This file comprises chapter seven of BODYRHYTHMS:  CHRONOBIOLOGY AND 
PEAK PERFORMANCE, by Lynne Lamberg.  Copyright (c) 1994 by Lynne 
Lamberg.  All rights reserved.  It appears here by kind permission of 
Lynne Lamberg and William Morrow and Company, Inc.  


                  THE RHYTHMS OF SICKNESS AND HEALTH 

Chronobiology is such a young science that most physicians practicing 
today did not study it in medical school, and many still do not know 
much about it.  There is always a time lag, of course, between 
discoveries made in the laboratory and their application to patient 
care.  The first scientific paper in chronobiology, the report of de 
Mairan's 1729 study of plant behavior, somberly concluded:  "The 
progress of true Physics (Science), which is experimental, can only be 
very slow." 

An even more significant reason for the slowness in acceptance of 
chronobiologic principles is that they pose a major challenge to the 
medical establishment.  Compared with chronobiology, the majority of 
advances in medicine, even so-called "breakthroughs," are merely baby 
steps forward.  Chronobiology is a radically new way of 
conceptualizing health and disease.  

To adopt chronobiology, physicians would have to discard much of the 
long-enshrined principle of homeostasis, or self-regulation.  The word 
"homeostasis," from the Latin words homeo , meaning the same, and 
stasis , state, was created in 1925 by the renowned Harvard Medical 
School physiologist Walter B.  Cannon.  The theory behind the 
principle had originated in 1885 with the French physiologist Claude 
Bernard, who suggested that the body strives to keep its milieu 
interieur, its inner environment, as constant as possible to shield it 
from the assaults of the outer world.  

Extending Bernard's work, Cannon suggested that ups and downs in 
various bodily functions represented the body's fine-tuning within a 
fixed range to maintain an equilibrium, which he called a "steady 
state." Homeostasis explains why, for instance, people sweat when they 
are hot and shiver when they are cold:  an internal temperature 
control system keeps the body from overheating or overcooling.  

Cannon observed variations in blood pressure, temperature, and even in 
concentrations of hormones in the blood.  But he did not see the time-
of-day patterns in these variations nor did he recognize their 
importance.  Cannon believed the changes he saw were random, and 
significant only when people were sick.  Widespread acceptance of 
homeostasis explains why a body temperature of 98.6 degrees F is 
commonly referred to as "normal," when it is merely an average.  As 
the chart, "The Daily Temperature Cycle," on page 35 shows, a reading 
of 98.6 degrees F at 4 am indicates a fever.  

Chronobiology studies have shown that blood pressure, hormone levels, 
urine volume, and many other measures of bodily performance not only 
fluctuate within a substantial range over the course of a day, week, 
month, or year, but also often deviate well beyond the range 
associated with disease.  Although Bernard and Cannon were right--
checks and balances are necessary for survival--there is no true 
constancy in the body.  Some substances present in the blood or urine 
at one time of day are virtually absent at another.  Nevertheless, 
many, perhaps most, physicians view such fluctuations as simply the 
effects of sleep, activity, or diet.  They regard these changes as 
"noise" in the system, a view that has served as a powerful braking 
force to the development of chronobiology.  

As early as the 1950s, researchers mounted a challenge to the steady-
state hypothesis by demonstrating that rhythms literally could make 
the difference between life and death.  Franz Halberg and his 
colleagues at the University of Minnesota showed that a fixed dose of 
a potential poison would kill nearly all mice that received it at one 
time of day, but would kill only a few or even none of those that 
received it twelve hours earlier or later.  The researchers also 
showed that loud noise caused mice to have seizures at one time of day 
but not at others, and that the damage caused by a given dose of X 
rays depended on when the animals received it.  

These findings can be applied directly to humans.  Drugs that can help 
at one time of day may harm at another.  Indeed, when one takes a 
medicine may be as critical as which medicine one takes.  There is 
often considerable variation over the day in the way the body absorbs, 
uses, and disposes of drugs, and the way drugs interact with other 
drugs.  It is impossible to achieve a steady state of most drugs in 
the bloodstream.  

Yet physicians typically prescribe medications to be taken in equal 
doses throughout the day, a practice that dismays and infuriates 
chronobiologists.  Decrying "the stupidity of three times a day drug 
administration," Alain Reinberg of the Rothschild Foundation in Paris 
has called this custom "obsolete and in some cases inappropriate or 
even dangerous." 

Chronobiologists assert that drug doses should be adjusted to meet the 
differing needs or functions of target organs or tissues at various 
times of day.  Some examples:  cancer medication given at the time of 
day when it will do the most harm to cancer cells and the least damage 
to normal cells may improve survival.  (For details, see cancer 
section.) 

Allergic rhinitis--hay fever--is a morning disorder.  People who 
awaken with stuffiness or a runny nose could take medicine to relieve 
their symptoms, but it would be even better if they could prevent the 
morning symptoms by taking medication before going to bed.  The 
treatment of short stature with growth hormone is most successful if 
it is given at night, in sync with the hormone's normal time of 
secretion.  

Rhythms that are longer than one day also need to be factored into 
treatment plans.  Take, for example, weekly rhythms.  In preantibiotic 
times, doctors noted that crises in pneumonia occurred on the seventh 
day, and deaths in malaria came most frequently on days 7, 14, and 21.  
A study of nearly 150 kidney transplant patients showed that the new 
organ was rejected more often on days 7, 14, and 21; drugs, such as 
cyclosporin, that suppress the immune system and boost the chance of a 
transplant's acceptance may work better when given in higher doses on 
the days of high rejection risk than in equal doses every day.  

The timing of radiation therapy and surgery may alter the benefits 
gained from these procedures.  In a study of patients receiving 
radiation therapy for mouth tumors, Franz Halberg and his colleagues 
in India found that people who were treated when their tumors were at 
a daily temperature peak improved the fastest and had the fewest 
recurrences.  

When Halberg needed bypass surgery himself, he calculated the best 
time not only on his own biologic clock but also on that of his 
surgeon, taking into account his own blood pressure pattern and his 
surgeon's sleep schedule.  The operation took place early in the 
morning; both patient and doctor came through just fine.  

Medical diagnoses also need to take rhythms into account.  For 
example, white blood cell counts are lowest in the morning and highest 
in the evening.  They vary by 30 percent over the day.  Many of the 
body's two hundred hormones are secreted episodically.  

Cortisol, for instance, is abundant in the morning (peak secretion is 
around 7 am) but near zero around midnight, a three- or fourfold 
difference.  The detection of diseases involving over- or 
underproduction of cortisol requires knowledge of the time a blood 
sample was obtained.  In many illnesses, single samples of blood or 
urine taken at arbitrary times of day may yield a much higher 
proportion of false positives and false negatives.  

The weight of evidence from animal and human studies would seem hard 
to brush aside.  And, indeed, as experience with a number of diseases 
described in this chapter suggests, the new ideas are beginning to 
catch on.  But they have not yet become part of mainstream wisdom.  
Overturning homeostatic precepts remains an uphill battle.  "I have 
twenty-five things to think about in planning treatment," a prominent 
researcher at one of the nation's leading cancer centers recently 
declared.  "Circadian rhythms are not even on the list." 

They should be at the top of the list, chronobiologists say.  
"Homeostasis is like looking at a house from the outside and trying to 
figure out what is going on in the house by watching what goes in the 
door or out the chimney," Halberg has asserted.  "Chronobiology goes 
inside the house." 


