181The body needs a completely different set of genetic programs to perform activities
than it does for sleep and restoration.
The knowledge of expression of gene relevant to circadian rhythms might enable
identifi cation of drugs whose effi cacy and side effects are most likely to be affected
by time of administration. The antihypertensive drug Diovan and Ritalin used for
attention defi cit hyperactivity disorder have half-lives of <6 h, which means that if
they are administered at the wrong time, they might break down before having a
chance to fully engage with their targets. The timing of drug administration could
also explain why some persons in clinical trials seem to respond to a medication
while others do not. It should be noted that most studies on mice are performed dur-
ing the day, when the animals should be asleep. Humans most often take drugs in
the daytime, during their wake cycle, which could explain why drug effects can fail
to translate from mice to humans.
Already there are several examples of how chronotherapy has improved man-
agement of several diseases. A clinical trial of low-dose glucocorticoid chrono-
therapy added to disease-modifying treatment produces rapid and relevant
improvements in signs and symptoms of rheumatoid arthritis with better results
than conventional glucocorticoid administration (Buttgereit et al. 2013 ). An oral
prednisone tablet was designed to release the drug at 2 AM, the time of best effi -
cacy. This formulation can be ingested before going to sleep, so that the patient’s
sleep does not have to be interrupted. Model-based personalized circadian drug
delivery aims at jointly improving tolerability and effi cacy of anticancer drugs
based on the circadian timing system of individual patients, using dedicated circa-
dian biomarker and drug delivery technologies (Ortiz-Tudela et al. 2013 ). In a com-
parison of overall survival of male patients with colorectal cancer there was a clear
advantage of applying a chronomodulated regimen of a combination of 5-fl uoroura-
cil, leucovorin and oxaliplatin over a conventional infusion of these drugs. However,
no statistically signifi cant overall survival difference between these treatments was
observed for the time-adapted treatment of female patients. More clinical studies
are required to assess the virtues of chronotherapeutic regimens in fi ghting cancer
and other diseases.
Environmental Factors in Disease
Environmental factors can precipitate a disease in an individual genetically predis-
posed to it. Most differences in responses to drugs in human are multifactorial,
caused by genetic plus environmental factors and this is an argument for the broader
approach of personalized medicine rather than the limited approach of pharmacoge-
netics or pharmacogenomics. Some adverse drug reactions are caused by interac-
tion of the drugs with environmental toxins, infectious organisms or dietary
constituents. Therefore, prescription of drugs based genotype tests to individuals
considered safe to receive the drugs, may not completely eliminate the possibility of
such a reaction. A patient matched to a drug on the basis of a genotyping test may
Environmental Factors in Disease