Timing Is Everything : Researchers Are Finding Evidence That Time--When Medicines Are Taken or When Tests Are Performed--Can Mean a Lot to Wellness

These days, we live in an around-the-clock world.

Stores stay open all night, 24-hour television stations rule, and computers allow us to communicate instantaneously with just about anyone at any time. As a result, we tend to ignore our inner clocks: We are more likely to go to bed after Jay Leno’s monologue than when our inner rhythm tells us it’s time to rest. And, apparently, we adapt. Following external rather than internal cues seems to do us no harm.

Or maybe not. In an emerging field of medicine known as chronobiology, scientists are discovering striking connections between time and disease.

It may sound farfetched, but even the most respected researchers have discovered that time can actually increase--or decrease--the effectiveness of some medical therapies. For instance, some drugs are more effective when taken at a certain time of day. And some diagnostic tests can miss symptoms if given at the wrong time. Timing can even save lives: having breast cancer surgery during a specific part of the menstrual cycle leads to a greater chance of long-term survival.

In ways you--or your doctor--might not expect, time may be on your side.

“In chronotherapy, you’re concerned with taking advantage of time to improve the ability to diagnose, to diminish toxicity of drugs and to enhance efficacy of drugs,” says Dr. William Hrushesky, senior attending oncologist at the Samuel S. Stratton VA Medical Center in Albany, N.Y., and a pioneer in the field of chronotherapy. “These goals are relevant to all aspects of medicine.”

As chronobiologists see it, the human body is a symphony of rhythms: an ebb and flow of differing heart rates, temperatures, neurotransmitters, white blood cells and hormones.

“Our biology is not the same throughout a 24-hour period,” says Michael Smolensky, a University of Texas physiologist who directs the Hermann Hospital Center for Chronobiology and Chronotherapeutics. He has done pivotal research on biological rhythms in human health. “We’re not the same physiologically, biochemically or hormonally,” he says.

It may seem that the light of day is what controls our sleeping and waking patterns. But put a human being in a cave with no natural light for a few weeks and the basic rhythms continue.

The idea that we have genetically inherited biological rhythms or clocks independent of environmental cues such as light should come as no surprise to anyone who’s suffered through jet lag. But our clocks can be gradually reset by light--that’s how we adjust to time shifts and stay synchronized.

Like our bodies, diseases have schedules too. Some examples (times are based on people sleeping during nighttime hours):

* Heart attacks are most likely to occur between 8 to 10 a.m.--the first few hours after waking--because this is when blood pressure and heart rate surge and when blood clots are most likely to form.

* Different types of arthritis have different schedules. Rheumatoid arthritis, caused by inflammation of joints, is worse in the morning when inflammation in general is a problem. But osteoarthritis, a use-induced injury, is worse in the evening.

* Asthma attacks peak at 4 a.m. because this is when hormones such as adrenaline, which open up airways, and cortisol, which controls the swelling of airways, are at a low. Meanwhile, histamine, which causes airways to narrow, is at a high, says Dr. Richard Martin, head of the Division of Pulmonary Medicine at the National Jewish Center for Immunology and Respiratory Medicine in Denver, and professor of medicine at the University of Colorado Health Sciences Center.

The goal of chronotherapy is to give medicine at the time it will be most effective, in contrast to traditional dosing that tries to keep medication levels constant or administers drugs when it is convenient, but not necessarily best for the patient. Why, say chronobiologists, have something in your bloodstream all the time if it’s only needed for a few hours?

The use of chronotherapy means fewer drugs are put into the body. And that means fewer side effects.

“The chronotherapeutic approach is to fight the disease when it’s worst--at night--and back off when it’s at its best during the day,” says Martin, who uses such an approach with both the common asthma drug theophyline and with oral steroids that can have potent side effects.

