisms' temporal structure and it will be important to find out whether such alterations are good, bad or indifferent for a given patient. Let us consider now an other chronopharmacologic aspect of drug optimization. With reference to experiments in rodents Halberg [22], Haus et al. [7], Haus et al. [65] documented circadian susceptibility-resistance cycles to cyclophosphamide and to arabinosyl cytosine (ara-C). In mice with L-1210 acute lymphatic leukemia a conventional treatment schedule consisting of 8 equal doses of ara-C over a 24-h span is compared with a chronotherapeutic treatment schedule consisting of 8 sinusoidally varying doses over a 24-h span. Both survival time and cure rate were statistically significantly improved by "chronochemotherapy" [7]. The error of the homeostatic approach in pharmacology is to believe that repeated constant doses in the 24 h scale lead to constant effect. As shown by Halberg [22], Haus et al. [7, 64], in mice,
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the effect o f equal (time-invariant) doses results, as a rule, in u n e q u a l responses. Similar fact c a n be d e m o n s t r a t e d in m a n : t i m e - i n v a r i a n t doses of ethanol (Wilson et al. [66] of e r y t h r o m y c i n ( H a l b e r g [22]) of m e t y r a p o n e ( T o u i t o u et al. [67]) along the 24 h scale result in circadian c h a n g e s in respectively blood c o n c e n t r a t i o n of ethanol a n d antibiotic, a n d u r i n a r y excretion of tetrahydro-11-deoxycortisol.
References 1. Aschoff, J.: Speech after dinner. In: Chronobiological aspects of endocrinology (J. Aschoff, F. Ceresa, F. Halberg, Eds.). Chronobiologia, Suppl. 1,473-496 (1974) 2. Virey, J. J.: Eph6m6rides de la vie humaine ou recherches sur la r6volution journali~re et la p~riodicit6 de ses ph6nom~nes dans la sant6 et les maladies. Th~se Fac. M6decine, Paris: 23 avril 1814 3. Jores, A.: Rhythmusforschung. Dtsch. med. Wschr. 21, 737 (1938) 4. Mfllerstr6m, J.: Rhythmus, Diabetes und Behandlung. Verhandlungen der 3 h. Konferenz der Int. Gesellsch. fur biologische Rhythmusforschung (Hamburg 1949). Acta med. scand., Suppl. 278, Stockholm 1953 5. Menzel, W.: Therapie unter dem Gesichtspunkt biologischer Rhythmen. Ergebn. phys.-digit. Ther. 5, 1 (1955) 6. Reinberg, A., Halberg, F.: Circadian ehronopharmaeology. Ann. Rev. Pharmacol. 11, 455492 (1971) 7. Haus, E., Halberg, F., Kuhl, J. F. W., Lakatua, D. J.: Chronopharmacology in animal. In: Chronobiological aspects of endocrinology (J. Aschoff et al., Eds.). Chronobiologia, Suppl. 1, 122 (1974) 8. Reinberg, A.: Hours of changing responsiveness in relation to allergy and the circadian adrenal cycle. In: Circadian clocks (J. Aschoff, Ed.), pp. 214-218. Amsterdam: North-Holland 1965 9. Reinberg, A.: The hours of changing responsiveness or susceptibility. Perspect. Biol. Med. 11, 111-128 (1967) 10. Reinberg, A.: Th6rapeutiques et rythmes circadiens. Chronoth6rapeutique. Rev. Prat. (Paris) 22, 4627--4638 (1972) 11. Reinberg, A.: Aspects of circannual rhythms in man. In: Circannual clocks (E. T. Pengelley, Ed.). AAAS meeting on circannual rhythms. San Francisco, Feb. 1974. New York: Academic Press 1974 12. Reinberg, A.: Chronopharmacology in man. In: Chronobiological aspects of endocrinology (J. Aschoff et al., Eds.). Chronobiologia. Suppl. 1, 157 (1974) 13. Halberg, F.: Physiologic 24-hour rhythms. A determinant of response to environmental agents. In: Man's dependance on the earthly atmosphere (K. E. Schaeffer, Ed.), pp. 48-49. New York: MacMillan 1962 14. Halberg, F.: Circadian (about 24-hour) rhythms in experimental medicine. Proc. roy. Soc. Med. 56, 253-256 (1963) 15. Halberg, F.: Ritmos y corteza suprarenal. IV: Simposio panamerican de farmacologie y terapeutica. Mexico 1967. Excerpta med. Int. Cong. Set. 7-39 (1967) 16. Halberg, F.: Chronobiology. Ann. Rev. Physiol. 31, 675-725 (1969) 17. Halberg, F., Bartter, F. C., Nelson, W., Doe, R., Reinberg, A.: Chronobiologie. J. Europ. Toxicol. 6, 311--318 (1969) 18. Halberg, F., Halberg, E., Montalbetti, N.: Premesse e sviluppi della cronofarmacologia. Quad. Med. Quant. 7, 7 (1969) 19. Halberg, F., Reinberg, A.: Rhythmes circadiens et rythmes de basses fr6quences en physiologie humaine. J. Physiol. (Paris) 59, 117--200 (1967) 20. Halberg, F., Tong, Y. L., Johnson, E. A.: Circadian system: an aspect of temporal morphology: procedure and illustrative examples, pp. 20--48. In: The cellular aspects of biorhythms. Symp. on Rhythmic Research, 8th Int. Cong. Anat. Berlin-Heidelberg-New York: Springer 1967