                           A DAY IN THE LIFE 

Some four hundred years ago, the English writer Robert Burton 
presciently observed, "Our body is like a clock; if one wheel be 
amiss, all the rest are disordered, the whole fabric suffers:  with 
such admirable art and harmony is a man composed." Events from birth 
to death cluster at specific times on the body clock.  Following are 
some of them:  

MIDNIGHT TO 4 AM :  This is the prime time for racing the stork to the 
hospital, the hours in which spontaneous labor is most likely to 
begin, according to a study of nearly 300,000 pregnant women.  

Between midnight and noon, natural births occur three times more often 
than between noon and midnight.  Early in human evolution, being born 
at night or in the early morning may have been advantageous, since 
such births probably would have occurred in a protected place.  Today, 
this rhythm may actually work against survival.  Researchers in 
Switzerland found that babies born in the evening had a higher death 
rate than those born during the day, perhaps, they suggested, because 
fewer staff people were around at night--a daily rhythm but obviously 
not a biologic one.  

1 AM :  Between 1 and 4 am, skin cell division peaks.  The notion of 
needing one's "beauty sleep" is not far-fetched.  Cosmetic 
manufacturers who advertise that skin tissue repair increases in 
people who wear night cream are telling the truth.  Not the whole 
truth, however, for cell turnover also increases in those not using 
the cream.  

2:30 to 8:30 AM :  These are the hours during which sudden infant 
death syndrome (SIDS) strikes most frequently.  This disorder, which 
claims the lives of 5,500 babies in the United States each year, may 
reflect a breathing abnormality that is undetectable during 
wakefulness, but is aggravated by sleep and by respiratory illnesses.  
This theory is supported by the annual rhythm in SIDS deaths.  
According to the National Center for Health Statistics, twice as many 
babies die from SIDS in January, a peak month for respiratory 
illnesses, as in July, the low month for SIDS deaths.  

3 to 8 AM :  These are the hours when toothaches most often start.  
Sensitivity to all types of pain is highest at this time.  

4 to 6 AM :  These are 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, on the days 
immediately before and after one's birthday and on the days after 
holidays.  Deaths from heart attacks, and suicides, are more common on 
Mondays.  The explanation in all cases may be the same:  the 
disruptive impact on biologic rhythms of even minor changes in usual 
daily routines--insignificant for most people but dangerous for those 
already ill.  Social influences are at work here, too.  People often 
refrain from "bothering" the doctor on a weekend, or disrupting a 
festive event.  

7 AM :  Aspirin taken at 7 am remains in the body for twenty-two 
hours.  Taken at 7 pm, it lasts only seventeen hours.  An 
antihistamine taken at 7 am lasts fifteen to seventeen hours, twice as 
long as it does if taken at 7 pm.  One time of day is not necessarily 
better than another to take these drugs, but the differences may be 
important in some circumstances.  

8 AM :  Between 8 am and noon, hay fever symptoms are worse.  These 
are not the same hours that pollens and many other airborne allergy-
inducers are highest; that time comes later in the day.  If the two 
periods coincided, hay fever sufferers undoubtedly would be even more 
miserable.  

3 PM :  People allergic to house dust who inhale it at this hour may 
suffer only minor symptoms.  If they inhale the dust at 11 pm, they 
are likely to have severe trouble breathing.  At 3 pm, lidocaine, a 
local anesthetic used by dentists, blunts sensitivity to pain nearly 
three times as long as it does at 7 am --thirty-two minutes in the 
afternoon compared with only twelve minutes in the morning.  The 
midafternoon may thus be a more desirable time to visit the dentist or 
undergo surgery.  Another plus:  motor skills are highest in the 
afternoon.  The dentist's or surgeon's hand will be at its steadiest 
then.  

5 PM :  Runners have their best performance on the fifty-yard dash at 
this time.  Indeed, peak performance in most sports is achieved in 
late afternoon and early evening when temperature is highest.  Between 
5 and 7 pm, the senses of hearing, taste, and smell are quite acute.  
They actually are most acute at 3 am and lowest at 6 am, but few 
people notice.  

7 PM :  Body weight is at its daily high.  The low occurs at about 7 
am.  Between 7 and 11 pm, itching is most severe in people with the 
skin disorder atopic dermatitis.  These are also the hours of peak 
daily production of histamine, a chemical that triggers itching and 
other allergic reactions.  8 PM:  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.  
(For more on social drinking, see Chapter 3.) 


                            A TIME TO HEAL 

Chronobiologic findings have advanced the understanding of some common 
illnesses and are beginning to have an impact on their treatment.  


                       HEART ATTACKS AND STROKES 

Heart attacks and strokes occur more often around 9 am than at any 
other time of day.  This pattern first showed up after the data from 
three thousand people admitted to the hospital after heart attacks was 
analyzed.  Researchers wondered if these attacks had truly occurred in 
the morning, or were merely discovered then.  Perhaps because they 
were asleep people did not notice the minor symptoms of pain that 
signaled an impending attack.  

In 1985, cardiologist James Muller and his colleagues at Harvard 
Medical School reported that they had found a way to pinpoint a heart 
attack's starting time by tracking an enzyme, creatine kinase, that 
first appeared in the bloodstream about four hours after the episode 
began.  In a study of seven hundred patients, the researchers found 
that heart attacks started most often between 9 and 10 am, and least 
often, between 11 pm and midnight, a threefold difference.  

Numerous other studies have substantiated the morning pattern.  
Although many heart attacks and strokes are not fatal, Merrill Mitler 
of the Scripps Clinic and Research Foundation and his colleagues found 
in their review of five thousand death records that people over age 
sixty-five were more likely to die from heart disease, high blood 
pressure, or stroke at 8 am than at any other time.  

While there is no enzyme test that shows when strokes begin, a study 
supported by the National Institute of Neurological and Communicative 
Disorders and Stroke, in which twelve hundred stroke patients, or 
their families, were interviewed by researchers at four university 
medical centers, found that in people who were awake when stricken, 
more strokes occurred between 10 am and noon than in any other two-
hour interval.  They also discovered that the incidence of strokes 
declined steadily through the rest of the day, and that strokes were 
least likely to occur between 10 pm and midnight.  Some 744 patients 
in this study suffered a stroke after waking, while 331 awakened with 
stroke symptoms.  

Because the records were not adjusted for the individual's habitual 
wake-up time or for variable work schedules, the true magnitude of the 
morning increase may be even greater, the researchers noted.  The key 
factor here, as for all biologic rhythms, is an individual's activity 
schedule, not clock time.  The most dangerous hours for heart attacks 
and strokes are the first ones after waking, no matter what time of 
day that is.  

Certain other cardiovascular events also occur more often in the 
morning.  People with angina, for example, are more likely to 
experience chest pain in the morning.  Transient ischemic attacks, 
episodes in which blood flow to the heart slows or stops briefly, 
occur most frequently within an hour or two after awakening.  Although 
these episodes may not produce any symptoms, they leave their 
characteristic signature on records of heart muscle activity 
registered by portable monitors worn around the clock.  Such attacks 
prove to be both more frequent and longer-lasting in the morning, and 
they are thought to be instrumental in triggering more severe heart 
attacks later on.  

Heart attacks occur when an obstruction in one of the coronary 
arteries keeps the heart from receiving an adequate oxygen supply.  
Strokes, which can be thought of as "brain attacks," result from an 
interruption in the flow of blood to part of the brain.  In the 
majority of strokes, a blood clot blocks an artery, usually one 
narrowed by fatty plaques; in the remainder of the attacks, the artery 
bursts, leaking blood onto the surrounding tissue.  

