Saturday, March 26, 2005

New York Times Gets It Right, Just To Screw Up At The End In Blind Adherence To The He Said/She Said Journalism

Ha! The New York Times has this neat article, that is almost half as good as my early (and so far most frequently linked) post "Everything You Always Wanted To Know About Sleep". Here are some excerpts, go read the rest:

The Crow of the Early Bird

THERE was a time when to project an image of industriousness and responsibility, all a person had to do was wake at the crack of dawn. But in a culture obsessed with status—in which every conceivable personal detail stands as a marker of one's ambition or lack thereof—waking at dawn means simply running with the pack. To really get ahead in the world, to obtain the sacred stuff of C.E.O.'s and overachievers, one must get up before the other guy, when the roosters themselves are still deep in REM sleep. And of course since so few people are awake at such an ungodly hour, the early risers of the world take special pains to let everyone else know of their impressive circadian discipline.
At least since Benjamin Franklin included the proverb "Early to bed and early to rise makes a man healthy, wealthy and wise" in his Poor Richard's Almanac, Americans have looked at sleeping habits as a measure of a person's character. Perhaps because in the agrarian past people had to wake at dawn to get in a full day's work outside, late sleepers have been viewed as a drag on the collective good.
Sleep researchers are casting doubt on the presumed virtue and benefits of waking early, with research showing that the time one wakes up has little bearing on income or success, and that people's sleep cycles are not entirely under their control. Buoyed by the reassessment of their bedtime habits, a few outspoken and well-rested night owls are speaking out against the creep of sleepism.
Whatever the negative associations with sleeping late, scientists say there's good reason to doubt the boasts of the early risers. Dr. Daniel F. Kripke, a sleep researcher at the University of California, San Diego, said that in one study he attached motion sensors to subjects' wrists to determine when they were up and about. While 5 percent of the subjects claimed they were awake before 4 a.m., Dr. Kripke said, the motion sensors suggested none of them were. And while 10 percent reported they were up and at 'em by 5 a.m., only 5 percent were out of bed.

Dr. Stepanski said the same is true of people who boast they need little sleep. In a study in which subjects claimed they could get by on just five hours' sleep, he said, researchers found the subjects were sneaking in long naps and sleeping in on weekends to make up for lost z's.
Variations in sleep patterns among the population, he added, may have benefited the species.

"The whole tribe is better off if someone is up all the night, listening for a lion walking through the grass," he said.

The rhythms of modern times are determined not by fanged predators, of course, but by the 9-to-5 schedule of the workaday world. While those hours would seem to benefit larks, there is little evidence that night owls are any less successful than early risers. Dr. Kripke said that a 2001 study of adults in San Diego showed no correlation between waking time and income. There's even anecdotal evidence of parity on the world stage; President Bush is said to wake each day at 5 a.m., to be at his desk by 7 and to go to sleep at 10 p.m., while no less an achiever than Russian President Vladimir V. Putin reportedly wakes at 11 a.m. and works until 2 a.m.

So, if I may ask, why on Earth did they decide to end this article with a quote from some idiotic inspirational guru whose very words are debunked by the rest of the article? Ah, the stupidities of the he said/she said journalism! Everything has to have two sides, or does it? Even if the article describes how an aspect of the world works, they just HAVE TO ruin it by digging out some moron who, out of ignorance, is going to provide that precious 'contrary' quote!

Thursday, March 24, 2005

Blog Of The Day

Hey, check Blog Of The Day today and tomorrow. Today is Circadiana, tomorrow is Science And Politics. I am supposed to put a cute little linking image on both blogs, but with my technical woes of the moment, that will have to wait a few days.

Monday, March 21, 2005

The SCN acts as an ensemble of individual oscillators

Heinrich wrote a great post about the organization of cellular pacemakers composing the mammalian pacemaker on his blog. It is a must read:

ClockNews #30: Miscellaneous Circadiana

Patterns within seemingly random events of physiological systems
In research on the dynamical features of the brief awakenings and sleep periods that occur in different mammalian species, the scientists found that the periods of wakefulness that snuggle between sleep periods of various mammalian species, are similar.

