Biological Rhythms : Part 2

by Food and Drug Administration (FDA)

(Page 2 of 2)

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.

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.

About the Author

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