Heart attacks and strokes account for about one third of all deaths in 
the United States each year.  About 1 million Americans have heart 
attacks annually, and 500,000 suffer strokes.  Determining why these 
problems occur most frequently in the morning may help reveal why they 
happen at all.  The last hours of slumber, which are dense with REM 
sleep, when the heart beats more irregularly and when the breathing 
rate varies more than at other times of day, may be a more vulnerable 
time.  These stresses present an added challenge to people with 
angina, irregular heart rhythms, and other heart diseases.  Changing 
from a horizontal to an upright posture, for instance, imposes an 
enormous demand on the cardiovascular system.  The heart pumps blood 
faster, blood pressure and temperature rise, and blood components 
called platelets increasingly clump together, possibly causing clots 
to form.  Together, these burdens may overwhelm fragile blood vessels 
in the heart or brain that have been weakened by age or narrowed by 
disease.  

Staying in bed is not the answer.  Even closely monitored patients in 
intensive-care units suffer more heart attacks and strokes in the 
morning.  Any hospital stay, of course, is far from tranquil, and 
patients get little chance to rest.  With doctors and nurses coming 
and going, X rays being taken, blood being drawn, procedures performed 
around the clock, and meals provided at unaccustomed times, sleep and 
other circadian rhythms may undergo vast disruption.  Hospitals would 
do well to heed the morning risk pattern in scheduling work hours, 
since at present, in most hospitals, the lowest number of staff 
members are on duty in the early-morning hours.  

The morning pattern holds many other implications for treatment.  
Researchers have found that fasting increases platelet stickiness, 
suggesting a simple strategy to reduce one's risk of a morning heart 
attack:  eat breakfast.  In the future, doctors may advise some 
patients to take their medications at bedtime, and others, when they 
awaken in the morning, perhaps even before they get out of bed.  
Chronobiologists forecast that eventually doctors may prescribe that 
fast-acting heart drugs, such as nitroglycerin and calcium-channel 
blockers, be taken in the morning, and that long-acting drugs, such as 
beta-blockers, be taken at bedtime.  

Several major studies have shown that simply taking an aspirin (325 
mg) every day or every other day (for men) or one to six times a week 
(for women) reduces the clumping of platelets, thereby offering 
protection against heart attacks.  The people in these studies did not 
take aspirin at any specific time of day.  Nor in fact would there 
have been any advantage in doing so:  aspirin eliminates morning 
increases in platelet activity for at least thirty-six hours after it 
is taken.  

Is it a bad idea for people with heart disease, indeed for anyone, to 
start the day with exercise? Theoretically, morning exercise is more 
risky because it imposes an additional strain on the heart.  To assess 
the risk, Paul Murray and his colleagues at Wake Forest University 
compared two groups of people participating in a cardiac 
rehabilitation program, all recovering from heart attacks, heart 
surgery, or other cardiac conditions.  

Both groups exercised three days a week, one group from 7:30 to 8:30 
am, and the other for an hour between 3 and 5 pm.  All told, the 
researchers examined the effects of nearly 170,000 hours of exercise 
on the 221 participants.  Only seven cardiac events occurred in the 
entire group, and time of day made no difference.  For people without 
heart problems who exercise regularly, the risk of suffering a heart 
attack while exercising presumably is even smaller.  

The bottom line:  according to this study, both times of day are safe 
and neither time is safer than the other.  To eliminate all 
uncertainty would require a huge number of subjects and many years of 
observation.  The consensus is that the benefits of regular exercise 
at any time of day outweigh any possible disadvantages.  Indeed, after 
reviewing all available medical literature in 1987, the Centers for 
Disease Control and Prevention of the United States Public Health 
Service concluded that a sedentary lifestyle virtually doubled the 
risk of having a heart attack.  Even for weekend athletes, time of day 
is probably far less significant than the impact of unusual stress.  

One can reduce one's risk of heart attack or stroke by not smoking, by 
controlling blood pressure, maintaining a healthy weight, and 
consuming a low-fat diet, according to neurologist John Marler of the 
National Institute of Neurological and Communicative Disorders and 
Stroke.  Most people also benefit from limiting their salt intake.  
"These are not circadian issues," Marler said, "but they are the 
strongest preventive advice we now have." 


                  HIGH BLOOD PRESSURE (HYPERTENSION) 

People commonly think of blood pressure as relatively static, with two 
numbers, such as 120/80, being a so-called normal reading.  But blood 
pressure rises when one is moving and falls when one is at rest, goes 
up when one stands and drops when one lies down.  Blood pressure is 
higher when one talks than when one is silent.  And, of course, it 
changes markedly over the day.  

Blood pressure starts to rise before one normally awakens, and 
continues to rise after waking, peaking in late afternoon or early 
evening.  It reaches its low point after sleep starts.  A person whose 
blood pressure is within the purported normal range in the morning may 
become a candidate for treatment when afternoon readings enter the 
equation.  

The term "blood pressure" refers to the force that the blood exerts 
against artery walls, as the heart pumps blood through the body.  With 
each beat, or systole, pressure rises, causing the walls of the 
arteries to stretch.  With each rest between beats, or diastole, 
pressure falls, letting the artery walls relax.  In blood pressure 
readings, the systolic number is written first, as in 130/85.  

High blood pressure is the most common chronic cardiovascular disease 
in the United States; as many as sixty million Americans suffer from 
it.  High blood pressure, or hypertension, has been called "the silent 
killer" because it may substantially weaken blood vessels before 
actual symptoms appear.  A sustained elevated blood pressure--140/90 
or higher--may trigger a heart attack, stroke, or kidney failure.  

Even physicians often speak of "the" blood pressure or "the average" 
blood pressure in a given patient.  Chronobiologists say that is a 
mistake.  "Trying to assess high blood pressure with a single 
measurement or even a series taken at arbitrary times is like taking 
snapshots of a roller coaster," chronobiologist Halberg has asserted.  

"Unless we monitor for a forty-eight-hour period and then interpret 
the data properly, we may treat people who simply have 'white coat' 
hypertension, a reflection of anxiety from the medical exam," he said.  
"We may unnecessarily give a patient drugs that render him impotent or 
give him gout.  We may give him a stigma of bad health for life or 
place his job in danger." 

One man routinely saw his doctor on his way to work in the morning.  
The doctor told him he was in great shape.  But when the man's blood 
pressure was monitored around the clock as part of a research study, 
it proved to be in the high range 65 percent of the time.  

Dramatic changes in blood pressure may emerge only in around-the-clock 
studies.  When monitored while asleep, one man showed a marked rise in 
blood pressure for nearly an hour, possibly the result of a panic 
episode in a dream.  On another occasion, his blood pressure fell 
sharply for about an hour.  Both episodes were outside the range of 
normal variability.  

New, portable automatic recording devices make it possible to take 
virtually continuous readings.  While such high-tech equipment is 
typically reserved for one- or two-day diagnostic studies, some 
doctors are beginning to ask patients under treatment to measure their 
blood pressure periodically at home to gauge their progress.  Home 
monitoring is easy to do, with inexpensive devices now widely 
available.  

Chronobiologists advise taking measurements every hour and even 
setting the alarm to get a reading in the middle of sleep.  One should 
sit quietly for five minutes before taking a reading.  A single high 
reading should not be viewed as cause for alarm; a regular pattern 
must be determined.  

