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Advances in clinical chronopharmacology
TIPS- November 1979
81
Advances in clinical chronopharmacology Alain Reinberg -.
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 common phenomenon. This is true for
both plants and animals, including man. Experimental evidence of circadian ( - 24 h). circamensual ( - 30 days) and circannual (_ I year) changes in human biologic response to various agents, including drugs, has been presented in review papers.‘“.“-‘h.‘N as well as in symposia’7~1y. This rapidly growing number of chronobiologic facts has led to new concepts such as chronesthesy, chronopharmacokinetics and chronergyl?-“. It has led also to a promising method of drug optimization taking into account the temporal structure of the treated subject.
Biological rhythms as adaptative phenomena to predictable changes of environmental factors The quantitative study of biological rhythms shows that biophysical and biochemical processes vary with respect to time in a periodic, regular and predictable manner’J.~. We know today that rhythmic
activity is a fundamental ing matter
property of liv-
Is. Biological rhythms can in
fact be demonstrated in all living beings from nucleated unicellular organisms to man; and at all levels: the entire organism, organ-systems, organs, tissues, cells Biological and subcellular material. rhythms exhibit similar basic properties in plants and animals: (a) they are genetic in origin; (b) they persist without time clue and cue; (c) they can be characterized for a given species (e.g. Rat, Mice, Man)
although interindividual differences can be demonstrated (e.g. differences between strains of mice; MZ v. DZ twin studies in man); (d) they can be influenced by cyclic of certain environmental variations factors called synchronizers or Zeitgeber.
These bioperiodic changes often result from adaptative phenomena to predictable variations of a set of factors directly related to the Earth’s rotation around ns axis (in -24 h) and around the Sun (in -365.25 days). In fact, most example5 of the temporal urganization of living being5 have been reported in circadian and circannual domains of biological rhythms. (Bioperiodic phenomena with period ~‘7 days, -1 month etc.. have been documented as well’.lY but to a lesser extent than circadian and circannual rhythms). Experimental data indicate that cells (from Eukaryote to Mammals) are not able to perform all their potential functions at any time in the e.g. 24 h scale. For example, the liver cell of mice and rats shows a temporal organization in its metabolic processes (RNA, DI\;A, enzymes, phospholipids. glycogen synthesis, among other9) as well as in its cytological peorganization associated to functional changes’. Crest times lacrophases) of each type of activity are not randomly di>tributed in the 24 h scale; on the contrary. the distribution of crest times is yenerically programed. This temporal organization at the cellular level can be viesed as an adaptative phenomenon for better use of the energy available. In rodents synchronized with light from 06.00 to 18.00 (rest) ant darkness from 18.00 to 06.00 (activity) the crest of glycogen synthesis in the liver cell occurs around the onbet of light, u bile the crest of the albumin synthesis occurs l.! h later or earlieP. It is not surprising. therefore, that the metabolic fate of a citemiial agent (drug, nutrient, etc.) is not constant. but varies as a function of time.
Temporal distribution of therapeutic procedures By time-honored tradition, patients are given therapeutic agents at specified clock hours in the 24 h scale. The temporal arrangement of therapeutic regimens is
freqcently related to psycho-social con5iderations. le+s frequently to empirical observations and sometimes, reference 1, made to the homeostatic hyporhe\is. On)) rarely, before the ’60s. the adiantagc of a well-defined chronotherapy tar a gl\en agent was demonstrated objectively by chronopharmacological experiments. The homeostatic hypothesis presumes that toxic, pharmacologic and therapeutic effects of a given agent are constant as a function of time. More precisely, both desired and undesired effects are supposed to be identical at any time of drug administration in the 24 h scale, or day m the month or month in the year. This hypothesis has not been validated in any experiments’~“‘ ‘9. It is, of course, interesting to know that the homeostatic approach for therapeutic methods is both obsolete and dangerous; but it is rather more significant that a chronobiologic approach may be useful to solve a number of therapeutte problems including the reduction of undesired effects of certain drugs, among many others. Development of chronopharmacolog> Modern chronopharmacolopy tn\ol\es both the investigation of drug effects as a function of biologic timing and the imestigation of drug effects upon the characteristics of :ne endogenous hiopertodicities: the period, T, and’or the acrophass. 9. the amplitude, A, and the rhythmadjusted mean or mc\or. \l. The circadian period. T. i> as 1 rule equal to 24 h tvhrn the perioi of the synchronizer is also equal to I4 h. In man. the most pouerful synchronizer for c’ircadian rhythms is the alterr.ation of the activity-rest cycle related t1.J our social life. Synchronizers may influence T. 4, 2nd A but they do not cause rhythms. The airophase, + (for a given T) is the peak time of the best-fitting