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21. Reinberg, A.: Chronopharmacology. In: Biological aspects of circadian rhythms (J. N. Mills, Ed.). London-New York: Plenum Press 1973 22. Halberg, F.: Protection by timing treatment according to bodily rhythms. In: Chronobiological aspects of endocrinology. (J. Aschoff et al. Eds.). Chronobiologia, Suppl. 1, 27 (1974) 23. Reinberg, A.: Methologic considerations for human chronobiology. J. Interdisc. Cycle Res. 2, 1 (1971) 24. Halberg, F.: Temporal coordination of physiologic function. In: Cold Spr. Harb. Symp. quant. Biol. 25, 289-310 (1960) 25. Reinberg, A.: Chronobiology and nutrition. Chronobiologia 1, 22-27 (1974) 26. Reinberg, A., Smolensky, M.: Circatrigintan secondary rhythms related to hormonal changes in the menstrual cycle: general considerations. In: Biorhythms and human reproduction (M. Ferin et al., Eds.). London-New York: Wiley 1974 27. Smolensky, M. H., Reinberg, A., Lee, R., McGovern, J. P.: Secondary rhythms related to hormonal changes in the menstrual cycle: special reference to allergology. In: Biorhythms and human reproduction (M. Ferin et al., Eds.) London-New York: Wiley 1974 28. Procacci, P., Moretti, R., Zoppi, M., Cappelletti, C., Voegelin: Rythmes circadiens et circatrigintidiens du seuil de la douleur cutante chez l'homme. Bull. Groupe d'Etude Rythmes Biol. 5, 65-75 (1973) 29. Reinberg, A., Sidi, E., Ghata, J.: Circadian reactivity rhythms of human skin to histamine or allergen and the adrenal cycle. J. Allergy 36, 273-283 (1965) 30. Reinberg, A., Zagulla-Mally, Z., Ghata, J., Halberg, F.: Circadian reactivity rhythms of human skin to house dust, penicillin and histamine. J. Allergy 44, 292--306 (1969) 31. De Vries, G., Goei, J. T., Booy-Noord, H., Orie, N. G.: Changes during 24-hours in the lung function and histamine hyperreactivity of the bronchial tree in asthmatic and bronchitic patients. Int. Arch. Allergy 20, 93 (1962) 32. De Vries, G., Tammeling, G. J.: Circadian changes in pulmonary function in healthy subjects and in patients with obstructive lung disease. Int. Soc. Chronobiology, Florence (1969) 33. Reinberg, A., Zagulla-Mally, Z., Ghata, J., Halberg, F.: Circadian rhythms in duration of salicylate excretion referrred to phase of excretory rhythms and routine. Proc. Soc. exp. Biol. (N.Y.) 124, 826-832 (1967) 34. Reinberg, A., Gervais, P., Morin, M., Abulker, Ch.: Circadian rhythms in the threshold of bronchial response to acetylcholine in healthy and asthmatic subjects. Int. Soc. Chronobiol. Meeting, Little Rock, Nov. 1971. In: Chronobiology. Tokio: Igaku Shoin 1974 35. Reinberg, A., Gervals, P., Morin, M., Abulker, Ch.: Rythme circadien humain du seuil de la rtponse bronchique h l'acttylcholine. C.R. Acad. Sci. (Paris) 272, 1879 (1971) 36. Fukami, N., Kotani, T., Shimoji, K., Moriaka, T., Isa, T.: Circadian rhythm and anaesthesia. Jap. J. Anesthesiol. 19, 1235 (1970) 37. Smith, I. D., Shearman, R. P., Korda, A. R.: Chronoperiodicity in the response to intra-amniotic injection of prostaglandin F2o~ in the human. Nature (Lond.) 241, 279 (1973) 38. Halberg, F.: Physiologic 24-hour rhythms. A determinant of response to environmental agents. In: Man's dependance on the earthly atmosphere, Vol. 48 (K. E. Schaefer, Ed.). New York: MacMillan 1962 39. Reinberg, A., Sidi, E.: Circadian changes in the inhibitory effects of an antihistaminic drug in man. J. invest. Derm. 46, 415-419 (1966) 40. Rutenfranz, J., Singer, R.: Untersuchungen zur Frage einer Abh~ngigkeit der Alkoholwirkung von der Tageszeit. Int. Z. angew. Physiol. 24, 1-17 (1967) 41. Swoyer, J., Lakatua, D. J., Hans, E., Warner, T., Sackett, L.: Circadian rhythm in ethanol disappearance rate from human plasma. Chronobiologia 2 (Suppl. I), 71 (1975) 42. Reinberg, A., Clench, J., Aymard, N., Galllot, M., Bourdon, R., Gervais, P., Abulker, Ch., Dupont, J.: Rythmes circadiens des paramttres de l'tthanoltmie provoquee chez six hommes adultes jeunes et sains. C.R. Acad. Sci. (Paris) 278, 1503 (1974) 43. Simpson, H. W., Bellamy, N., Bohlen, J., Halberg, F.: Double blind trial of a possible chronobiotic (quiadon| Int. J. Chronobiology 1, 287 (1973) 44. Serio, M., Della Corte, M., Piolanti, P., Romano, S., Giglioli, L., Giusti, G.: Transverse circadian rhythmometry of plasma cortisol of plasma cortisol in diabetic subjects in relation to therapy. Ann. endocr. (Paris) 32, 403-408 (1971)