Many doctors advise that antihypertensive drugs be taken at bedtime to 
minimize common side effects of the medication, such as dizziness.  
However, chronobiologists contend that, since blood pressure is 
ordinarily lower at night, physicians should instead study a patient's 
profile and prescribe that medications be taken only when blood 
pressure is characteristically high, not when it already is low.  

Chronobiologic findings may help prevent high blood pressure.  Halberg 
and colleagues in Italy and Spain monitored the blood pressure and 
heart rate of 144 newborn babies every thirty minutes for forty-eight 
hours.  Babies whose families had a history of high blood pressure or 
related cardiovascular disease showed more daily variability than 
babies whose families had no such problems.  The mother's family 
proved to be a stronger influence than the father's.  

This suggests that intervention strategies might begin during 
pregnancy, with, as one possibility, a low-salt diet for a woman with 
a family history of high blood pressure.  Moreover, vulnerable 
children could be taught at an early age to pay attention to their own 
diet, to exercise regularly, avoid smoking, and adopt other preventive 
measures to minimize risk of high blood pressure.  


                                CANCER 

Drugs that kill cancer cells also destroy normal cells.  Ideally, such 
medication should kill only the malignant cells.  New treatment 
schedules that acknowledge rhythms of both cancer cells and normal 
cells may bring that goal closer.  So far, researchers have plotted 
optimal delivery schedules for about twenty of the approximately fifty 
common anticancer drugs, mainly in animals.  Human studies have begun 
only recently.  Certainly, the need for improved treatment is urgent:  
cancer claims 500,000 lives in the United States annually.  

While all cells are more vulnerable to damage when they are dividing, 
cancer cells typically divide more rapidly than normal cells.  
Plotting daily rhythms of normal cells may enable doctors to 
administer anticancer drugs when fewest normal cells are dividing.  
Timing treatment this way may make it possible both to use higher, 
potentially more effective doses than would otherwise be safe and to 
reduce side effects.  For example, giving drugs at a time when 
intestinal cells divide slowly may eliminate the diarrhea that causes 
many patients to discontinue therapy.  

Moreover, some types of cancer cells themselves divide according to a 
daily rhythm.  This may make it easier to target them for treatment.  
For example, Robert Klevecz and his colleagues at the Beckman Research 
Institute of the City of Hope in Duarte, California, analyzed cells 
taken after surgery from the abdominal cavity of ovarian cancer 
patients in two- to four-hour intervals around the clock.  The 
researchers found that the cancer cells reproduced at twelve-hour 
frequencies and sometimes even faster.  The peak most commonly 
occurred around 10 am and 10 pm.  These rhythms, Klevecz suggested, 
"should be exploited for therapeutic benefit." 

Oncologist William Hrushesky of New York's Albany Medical College and 
his colleagues at the University of Minnesota assessed the impact of 
different treatment schedules of two commonly used anticancer drugs, 
adriamycin and cisplatin, in sixty women with advanced cancer of the 
ovaries.  The women who took adriamycin a little earlier than their 
usual time of awakening and then took cisplatin twelve hours later--6 
am and 6 pm, in most cases--fared much better than women who took the 
same doses of the same drugs in reverse order.  

At one time of day, the drugs were more effective and less toxic.  At 
the other time, they were more toxic and less effective.  The reason 
for these differences apparently lies in the way the body handles the 
drugs.  One adverse effect of cisplatin, for example, is kidney 
damage.  The drug may cause less damage, Hrushesky said, if it is 
taken when it can be most rapidly excreted from the kidneys.  

The women who received adriamycin in the morning and cisplatin in the 
evening had far fewer infections and instances of bleeding than those 
on the opposite schedule.  They needed fewer transfusions.  Fewer 
needed to have their dosages lowered or treatment postponed because of 
nausea, vomiting, or other adverse reactions.  Most important, half of 
the women who received adriamycin in the morning and cisplatin in the 
evening were still alive five years later.  Only 11 percent of those 
on the opposite schedule survived that long.  

Another group of women received adriamycin and cisplatin at different 
times of day with no consistent sequence or interval between dosages.  
This remains the standard way these drugs are given at most of the 
nation's leading medical centers.  Tragically, all of these patients 
died within three years.  The side effects were so severe that the 
women typically dropped out of treatment after only three months.  By 
contrast, those who received the time-specified treatment completed at 
least eight courses.  

In another study, Hrushesky and his colleagues assessed timed 
treatment with the same two drugs in sixteen patients whose bladder 
cancer had been found during surgery to have begun to spread.  Within 
two years of the surgery, this type of cancer ordinarily continues to 
spread in more than 90 percent of the patients.  The timed drug 
regimen appeared to delay, and possibly prevent, further spreading.  
Eleven of the sixteen patients showed no recurrence of their disease 
when doctors examined them one to five years later.  

A Canadian study published in 1985 focused on 118 children with acute 
lymphoblastic leukemia.  After their initial treatment produced a 
remission, the children were given their daily maintenance dose of 
chemotherapy at home by their parents.  Because it was not known 
whether the time of treatment made any difference, the parents chose 
the hour that was most convenient.  The parents were instructed, 
however, to give the drugs at the same time each day.  Georges Rivard 
and his colleagues at the University of Montreal in Canada found that 
80 percent of the children who regularly received their medication 
after 5 pm were free of their disease five years after treatment 
began.  Only 40 percent of those treated before 10 am were disease-
free--a clear demonstration, the researchers said, that evening 
treatment is better.  Timed treatment, despite its potential benefits, 
is not yet practical in most instances for general use.  

Timed drug delivery schedules are highly labor-intensive.  Today's 
treatment regimens for cancer increasingly involve multiple drugs.  
"Where would we get the staff to treat forty or even four patients at 
exactly 6 am?" one oncologist wondered.  

New programmable, automatic delivery systems may make chronotherapy 
for cancer, as well as for other diseases, more feasible in the 
future, when more and more people will receive their treatment as 
outpatients.  Wearable or implantable devices are already being used 
in some medical centers.  About the size of a hockey puck, the devices 
have one or more reservoirs for drugs.  Eventually, doctors hope to 
have closed-loop systems that monitor the body's use of the various 
drugs or hormones and automatically adjust the dosage according to a 
predetermined formula.  

Drug treatment is not the only area in which chronobiology studies may 
benefit cancer patients.  Some additional avenues are illustrated by 
research on breast cancer, a disease that annually strikes 182,000 
American women and causes 46,000 deaths in the United States alone.  
Some recent findings indicate that:  

WHEN surgery for breast cancer is performed may determine its success.  
Premenopausal women with early-stage breast cancer who had breast-
removal surgery in the middle of their menstrual cycle--that is, 
around the time of ovulation--experienced fewer and later recurrences, 
and they lived longer than those operated on around the time of 
menstruation, according to Hrushesky and his colleagues who studied 
forty-four women five to twelve years after surgery.  The hormone 
estrogen, which is at its highest midcycle, may exert a protective 
effect, the researchers speculated.  Findings from this study, if 
replicated by other scientists, may prompt radical changes in 
scheduling surgery for breast cancer or use of supplemental hormones 
in women undergoing surgery.  

Recognition of seasonal rhythms in breast cancer may improve the 
likelihood of discovering it in an earlier, more treatable stage.  The 
incidence of breast cancer in premenopausal women peaks in the spring, 
and declines in the fall.  In those who have completed menopause, it 
follows the opposite course.  In premenopausal women, estrogen 
receptor concentrations, which are used to guide drug selection, are 
lowest in the early spring and highest in the late fall.  In 
postmenopausal women, this pattern is reversed.  Breast cancer causes 
more deaths in the spring.  