82
TIPS- Nobmember 1979 The metabolic fate of a pharmacologic agent as well as that of a nutrient should not be lexpectrd to be constant as a function of time. Indeed, experiments clearly prove th.at rhythms strongly irlfluence the metabolism of medication and nutrients. The metabolic pathways are neither open permanently, nor open with a constant patency in the 24 h scale. Chronesthesia of a biosystem
Rums-i beings as a function of a timed animals (including man) have been published and reviewedd’a.8-‘h.“. Therefore, admitirsrration. requires a more elabrorate experimental protocol. For example, cirnew concepts ard definitions have been cadian rhythms of a set of variables must proposed’?-1 fo: a better understanding of be documented prior to. during and after chronophrrmacologic facts (Fig. 2). drug administr.ation. taking into account the timing (e.g. clock hour) of administraCbronopbarmncokinetics or tion as well as other F;onventional expericbronokieetics of a drag mental circumstance; such as r~oute. dose, etc. %~rd studies document this effect These kinetics are defined as rhythmic inslading those on reserpine. cyprohepta(circadian) changes in either the bioavail?inc irrja!in, hypoglycemic agenti. glucaab,iity of a drug, or its pharmacokinetics, metyrapone and gon, ox)-rnetholonc. and/or in its excretion in the urine or by ACTli, cortisr 11and corticosteroids’ !0.11-!6. other routes (feces, sweat. saliva, etc.). The exist.sr;.ce of these two types of effect When the timing of adininistration is is Important ftom both a theoretical and a manipulated (e.g. single daily dose; four practlca! p&: of view; howzter, it must fixed times in the 24 h scale, each one be kept in niind that a drarp, sL.ch as being explored one week apart), statisticahaool or a corticosteroi,d, involve> boorh ally significant circadian rhythms can be ef&ts as a function of biologic timing demonstrated in the parameters used to and effects upon rhyrhnu ctaracteristics characterize the pharmacokinetics of sublmaialy 9’s attd M’s of certei.n circadian stances such as sodium salicylate. indorhythms). methacin, ethanol, erythromycin, digoxin, A large number of illustrative examples digitalis. benzodiazepine and theophylof circadian chronopharmacoiogy in linelZ 4.,&I-
Chrcmesthesia is defined as the rhythmic ctuanges in the susceptilbility of a biosystem: it includes both molecular and membrane phenomena and related metabolic processes. The rhronesthesia involves cells, tissues, organs and ‘organsystems of the host as well as the susceptibility of parasites, bacteria, ttllmors, etc. A biiosystcm can be completely unresponsive to a given drug at cerl.ain times in the 24 h scale, while the same dose is highly effective at other hours, of the day. This chronesthesia can be expressed and quanti!Led in terms of chronotoleramce4 as well as in terms of bioperiodilcal clhanges of receptors- of a given system to a given drug. The chronesthesia can1 be explored more or less directly in human subjects, e.g. the bronchial reactivity to agents inhaled as aerosols including histamine, acetylcholine!, orciprenaline, ipratropium bromide, and house dust extract and also the local skin reaction to intradermal injection of substances >,uch as histamine and a histamine liberator as well as the anesthetics, betoxicainc and lidoCaine’?-IJ.lh.1‘ Cbrooergy of a chemical (or 81physical) agent Chronergy is defined as rhythmic changes in any effect(s) of a chemical or physical agent, either desired (chronoeffectivenesr) or undesired. The chronergy of a chemical agent involves its chronopharmacl,kinetics as well as the chronesthesia of a set of biosystems. The acrophase of the chronergy does not nlecessarily co’incide with the acrophase of the drug level in the blood as demlonstrated, e.g. for ethanlol”. Clinical cbroaopharmnrology drag aptimization
and
Chronopharmacology has been used to optimize corticosteroid prescription (chronocorticotherapy)‘*9,L4. Adverse or undesired effects resulting from a conventional (homeostatic) corticcj!Iteroid treatment, both during the administration
TIPS-
November
1979
SUBJECT’S
SYNCHRONIZATION +
TIMING
ENVIRONMENTAL FACTORS
IN ADMINlSlRATION OF DRUG OR FOOD +
IN
CIRCADIAN METABOLIC
BIOSYSTEM
/( CHRONOKINETICS OF
CHANGES PROCESSES
1
ORGANISMIC BIOPERIODICITY
CHRONESTHESIA
+ DRUG
OR
\ CHRONERGY FOOD
perijod and after the withdrawal of the drug are related, at least in part, to the critical drop in the endogenous glucocorticoid production following ACTH inhibition. Conventional attempts to reduce the most conspicuous side effects have been made by changing the molecular structure of the drug, its vehicle, as well as its route of administration, with reference to a homeostatic point of view of pharmacological processes. The ensuing results have not been very encouraging. The chronopharmacoloyical approach on the other hand has made significant progress. First of all, corticosteroids hate been given at fixed hours in the 24 h scale, selected in such a way as not to affect the cndogenous secretion of cortibol. The cortisol acrophase occurs in the early morning hours ( -08.00) for subjects with diurnal activities and nocturnal rest (from -23.00 to -07.00). When corticosteroid