Night eaters
The University of Pennsylvania research has shown that the circadian cycle, 24-hour biological rhythm, for eating becomes disturbed in those with night eating syndrome, while their circadian cycle for sleeping does not. Imagine that your body's 24-hour cycle for eating and 24-hour cycle for sleeping were at odds with each other. This is the first disorder to be discovered in which the two biological rhythms have been dissociated, the researchers report. With the biological rhythm for food intake shifting to about six hours later than normal, sleep becomes more and more troubled by episodes of waking up hungry and stress builds.

Business Travel: A Good Flight's Sleep
Jet lag has been the bane of business travelers since the birth of international flight. But while aviation technology has advanced well beyond Charles Lindbergh's monoplane, a cure for "circadian-rhythm stress" has remained as elusive as a fix for the common cold.

The beneficial powers of darkness
According to a growing band of scientists and doctors, many of us are no longer getting enough darkness in our lives. The theory is based on a simple premise. Our biological rhythms evolved in a time before artificial light, to take advantage of both bright days and dark nights. By succumbing to the temptations of 24-hour living, and ignoring or reducing our natural dark time, we could be putting our health at risk.

Sleep Loss Deadly
According to a 2004 Circadian Technologies report, about 25 percent of night shift workers have Shift Work Sleep Disorder, a mismatch between required sleep-wake schedules and internal circadian clocks.Night shift work increases injury risk 23 percent and risk grows with consecutive nights worked.About 1.1 million men sleep less than 4.5 hours a day and about 1.1 million women sleep less than 3.5 hours a day, Birky said.It’s associated with a six-year mortality rate — "in six years, 15 percent are dead," he said.

The Circadian Clock: Understanding Nature's Timepiece
A cluster of brain cells less than half the size of a pencil eraser tells you when to wake up, when to be hungry and when it's time to go to sleep. The same cells also cause you to be disoriented after you've flown across multiple time zones.

13 things that do not make sense
Levin stands by his claim, and he is no longer alone. Joe Miller, a cell biologist at the University of Southern California in Los Angeles, has re-analysed the data and he thinks that the emissions show evidence of a circadian cycle. That is highly suggestive of life.

The dandelion: A worthy weed
Behaviorally, dandelions take after yet another cousin, the classic American sunflower. A spring day is well spent in the garden watching a dandelion tilt with perfect attentiveness as the sun crosses the sky. The flowers that open at dawn demurely fold up at dusk against the night chill. Why the dandelion should be such a graceful observer of the circadian clock, while other spring flowers such as the rose open and stay open, is anyone's guess. For this exquisite ritual alone, the dandelion flower is every bit as poetic as the rose, but useless to flower arrangers. Cut the flower, and it curls up and dies before a vase has been filled with water.

This St. Patrick's Day We Ask: Who's Drunk... and Who's Sleepy?
The guy on the next barstool may not have Guinness to blame for his slurred speech and impaired hand-eye coordination. He could be very, very sleepy. Data from CIRCADIAN, a Lexington, MA-based research and consulting firm, confirm a similarity in performance ability between someone who has been awake for 22 consecutive hours and someone with a blood alcohol count of 0.08 -- legally drunk in all 50 states.

Have asthma? Try working out in the afternoon
End-of-the-day workouts can relieve some of the huffing and puffing — at least for people with asthma. When researchers at Long Island Jewish Medical Center followed 4,835 people over a 5-year period, they found that lungs are strongest late in the afternoon.

Frank Hall architect Duffy intrigues University officials
Fawcett said SOM is also able to "mimic the beneficial effects of natural light" and therefore create a more appealing learning environment that "reinforces circadian rhythm."

Pilot fatigue: undefined safety menace
Flight does not involve much physical effort but the mental stress of being responsible for a safe flight, regardless of weather can be tiring. Sleep deprivation is an inherent thing for pilots who work on irregular hours. Printup said the nature of sleep is such that it follows circadian rhythms that run the biological clock of the human brain. It tells the brain to work during day and rest at night. Most pilots have variable schedules working several days on, then several days off. Long flight schedules thus disrupts the cycle or changes circadian rhythms causing fatigue to set in.

Keeping baby in the dark,,8124-1520013,00.html
The only potential problem could be that a light at night might alter a baby’s circadian rhythm, which governs normal sleep cycles. It would have to be very bright, though. In general, plug-in night lights are too low in intensity to cause problems.