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45. Levine, H., Halberg, F.: Circadian rhythms of the circulatory system. U.S.A.F. School of Aerospace Medicine (AFSC) Brooks Air Force Base, Texas, April 1972 46. Moor Ede, M. C., Burr, R. G.: Circadian rhythm of therapeutic effectiveness of oxymetholone in paraplegic patients. Clin. Pharmacol. Ther. 14, 448-454 (1973) 47. Gaultier, C., Reinberg, A., Girard, F.: Etude circadienne de la rtsistance pulmonaire totale et de la compliance dynamique chez l'enfant sain. C.R. Acad. Sci. (Paris) 280, 1253--1255 (1975) 48. Gibson, T., Stimmler, L., Jarrett, R. J., Rutland, P., Shiu, M.: Diurnal variations in the effects of insulin on blood glucose, plasma non-esterified fatty acids and growth hormone. Diabetologia 11, 83 (1975) 49. Reinberg, A., Clench, J., Ghata, J., Halberg, F., Abulker, C., Dupont, J., Zagula-Mally-Z.: Rythmes circadiens des param&res de l'excr&ion urinaire du salicylate (chronopharmacocin&ique) chez l'homme adulte sain. C.R. Acad. Sci. (Paris) 280, 1697 (1975) 50. Nichols, T., Nugent, C. A., Tyler, F. H.: Diurnal variations in suppression of adrenal function by glycocorticoids. J. clin. Endocr. 25, 343 (1965) 51. D'Agata, R., Di Stefano, C., Furno, C., Mughini, L.: Sulle variaziorti del ritmo circadiano surrenalico dopo somministrazione orale di glicocorticoidi. Riv, crit. Clin. med. 68, 652 (1968) 52. Segre, E. J., Klaiber, E. L.: Therapeutic utilization of the diurnal variation in pituitary-adrenocortical activity. Calif. Med. 104, 363 (1966) 53. Grant, S. D., Forsham, P. H., Di Raimondo, V. C.: Suppression of 17-hydroxycorticosteroids in plasma and urine single and divided doses of triamcinolone. New Engl. J. Med. 21, 273 (1965) 54. Ceresa, F., Angeli, A., Boccuzzi, G., Molino, G.: Once-a-day neutrally stimulated and basal ACTH secretion phases in man and their response to corticoid inhibition. J. olin. Endoer. 29, 1704 (1969) 55. Martin, M. M., Hellman, D.: Temporal variation in SU-4885 responsiveness in man; evidence in support of circadian variation in ACTH secretion. J. olin. Endocr. 24, 253 (1964) 56. Martin, M. M., Mintz, D. H.: Effect of altered thyroid function upon adrenocortical ACTH and methopyrapone (SU 4885) responsiveness in man. J. olin. Endocr. 25, 20 (1965) 57. Montalbetti, N.: Non-interference in circadian rhythm during clinical use of corticoids. In Chronobiological aspects of endocrinology (J. Aschoff et al., Eds.). Chronobiologia 1, Suppl. 1, 281 (1974) 58. Reinberg, A., Ghata, J., Halberg, F., Apfelbaum, M., Gervais, P., Boudon, P., Abulker, Ch., Dupont, J.: Distribution temporelle du traltement de l'insuffisance corticosurr~nalienne. Essal de chronoth&rapeutique. Ann. endocr. (Paris) 32, 566 (1971) 59. Reinberg, A., Ghata, J., Halberg, F., Apfelbaum, M., Gervals, P., Abulker, Ch., Dupont, J.: Treatment schedules modify circadian timing in human adrenocrotieal insufficiency. Int. Soc. Chronobiol. Meeting, Little Rock, Nov. 1971. In: Chronobiology. Tokyo: Igaku Shoin 1974 60. Reindl, K., Falliers, C., Halberg, F., Chal, H., Hiliman, D., Nelson, W.: Circadian acrophase in peak expiratory flow rate and urinary electrolyte excretion of asthmatic children: phase shifting of rhythms by prednisone given at different circadian system phases. Rass. Neurol. reg. 23, 5 (1969) 61. Serafini, U., Bonini, S.: Corticoid therapy in allergic diseases. Clinical evaluation of a chronopharmacological attempt. In: Chronobiological aspects of endocrinology (J. Aschoff et al., Eds.). Chronobiologia 1, Suppl. 1, 399 (1974) 62. Reinberg, A., Halberg, F., Falliers, C.: Circadian timing of methylprednisolone effects in asthmatic boys. Chronobiologia 1, 333 (1974) 63. Apfelbaum, M., Reinberg, A., Assan, R., Lacatis, D.: Hormonal and metabofic circadian rhythms before and during a low protein diet. Israel J. med. Sci. 8, 867-873 (1972) 64. Reinberg, A., Clench, J., Aymard, N., Galliot, M., Bourdon, R., Gervals, P., Abulker, C., Dupont, J.: Variations circadiennes des effets de l'&hanol et de l'&hanol~mie chez l'homme adulte saln (~tude chronopharmacologique). J. Physiol. (Paris) 70, 435--456 (1975) 65. Hans, E., Halberg, F., Scheving, L., Cardoso, S., Kuhl, J., Sothern, R., Shiotsuka, R., Hwang, D. S., Pauly, J. E.: Increased tolerance of leukemic mice to arabinosyl cytosine given on schedule adjusted to circadian system. Science 177, 80 (1972) 66. Wilson, J. L., Newman, E. J., Newman, H. W.: Diurnal variation in rate of alcohol metabolism. J. appl. Physiol. 8, 556 (1966)
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67. Touitou, Y., Bogdan, A., Reinberg, A.: Circadian changes in urinary steroids before, during and after a 36-hr 4-hourly sustained administration of metyrapone in eight healthy young human males. Chronobiologia, Suppl. 1, 57 (1975) 68. Haus, E., Halberg, F.: Stage of adrenal cycle determining different corticosterone response. Proc. 1. Int. Congress of Endocrinology, p. 219. Copenhagen 1960 69. Ungar, F., Halberg, F.: Circadian rhythm in the in vitro response of mouse adrenal to adrenocorticotropic hormone. Science 37, 1058 (1962)