This suggests the necessity for more screening programs in the spring 
and perhaps more aggressive treatment at that time.  Seasonal breast 
cancer rhythms may be related to seasonal fluctuations in sexual and 
thyroid hormones.  The same mechanism may underlie some cancers in 
men:  prostate cancer shows a spring peak and fall decline, and a type 
of cancer of the testes called seminoma--most common in men under age 
thirty-five--surges in winter.  

The incidence of breast cancer appears to be higher in women living in 
northern cities with low levels of winter daylight than in women 
living in sunnier climes.  Frank Garland, Cedric Garland, and their 
colleagues at the University of California at San Diego, reached this 
conclusion after comparing breast cancer rates with the amount of 
solar radiation striking the ground in eighty-seven areas of the 
United States.  Lack of light may disrupt hormonal rhythms.  Like the 
discovery of high rates of sleep disorders in the blind, the finding 
underscores the importance of light in assuring the normal functioning 
of the body.  

Skin temperature in healthy breasts follows a predictable daily, 
weekly, and monthly pattern.  These rhythms change if cancer develops, 
even when tumors are too small to feel:  normal monthly rhythms fade, 
while weekly rhythms become more prominent, according to Hugh Simpson 
of the Royal Infirmary in Glasgow and his colleagues.  The researchers 
fabricated an experimental "chronobra" to monitor and record breast 
skin temperature automatically.  They envision that the chronobra 
would eventually be worn by women with a strong family history of 
breast cancer, who would use it to detect abnormal temperature rhythms 
just as they now perform breast self-exams or receive mammograms.  It 
would be an additional aid to diagnosis rather than a replacement for 
such measures.  


                                ASTHMA 

Asthma, a breathing disorder whose name comes from a Greek term 
meaning "panting," has a profoundly circadian pattern:  without 
treatment, asthma attacks occur fifty to one hundred times more often 
during the customary hours for sleep than in the daytime.  They occur 
most frequently at 7 am, and least frequently at 3 pm.  A British 
study of nearly eight thousand people with asthma found that even 
among those who regularly took their medicine, four out of ten still 
awakened at least once every night wheezing and coughing.  More than 
four thousand Americans die each year as the direct result of an 
asthma attack; such deaths are most likely to occur between midnight 
and 8 am.  

Recognition of this pattern is not new.  John Floyer, a seventeenth-
century British physician who suffered from asthma himself, theorized 
that wheezing occurred more often at night, "where nerves are filled 
with windy spirits." Asthma affects one out of every twenty Americans 
_ more than fifteen million people.  It is the single most frequent 
cause of hospital admissions in children in the United States, and it 
is the leading cause of absenteeism from American schools.  

Asthma causes the bronchial tubes and other airways in the chest to 
narrow or clog up, interfering with the normal flow of air in and out 
of the lungs.  Wheezing accompanies each breath, making a rough, 
raspy, whistling sound as air is forced through the blocked or 
constricted passages.  People often cough in an attempt to loosen the 
excess mucus that clogs the airways and lungs; they may gasp for air 
and, in extreme cases, suffocate.  

Allergies are the main cause of asthma; the long list of possible 
offenders includes pollens, molds, flowers, trees, weeds, grasses, 
house dusts, grain dusts, feathers, animal hairs and dander, and 
chemicals.  People may also develop asthma as a result of irritation 
from fumes, smoke, and other industrial substances; in some people, 
asthma starts after a cold or other virus infection.  In extremely 
sensitive people, coughing, laughing, crying, exercising, and even 
exposure to cold air can set off an asthma attack.  Stress, anxiety, 
and other intense emotions do not cause asthma, but they may worsen an 
attack.  

Monthly and yearly biologic rhythms further complicate the lives of 
people with asthma:  the attacks often appear in women in the week 
before and during menstruation, probably because of hormone 
fluctuations.  Yearly cycles in hormone production interact with 
increased pollens in the air in the spring and fall to make asthma 
attacks more common in those seasons.  The illness is more severe in 
the winter months, when other respiratory diseases proliferate.  Not 
surprisingly, deaths from asthma occur more often in the winter, too, 
particularly in those over age sixty-five who are hit hardest by the 
disease.  Because of the obvious day/night differences in asthma 
attacks, doctors have sought to minimize nighttime exposure to 
pillows, blankets, pets in the bedroom, and other presumed irritants.  
Such tactics may lessen the severity of the illness, but will not 
change its time course.  The impact of posture during sleep is still 
under investigation; because most people go to bed at night, it is 
hard to separate sleep from circadian rhythms.  Being in a horizontal 
position narrows the airways and permits fluids to pool in the lungs, 
but nighttime changes in airway size occur even in people who stay 
awake.  Fewer asthma attacks occur in the first half of the night, 
when sleep is deepest, but it has been suggested that deep sleep may 
suppress an allergic response, while the lighter sleep during the 
second half of the night may permit it to emerge.  People with asthma 
typically sleep more lightly than those without the disorder.  
Moreover, loss of sleep often makes their breathing worse.  

In the early morning, when most asthma attacks occur, the airways are 
most constricted, and in the midafternoon, when attacks are less 
frequent, the airways are most relaxed and open.  In people with 
asthma, normal daily variation in airway size is much exaggerated:  
their peak airflow over the day may vary by as much as 50 percent, 
while in people without asthma, it varies by only 8 percent.  The more 
severe the asthma, the greater the daily variation.  

Paying attention to the pattern of daily variation can help identify a 
worsening condition before a crisis occurs.  That is why doctors 
advise many asthma patients to use a peak- flow meter--an asthma 
"thermometer"--to measure at home how fast air can be blown out of the 
lungs at different times of the day.  Recognition of the morning dip 
in airway size has also prompted doctors to monitor early-morning 
breathing more closely, particularly in patients who are at increased 
risk of suffering a potentially life-threatening bronchospasm at that 
time.  

"As more is learned about how asthma changes on a twenty-four-hour 
basis, treatment should start following suit, but it may still be a 
while before pharmaceutical companies start designing medications to 
meet the needs of this disease," according to Richard Martin of the 
National Jewish Center for Immunology and Respiratory Disease at the 
University of Colorado.  He called present-day therapy "hit or miss." 

In recent years, asthma has been viewed less as a disease in which 
airways shut down and more as a disease of inflammation.  This shift 
in thinking has altered treatment somewhat, although here, as 
elsewhere, doctors' drug-prescribing habits have resisted change.  
Bronchodilators to open constricted airways, such as theophylline, 
were once the most commonly prescribed medications and are still 
widely used; these may be inhaled or taken by mouth.  There are more 
than three dozen types of bronchodilators available, and they are 
generally prescribed in equal daily doses.  

Inhaled corticosteroid drugs to suppress inflammation are becoming the 
mainstay of treatment; they are also generally prescribed in equal 
daily doses.  Asthma's nighttime pattern has prompted some physicians 
to prescribe unequal doses of asthma drugs, two thirds of the drug to 
be taken at night and one third, in the morning, for example.  
Unfortunately, there are no studies of the drugs' safety and efficacy 
when used this way.  The difference between the dosage that is safe 
and one that is not may be quite close, so identifying the times when 
larger doses could be given safely, or when smaller doses would work 
as well, would be an important advance.  

Chronobiologically designed drugs also may enable people with asthma 
to rest easier soon.  A once-a-day antiasthmatic drug available in 
Europe, but not yet in the United States, is specifically designed to 
give its peak effect between 2 and 6 am to prevent nighttime wheezing.  


