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Circadian Rhythms and Personalized Medicine
Various physiological and metabolic processes in the human body including sleep-
wake cycles, metabolism, heart rate, blood pressure, body temperature, renal activ-
ity, and endocrine secretions fl uctuate in a daily manner. They are attributed to
circadian rhythms, which are endogenous self-sustained oscillations with a period
of ~24 h. Circadian rhythms are coordinated by a biological clock situated in the
suprachiasmatic nuclei (SCN) of the hypothalamus. These rhythms persist under
constant environmental conditions, demonstrating their endogenous nature. Some
rhythms can be altered by disease. Several clock genes and clock-controlled tran-
scription factors regulate, at least in part, gene expression in central and/or periph-
eral clocks. However, virtually all of our 35 trillion body cells also possess their
own clocks, which are indistinguishable from those operative in SCN neurons
(Bollinger and Schibler 2014 ).
The rhythms of disease and pharmacology can be taken into account to modulate
treatment over the 24-h period, i.e. chronotherapy. The term “chronopharmacology”
is applied to variations in the effect of drugs according to the time of their adminis-
tration during the day. “Chronopharmacokinetics” is defi ned as the predictable
changes observed in the plasma levels of drugs and in the parameters used to char-
acterize the pharmacokinetics of a drug. Half-life of a drug can vary as a function of
the hour of administration.
The effi cacy and/or toxicity of drugs depend on an individual’s body time (BT).
Drug administration at the appropriate BT can improve the outcome of pharmaco-
therapy by maximizing potency and minimizing the toxicity of the drug, whereas
drug administration at an inappropriate BT can induce severe side effects.
Information obtained by detection of individual BT via a single-time-point assay
can be exploited to maximize potency and minimize toxicity during drug adminis-
tration and thus will enable highly optimized medication. Genome-wide gene
expression analyses using high-density DNA microarrays have identifi ed clock-
controlled genes. BT based on expression profi les of time-indicating genes refl ects
the endogenous state of the circadian clock. In clinical situations, methods for BT
detection should be applicable for populations with heterogeneous genetic
backgrounds.
A molecular timetable is consists of >100 time-indicating genes, whose gene
expression levels can represent internal BT. A study in mice has shown that 43 % of
genes follow a daily schedule in at least 1 of the 12 organs profi led, and that 56 of
the 100 best-selling drugs in the US target products of genes whose expression
cycles oscillate according to circadian rhythms in clinically relevant organs (Zhang
et al. 2014 ). Using samples taken every 2 h, the researchers probed mRNA using
microarrays and quantifi ed expression of ~20,000 protein-coding genes. They also
used RNA-sequencing on organs sampled every 6 h, which enabled them to profi le
the cycling of non-coding RNA. Most of these genes were previously recognized
clock genes that are responsible for the keeping the body’s internal daily rhythm.
There also seemed to be gene-expression “rush hours,” just before dawn and dusk.
8 Non-genomic Factors in the Development of Personalized Medicine