Keeping Time to Circadian Rhythms

by: Judith Levine Willis

The year is 1729; the place, Paris, France. Astronomer Jean Jacques d'Ortous de Mairan has just locked a heliotrope in his closet.

Investigating this flower's well-known inclination to respond to the sun, de Mairan's expectation is that the plant will stay folded up in the dark. But to his surprise he discovers that, instead, the heliotrope, whose name means "turning towards the sun," continues to open its leaves by day and close them by night even without the sunlight.

A few years later, another researcher, Henri-Louis Duhamel, dubious about de Marian's results, repeats the experiment, removing not only light but heat cues as well. He finds that, as before, the plant continues opening and closing in a daily rhythmical pattern.

In the centuries since these early experiments, research has shown that not only plants, but also animals--including humans--are governed by biological rhythms. The study of biological rhythms is technically known as chronobiology. Researcher Franz Halberg, M.D., of the University of Minnesota coined the term "circadian" (from circa--about--and dian--day) to describe body rhythms that approximate a 24-hour cycle.

Like the lovely heliotrope, the human body has observable daily rhythms that seem to be governed by what some have called a "biological clock." Heart rate, blood pressure, respiration rate, body temperature, and urine excretion all have higher levels (called "peaks") that occur during the day, and lower levels (called "troughs") that occur at night. But, like the opening and closing of the heliotrope, it is not merely the presence or absence of sunlight that triggers these rhythms.

While these rhythms may be set off to a certain extent by environmental cues (called "zeitgebers") such as the dark/light cycle and food consumption, many rhythms persist even when environmental cues are removed. In experiments in which people live for weeks with no social or geophysical cues such as set meal times and the light-dark cycle, the basic rhythms continue, but they shift from a 24-hour cycle to one of approximately 25 hours. One theory to explain this phenomenon is that the 25-hour cycle is somehow genetically predetermined in all humans.

The most well-known circadian rhythm is that of body temperature, which varies daily a degree or two in a healthy person, peaking in late afternoon and troughing in the early morning hours. This rhythm persists even when the individual is confined to bed for the entire 24 hours, when the time of meals is varied, or if the person fasts. Pulse rate and blood pressure also peak around the same time as body temperature.

Levels of glycogen, a carbohydrate essential to fuel the body, start decreasing about noon. By 3 to 6 a.m., the body has used up much of its supply. This rhythm may help explain why people with diabetes experience "low blood sugar" in the morning. (Glycogen is metabolized into glucose, a sugar.)

Though human body rhythms have been systematically studied for about 30 years, practical medical application of the knowledge gained has been slow. One reason for this is that the new information challenges the long-held theory of "homeostasis," which sees the internal conditions of the human body as more or less constant. Although this concept allows for minor body fluctuations, it maintains that the fluctuations are meaningless when it comes to the treatment of disease. Another reason is the difficulty of devising human studies that can control all environmental factors.

Says Ritchie J. Feuers, Ph.D., a researcher at the Food and Drug Administration's National Center for Toxicological Research who has published on the subject, "Though it's an old field, for a long time most researchers have chosen to ignore it. But now scientists are beginning to recognize the medical implications of our findings."

Jet Lag, Shift Work, and Depression

Three areas that are beginning to benefit from knowledge about body rhythms are jet lag, shift work, and some types of depression. The biological rhythm of the hormone melatonin appears to affect all of these somewhat, but much controversy still exists about its precise role.

Melatonin is secreted at night by the pineal gland, located in front of the brain in about the middle of the forehead. Some researchers believe that hormones secreted by this gland somehow transmit information concerning the light-dark cycle, which helps to regulate the "biological clock."

"Jet lag" is more than an excuse for sleeping until noon the day after a plane trip across time zones. Research in biological rhythms has led to the realization that jet lag is a legitimate medical condition. When people jet across time zones, their bodies continue to operate on the rhythms established at their homes, and it can take several days for body rhythms to adjust to local time. Symptoms of jet lag include daytime sleepiness and nighttime insomnia, confusion, poor concentration, slowed reflexes, indigestion, hunger at odd hours, irritability, and sometimes mild depression. For people whose careers required frequent travel between time zones, these problems can be crucial.