                               DIABETES 

Diabetes mellitus, or sugar diabetes, interferes with the way the body 
uses glucose, the simple form of sugar that provides energy.  In 
healthy people, the hormone insulin, produced by the pancreas, enables 
body tissues to take up glucose from the blood.  Insulin secretion 
follows a predictable daily cycle, with the peak secretion around 3 
pm, and the low around 3 am, with increases in response to the 
ingestion of food.  

People with diabetes produce insufficient or no insulin, and too much 
glucose circulates in their blood, a condition called hyperglycemia .  
The body's efforts to remove the excess glucose--a homeostatic 
mechanism--causes both copious urination and excessive thirst.  

For those who require insulin, it is tricky to adjust the dosage to 
mimic what the body ordinarily does automatically and precisely.  
Taking more insulin than needed will make blood glucose fall too low, 
producing hypoglycemia , which is accompanied by such symptoms as 
sweating, dizziness, and faintness.  Tight control is important:  
results published in 1993 from a major national study that tracked 
more than 1,400 people with diabetes for more than six years indicated 
that the better the control of blood glucose, the fewer the 
complications the patients experienced.  

There are two principal types of diabetes mellitus:  insulin-
dependent, or type I, the more severe form, usually appears in 
childhood or early adulthood; without insulin injections one or more 
times a day to counter hyperglycemia, people with type I diabetes 
would die.  Non - insulin-dependent, or type II diabetes, usually 
develops in people over age forty and frequently can be controlled by 
diet, maintaining a normal body weight, and, sometimes, oral 
medications.  

Glucose circulates in the blood for six to eight hours.  That is why a 
continuous uniform dose of insulin, now possible with a wearable or 
implanted insulin pump, is not the complete answer for people with 
diabetes.  Ideally, treatment would imitate the normal circadian 
pattern.  

Some of the six million Americans with insulin-dependent diabetes 
experience an abrupt rise in the level of glucose in their blood, or 
in their need for insulin, or both, between 5 and 9 am.  In some, the 
need for insulin may become six times greater than it was earlier in 
the night.  Previously, those who experienced this so-called "dawn 
phenomenon" might have been advised to compensate for the change by 
increasing their morning insulin dose.  Unfortunately, the added 
insulin sometimes had a rebound effect, causing blood sugar levels to 
fall too low later.  Many doctors now recommend that the insulin dose 
be increased the night before in order to prevent or minimize a large 
early-morning change.  

Knowing the daily insulin cycle enables doctors to tell their diabetic 
patients the best time to engage in exercise and other activities.  
Exercising in the early morning before breakfast when blood sugar is 
normally low, for example, carries less risk of hypoglycemia than 
late-afternoon exercise.  

A better understanding of daily body rhythms has also given people 
with diabetes more employment options.  Until recently, rotating shift 
work was regarded as impractical for most people with diabetes:  the 
frequent changes in hours of work and sleep as well as mealtimes all 
complicate blood sugar control.  It is still true that persons with 
diabetes usually find it easier to work permanent shifts with 
consistent physical demands that do not require constant tinkering 
with carbohydrate intake and insulin use.  But "people with diabetes 
should not be systematically excluded from shift work," according to 
Gary Richardson of Harvard University.  "With reasonable, intuitive 
adjustments of scheduling," he asserted, "the majority of people with 
diabetes can work on any shift." Diabetes is only one of many diseases 
affected significantly by work-schedule changes; for more information, 
see Chapter 10.  


                               ARTHRITIS 

Biologic clocks determine the time of day that pain appears in the two 
most common forms of arthritis, or inflammatory joint disease.  In 
osteoarthritis, also called degenerative arthritis , pain and 
stiffness are typically worse late in the day, reflecting wear and 
tear from daily activities.  In rheumatoid arthritis, the pain is 
generally worse at the start of the day.  Once attributed to 
immobility at night, this pattern now is recognized as the body's 
reaction to both immobility and the nighttime absence of cortisol, an 
inflammation fighter; after the normal 7 am surge in cortisol 
secretion, pain lessens.  Some thirty-seven million Americans, 
children as well as adults, have some form of arthritis.  

People with rheumatoid arthritis who visit their doctors in the 
morning may appear to be in worse shape than they really are.  In the 
afternoon, they may seem better than is actually the case.  Physicians 
who see patients at different times of day from one visit to the next 
may have trouble telling how well treatment is working.  Many doctors 
now ask patients with rheumatoid arthritis to measure grip strength 
and finger-joint swelling at home at different times of the day to 
help chart the course of their illness and the effectiveness of 
treatment.  

Fatigue is a common complaint in rheumatoid arthritis, and this 
symptom has long been thought to be inseparable from the illness.  
Mark Mahowald and his colleagues at the Minnesota Regional Sleep 
Disorders Center in Minneapolis found it may simply be a symptom of 
poor sleep.  All sixteen of the patients they studied moved their arms 
and legs excessively, and awakened frequently during the night.  This 
is actually good news because it is much easier to treat the sleep 
problem than a vague ailment like fatigue.  

Synchronizing arthritis medications with circadian rhythms may permit 
smaller or less frequent doses, thus reducing side effects.  For 
rheumatoid arthritis, in which the joints are attacked by the body's 
own immune system, doctors commonly prescribe corticosteroid drugs to 
suppress the inflammatory response.  These drugs work best and have 
the fewest negative effects when taken in the morning in sync with 
normal cortisol secretion.  There is some evidence that cortisol-
secretion rhythms are disturbed in people with rheumatoid arthritis, 
and that giving cortisol-based drugs at the right time can help 
normalize the pattern.  

People with osteoarthritis who have nighttime or early-morning pain 
may get more benefit from pain-relievers in the evening.  Those whose 
pain is greater in the afternoon or evening may find it more helpful 
to take pain-relievers in the morning or midday.  Alain Reinberg and 
Francis Levi at the Rothschild Foundation in Paris studied five 
hundred patients with osteoarthritis of the hip or knee who took a 
commonly used pain-reliever, indomethacin, in a sustained-release form 
once a day at 8 am, noon, or 8 pm.  At different times of day, 
patients suffered only one quarter of the side effects, while gaining 
twice the pain relief.  Patients differed in whether their best time 
was morning, noon, or night, a finding that attests to the need to 
tailor drug treatment to the individual.  


                               HEADACHES 

Some headaches wake people from sleep so frequently that they have 
been called alarm-clock headaches.  These include migraines , 
typically worse in the morning, and cluster headaches , so-named 
because they come in groups.  Both involve an abnormal stretching or 
dilation of the blood vessels.  One study showed that three fourths of 
cluster headaches occurred between 9 pm and 10 am, with the highest 
frequency between 4 and 10 am.  This points to a relationship between 
the headaches and REM sleep, a time of considerable variability in 
blood vessel size.  Sleep laboratory studies have confirmed that 
cluster headaches often start in REM sleep or immediately after it.  

Migraines occur mostly in women, and cluster headaches, in men.  Some 
people have bouts of cluster headaches in the spring and fall, 
suggesting a link with seasonal hormone changes or changes in light.  
The typical female sufferer has 12 to 15 migraines a year, most around 
the time of menstruation, when estrogen levels are lowest.  In one 
study, one third of the 512 migraines experienced by fifty-two women 
appeared four days before a menstrual period, and one third, while a 
period was under way.  Shifts in hormone levels may themselves be a 
factor:  birth control pills make migraines worse in some women, 
better in others.  During pregnancy, some women's migraines disappear, 
but other women experience them for the first time.  Migraines usually 
appear before age thirty-five, but some women develop them only after 
menopause.  