Received May 19, 1976
Arch. Toxicol. 36, 327-339 (1976)
TOXICOLOGY 9 by Springer-Verlag 1976
New Aspects of Human Chronopharmacology* Alain Reinberg Equipe de Recherches de ChronobiologieHumaine (C.N.R.S. No. 105), Laboratoire de Physiologie,Fondation A. de Rothschild, 29, rue Manin, F-75019 Paris, France Abstract. Regular and thus predictable changes in biologic susceptibility and response to a large variety of physical as well as chemical agents can now be viewed as a rather common phenomenon. Chronopharmacology involves both the investigation of drug effects as a function of biologic timing and the investigation of drug effects upon rhythm characteristics. Illustrative examples of circadian chronopharmacology in man are discussed, keeping in mind that the objective demonstration of chronopharmacologic facts needs the use of an appropriate methodology. Circadian changes in the effects of various chemical agents have been documented: histamine, sodium salicylate, acetylcholine, halothane, prostaglandine F, reserpine, cyproheptadine, ethanol, insulin, chlorothiazide, oxymetholone, orciprenalin and SCH 1000 (bronchodilators), indomethacin, ACTH, cortisol and various synthetic corticosteroids. Three new concepts have to be considered: a. The Chronokinetic of a Drug. This term includes both rhythmic changes in the drug bioavailability, pharmacokinetic and its excretion. b. The Chronesthesy of a Biosystem to a Drug. i.e. circadian changes in the susceptibility of any biosystem to a drug. c. The Chronergy of a Drug, taking into consideration its chronokinetic and the chronesthesies of the involved organismic biosystems. Chronopharmacology is useful to solve problems of drug optimization, i.e. to enhance the desired efficiency or to reduce its undesired effects. In the human organism (among other animal species) the metabolic fate of a pharmacologic agent (as well as that of a nutrient) is not constant as a function of time. * Read at the Symposium"Relevanceof Chronobiologyfor Toxicologyand Pharmacology"held at the 16th Spring Meeting of the Deutsche PharmakologischeGesellschaft,Section: Toxicology,March 6, 1975, Mainz
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Thus, the chronobiologic approach of pharmacologic phenomena involves a lesser risk of errors and/or false information than the conventional homeostatic approach. Key words" Drugs - Chronokinetic - Chronesthesia - Chronergy - Optimization. Zusammenfassung. Regelm~iBig auftretende und daher vorhersehbare Ver~inderungen der biologischen Empfindlichkeit und Reaktion gegeniJber einer groBen Anzahl physikalischer und chemischer Agentien k6nnen heute als ein recht allgemeines Ph~inomen betrachtet werden. Die Chronopharmakologie umfaBt die Untersuchung der Effekte von Arzneimitteln als Funktion der Zeit und die Auswirkung von Arzneimitteln auf die Charakteristika biologischer Rhythmen. Beispiele fiir circadiane Chronopharmakologie beim Menschen werden unter Hinweis auf den Einsatz hierfiir geeigneter Methoden geschildert. Circadian bedingte Ver~inderungen von Substanzeffekten sind inzwischen ffir verschiedene chemische Agentien bekannt geworden. Sie wurden f'tir Histamin, Natriumsalicylat, Acetylcholin, Halothan, Prostaglandin F, Reserpin, Cyproheptadin, Athanol, Insulin, Chlorothiazid, Oxymetholon, Bronchodilatatoren wie Orciprenalin und SCH 1000, Indomethacin, ACTH, Cortisol und verschiedene andere synthetische Corticosteroide nachgewiesen. Drei neue Konzepte mfissen berficksichtigt werden: a. Die ,,Chronokinetik" eines Arzneimittels. Dieser Begriff beinhaltet die rhythmischen Ver~inderungen der biologischen VerfiJgbarkeit, der Pharmakokinetik und der Ausscheidung eines Arzneimittels. b. Die ,,Chronaesthesie" eines biologischen Systems gegeniiber einem Arzneimittel. Diese umfai3t circadiane Ver~inderungen der Empfindlichkeit eines Biosystems gegeniiber einem Arzneimittel. c. Die ,,Chronergie" eines Arzneimittels. Hierbei werden die ,,Chronokinetik" und die ,,Chronaesthesie" der betroffenen versehiedenen Biosysteme beriicksichtigt. Die Chronopharmakologie ist niitzlich zur Optimierung der Wirkung yon Arzneimitteln durch Verst~irkung erw~nschter Effekte oder durch Reduktion unerwiinschter Effekte. Wie bei allen Tierarten, ist auch beim Menschen der Metabofismus eines Pharmakons oder eines Nahrungsmittels nicht konstant, sondern unterliegt zeitabh/ingigen Schwankungen. Daher kommt es bei der Untersuchung pharmakologischer Ph~inomene unter Beriicksichtigung der chronobiologischen Erkenntnisse weniger zu Fehlern und/oder falschen Informationen als bei konventioneller homfostatischer Testung.