Symptoms of jet lag are commonly more severe when traveling from west to east. This may be due, at least in part, to the body's tendency when separated from time cues to gravitate to a day that is closer to 25 hours than 24. For this reason, body rhythms may have an easier time adapting to westward travel--which lengthens the day. Because melatonin secretion is thought by some to play a part in regulating the biological clock, researchers are currently investigating whether administering the hormone in pill form will help alleviate jet lag symptoms. Preliminary studies involving 25 people traveling from New Zealand to London and back gives some evidence that the medication is effective. However, it will take years of additional studies to determine what the long-term side effects of this drug use of a hormone might be and whether it is best taken before, during and after a flight, or just after it.

In the meantime, some experts recommend that jet setters might try the following:

• If staying in the new location more than two days, adopt local time for routines immediately upon arrival. If staying less than two days, maintain home schedule if possible.
• If staying more than two days, several days before departure, try to gradually shift sleeping and eating routines to coincide with time at destination.
• Before flight, avoid overeating and alcohol.
• In flight, drink water and juices, not alcohol. Don't smoke.
• If possible, break up long flights in one direction with layovers of at least a day.
• Allow plenty of time for sleep in the new location.
• After flying east, take walks outside in the morning to get used to earlier appearance of light. After traveling west, take walks outside in the afternoon to acclimate to later waning of light.

Melatonin is also being investigated for use in helping people adapt to shift work and to treat a particular type of depression known as winter depression or seasonal affective disorder (SAD). This particular type of depression, according to one theory, may, in some cases, be related to desynchronization of body rhythms. One symptom of this, some researchers think, is the early morning awakening symptomatic of this illness. It is not clear, however, whether such observed desynchronization is a cause or an effect of the depression.

Treating Illnesses

For most medications, as far as is currently known, the daily variation in body rhythms usually is not enough to make a difference in drug treatment. However, in a few instances, knowledge of the effect of circadian rhythms may help doctors devise more effective ways of administering therapies.

For example, there have been reports that the effects of heparin, a drug used to thin blood, apparently vary with the individual because of circadian rhythms. In particular, physicians have observed that the drug seems to be more "active" (has a stronger effect) in the evening. What is not known is whether this variation is substantial enough to make a difference when treating patients. It is important to find out, however, because in the last few years some problems (such as blood clots) have come to be treated most commonly by continuous intravenous infusion, in which the dose of the drug is the same at all times.

In treating asthma, the circadian rhythms of the lung's airways are now taken into consideration when giving the drug theophylline, used to open airways. Researcher Jay Grossman, M.D., of Albany Medical College observed that circadian rhythms may underlie nocturnal asthma. Writing in the July 29, 1988, issue of the American Journal of Medicine, Grossman says that both nonasthmatic people and asthma sufferers have the same daily rhythms as far as when airways are the most open and the most closed. (In this daily pattern, airways are most constricted at night.) But, while a healthy person's airway openness varies up to only about 8 percent, that of an asthma sufferer can vary up to 50 percent. Grossman theorizes that because asthmatic airways react more strongly to many different stimuli that constrict airways, they also react more strongly to circadian factors responsible for the daily variation in airway openness.

This knowledge is beginning to be applied to the way theophylline is given. Theophylline is a tricky drug. Because the toxic dose can be close to the therapeutic dose, monitoring the patient's blood levels of the drug is standard practice. Finding a time when a larger dose could be given more safely, or when a smaller dose would be more effective, therefore, would represent an important step forward in therapy.

Robert Donohoe, M.D., a consultant to FDA on the approval of theophylline products, says that recent human trials of theophylline formulations have shown that the same dose of the drug given to the same patient may act differently at night than during the day. He credits this to two factors: posture (the drug is absorbed more slowly when a person is lying down) and circadian rhythms affecting the airways.

"At night the patient's airways narrow," Donohoe says, "so that by early morning they are at their narrowest. This is what we call the ?early morning dip'."

This information has led some doctors to alter the dosing regimen for sustained-release theophylline from two divided doses daily to one dose in the evening. This is particularly effective for patients whose asthma symptoms wake them in the middle of the night or early in the morning. The physician labeling of one theophylline product has been changed to reflect circadian variations, and, Dr. Donohoe says, labeling revisions for other theophylline products are under consideration. (For more on the use of theophylline to treat asthma, see "More Than Snuffles: Childhood Asthma" in this issue.)