Migraines cause dull pain, typically worse on one side of the head.  
Some people become very sensitive to light and experience nausea.  
Migraines usually last from two to six hours.  

Cluster headaches, said to be the most excruciating of all headaches, 
may cause such intense pain--sometimes likened to being stabbed with a 
burning poker--that sufferers cannot lie down.  Instead, they feel 
compelled to pace the floor or rock back and forth.  Some bang their 
head against the wall.  Cluster headaches begin as a pain around one 
eye that eventually spreads to that side of the face.  They often 
cause reddening and tearing of the eye and a stuffed nostril on the 
painful side, and typically last about thirty minutes.  Their 
periodicity is a unique feature that implicates an underlying disorder 
in the biologic clock:  cluster headaches typically recur once or 
twice a day at the same times each day for weeks or months; then they 
cease for months, even years, before starting up again.  Their 
predictability can be employed in treatment:  taking the medication 
ergotamine a few hours before a headache is expected may lessen the 
intensity of the pain.  

Fatigue, stress, and weather changes may trigger both migraine and 
cluster headaches.  Glaring or flickering lights, and certain foods, 
including red wine and chocolate, have been implicated in migraines, 
while alcohol and a change in sleep schedule, particularly taking an 
afternoon nap, often induce cluster headaches.  

Another type of morning headache, not necessarily violent enough to 
disrupt sleep but typically noticed on awakening, may stem from sleep 
apnea, a disorder in which breathing stops repeatedly during sleep.  
People with sleep apnea develop headaches because insufficient oxygen 
reaches the brain during the night.  Sleep apnea occurs most 
frequently in overweight middle-aged men who snore raucously, the 
telltale indicator of impaired breathing.  The most common type of 
headache is aptly called a tension headache.  Its name comes from the 
associated muscle tension, although emotional stress is a common 
cause.  Here, muscles in the neck, face, and scalp tighten, producing 
a sensation of pressure being applied to the head or neck.  Patients 
liken it to feeling their head trapped in a vise.  

Some tension headaches recur at predictable times of the day or week, 
demonstrating how clock and calendar times can be transformed into 
biologic time.  One teacher developed tension headaches at 11 am, just 
before she had to face a classroom full of unruly students.  A 
salesman's headaches started at 5 pm, when he reported the day's 
efforts to his manager.  The stress of delivering a sermon causes a 
headache in clergymen so often that it has been dubbed a "preacher's 
headache." 

People who have unrewarding jobs often experience headaches on 
Saturday morning; during the week, they may keep their distress in 
check, but on Saturday, when they are freed from having to go to work, 
that is no longer possible.  Additionally, they may sleep late, and 
schedule changes themselves may unleash tension headaches.  

Physical factors also can bring on muscle-contraction headaches at 
particular times of the day.  Gripping the steering wheel of a car 
during rush-hour traffic, and hunching over books in an evening study 
session, are common examples.  

The National Institute of Neurological and Communicative Disorders and 
Stroke reports that forty million Americans suffer chronic headaches.  
Seeking relief from severe, even disabling pain, they spend about $400 
million annually on aspirin and other over-the- counter painkillers.  
Migraine sufferers alone lose more than sixty-four million workdays.  

Better understanding of the rhythmicity of headaches may eventually 
lead to treatment that can forestall them.  Recent studies, for 
example, have shown that one aspirin tablet (325 mg) every other day 
can help stave off migraines.  Doctors' present arsenal includes 
several drugs designed to create a climate in the body that is less 
receptive to headaches.  Many of these drugs alter the activity of 
serotonin, a brain chemical believed to play a role in the regulation 
of sleep and other biologic rhythms.  Among these drugs are 
antidepressants that change the way brain cells communicate, and beta-
blockers and anti-inflammatory drugs that relax blood vessels.  


                               EPILEPSY 

Epilepsy, a disorder involving recurrent seizures, is also highly 
rhythmic in nature.  Nearly 80 percent of people with epilepsy suffer 
seizures predominantly during sleep or on arousal from sleep.  One 
study found that seizures occur most often between 7 and 8 am.  Thus, 
shifting sleep periods around will change the time seizures occur.  

The role that sleep processes play in triggering seizures remains 
unclear.  People with epilepsy toss and turn and awaken frequently, 
perhaps compounding existing sleep abnormalities.  Sleep deprivation 
so reliably intensifies seizure activity that it is used to elicit 
symptoms when epilepsy is suspected.  

While anticonvulsant drugs appear to reduce both sleep problems and 
seizures, tailoring the drug to the individual patient is often more 
difficult and time consuming than for many other illnesses.  According 
to the National Institute of Neurological and Communicative Disorders 
and Stroke, "sometimes the problem is one of dosage, or of finding the 
right combination of drugs administered in the right proportion at the 
right time of day." 

Perhaps one quarter to one half of women with epilepsy find that their 
illness worsens during menstruation.  In one study of 23,000 seizures 
that occurred in fifty institutionalized women over twenty-five years, 
researchers found that episodes occurred twice as often on the day a 
woman's period started as seven days earlier.  This pattern persisted 
regardless of the regularity of the cycle or its length.  Researchers 
suspect that progesterone may play a role in this pattern, perhaps by 
disrupting sleep.  


                             PEPTIC ULCERS 

Peptic ulcer pain strikes most often during the day between meals and 
between midnight and 2 a .  m .  Peptic ulcers affect only those areas 
of the gastrointestinal tract that are bathed by digestive juice:  the 
lining of the stomach and the duodenum, which is the first part of the 
small intestine.  Digestive juice, which helps break down food, 
contains hydrochloric acid and the enzyme pepsin--thus accounting for 
the use of the word "peptic." 

Normally, the stomach secretes just the amount of digestive juice 
needed, when needed:  secretion ordinarily peaks at midday and falls 
during sleep.  When digestive juice appears at the wrong time, in the 
absence of food, it may erode the lining of the gastrointestinal 
tract, causing sores that produce a gnawing or burning sensation in 
the abdomen between the navel and lower end of the breastbone.  Peptic 
ulcers affect one in ten Americans at least once in a lifetime.  

Long-term use of aspirin and alcohol, as well as stress, may disrupt 
the normal secretion patterns.  Frequent changes in mealtimes may play 
a role, too, as is suggested by the fact that ulcers occur more 
frequently in shift workers than in the general population.  

Theories about the genesis of ulcers have undergone a dramatic change 
since research in the 1980s implicated a chronic bacterial infection 
of the stomach lining as a causative factor in ulcer formation.  The 
bacteria are thought to neutralize stomach acid, providing them with a 
more hospitable place in which to live.  Antiulcer drugs such as 
cimetidine (Tagamet) and ranitidine (Zantac) have been widely 
prescribed to heal ulcers.  Antibacterial drugs and bismuth (the 
active ingredient in Pepto-Bismol), which coats the stomach, have been 
found to cure ulcers and prevent many recurrences by wiping out the 
offending bacteria.  

One exception has been in people who take more than twelve aspirin a 
week--for arthritis, for example--who run an increased risk of 
suffering a peptic ulcer in the lining of the stomach.  But circadian 
studies in animals suggest that when the aspirin is taken may either 
double the risk or halve it.  In these studies, aspirin taken early in 
the morning caused little gastric erosion, while aspirin taken late in 
the evening caused considerable damage.  