Some of the most dramatic evidence for the importance of timing in medicine comes from cancer treatment. In clinical trials, when some chemotherapy drugs were given at certain times of day, patients suffered fewer side effects. This is because chemotherapy drugs kill more than cancer cells: They kill healthy bone marrow, as well as kidney, nerve and stomach cells. Because those cells all divide according to specific daily rhythms, a well-timed treatment is a more benevolent one, and more drug can be given with fewer side effects.

Other studies by Hrushesky demonstrated that parents with ovarian or colorectal cancer were more likely to survive for five years if they were given cancer drugs at times of day when those drugs were most effective. (Each drug has its own schedule.)

Ideally, a cancer-killing drug should be given at a time when a cancer cell is the most vulnerable and the patient’s body the least vulnerable, but more research needs to be conducted before precise schedules are worked out.

To Hrushesky’s dismay, timing is not a factor in clinical drug trials, even though, he says, timing could be considered and would ultimately reduce the costs associated with drug development.

In another line of research, Hrushesky found that the optimal timing of breast cancer surgery within a woman’s menstrual cycle could significantly increase long-term survival--if surgery were conducted in the middle of a patient’s menstrual cycle. This is because of the marked effect of hormones on the growth of breast cancer tumors. A dozen studies have confirmed this result, while others have been more ambiguous, Hrushesky says.

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Today, chronotherapy is standard treatment at only a handful of hospitals in the world--Hermann in Texas, Stratton in Albany, the University of Toronto, and the University of Paris. If you think chronotherapy might benefit you, ask your physician. Thanks to an increasing number of articles in medical journals and conferences on chronotherapy, more physicians are learning about and applying findings in the field to their own patients.

Unfortunately, says Hrushesky and others, some physicians hesitate to embrace chronotherapy.

Why? A major factor, Smolensky says, is that many doctors are wedded to the concept of homeostasis--or the idea that the body maintains a steady state--a fixed temperature of 98.6 degrees, for example. Ironically, even our so-called stable temperature fluctuates with a daily rhythm.

As results come in, however, the idea of chronotherapy is coming of age. Critics once dismissed the field entirely, but now even skeptics say the questions raised by chronobiologists are worthy of further study.

Indeed, when Smolensky and others first touted the idea of chronotherapy years ago, people literally treated the ideas as alien. “People would look at us as if we had stepped out of a spaceship,” Smolensky is fond of saying. Now, though, he says, “It has changed dramatically. Doctors want more of it.”

To that, the chronobiologists say, it’s about time.

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The Good Times and the Bad Times, According to the Clock At certain times of the day, some drugs work better, some ailments hit harder. (The times listed in this chart are approximate and are based on people sleeping during nighttime hours. The times listed are averages--individual responses may vary.)

* 11:30 p.m.-2:30 a.m.: Women most likely to go into labor.

* 3-5 a.m.: Most asthma attacks occur.

* 4-6 a.m.: Death (by all causes) most likely to occur.

* 6-10 a.m.: Nasal allergies worst.

* 7 a.m.: Aspirin taken now will stay in the body longer than aspirin taken at 7 p.m.

* 7-11 a.m.: Testosterone levels peak.

* At wake-up: Heart rate and blood pressure surge; platelets most likely to aggregate.

* First three hours: Heart attacks and cardiac death most likely; strokes caused by blood clots most likely.

* Morning: Rheumatoid arthritis worst; migraine headaches most likely to occur; dental pain most acute.

* Early afternoon: Daytime drowsiness sets in.

* Afternoon and evening: Skin reactivity to allergy tests three times stronger than in the morning hours.

* 3-6 p.m.: Grip strength greatest and reaction time shortest.

* 4-5 p.m.: Daily temperature highest.

* 5 p.m.: Alcohol has least effect on body temperature regulation.

* 6 p.m.: Urine production peaks.

* Early evening: Production of cholesterol and blood fats increase.

* Middle to late evening: Osteoarthritis pain worst.

* Late evening: Acidic stomach secretions peak; highest risk of hemorrhagic stroke.

* Night: Chronic pain worse.

* After midnight: Lower tolerance for alcohol.