According to Aschoff [1] the first doctorial thesis on "biological clocks" was written by Julien-Joseph Virey in 1814 [2]. From (unquantified) examples, Virey concludes
New Aspects of Human Chronopharmacology
329
that any given drug (or food) is not indicated equally 1 at all hours (within the 24 h scale) and that we need urgently to learn more about this problem. As a matter of fact what is called now chronopharmacology has been simply ignored, from a scientific point of view, during more than 120 years. Credit has to be given to Jores [3], M t l l e r s t r t m [4] and Menzel [5] since the publication of their pioneer works shows the beginning of modern investigations in this field. Regular and thus predictable changes in biologic susceptibility and response to a large variety of physical as well as chemical agents (including foods and drugs) can now be viewed as a rather, c o m m o n phenomenon. This is true for both plants and animals [6, 7] including man. Experimental evidence of circadian ( ~ 24 h) circatrigentan ( ~ 30 days) and circannual ( ~ 1 year) changes in human biologic response to various agents, including drugs, has been presented in review papers by Reinberg et al. [6, 8 - 1 2 ] and/or Halberg et al. [ 13-20]. This rapidly growing number of chronobiologic facts leads to concepts such as: the hours of changing responsiveness (Halberg , [13, 14]; Reinberg [8, 9] circadian chronopharmacology [6], chronosusceptibility [9] etc. It has to be added that chronopharmacology involves both the investigation of drug effects as a function of biologic timing and the investigation of drug effects upon rhythm characteristics: the period, z, and/or the acrophase, ~, the amplitude, A, and the rhythm adjusted mean or mesor, M s. Taking into consideration that review papers have been published recently [6, 7, 12, 21, 22], aims of this presentation are mainly: 1. to give up-to-dated tables summarizing illustrative examples of circadian chronopharmacology in man; 2. to propose new concepts in chronopharmacology" mainly the biosystem chronesthesy, the chronopharmacokinetics and the chronergy of a drug (or a nutrient as well); 3. to show that chronopharmacology is useful to solve problems of drug optimization.
I. A Large Number of Illustrative Examples of Circadian Chronopharmaeology in Man has been Published and Reviewed
The objective demonstration of chronopharmacologic facts needs the use of an appropriate methodology [6, 19, 23, 24]. The chronobiologic study of any bioperiodic phenomenon, as to whether or not it can be called evident, must follow a set of elementary r u l e s , [16, 23] regarding 1 "... les hypnotiques, les narcotiques, ropium, hors les conjonctures extremes, ne seraient pas bien plac+s dans la matinte, lorsque routes les facultts tendent au r+veil; mais ces remtdes ont une action plus intense et plus salutaire, dans la soir+e, parce que les forces de la nature aspirent au sommeil et au repos" 2 The circadian period, T, is as a mean equal to 24 h when the period of synchronizer is also equal to 24 h. In man, the most powerful synchronizer for circadian rhythms is the alternation of the activityrest cycle related to our societal life [16, 19, 23]. Synchronizers may influence T, #, and A but they do not cause rhythms. The acrophase, # (for a given T) is the peak time of the best fitting sine function least squares method -- used to approximate all data. The amplitude A is equal to 1/2 the within-zrhythmic variability. The mesor, M, is the rhythm adjusted mean for the considered T
1 (4)
1 (4)
1 (4)
1 (4)
1 (4)
4 (6)
1 (6)
(6)
(~ 6)
12
06
11a
5
6
6
7
165 b
60 b
Prostaglandine b
Halothane b
Acetylcholine
Sodium salicylate
House dust extract
Penicillin
Histamine
48/80 (Histamine liberator)
Histamine
Chemical agent (fixed doses and multiple test times)
shorter induced abortion interval after injection
Lower amount of halothane used for anaesthesia
Bronchial reaction
Total duration of salicylate excretion in urines (oral administration)
Immediate skin reaction (erythema) to the antigen
Immediate skin reaction (erythema) to the antigen
Airways reactivity
Skin reactions (erythema and wheal) to intradermal injection
Skin reactions (erythema and wheal) to intradermal injection
Variable investigated
Nocturnal rest
Nocturnal rest
L (07.00--23.00) D (23.00--07.00)
L (07.00--23.00) D (23.00--07.00)
L (07.00--23.00) D (23.00--07.00)
L (07.00--23.00) D (23.00--07.00)
Nocturnal rest
L (07.30--23.30) D (23.30-07.30)
L (07.30--23.30) D (23.30--07.30)
