Hector Warnes: Historical Overview of Sleep Medicine
3. Chronopharmacotherapeutics


In the Introduction to this series (Warnes 2018a) I presented the highlights of the historical developments of Sleep Medicine which were pivotal with the discovery of sleep apneas and the anatomo-physiology of the centers of sleep by Constantin von Economo (PeretzLavie 1993); narcolepsy;the architecture of sleep including the REM sleep and delta sleep; and the restless leg syndrome.


In the second installment(Warnes 2018b) I showed that most biological functions have their own rhythm and periodicity determined by the light-dark cycles of the sun (BRAC, basic rest-activity cycle). The master circadian clock is composed of the paired suprachiasmatic nucleus located in the hypothalamus and pineal gland. It acts like a multifunction timer to regulate homeostatic systems such as sleep-wake consciousness; activity and hormones levels; appetite; body temperature; heart rate; metabolism; and many other bodily functions within a 24-hour cycle. Under normal conditions the suprachiasmatic nucleus is reset everyday by light alternationthrough the retino-hypothalamic tract.

Most behavioral, physiological and biochemical variables display circadian rhythms in their expression (e.g.,cortisol, growth hormones, leptin and melatonin). Further, I would like to cite Garaulet and Gómez-Abellán (2010): “From microarrays studies it is accepted that 10 to 30% of the human genome is under the control of circadian molecular clocks.  Circadian clocks are composed of a set of proteins that generate self-sustained circadian oscillations. The molecular clock compresses two transcription factors, clock and BMAL 1 while PERs and CRYs are responsible for the negative limb.” This prolific research team studied the effect of glucocorticoids on the clock genes expression in human adipose tissue explant culture and on human adipose tissue.

Chronodisruption is a risk factor for diseases related to aging, obesity, cardiovascular events, depression and many others noted above. We are aware of the often-observed cleavage between the chronological time, the biological time and the subjective time (chronognosis) of the organism.  Based on this consideration, a new type of drug delivery system was introduced which Garaulet and Gómez-Abellán (2010) called “chronotropic or pulsatile drug delivery.”

Chronopharmacokinetics deals with the study of the temporal changes in absorption, distribution, metabolism and elimination of therapeutic agents taking into account the optimal timing for the administration of the therapeutic drug. In ancient Greece it was observed that there was a propitious time they called it Kairos (for the shift of the illness or the curative action of a potion).

Chronodisruption in obesity, aging, gene polymorphism, jet lag, shift work andlight at night are to be reckoned as risk factors of many diseases including cancer, cardiovascular illnesses and obesity. The latter was studied in a far-reaching research by Gomez-Abellan et al. (2013).  As concerned bipolar disorder and the Seasonal Affective Disorder (in less pathological form, the Winter blues), light therapy was shown to be therapeutic.The most complete book on the subject of periodicity of bipolar disorders is Chronotherapeutics for affective Disordersby Wirz-Justice, Benedetti and Terman (2013), now in its second edition.




Bi-Botti C. Youan (Editor) Chronopharmaceutics: Science and Technology for Biological Rhythm Guided Therapy and Prevention of Diseases. New Jersey: John Wiley and Sons, Jul. 2009.


Chhabra VS, Tilloo SK, Walder SR and Ittadwar AM.The esentials of Chronopharmacotherapeutics. Intern. J. of Pharmacology and Pharmaceutical Sciences. Vol 4, issue 3, pp. 1-8, 2012.


Garaulet M and Gómez-Abellán P. Chronobiology and obesity. Nutr. Hosp. 28 (supl.5) 114-120, 2013.


Gómez-Abellán P, Gómez-Santos C, Madrid JA, Milagro FI, Campion J, Martínez JA, Ordovás JM, Garaulet M. Circadian expression of adiponectin and its receptors in human adipose tissue. Endocrinology 1511:115-122, 2010


Králiková R and Sobotová L. Linking of Daylight effects and Human Health.  Journal of Environmental Protection, Safety, Education and Management. No 7, vol. 4, June 30th, 2016.


LaviePeretz J. The Sleep Theory of Constantin von Economo.  Sleep Res. 2; 175-178, 1993.


Maurya KK, Semwal BC, Singh N, Vivek S, Khatton R. Chronopharmacology: a tool for therapy of diseases. International Research J. of Pharmacy. 3(5), pp 128-132, 2012.


WarnesH. Historical Overview of Sleep Medicine.1.Introduction. Historical discoveries in the field. inhn.org. E-Books; April 19, 2018a.


Warnes H. Historical Overview of Sleep Medicine.2. Chronobiology and periodicity. inhn.org. E-Books; May 10, 2018b.

Wirz-Justice A, Benedetti F.  and Terman M.Chronotherapeutics for affective Disorders- 2nd Edition. Basel: Karger, Switzerland, 2013. 


May 17, 2018