"Wal-Mart Amendment" Discounts Danger of Tired Truckers; Creates Sweatshops on Wheels with 16-Hour Workdays
We believe that a final rule should allow no more than 10 consecutive hours of driving time, and no more than 14 hours of on-duty time in each shift, with at least 10 hours of rest each day and a full weekend off work. The workday for drivers should follow the circadian cycle – or a 24-hour day – as opposed to the 21-hour shift rotation permitted under the 2003 vacated standard.

Studies clash on safety impact of hours rule
The 34-hour recovery and restart help to avoid the shifting of daytime to nighttime schedules, which can affect the circadian rhythm and decrease alertness.

Volunteers help solve puzzle of circadian clock
New research at Massey University will provide another piece in the puzzle of why some people are a "morning person" and others a "night person".

Sunday, March 20, 2005

Heinrich Guest-Blogging: Sleep Deprivation - Societal Causes and Effects

Here is the #2 guest contribution by Heinrich (not Heindrocket) of She Flies With Her Own Wings (

Most of this post was inspired by a grand rounds / journal club given by DavidDinges about two weeks ago based on years of his own research and large surveys. One line of argument in the presentation that I thought was particularly interesting--one that we as sleep researchers might want to remember when we write grants and perform our research--was that we need to keep in mind the motivations behind why people willingly sleep-deprivethemselves, and what we as sleep researchers can therefore offer society when it comes to public policy.

Any number of studies have shown that 7.5 hours out ofevery 24 hours is about as close to ideal as you can come for sleep duration: cognitive abilities are optimal with this amount of sleep, but also other indices of general health as for instance body mass index are ideal with this average amount of sleep (fora no-subscription-required review of these findings,click here).

And yet, significant numbers of people still get too little sleep. Recent surveys have found that beyond anything else, the number one motivator for voluntary sleep deprivation is financially reimbursed work: more so than socializing, spending time with family or spending time doing things for the household. This trend more or less cuts across all ages and genders.

The most recent census and a National Highway Transportation Safety Association studygive some insight into when this sleep deprivation might take place, and when its effects can be noticed. The picture that arises is that an increasing number of people are commuting to work earlier than before. As the census shows, commute times have increased for all categories of commuters that spend more than 25minutes on their way to work, implying that if you live and work in downtown your commute time is unlikely to have changed over the last 10 years. At the same time, the number of people commuting between midnight and 5:00 AM has shown the greatest increase in the last 10 years. These trends could have significant implications on worker productivity.

The NHTSA study additionally shows that drowsy driving occurs at almost any time during the day, and thus, the compunction to work more, and start work earlier may already have its effect in driving safety. The challenges that lie ahead are to ask where else might sleep deprivation be detrimental? In other words, people are working more, but at the expense of sleep duration, so are they really being more productive when they do that? And, given that people will tend to sacrifice sleep for work (something that probably can't be changed), what can we suggest on a larger, public policy level that might reduce commute time, such as supporting a trend away from people living in outer suburbs and the exurbs?

Friday, March 18, 2005

Heinrich - Guest-blogging: What Is Sleep For?

I am really excited to introduce to you my first guest blogger here on Circadiana, Heinrich, not Hindrocket whose blog, She Flies With Her Own Wings ( is a worthy daily read. Heinrich does research on mammalian clocks and sleep, and his first contribution is this post about exciting new research on adaptive function of sleep. Here it is - enjoy:

One intriguing question in sleep research has been what, exactly, is bad about not sleeping? What's going on in neurons during sleep deprivation that might eventually lead to certain cognitive deficits we experience while we're sleep deprived? A growing body of research suggests that proteins - possibly those responsible for cell-to-cell communication that is important in learning and cognition - are not made properly within neurons during sleep deprivation.

A recent paper in Journal of Neurochemistry examines the temporal expression of "BiP/GRP78, a molecular chaperone,[that] is a classical marker of the ER stress response/unfolded protein response (UPR) activation in yeast and mammalian cells" in various time points during sleep deprivation. In other words, the more you have of BiP/GRP78, the less likely your cells are of producing properly folded proteins.