Synchronizer schedule
--
--
29% (4--53)
12.3% (7.5--16.8)
38% (5--72)
41% (10--71)
--
38%
24% (19--29)
Amplitude C as per cent of 24 h mean (95% confidence
Reinberg et al. [29]
De Vries et al. [31], De Vries and Tammeling [32]
23.00
Midnight to 04.00
18.00
Between midnight and 06.00
14.2Z (11.01--17.53)
06.41 01.45--10.52
21.52 (16.32--01.08)
D. Smith et al. [37]
Fukani et al. [36]
Reinberg et al. [34, 35]
Reinberg et al. [33]
Reinberg et al. [30]
Reinberg et al. [30]
Reinberg et al. [29, 30] Smolensky et al. [24]
23.08 (21.44--00.48)
20.32 (18.48--04.00)
References
Acrophase c ~ in hour O origin: 00.00 h interval)
a Allergic patients b Presumably similar time groups; only one datum obtained from each patient c The acrophase (peak of the cosine function used to approximate the rhythm) is expressed in hours, minutes, with its 95% confidence interval when time series were analysed by cosinor method. Chronogram peak time for airway reactivity to histamine, and reactions to halothane and prostaglandine
No. of days (At, h)
No. of subjects
Table 1. Effects of chemical agents, including drugs, as a function of circadian system stage in human beings
o
7~
.>
New Aspects of Human Chronopharmacology
331
Table 2. Chemical agent effects upon circadian rhythms of human beings as a function of circadian state Group
Chemical agent Effect on circadian (fixed dose, rhythm multiple test times)
References
Mentally deficient adults
Reserpine
Alteration of body temperature circadian rhythm
Halberg [38]
Healthy adults
Cyproheptadine (per os) (antihistaminic drug)
Circadian changes in the duration of the inhibitory effect on skin reaction to histamine
Reinberg and Sidi [39]
Healthy adults
Ethanol (per os)
Circadian changes in blood ethanol concentration. Alteration in psychologic test circadian rhythms
Rutenfranz [40] Haus et al. [41] Reinberg et al. [42]
Healthy adults males
Quiadon | (tranquilizer)
Chronobiotic effect: rapid resynchronization of temperature rhythm
Simpson et al. [43]
Diabetics adults
Regular insulin
Alteration of eortisol circadian rhythm in plasma
Serio et al. [44]
Midly hypertensive subject
Chlorothiazide
Systolic and diastolic blood pressure mesor
Levine and Halberg [45]
Paraplegic patients
Oxymetholone
Minimization of hypercalciuria and bone demineralization
Moore Ede and Burr [46]
Healthy children
Orciprenalin
Chronoeffectiveness on lung resistance and dynamic compliance
Gaultier et al. [47]
Healthy children
SCH 1 0 0 0
Chronoeffectiveness on lung resistance and dynamic compliance
Gaultier et al. (unpublished)
Healthy adults
Insulin
Changes in plasma glucose, NEFA, growth hormone circadian rhythms
Gibson et al. [48]
Healthy adults
Sodium salicylate
Circadian changes in urinary pharmacokinetic
Reinberg et al. [49]
Healthy adults
Indomethacin |
Circadian changes in rhythm detection, and side effects
Reinberg and Clench (unpublished)
a) the subjects' synchronization (timing and regularity of the socio-ecologic synchronizer; i.e. light-on and light-off hours, meal timing, [22, 25] etc.; b) the time series of each of the studied physiological a n d / o r pathological variables (accuracy of measurements or determinations, span o f time for d a t a gathering - at least 24 h sampling interval - usually A t = 4 h - etc.); c) statistical analyses o f time series thus obtained: cosinor and related methods [20]. Moreover, circadian r h y t h m s can be modulated and modified b y coexisting r h y t h m s o f ~ 1 year and ~ 30 d a y s (mainly but not exclusively documented in women for the latter). Therefore, the month of the year (and the d a y of the monthly
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A. Reinberg
Table 3. Studies demonstrating that no or small adrenal inhibition and no or small subject's temporal structure alteration (e.g. acrophase shift) occurs when the corticosteroid is given once (or twice) a day not far from the expected acrophase of plasma cortisol circadian rhythm (i.e. around 08.00 for subjects synchronized with light-on at 07.00 and light-off at 23.00) Group
Used corticosteroid or ACTH fixed dose, multiple test times, (c) chronic, (a) acute medication (Route)
Explored variables
References
Healthy adults
Dexamethazone (c) (per os)
Plasma and urinary 17-OHCS
Nichols et al. [50] D'Agata et al. [51]
Healthy adults
Flumethazone (c) (per os)
Urinary 17-OHCS
Segre et al. [52]
Healthy adults
Triamcinolone (c) (per os)
Plasma and urinary 17-OHCS
Grant et al. [53]
Healthy adults
Methylprednisolone (a) (i.v. infus.)