or ACTH is given far from the cortisol acrophase timing (e.g. up to 8-12 h later or earlier) as a single daily dose, or is given in divided doses with different timing , cortlsol secretion is reduced and: or a number of physiological circadian rhythms are all ered. Recently, he chronopharmacologic approach to rational corticosteroid therapy has achieved further progress. Bs utilizing both a particular combination of corticosteroids with different characteristies of absorption and metabolism, and timed administration at tixed hours in the
24 h scale (08.00 and 15.00). the endogenous rhythmic organization can be preserved almost entirely, at the same time
gaining clinicopharmacological results which can be superimposed on those obtained by the conventional administration of larger doses of corticosteroids” lJ. The favorable results achieved by this pluriihronocortxosteroid provide a basis for the practica pplication of up-to-date concepts in cortlcostercid chronopharmacokinetics and III pituitary-adrenal chronesthesia. Anjother chronopharmacologls a>pect of drug optimization concerns experiments in rodents, m 6% hich Halberg _ and Haus er 01.~documented circadian susieptibility-resistance cy;lr: to cyclophosphamide and to arabinosyl cytosine (ara-0. In mice, with L-1210 acute lymphatic leukemia. a con\eniional treatment regimen consisting of eight equal doses of ara-C over a 24 h span Has compared with a chronotherapeutic treatment regimen consisting of eight sinusoidally varying doses over a 24 h span. Both sur\i\al time and cure rate acre htatistically signifiimpro\ed t-1 chrono
dov3
unequal
respon5e5“
Hcadin~
list
rc‘sulry. ‘.
a\ a rulr.
in
81
Advances in clinical chronopharmacology Alain Reinberg -.
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 common phenomenon. This is true for
both plants and animals, including man. Experimental evidence of circadian ( - 24 h). circamensual ( - 30 days) and circannual (_ I year) changes in human biologic response to various agents, including drugs, has been presented in review papers.‘“.“-‘h.‘N as well as in symposia’7~1y. This rapidly growing number of chronobiologic facts has led to new concepts such as chronesthesy, chronopharmacokinetics and chronergyl?-“. It has led also to a promising method of drug optimization taking into account the temporal structure of the treated subject.
Biological rhythms as adaptative phenomena to predictable changes of environmental factors The quantitative study of biological rhythms shows that biophysical and biochemical processes vary with respect to time in a periodic, regular and predictable manner’J.~. We know today that rhythmic
activity is a fundamental ing matter
property of liv-
Is. Biological rhythms can in
fact be demonstrated in all living beings from nucleated unicellular organisms to man; and at all levels: the entire organism, organ-systems, organs, tissues, cells Biological and subcellular material. rhythms exhibit similar basic properties in plants and animals: (a) they are genetic in origin; (b) they persist without time clue and cue; (c) they can be characterized for a given species (e.g. Rat, Mice, Man)
although interindividual differences can be demonstrated (e.g. differences between strains of mice; MZ v. DZ twin studies in man); (d) they can be influenced by cyclic of certain environmental variations factors called synchronizers or Zeitgeber.
These bioperiodic changes often result from adaptative phenomena to predictable variations of a set of factors directly related to the Earth’s rotation around ns axis (in -24 h) and around the Sun (in -365.25 days). In fact, most example5 of the temporal urganization of living being5 have been reported in circadian and circannual domains of biological rhythms. (Bioperiodic phenomena with period ~‘7 days, -1 month etc.. have been documented as well’.lY but to a lesser extent than circadian and circannual rhythms). Experimental data indicate that cells (from Eukaryote to Mammals) are not able to perform all their potential functions at any time in the e.g. 24 h scale. For example, the liver cell of mice and rats shows a temporal organization in its metabolic processes (RNA, DI\;A, enzymes, phospholipids. glycogen synthesis, among other9) as well as in its cytological peorganization associated to functional changes’. Crest times lacrophases) of each type of activity are not randomly di>tributed in the 24 h scale; on the contrary. the distribution of crest times is yenerically programed. This temporal organization at the cellular level can be viesed as an adaptative phenomenon for better use of the energy available. In rodents synchronized with light from 06.00 to 18.00 (rest) ant darkness from 18.00 to 06.00 (activity) the crest of glycogen synthesis in the liver cell occurs around the onbet of light, u bile the crest of the albumin synthesis occurs l.! h later or earlieP. It is not surprising. therefore, that the metabolic fate of a citemiial agent (drug, nutrient, etc.) is not constant. but varies as a function of time.
