RHYTHM RULES : DOCTORS GETTING IN STEP WITH TREATMENT OF MALADIES THAT STRIKE LIKE CLOCKWORK.

Byline: Judy Foreman Boston Globe

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 distinctive 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 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 midafternoon, then sinks to its nadir 12 hours later, so that airway function is best in midafternoon 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 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. The anti-hypertensive drug taken at bedtime has coatings that delay absorption for four to five hours, so that it kicks in early in the morning, when odds peak for heart attack, angina or stroke.

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.

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.

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for your medicine

(2) Many doctors are beginning to prescribe medications with the body's rhythms in mind. For instance, a new anti-hypertensive drug is meant to be taken at night, but the pill is coated so it won't dissolve until morning, when the risk of heart attack, stroke or angina is greatest.

Myung J.Chun/Daily News