Urinary 17-OHCS
Ceresa et al. [54]
Healthy adults
ACTH (a) (i.v. infusion)
Urinary 17-OHCS (phase shift)
Martin et al. [55, 56]
Healthy adult males
Dutimelan| (c) (per so)
Urinary 17-OHCS (phase shift)
Montalbetti [57]
Adrenal insufficiency adults
Cortisol (c) (per os)
Acrophase shift of Reinberg et al. circadian rhythms for [58, 59] grip strength and K, Na, 17-OHCS, 17-KS urinary excretion
Asthmatic children
Prednisone (c) (per os)
Aerophase shift of circadian rhythms for PEF and urinary K
Reindl et al. [60]
Asthmatic adults
Dutimelan| (c) (per os)
PEF and plasma cortisol
Serafini et al. [61]
Symptom-free asthmatic children
Methylprednisolone (a) (s.c. injection)
Acrophase shift of Reinberg et al. PEF circadian rhythm [62]
N.B.: Results on human subjects summarized in this table are in good agreement with those obtained by Hans and Halberg [15, 68] and Ungar and Halberg [69] in mice, including adrenal in vitro experiments
cycle) m u s t be given in a n y study devoted to c h r o n o p h a r m a c o l o g i c (as well as other) c i r c a d i a n r h y t h m s [11, 2 6 - 2 8 ] . C h a n g e s in effects of chemical agents, including drugs, as a f u n c t i o n o f circadian s y s t e m stage, in h u m a n beings, are s u m m a r i z e d in T a b l e 1. This type o f effects is relatively easy to d e m o n s t r a t e a n d to describe. A n other type o f effect: drug i n d u c e d
New Aspects of Human Chronopharmacology
333
changes in circadian rhythms of human being - as a function of a timed administration - needs a more elaborated experimental protocol. Circadian rhythms in a set variables must be documented both without and with drug administration, taking into account, for the latter, the timing (e.g. clock hour) apart from other conventional experimental circumstances such as route, dose, etc. The corresponding results are summarized in Table 2 and 3. The existence of two types of effects is important for both a theoretical and a practical point of view; however one must keep in mind that a drug such as ethanol [40-42] or a corticosteroid [62] involves both effects as a function of biologic timing and effects upon rhythms characteristics (mainly Cs and M s of certain circadian rhythms). Circadian changes in the effects of various drug have been documented: histamine [27, 29-32], sodium salicylate [33, 49] acetylcholine [34, 35], halothane [36], prostaglandine F2ce [37], reserpine [38], cyproheptadine [39], ethanol [40--42], quiadon | [43], insulin [44, 48], ehlorothiazide [45], oxymetholone [46], oreiprenalin and SCH 1000 (bronchodilators), indomethacin | ACTH, cortisol and corticosteroids [50-62]. Chronopharmacology is not restricted to circadian rhythms but can be extended to rhythms with period ~" > 24 h. For examples a menstrual chronopharmaeology in women has been explored with: a) days of changing responsiveness to chemical as well as to physical agents during the menstrual cycle; and b) drug induced menstrual rhythm alteration [12, 27, 28]. However, only the circadian chronopharmacology is well documented as yet.
II. New Concepts have to be Considered for a Better Understanding of Chronopharmaeologic Faets
The chronopharmacokinetics of a drug (or chronokinetics). Several parameters can be used to characterize the pharmacokinetic of a drug. When the timing of administration is manipulated (e.g. single daily dose; 4 fixed times in the 24-h scale each one being explored one week apart) statistically significant circadian rhythms can be demonstrated in the pharmacokinetic of substances such as ethanol (blood) [42] and sodium salicylate (urine) [33, 491. This means that in the human organism (among other animal species) the metabolic fate of a pharmacologic agent as well as that of a nutrient [25, 63] is not constant as a function of time. The metabolic pathways are neither open permanently nor open with a constant patency in the 24 h scale among other bioperiodic domains. The chronokinetics 3 of a drug includes both rhythmic (circadian) changes in the drug bioavailability (or phamacokinetic) and in its excretion, urinary among others. 3 "Chronobioavailability"was first proposed [12, 22, 42]. "Chronopharmacokinetic"or "chronokinetic" seems to be a better choice: a) the chronokineticof a substance can be studied in urine when it is no more biologicallyavailablefor the organism; b) two greekroots are use instead of a mixtureof greek and latin ones
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Concepts in Temporal Pharmacology Subjects' synchronization + Timing in administration of drug (or food) +
Environmental factors
Circadian cfianges in metabolic processes Biosystem chronesthesy
Organismic bioperiodicity
Chronokinetics ~ Chronergy of drug or food Fig. 1
To understand rhythmic changes in a drug pharmacokinetic, as well as in its effects, rhythmic changes in the susceptibility of solicited biosystems have to be assumed. The chronesthesy of a biosystem (rhythmic changes in its susceptibility) includes both molecular and membrane phenomena, and related metabolic processes; it involves cells, tissues, organ, organ-systems as well as parasites, bacteria, etc. The chronergy corresponds to rhythmic (e.g. circadian) change(s) either in any drug effect(s) or in biosystem response(s) to it. The acrophase, r in the chronergy of a biosystem does not necessarily coincide in time with the acrophase of the drug blood level. The ethanol chronopharmacologic study [42, 64] shows that the peak of ethanol blood level correspond to an about 11 a.m. ingestion of the substance (r = 10.40; from 06.16 to 15.02 = 95% confidence