Chronobiology and chronotherapy in medicine

There is a fascinating and exceedingly important area of medicine that most of us have not been exposed to at any level of our medical training. This relatively new area is termed chronobiology; that is, how time-related events shape our daily biologic responses and apply to any aspect of medicine with regard to altering pathophysiology and treatment response. For example, normally occurring circadian (daily cycles, approximately 24 hours) events, such as nadirs in epinephrine and cortisol levels that occur in the body around 10 PM to 4 AM and elevated histamine and other mediator levels that occur between midnight and 4 AM, play a major role in the worsening of asthma during the night. In fact, this nocturnal exacerbation occurs in the majority of asthmatic patients. Because all biologic functions, including those of cells, organs, and the entire body, have circadian, ultradian (less than 22 hours), or infradian (greater than 26 hours) rhythms, understanding the pathophysiology and treatment of disease needs to be viewed with these changes in mind. Biologic rhythms are ingrained, and although they can be changed over time by changing the wake-sleep cycle, these alterations occur over days. However, sleep itself can adversely affect the pathophysiology of disease. The non-light/dark influence of biologic rhythms was first described in 1729 by the French astronomer Jean-Jacques de Mairan. Previously, it was presumed that the small red flowers of the plant Kalanchoe bloss feldiuna opened in the day because of the sunlight and closed at night because of the darkness. When de Mairan placed the plant in total darkness, the opening and closing of the flowers still occurred on its intrinsic circadian basis. It is intriguing to think about how the time of day governs the pathophysiology of disease. On awakening in the morning, heart rate and blood pressure briskly increase, as do platelet aggregability and other clotting factors. This can be linked to the acrophase (peak event) of heart attacks. During the afternoon we hit our best mental and physical performance, which explains why most of us state that "I am not a morning person." Even the tolerance for alcohol varies over the 24-hour cycle, with best tolerance around 5 PM (i.e., "Doctor, I only have a couple of highballs before dinner"). Thus, all biologic functions, from those of the cell, the tissue, the organs, and the entire body, run on a cycle of altering activity and function. Biologic responses to many agents such as medications, chemical substances, and poisons are not constant over a 24-hour period, nor are the responses random variations. These responses do not apply only to the human body. The response of antibiotics to bacteria and of cancer cells to chemotherapeutic agents or radiotherapy are but two examples of the way that circadian changes alter therapeutic response. Looking at a mouse model of leukemia, Scheving snowed that giving Ara-C on a chronotherapeutic basis produced superior results compared with the same total dose but equally divided (as we are taught). There was twice the survival and no drug toxicity death with the chronotherapeutic approach compared with the equal-dosing regimen.¹ Applying this concept to human beings, Rivard and coworkers studied children with acute lymphoblastic leukemia that was in remission.² The children had remission chemotherapy either before 10 AM or after 5 PM. The dose and drugs used were identical for both groups; only the dosing time was different. After 1 year, the children who received morning chemotherapy had a relapse rate that was 4.6 times that of the children who received evening chemotherapy. In these children, the results held up for an additional 6 years,³ with the relative risk for relapse remaining at 2.56 times greater for the morning regimen. What follows in this issue of DISEASE-A-MONTH is an overview of chronobiology and chronotherapy for the many areas of medicine. Because much needs to be learned about time-related biologic and therapeutic events, the future will add greatly to what is reviewed here. Within the next decade, we will all have to understand circadian (and other) time-related events to better understand the pathophysiology and treatment of diseases.