                        LEG MOVEMENT DISORDERS 

Two related disorders that affect the legs--restless legs, which occur 
during wakefulness, and periodic limb movements (PLMs), which occur in 
sleep--have been found to have previously unsuspected daily rhythms.  

In restless legs, the symptoms are disagreeable deep, creeping, 
crawling sensations in the calves and often the thighs, typically 
likened to electric shocks.  The sensations usually occur when a 
person is sitting or lying down, prompting the urge to move the legs 
around and giving the disorder its name.  The symptoms understandably 
often make it hard to fall asleep.  Richard Allen and his colleagues 
at Johns Hopkins University asked patients with restless legs to stay 
in bed for thirty minutes before and after a night's sleep.  They 
found that the subjects' legs moved two to four times as often at 
night as in the morning.  Nearly everyone who suffers from restless 
legs during the day also has PLMs at night, a disorder in which the 
feet, toes, and sometimes the knees, hips, and legs move abruptly and 
jerkily.  Although these movements last only a second or two, they 
recur almost immediately, often hundreds of times during the night, 
causing extraordinarily restless sleep.  Some people even wear out 
their sheets.  

The existence of an underlying disorder of the biologic clock is 
suggested by the fact that people with PLMs also experience unusual 
periodic fluctuations at twenty- to forty-second intervals in other 
bodily functions, including blood pressure, heart rate, and pupil 
size.  William Culpepper of Bowling Green State University in Bowling 
Green, Ohio, and his colleagues studied seventy-two patients with 
PLMs.  In these studies, two distinct patterns appeared:  in one, the 
PLMs occurred mostly in the early part of sleep, and in the second, 
they were evenly distributed across the night.  

Restless legs and PLMs are not rare; about one in ten people who 
complain of insomnia, and one in ten who experience excessive daytime 
sleepiness, has one or both of these problems.  These two disorders 
become more common as people grow older.  Several types of medication 
may be helpful in helping to alleviate symptoms:  anti-Parkinson's 
drugs (although there is no relationship's between these disorders and 
Parkinson's disease), benzodiazepine sleeping pills, and opiates.  
Knowledge of the time course of these disorders has enabled doctors to 
adapt medication schedules to individual patients' needs.  Some, for 
example, need medicine only at night or for only part of the night.  


                            WEIGHT CONTROL 

WHEN one eats may be as important as what one eats in determining 
whether weight is maintained, gained, or lost.  The now-classic 
studies in weight control, conducted in the mid-1970s by Halberg and 
his colleagues at the University of Minnesota, showed that people who 
ate nothing but the same 2,000-calorie meal once a day for a week lost 
weight when they ate only breakfast, but gained weight when they ate 
only supper.  In these studies, breakfast-only meant that people ate 
the meal within an hour of awakening, and supper-only meant that they 
fasted at least twelve hours after awakening.  Apparently, the body is 
more likely to burn fuel that is ingested in the morning and to store 
it in the evening.  This information may benefit people trying to lose 
or gain weight; it also has far-reaching public health implications 
for the design of food relief programs for starving populations, 
suggesting that limited resources may go further if consumed late in 
the day.  

The same researchers also showed that subjects on a breakfast-only 
regimen consumed fewer calories when they chose their own foods 
instead of eating those selected by the researchers.  Surprisingly, 
they lost less weight on the self-selected lower-calorie diet than 
they did on the 2,000-calorie regimen.  Eating foods one dislikes, the 
researchers concluded, may be a speedier way to lose weight than 
eating those one likes.  Or the body may expend more calories in 
burning some foods--for example, vegetables and others high in fiber--
than it does foods high in fat, such as ice cream.  This notion 
challenges the nutritional axiom that "a calorie is a calorie." 

There are circannual rhythms in body weight:  humans act somewhat like 
hibernating animals in that they tend to put on pounds in the fall and 
shed them in the spring.  This tendency is much exaggerated in people 
with winter depression, who often gain twenty pounds or more in two or 
three months.  Many have more extensive summer wardrobes, reflecting 
more active summer lives.  One man suffering from winter depression 
reported that his winter pants were two sizes larger than his summer 
pants.  (For more on this disorder, see Chapter 8.) 


                 MEDICINE IN THE TWENTY-FIRST CENTURY 

Chronobiology research may transform the practice of medicine.  A 
chronobiologic profile may become a standard part of a person's 
medical history--a map of the roads one's body travels from morning to 
night, day to day, winter to summer.  Periodic chrono checkups may 
help to identify illnesses in their earliest, most treatable stages, 
and patients may participate actively in their own care by keeping 
self-measurements.  This can be done today, as was demonstrated in a 
high school science class project in which students took their own 
temperature and blood pressure, and rated their moods six to nine 
times a day for several days.  

The difficulty of acquiring time-of-day data has been until recently a 
major obstacle to the widespread application of circadian principles 
to medical practice.  Since taking numerous samples of blood and urine 
is often impractical, chronobiologists have determined many time-of-
day norms.  Some labs already provide results with a time-of- day 
correction factor.  The recent development of portable, ambulatory 
monitors to collect data, and of computer programs to analyze the 
information, has made around-the-clock assessments easier.  

Computers will one day help determine the best timing and optimal dose 
of drugs.  For some illnesses, portable, programmable drug pumps, 
implanted or worn on the body, will dispense drugs, monitor the body's 
use of them, and adjust the dosage as necessary.  Ultra - short-acting 
drugs, targeted to specific phases of daily cycles, may be developed.  
Doctors' offices and outpatient treatment centers may stay open more 
frequently in the evening and at night.  

More chronobiologic ways to deliver drugs may include long-term 
pulsatile polymer controlled-release systems.  Already in existence 
are skin patches that are used to treat angina pectoris, for instance, 
and under-the-skin implants to prevent conception; these delivery 
systems release the drugs at decreasing, or constant, rates.  By 
contrast, polymers can be made with many different physical properties 
to alter the rate of drug release.  Hormones, for instance, could be 
delivered in a circadian pattern.  

Drug testing will change, too.  To date little heed has been paid to 
chronobiologic principles.  Drug evaluation studies have traditionally 
employed a fixed dose; moreover, the rodents typically used are 
nocturnal animals, although researchers and patients generally are 
not.  Chronobiologists question the logic of predicting human 
responses on the basis of tests in animals awakened from rest.  Test 
results indicating that many substances are carcinogens, some suggest, 
may show merely the failure to consider biologic time.  

The Food and Drug Administration (FDA) currently does not require 
manufacturers applying for approval of a new drug to conduct animal or 
human studies showing the influence of the drug's time of 
administration on its effectiveness or toxicity.  Timed trials would 
be extremely costly, but money is not the only barrier.  "You cannot 
make a requirement that would fit all drugs in all situations," John 
Harter, director of the FDA's pilot drugs evaluation staff, asserted.  
"Humans follow social schedules that are vastly different from those 
of animals.  If you tried to study animals that were going to sleep 
and waking at different times from day to day, what event would you 
use to coordinate the effects of the medicine you want to give? What 
is the effect of meal timing, of varying meal timing, of skipping a 
meal?" Although chronobiology is not yet a household word, a growing 
body of studies suggests that physicians--and patients--are beginning 
to think circadian.  The sooner, the better, chronobiologists say.  
Factoring body clocks into treatment decisions, according to chrono-
oncologist Hrushesky, "provides a golden opportunity to use what few 
imprecise chemical weapons we have a little more effectively." 


            Copyright 1995 by Lynne Lamberg, Baltimore, MD