interval) while the self-rating of ebriety peaks for the ethanol intake around midnight (r = 01.15, from 21.02 to 05.28) and the shortest span of time to perform a random number addition test is found for an early morning intake (~ = 06.14; from 01.08 to 11.20). The term chronergy includes rhythmic changes in the biosystem effect(s) and in the effectiveness of any drug. This term being "neutral" one can refer easely to the circadian chronergy of ethanol rather than to its chronoeffectiveness. Concepts in temporal pharmacology are summarized in Figure 1. In any pharmacological study one must take into consideration - in addition to conventional items such as species, sex, age, dose, route and mode of the drug administration, etc. a) environmental factors, mainly: subject's synchronization and timing in administration of any drug (or food); b) organismic bioperiodicity which involves: rhythmic (e.g. circadian) changes in metabolic processes, biosystem chronesthesy, chronokinetics and chronergy of any drug (or food). This set of new concepts are deduced from pharmacologic investigations in which chronobiologic methods have been applied. Actually, the chronobiologic approach of pharmacologic phenomena involves a lesser risk of error and/or false information than the conventional homeostatic approach. -
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III. Chronopharmaeology is Useful to Solve Problems of Drug Optimization It would be naive to think that the major aim of chronopharmacology is to give the right standardized time for any drug prescription. Such a time does not exist since, for a chronotherapeutic approach [ 10, 59, 62] we must take into consideration two types of individual requirement: the patient's synchronization and the desired (expected) effect(s) from the administration of a given medication. As illustrative example, chronopharmacology has been temptatively used to optimize corticosteroid prescription. Adverse or undesired effects resulting from corticosteroid medication are related, at least in part, to adrenal suppression and to alteration of rhythm in muscular activity, airway patency, potassium and sodium metabolism etc. [50, 51, 57, 58, 60, 62]. A conventional attempt to reduce these undesired effects consists in changing the molecular structure of the drug, its vehicle as well as its route of administration, with reference to an homeostatic point of view of pharmacologic processes. The chronopharmacologic approach to solve this problem is to give the drug, once (or twice) a day, in the 24 h scale, at clock hours selected in such a way that the endogenous secretion of cortisol is not affected e.g. the early morning hours (~ 08.00) for subjects with diurnal activities and nocturnal rest (from ~ 23.00 to ~ 07.00) (Table 3). When the corticosteroid is given far from the cortisol acrophase timing ( 8 - 1 2 h apart) or given in divided doses, with different timing, cortisol secretion is reduced and/or a set of physiological circadian rhythms are altered. But a timed administration can be used as well to enhance the activity of a corticoid. Reinberg et al. [62] demonstrated a statistically significant rise in the circadian mesor of the peak expiratory flow: PEF, induced by a 40 mg methylprednisolone s.c. injection, greater when timed at 15.00 than at other clock hours (03.00, 07.00 and 19.00), in symptom-free asthmatic children. A high PEF mesor indicates a correspondingly high airway patency, i.e. little or no airway obstruction. However, the injection at 15.00 is associated with the major acrophase-shift in PEF circadian rhythm. Thus, from a chronotherapeutic point of view it appears that corticosteroid administration can be timed with two main possibilities in mind. (1) When one wants to reduce undesired effects, administration at the time of the cortisol peak is preferred. (2) When the desired activity of the drug is to be enhanced, a different timing seems to be more pertinent. However, in so doing one, at least partially, alters the organisms' temporal structure and it will be important to find out whether such alterations are good, bad or indifferent for a given patient. Let us consider now an other chronopharmacologic aspect of drug optimization. With reference to experiments in rodents Halberg [22], Haus et al. [7], Haus et al. [65] documented circadian susceptibility-resistance cycles to cyclophosphamide and to arabinosyl cytosine (ara-C). In mice with L-1210 acute lymphatic leukemia a conventional treatment schedule consisting of 8 equal doses of ara-C over a 24-h span is compared with a chronotherapeutic treatment schedule consisting of 8 sinusoidally varying doses over a 24-h span. Both survival time and cure rate were statistically significantly improved by "chronochemotherapy" [7]. The error of the homeostatic approach in pharmacology is to believe that repeated constant doses in the 24 h scale lead to constant effect. As shown by Halberg [22], Haus et al. [7, 64], in mice,
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the effect o f equal (time-invariant) doses results, as a rule, in u n e q u a l responses. Similar fact c a n be d e m o n s t r a t e d in m a n : t i m e - i n v a r i a n t doses of ethanol (Wilson et al. [66] of e r y t h r o m y c i n ( H a l b e r g [22]) of m e t y r a p o n e ( T o u i t o u et al. [67]) along the 24 h scale result in circadian c h a n g e s in respectively blood c o n c e n t r a t i o n of ethanol a n d antibiotic, a n d u r i n a r y excretion of tetrahydro-11-deoxycortisol.
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Received May 19, 1976
