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New aspects of human chronopharmacology

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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:

  1. a.

    The Chronokinetic of a Drug. This term includes both rhythmic changes in the drug bioavailability, pharmacokinetic and its excretion.

  2. b.

    The Chronesthesy of a Biosystem to a Drug. i.e. circadian changes in the susceptibility of any biosystem to a drug.

  3. 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.

Thus, the chronobiologic approach of pharmacologic phenomena involves a lesser risk of errors and/or false information than the conventional homeostatic approach.

Zusammenfassung

Regelmäßig auftretende und daher vorhersehbare Veränderungen der biologischen Empfindlichkeit und Reaktion gegenüber einer großen Anzahl physikalischer und chemischer Agentien können heute als ein recht allgemeines Phänomen betrachtet werden. Die Chronopharmakologie umfaßt die Untersuchung der Effekte von Arzneimitteln als Funktion der Zeit und die Auswirkung von Arzneimitteln auf die Charakteristika biologischer Rhythmen.

Beispiele für circadiane Chronopharmakologie beim Menschen werden unter Hinweis auf den Einsatz hierfür geeigneter Methoden geschildert. Circadian bedingte Veränderungen von Substanzeffekten sind inzwischen für verschiedene chemische Agentien bekannt geworden. Sie wurden für Histamin, Natriumsalicylat, Acetylcholin, Halothan, Prostaglandin F, Reserpin, Cyproheptadin, Äthanol, Insulin, Chlorothiazid, Oxymetholon, Bronchodilatatoren wie Orciprenalin und SCH 1000, Indomethacin, ACTH, Cortisol und verschiedene andere synthetische Corticosteroide nachgewiesen.

Drei neue Konzepte müssen berücksichtigt werden:

  1. a.

    Die „Chronokinetik” eines Arzneimittels. Dieser Begriff beinhaltet die rhythmischen Veränderungen der biologischen Verfügbarkeit, der Pharmakokinetik und der Ausscheidung eines Arzneimittels.

  2. b.

    Die „Chronaesthesie” eines biologischen Systems gegenüber einem Arzneimittel. Diese umfaβt circadiane Veränderungen der Empfindlichkeit eines Biosystems gegenüber einem Arzneimittel.

  3. c.

    Die „Chronergie” eines Arzneimittels. Hierbei werden die „Chronokinetik” und die „Chronaesthesie” der betroffenen verschiedenen Biosysteme berücksichtigt.

Die Chronopharmakologie ist nützlich zur Optimierung der Wirkung von Arzneimitteln durch Verstärkung erwünschter Effekte oder durch Reduktion unerwünschter Effekte.

Wie bei allen Tierarten, ist auch beim Menschen der Metabolismus eines Pharmakons oder eines Nahrungsmittels nicht konstant, sondern unterliegt zeitabhängigen Schwankungen. Daher kommt es bei der Untersuchung pharmakologischer Phänomene unter Berücksichtigung der chronobiologischen Erkenntnisse weniger zu Fehlern und/oder falschen Informationen als bei konventioneller homöostatischer Testung.

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Authors and Affiliations

  1. Equipe de Recherches de Chronobiologie Humaine (C.N.R.S. No. 105), Laboratoire de Physiologie, Fondation A. de Rothschild, 29, rue Manin, F-75019, Paris, France

    Alain Reinberg

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Read at the Symposium “Relevance of Chronobiology for Toxicology and Pharmacology” held at the 16th Spring Meeting of the Deutsche Pharmakologische Gesellschaft, Section: Toxicology, March 6, 1975, Mainz

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Reinberg, A. New aspects of human chronopharmacology. Arch. Toxicol. 36, 327–339 (1976). https://doi.org/10.1007/BF00340538

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