The night belongs to asthma.
If you’re one of America’s 10 million asthmatics, you may find that your symptoms vary like, well, night and day, with the odds of an attack vastly greater in the wee hours — about 4 a.m.– than in daylight.
But if it’s heart attacks and strokes that worry you, early morning is definitely prime time. That’s when cardiovascular problems — as well as more minor troubles like allergies and rheumatoid arthritis — are most likely to strike.
And if pain is your worst enemy, you probably already know when the witching hour comes: late evening.
For years, scientists have known that nearly everything in biology seems to be imbued with its own distintive circadian — or daily — rhythms, from the lowliest bacterial colony to the deadliest of cancer cells to the most complicated human hormones that ebb and flow through our veins according to timetables laid down long ago by evolution.
They’ve found, for instance, that adrenal glands in a test tube secrete hormones at precise times of day, just as they do in the body. And that plants, stashed in closets, furl and unfurl their leaves according to deep, genetically-set rhythms.
Researchers are now making the leap from chronobiology, the study of these basic rhythms, to chronotherapy, the tailoring of drugs to the rhythms of the body and of disease.
“In the old days, doctors used to think that a `steady state’ of drugs in the system was best,” says Michael Smolensky, a physiologist at the University of Texas-Houston School of Public Health, largely because they had been indoctrinated with concept of homeostasis — the idea that the body likes to keep its internal milieu reasonably constant.
But with 24-hour monitoring of blood pressure, hormone secretion and other variables, chronobiologists have shown that homeostasis is more complicated than that. It’s now clear there is fluctuation in many body rhythms every 24 hours — and that it can pay to synchronize treatments to these rhythms.
This insight has led to a such a scramble among researchers and drug companies that doctors are struggling to keep up. According to a Gallup survey done for the American Medical Association, only one doctor in 20 really understands chronobiology.
But most said they were eager to learn, recognizing there’s more to chronotherapeutics than, say, just popping a sleeping pill or even melatonin, the popular but controversial hormone, in the evening to get a better night’s sleep.
Consider asthma, for instance, an inflammatory lung disease with a clear circadian pattern — and treatment strategy.
One reason asthma flares at night is adrenalin, a stress hormone that is also a bronchodilator, or airway opener. Adrenalin peaks in mid-afternoon, then sinks to its nadir 12 hours later, so that airway function is best in mid-afternoon and worst at 4 a.m., says Dr. Richard Martin, head of the division of pulmonary medicine at the National Jewish Center for Immunology and Respiratory Medicine in Denver.
Histamine, a natural substance that constricts airways, makes things worse. At night, when adrenalin is low, histamine soars, adding to the tendency of airways to narrow.
And then there’s cortisol, a hormone that dampens immune response and inflammation. Cortisol peaks in the early morning, but during the night, when it would help to have cortisol available to curb inflammation in the airways, levels are low.
The result is that airway function varies somewhat in everybody over a 24-hour period. In people with severe asthma, the difference can be as much as 50 percent — potentially the difference between life and death.
To combat this pattern, researchers years ago developed the first genuine chronotherapeutic drug, Uniphyl. If the drug is taken in the evening, its efficacy peaks when it’s needed most — in the middle of the night — then wanes during the day.
Other asthma remedies have also been shown to be most effective at particular times of day, including oral steroids, which seem to work best when given around 3 p.m., says Martin. But he cautions that patients should not alter the timing of these medications without talking to their doctors.
Other chronotherapeutics are fast becoming available.
Last month, Searle, the pharmaceutical arm of Monsanto — began marketing its recently-approved drug, Covera-HS, for high blood pressure and the chest pain of angina.
Doctors have long known that the odds of heart attack, angina or stroke peak in the early morning, as blood pressure soars and platelets become sticky and more likely to form clots.
One obvious solution is to get blood pressure medications into the patient’s system before he wakes up and enters this danger zone. But this can be trickier than it sounds, says Dr. William B. White, chief of hypertension and vascular disease at the University of Connecticut Health Center in Farmington.
Taken at bedtime, some anti-hypertensive drugs may lead to a too-severe drop in blood pressure during sleep, when blood pressure is already comparatively low, and leave too little in the system to be effective in the morning, he says.
Covera-HS, a once-a-day bedtime drug, is designed to get around that problem. The pill has coatings that delay absorption for four to five hours, so that it kicks in early in the morning, says White, who has studied the drug.
Other studies show it can help to take cholesterol-lowering drugs at night, when the liver is busiest making cholesterol.