Cancer Research

Some work is being done on the relevance of biological rhythms to cancer treatment. In animal research with Lawrence E. Scheving, M.D., and Tein H. Tsai, Ph.D., of the University of Arkansas for Medical Sciences, and Lawrence A. Scheving, M.D., of Stanford University, FDA's Feuers has been able to lower the death rate from drug toxicity with drugs used to treat leukemia by varying dosages according to circadian rhythms. The researchers also showed that when combination drugs are used, therapeutic efficacy depends on the circadian stage at which they were given. Similar work has been carried out at the University of Minnesota by Halberg, Erhart Haus, Ph.D., and associates.

"Most cancer cells tend to lose their rhythmicity," Feuers explains. "You want to try to find a time when the normal cells are not as sensitive and administer the treatment at a time when few bone marrow and intestinal cells are dividing, thereby ?shielding' in time the normal tissue."

Feuers believes that, in most instances, tumor cells have escaped from circadian control. He cautions, however, that some tumors may show some circadian variation at times when cells are not dividing rapidly.

Clinical studies of a number of drugs in patients with ovarian and bladder cancer as well as kidney cancer have been conducted to determine if higher doses given at certain times of the day will be both less toxic and more effective. For example, researchers have found that the kidney toxicity of cis-platinum can be reduced in patients with advanced cancer by varying the dose according to time of day. Similarly, by dosing according to circadian rhythms, the human bone toxicity of adriamycin can apparently be reduced.

Implantable computerized drug pumps, currently under investigation, will make it possible to vary dosage of medication according to the time of day as well as other factors. These devices infuse drugs via catheter and can be programmed to deliver various dosages at different times.

Because some tumors have daily temperature cycles, research is now being done to determine whether radiation therapy can be both more effective and have fewer side effects if done at certain times of day. Feuers, Scheving and associates have shown, for example, that in mice, the death rate of the animals is affected by the time of day radiation is given.

Research into specific kinds of cancer is also yielding important information. For example, studies show that the temperature pattern of a breast containing a cancerous tumor is different from a breast with no cancer. A noncancerous breast has both 24-hour and 7-day temperature rhythms. A breast with malignancies has 20-, 40-, and 80-hour periodicities.

It is also known that breast tumors grow most actively around midnight. Other tumors, however, may not have daily rhythms, although normal cells do. According to Scheving's research, most normal skin cells divide between 1 a.m. and 4 a.m. With this knowledge, doctors hope to be able to determine how to administer radiation treatment so that the damage to normal cells is minimized.

Like the early investigator de Mairan, today's researchers are discovering surprising things from their studies of biological rhythms. Though once considered a field on the outer edges of science whose theories were interesting but without practical application, today the science of chronobiology is gaining wider acceptance in the scientific community, and its applications are beginning to change medical therapy.

Judith Levine Willis is editor of FDA Consumer.

A Circadian 'Believe It or Not'

Studies of circadian rhythms have turned up the following sometimes hard-to-believe information:

• The length of time a person sleeps is related more closely to body temperature rhythms and bedtime than to how long the person has been awake. In experiments, even after being awake more than 20 hours, people free of time cues slept twice as long when they went to bed when their temperature was at its highest (in early evening) than when it was at its lowest (in the early morning).
• The senses of hearing, taste and smell are more acute at certain times of day. Studies show sensory acuity is highest at 3 a.m., falls off rapidly to a low at 6 a.m., then rises to another peak between 5 and 7 p.m. (This cycle is related to the hormone cycle; when steroid hormones are released, sensory acuity falls.)
• People react more strongly to substances they're allergic to around 11 p.m., while antihistamine drugs have the greatest impact in the morning.
• Aspirin stays in the body longer when taken at 7 a.m. than when taken at 7 p.m.
• Women go into labor most often between 1:30 and 2:30 a.m. and least frequently about midday. Births between 2 and 4 p.m. are associated with increased probability of complications in both the baby and the mother.
• In one study, eating one meal a day of 2,000 calories resulted in a weight loss when eaten as breakfast, but produced a weight gain as supper.
• Heart attacks are twice as likely to occur between 8 and 10 a.m. as between 4 and 6 a.m. and between 6 and 8 p.m.

--J.L.W.

This article was published in FDA Consumer magazine several years ago. It is no longer being maintained and may contain information that is out of date.

About the Author

Judith Levine Willis