Temporal distribution of therapeutic procedures By time-honored tradition, patients are given therapeutic agents at specified clock hours in the 24 h scale. The temporal arrangement of therapeutic regimens is
freqcently related to psycho-social con5iderations. le+s frequently to empirical observations and sometimes, reference 1, made to the homeostatic hyporhe\is. On)) rarely, before the ’60s. the adiantagc of a well-defined chronotherapy tar a gl\en agent was demonstrated objectively by chronopharmacological experiments. The homeostatic hypothesis presumes that toxic, pharmacologic and therapeutic effects of a given agent are constant as a function of time. More precisely, both desired and undesired effects are supposed to be identical at any time of drug administration in the 24 h scale, or day m the month or month in the year. This hypothesis has not been validated in any experiments’~“‘ ‘9. It is, of course, interesting to know that the homeostatic approach for therapeutic methods is both obsolete and dangerous; but it is rather more significant that a chronobiologic approach may be useful to solve a number of therapeutte problems including the reduction of undesired effects of certain drugs, among many others. Development of chronopharmacolog> Modern chronopharmacolopy tn\ol\es both the investigation of drug effects as a function of biologic timing and the imestigation of drug effects upon the characteristics of :ne endogenous hiopertodicities: the period, T, and’or the acrophass. 9. the amplitude, A, and the rhythmadjusted mean or mc\or. \l. The circadian period. T. i> as 1 rule equal to 24 h tvhrn the perioi of the synchronizer is also equal to I4 h. In man. the most pouerful synchronizer for c’ircadian rhythms is the alterr.ation of the activity-rest cycle related t1.J our social life. Synchronizers may influence T. 4, 2nd A but they do not cause rhythms. The airophase, + (for a given T) is the peak time of the best-fitting
82
TIPS- Nobmember 1979 The metabolic fate of a pharmacologic agent as well as that of a nutrient should not be lexpectrd to be constant as a function of time. Indeed, experiments clearly prove th.at rhythms strongly irlfluence the metabolism of medication and nutrients. The metabolic pathways are neither open permanently, nor open with a constant patency in the 24 h scale. Chronesthesia of a biosystem
Rums-i beings as a function of a timed animals (including man) have been published and reviewedd’a.8-‘h.“. Therefore, admitirsrration. requires a more elabrorate experimental protocol. For example, cirnew concepts ard definitions have been cadian rhythms of a set of variables must proposed’?-1 fo: a better understanding of be documented prior to. during and after chronophrrmacologic facts (Fig. 2). drug administr.ation. taking into account the timing (e.g. clock hour) of administraCbronopbarmncokinetics or tion as well as other F;onventional expericbronokieetics of a drag mental circumstance; such as r~oute. dose, etc. %~rd studies document this effect These kinetics are defined as rhythmic inslading those on reserpine. cyprohepta(circadian) changes in either the bioavail?inc irrja!in, hypoglycemic agenti. glucaab,iity of a drug, or its pharmacokinetics, metyrapone and gon, ox)-rnetholonc. and/or in its excretion in the urine or by ACTli, cortisr 11and corticosteroids’ !0.11-!6. other routes (feces, sweat. saliva, etc.). The exist.sr;.ce of these two types of effect When the timing of adininistration is is Important ftom both a theoretical and a manipulated (e.g. single daily dose; four practlca! p&: of view; howzter, it must fixed times in the 24 h scale, each one be kept in niind that a drarp, sL.ch as being explored one week apart), statisticahaool or a corticosteroi,d, involve> boorh ally significant circadian rhythms can be ef&ts as a function of biologic timing demonstrated in the parameters used to and effects upon rhyrhnu ctaracteristics characterize the pharmacokinetics of sublmaialy 9’s attd M’s of certei.n circadian stances such as sodium salicylate. indorhythms). methacin, ethanol, erythromycin, digoxin, A large number of illustrative examples digitalis. benzodiazepine and theophylof circadian chronopharmacoiogy in linelZ 4.,&I-
