Asthma and allergy specialist John Bacon remembers wheezing through agonizingly long nights as a child in the 1950s. His asthma was so debilitating that he usually missed 30 or 40 days of school a year. Although exercising provoked asthma, too, his scariest moments with the disease came after he went to bed.
"I would be up all night just waiting for sunrise," he says. "As soon as the sun came up, I knew I'd make it. I knew that I would start feeling better and that I could get some rest."
It wasn't until he went to medical school, however, that Dr. Bacon learned the biological basis for the cycle of night-time wheezing and morning relief: The body's production of cortisol steroids, which control inflammation, is lowest at night and peaks in the morning. Likewise, blood levels of histamine increase at night, provoking more severe reactions to the allergens that can trigger asthma.
Taking their cues from the body's own clock, many physicians now prescribe asthma medications that pack an extra punch at night. And research suggests that other conditions such as heart disease and epilepsy may be treated most successfully according to the timetables of human biology. Even timing chemotherapy to the body's rhythms may prove important to cancer treatment, studies indicate.
The internal workings of the human body are controlled by circadian, or daily, rhythms that change the body's environment constantly over a 24-hour period. The ebb and flow of hormones, the division of cells and the activities of organs that regulate body functions all follow predictable patterns.
These body tides, long known to cause sleep and wake cycles, also affect many illnesses, says Baltimore medical writer Lynne Lamberg in her new book "Bodyrhythms: Chronobiology and Peak Performance" (William Morrow, $25).
Ms. Lamberg believes chronobiologic research may transform the practice of medicine. She foresees a time when physicians will consult their patients' circadian profiles, use programmable drug pumps and prescribe more pills and patches that release drugs at rates most appropriate to individual body clocks.
"Every single function of body and mind has some sort of circadian cycling," she says.
For instance, the period after a person wakes up is known to be the peak time for heart attacks, strokes and angina-caused chest pains.
"It's not just that heart rate and blood pressure go up in the morning, but that the blood is more apt to coagulate then," says Sidney Gottlieb, director of cardiac catheterization at Greater Baltimore Medical Center. "And not only are the platelets more likely to stick together and cause a clot, but the system made to dissolve clots in the body isn't working as efficiently at that point."
In recognition of this circadian danger zone, many physicians now prescribe such heart drugs as beta blockers, calcium channel blockers and ACE inhibitors in long-acting forms that guarantee greater protection for heart patients during vulnerable times.
And, as chronobiologic research accumulates, it is becoming more common to plan other treatments according to body time.
"God never told us we had to divide drug dosing into equally spaced times," says Dave Newton, chairman of the pharmacology department at Albany College of Pharmacy. "We're just finding that there may be specific times of the day that make a drug the most effective with the least number of side effects."
As soon as physicians recognize a pattern in a patient's disease symptoms, they can time medication to better relieve them. But they often remain unsure as to why flare-ups occur at certain times of the day.
"The major problem with chronobiology is the actual mechanism of causation," says Gregory Bergey, director of the University of Maryland Epilepsy Center. "You don't see Lyme disease in January -- you can explain that cyclical nature -- but it's more difficult with other things."
Seizures at night
He says some of his patients' seizures occur mainly at night, suggesting they are caused by transitions in sleep stages. Another pattern of seizures occurs upon awakening. Some female patients have a cluster of seizures in the week before menstruation, suggesting monthly hormonal triggers.
Another promising -- and controversial -- area of chronobiologic research concerns circadian timing of cancer medication. Some American and European studies suggest that the timing of chemotherapy for certain cancers make the drugs less toxic to the body and more effective at killing cancer cells.
Among them:
* A large-scale clinical trial by the National Cancer Institute, scheduled to be completed in 1996, will show whether circadian timing of medication aids in the treatment of endometrial cancer, which affects the lining of the uterus. Last year's preliminary trials brought significant results: They showed that cancer patients using chronotherapy had a 60 percent response rate to the medication; the highest previous response rate had been 40 percent.
* A large-scale randomized clinical trial of advanced colon cancer patients in Europe recently showed tumors shrank by at least half in 51 percent of the patients who received chronotherapy as compared with 28 percent of the patients getting medication as usual.
* Various research labs across the country are using circadian timing to test mice with such cancer-fighting substances as interferon and interleukin 2. The current data suggests the timing of these medications may also make a difference in outcome.
Although no one knows why circadian timing of chemotherapy may work, researchers suspect that the body's healthy cells can better withstand the drugs' devastating effects at certain times of day, therefore permitting greater doses of the cancer-killing chemicals.
Clinical research scientist Jeffrey Abrams, a cancer therapy evaluator at the National Cancer Institute, says most American oncologists doubt the importance of circadian-timed chemotherapy.
"Chronotherapy has not generally caught on in cancer medicine, despite positive studies," he says. "I don't think doctors are convinced that the differences in the results are either important or that they can't be explained by other factors.
"If the trials which are ongoing now should also be positive, perhaps more people will begin timing their treatments."
William Hrushesky, an oncologist at Stratton VA Medical Center in Albany, is a pioneer in the field of chronotherapy cancer research and one of few American physicians to offer chronotherapeutic treatment to his cancer patients.