And just 10 days ago, a Charlestown company, Ergo Science, released tests of a new diabetes drug designed with chronobiology in mind.
Scientists have long known, say Ergo physiologists Anthony Cincotta and Albert Meier, that in healthy, lean animals, certain brain chemicals — notably dopamine — surge in the early morning, then taper off at night. The same pattern is believed to hold for people.
But in Type II diabetes, a condition in which the body becomes resistant to the sugar-transporting hormone insulin, the body clock seems to go haywire: Dopamine drops in the morning.
Ergo’s new drug, still unapproved, seems to fix this errant biorhythm. Taken at breakfast, it dissolves fast, providing a quick blast of a dopamine substitute just as the body needs it.
In 400 people with diabetes, the drug has improved blood levels of glucose, cholesterol, triglycerides and fatty acids.
Timing of treatment may also be important in cancer chemotherapy, says Dr. William Hrushesky, senior attending oncologist at the Samuel S. Stratton Department of Veterans Affairs Medical Center in Albany.
Hrushesky, a pioneer in the study of biorhythms in cancer treatment, says there is a distinct rhythm for cell division, for cell suicide, for the growth of new blood vessels around tumors and for the metabolism of drugs given to combat cancer.
Because of these rhythms, he says, “timing is everything” — with different drugs having different windows of effectiveness.
Adriamycin, for instance, may work best in the early morning, 5-FU (Fluorouracil) does best at night and platinum-based drugs like Cisplatin in late afternoon, he says. Pumps worn by the patient make it relatively easy, he adds, to take drugs on a schedule that’s most effective, not just convenient for doctors.
Though the timing of chemotherapy to fit biorhythms is not yet mainstream practice, Hrushesky and French researchers have evidence that survival rates can be quadrupled in ovarian cancer and doubled in advanced colon cancer if chemotherapy is timed right.
And Canadian researchers have shown that children in remission from acute lymphoblastic leukemia who take the drug 6-MP (mercaptopurine) in the evening are three times less likely to relapse than those who take it in the morning.
As with any other new field, of course, much research still needs to be done. But the field is clearly exploding, says Smolensky of Texas. Ten to 15 years ago, when chronobiologists began promoting their findings, “people would look at us as if we had stepped out of a spaceship,” he says.
Now, they’re eager to know more.
SIDEBAR:
With medication, timing is everything
While researchers are developing new drugs to take advantage of the daily rhythms of the body or to fix errant rhythms, research in chronobiology suggests you may be able to enhance the effectiveness of old ones by taking them at just the right time.
If you suffer from hot flashes, for instance, taking estrogen replacement therapy at night — when hot flashes can wake you — may make sense, says Dr. Gary Richardson, director of the neuroendocrine clinic at Brigham and Women’s Hospital.
Rheumatoid arthritis, an inflammatory disease, is often worst in the morning, says Dr. Martha Barnett, a rheumatologist at Beth Israel Hospital. Though she believes morning stiffness stems from inactivity at night, others think it may be a result of circadian rhythms in hormone secretions and other factors.
Whatever the reason, taking nonsteroidal anti-inflammatory drugs (NSAIDS) may help most in the evening. But be sure to take them with food, to help prevent ulcers and other stomach problems. In fact, ulcers have their own circadian rhythms, with many flare-ups occuring during the early hours of sleep.
On the other hand, osteoarthritis, which results from wear and tear on joints, is worse at night, after a day of activity, so taking medications in the morning may be most effective.
Runny noses, colds and nasal allergies are often worst in the morning, notes Michael Smolensky, a physiologist at the University of Texas-Houston School of Public Health. Thus, time-release anti-histamines taken at nighttime may help.
Aerobic exercise, while not a drug, does impact health and can also be timed for optimal effect. Studies by the US and German armies suggest that the biggest increase in endurance comes if you exercise in the afternoon and early evening, says Dr. William Hrushesky, a chronobiologist in Albany, N.Y. It’s also much easier to exercise at this time of day, he adds.
Sunlight isn’t exactly a drug, either. Though it can increase the risk of skin cancer, it is also beneficial because it suppresses the sleep hormone melatonin and helps re-set circadian rhythms so you sleep better at night, says Dr. Michael Holick, chief of endocrinology at the Boston Medical Center.
In fact, one explanation for “winter depression” is that the weaker sunlight in winter may not suppress melatonin well enough.
And there’s another reason sunlight may make you happy. In skin cells at least, sunlight boosts levels of the feel-good hormone, beta-endorphin.