Chrcmesthesia is defined as the rhythmic ctuanges in the susceptilbility of a biosystem: it includes both molecular and membrane phenomena and related metabolic processes. The rhronesthesia involves cells, tissues, organs and ‘organsystems of the host as well as the susceptibility of parasites, bacteria, ttllmors, etc. A biiosystcm can be completely unresponsive to a given drug at cerl.ain times in the 24 h scale, while the same dose is highly effective at other hours, of the day. This chronesthesia can be expressed and quanti!Led in terms of chronotoleramce4 as well as in terms of bioperiodilcal clhanges of receptors- of a given system to a given drug. The chronesthesia can1 be explored more or less directly in human subjects, e.g. the bronchial reactivity to agents inhaled as aerosols including histamine, acetylcholine!, orciprenaline, ipratropium bromide, and house dust extract and also the local skin reaction to intradermal injection of substances >,uch as histamine and a histamine liberator as well as the anesthetics, betoxicainc and lidoCaine’?-IJ.lh.1‘ Cbrooergy of a chemical (or 81physical) agent Chronergy is defined as rhythmic changes in any effect(s) of a chemical or physical agent, either desired (chronoeffectivenesr) or undesired. The chronergy of a chemical agent involves its chronopharmacl,kinetics as well as the chronesthesia of a set of biosystems. The acrophase of the chronergy does not nlecessarily co’incide with the acrophase of the drug level in the blood as demlonstrated, e.g. for ethanlol”. Clinical cbroaopharmnrology drag aptimization
and
Chronopharmacology has been used to optimize corticosteroid prescription (chronocorticotherapy)‘*9,L4. Adverse or undesired effects resulting from a conventional (homeostatic) corticcj!Iteroid treatment, both during the administration
TIPS-
November
1979
SUBJECT’S
SYNCHRONIZATION +
TIMING
ENVIRONMENTAL FACTORS
IN ADMINlSlRATION OF DRUG OR FOOD +
IN
CIRCADIAN METABOLIC
BIOSYSTEM
/( CHRONOKINETICS OF
CHANGES PROCESSES
1
ORGANISMIC BIOPERIODICITY
CHRONESTHESIA
+ DRUG
OR
\ CHRONERGY FOOD
perijod and after the withdrawal of the drug are related, at least in part, to the critical drop in the endogenous glucocorticoid production following ACTH inhibition. Conventional attempts to reduce the most conspicuous side effects have been made by changing the molecular structure of the drug, its vehicle, as well as its route of administration, with reference to a homeostatic point of view of pharmacological processes. The ensuing results have not been very encouraging. The chronopharmacoloyical approach on the other hand has made significant progress. First of all, corticosteroids hate been given at fixed hours in the 24 h scale, selected in such a way as not to affect the cndogenous secretion of cortibol. The cortisol acrophase occurs in the early morning hours ( -08.00) for subjects with diurnal activities and nocturnal rest (from -23.00 to -07.00). When corticosteroid
or ACTH is given far from the cortisol acrophase timing (e.g. up to 8-12 h later or earlier) as a single daily dose, or is given in divided doses with different timing , cortlsol secretion is reduced and: or a number of physiological circadian rhythms are all ered. Recently, he chronopharmacologic approach to rational corticosteroid therapy has achieved further progress. Bs utilizing both a particular combination of corticosteroids with different characteristies of absorption and metabolism, and timed administration at tixed hours in the
24 h scale (08.00 and 15.00). the endogenous rhythmic organization can be preserved almost entirely, at the same time
gaining clinicopharmacological results which can be superimposed on those obtained by the conventional administration of larger doses of corticosteroids” lJ. The favorable results achieved by this pluriihronocortxosteroid provide a basis for the practica pplication of up-to-date concepts in cortlcostercid chronopharmacokinetics and III pituitary-adrenal chronesthesia. Anjother chronopharmacologls a>pect of drug optimization concerns experiments in rodents, m 6% hich Halberg _ and Haus er 01.~documented circadian susieptibility-resistance cy;lr: to cyclophosphamide and to arabinosyl cytosine (ara-0. In mice, with L-1210 acute lymphatic leukemia. a con\eniional treatment regimen consisting of eight equal doses of ara-C over a 24 h span Has compared with a chronotherapeutic treatment regimen consisting of eight sinusoidally varying doses over a 24 h span. Both sur\i\al time and cure rate acre htatistically signifiimpro\ed t-1 chrono
dov3
unequal
respon5e5“
Hcadin~
list
rc‘sulry. ‘.
a\ a rulr.
in