"Regular circadian rhythms in the division of cells in the bone marrow and gut may partly explain why chemotherapy is more toxic to those normal cells at certain times of day," he writes in a recent issue of The Sciences.
He also suspects that human tumor cells divide according to a synchronized circadian pattern. If the daily periods of cell division in healthy and cancerous cells are not identical, he says, physicians could administer chemotherapy at a time when only cancerous cells were dividing.
Perhaps more controversial is Dr. Hrushesky's conviction that the outcome of breast cancer surgery in pre-menopausal women can be influenced by where they are in their menstrual cycles when surgery occurs.
So far, supporting studies in America and Europe have been conducted retrospectively, which makes them vulnerable to various inaccuracies, says Dr. Abrams.
Test the theory
Nevertheless, on the basis of Dr. Hrushesky's research and other similar findings, the National Cancer Institute is working to develop a clinical trial to test the theory.
"The results certainly merit a trial, but I don't believe we've proven there's a best time of month to do [breast cancer #F surgery]," says Dr. Abrams, who is the breast cancer specialist in the clinical investigations branch of NCI.
"The questions are whether the people who run the co-operative groups [between research institutions] really think this is one of the most interesting questions [about breast cancer] or not -- and whether they want to put patient resources into this sort of trial."
Physician Adriane Fugh-Berman, a board member of the National Women's Health Network, believes a chronotherapeutic approach to breast cancer surgery should be given high priority.
"It's low-tech, non-invasive, a simple thing to do [as far as scheduling surgery] and more than one study has shown the benefit," she says. "It's being ignored and that's a crime."
Market forces tend to work against the circadian testing of existing drugs, says Rebecca Finley, associate professor of pharmacy practice at the University of Maryland School of Pharmacy.
"To the people who hand out the money, it's more important to try to find new drugs than to take the ones we have and make them work better," she says. "There's more money to be made with new drugs. Optimizing the therapy by changing the time of day is unlikely to increase the market share of an existing product."
Some drugs are also more suitable for chronotherapy than others, says pharmacologist David Newton. In order to time medication to circadian rhythms, physicians must be able to predict exactly when the drug will begin acting. Anti-cancer drugs begin to work as soon as they enter the bloodstream. Certain anti-depressant drugs, on the other hand, may require several weeks of therapy before a patient responds.
Asking your doctor
Author Lynne Lamberg suggests that people become aware of recurring patterns in their disease symptoms and that they ask their physicians about chronotherapy.
"It's important to find out, if you can, whether circadian timing matters for a particular illness or a particular drug," she says. "A drug like aspirin stays in the body for a very long time; it may not make any difference what time it's taken. Other drugs disappear within three or four hours, so the timing may be important."
Michael Fisher, director of clinical cardiology at the University of Maryland Medical Center, is another physician who prescribes medication with circadian patterns in mind.
"We don't have the studies yet to prove this timing of medication actually works better, but we have the studies to prove certain events occur at certain times," he says. "If you have to take medication, why not take it at the time where it can offer greatest protection?"
THE TIMES OF YOUR LIFE
Certain events cluster at specific times on the body clock, writes Baltimore medical writer Lynne Lamberg in "Bodyrhythms: Chronobiology and Peak Performance." The following list provides a sampling of what tends to happen to humans at various times of day:
* Midnight to 4 p.m.: This is the time at which spontaneous labor is most apt to begin. Between midnight and noon, natural births occur three times more often than between noon and midnight.
At this time, skin cell division also peaks, lending credence to the notion of "beauty sleep."
* 2:30 a.m.-8:30 a.m.: Sudden infant death syndrome strikes most commonly at these hours. The disorder may reflect an undetected breathing abnormality that is aggravated by sleep.
* 3 a.m.-8 a.m.: Toothaches most often start now. Sensitivity to all types of pain is at its height.
* 4 a.m.-6 a.m.: The most frequent hours of death from all causes in people of all ages. The odds of dying at night are about 30 percent greater than dying during the day. Deaths from all causes are also more common on weekends.
* 7 a.m.: Aspirin taken now remains in the body for 22 hours. Taken at 7 p.m. it lasts only 17 hours. An antihistamine taken at 7 a.m. lasts 15 to 17 hours -- twice as long as if it is taken at 7 p.m.
L * 8 a.m.: Hay fever symptoms are worse between now and noon.
* 3 p.m: People allergic to house dust may suffer only minor symptoms to exposure now. If exposed at 11 p.m., however, they may have trouble breathing.
At this time, lidocaine, an anesthesia used by dentists, blunts sensitivity to pain nearly three times as long as it does at 7 a.m.
* 5 p.m.: Peak performance in most sports is achieved in late afternoon and early evening when body temperature is at its highest.
Between 5 p.m. and 7 p.m., senses of hearing, taste and smell are acute. They are most acute at 3 a.m. and lowest at 6 a.m.
* 7 p.m.: Body weight is at its highest. The low occurs about 7 a.m.
Peak daily production of histamine, a body chemical that triggers itching and other allergic responses, occurs from 7 p.m. to 11 p.m.
* 8 p.m.: A martini cocktail drunk in the evening takes longer to get into the bloodstream and has a less intoxicating effect than a Bloody Mary in the morning. In the evening, however, the same amount of alcohol stays in the body longer.