The authors show that "all of the components of the UPR occur" in mouse cortical areas, and hence possibly other areas of the brain. Hence, in the words of the authors: "In humans, it has recently been shown that there is the beginning of impairment in performance when continued wakefulness exceeds 16 h" (Van Dongen and Dinges 2003). Beyond this time, wakefulness is much more difficult to sustain and is unstable (Van Dongen and Dinges 2003). There are increasingly frequent performance lapses when wakefulness exceeds this limit (Van Dongen and Dinges 2003). This is important clinically because performance of activities such as driving a vehicle will be impaired. Epidemiological studies show that being awake for more than 20 h is a major risk factor for crashes that result from the driver falling asleep at the wheel (Stutts et al. 2003). Although we do not know whether in humans UPR occurs when wakefulness is prolonged, our data raise this as a hypothesis."

Monday, March 14, 2005

Quarterly Summary

This blog is now three months old and, as it is Spring Break, this may be a good time to take a little break, take stock of what was accomplished so far and indicate the plans for the future.

Who am I trying to attract to this blog?

First, I'd like to see laypeople - non-scientists who are interested in clocks and sleep. Most of my readers are in this category, arriving here through the links on Boing Boing, Andrew Sullivan, Blogdex and Delicious. While you may come in through a link to a "fun" post, perhaps something in the categories of ClockNews, ClockQuotes or ScienceBlogging, I hope you look around and read the more serious stuff, too. Hopefully you will get "hooked". I will continue to write posts on various topic and at various level of detail, so hang around - there is something for everybody here.

Second, I want to see here biologists who want to keep up with chronobiology although it is not their area of expertise. Many such bloggers are already familiar with this blog through The Tangled Bank, the blog carnival of biology blogging, and Grand Rounds, the carnival of medical blogging.

Third, I hope to see more chronobiologists who want to find each other, chat, gossip, exchange information, etc. Only a couple are aware of this blog to date. In a couple of more months, when I think that the quantity and quality of content warrants it, I will inform the chronobiological community and actively recruit guest-bloggers.

Finally, I would like to see here students taking classes in chronobiology. The category Clock Tutorials is specially designed for you, as no good textbook is available at the moment. In fact, I am aware of four such students who have used my ClockTutorials as an aid in studying and they did remarkably well - at the top of their class - on the last mid-term exam. But watch out! When you check the ClockTutorials category, those posts marked as "CT" are likely to be basic non-controversial stuff. The other posts are, in the good blog tradition, strongly opinionated and have more of my voice in them, so you need to think carefully while reading those as your instructor may not neccessarily agree with all of my opinions.

What is the purpose and goal of this blog?

I wish to develop this blog in three phases. I think that this blog is currently in the middle of the first phase: building content and building readership, particularly non-scientific readers. The second phase will involve expanding the blog into a website of which the blog is going to be just one part. This will entail some technical learning on my part, some tweaking of design, and further expansion of content, i.e., not just my posts, but also links to other websites and blogs, to homepages of researchers in the field, etc.

I will try to make data-analysis software available, links to online versions of scientific papers, archives of historical documents (e.g., scans of Aschoff's doodles), job ads, links to related books on Amazon (or other bookseller), etc. Once I finish building the site, it will enter the third phase, where it will serve as the online hub for the chronobiological community: the starting place in a search for all information related to clocks and sleep, with the blog serving as a meeting-place where information is exchanged, meetings announced, job searches and student positions posted, collaborations started, etc.

An important part of this endeavor is the ClockTutorials series. I intend to finish this series of posts containing very basic information on various topics by May. After that, I will go back and add a couple of more posts on each topic containing much more detailed information, more references, and more figures (for some of which I will have to ask for permission). Thus I will build a layered inter-linked "textbook" containing, for each topic, a starting post that is very basic that further links to more advanced posts. Instructors can then use this as a teaching resource. Perhaps I can even edit the final product and form a PDF file that can be downloaded here for free (perhaps with a tip-jar if someone feels I deserve a donation). The best thing about an online "textbook" is that it is not a dead object - it can be and will be updated in real time, as the new findings get published.

Clock Tutorials

So far, in the ClockTutorials series I have written an introduction to chronobiology and a post explaining the basic terms and concepts one needs in order to be able to read the rest of the series. I have written a big, four-part post situating chronobiology within its philosophical and historical context, the first part describing Darwinian methodology, the second part covering early history of the field, the third part looking at evolution of clocks through Darwinian prizm, and the fourth part coming back to philosophical and methodological issues. Later, I have expanded on the historical part by also covering more recent history of the field, and expanded on clock evolution from a slightly different perspective. If you are interested in history, I have also written two posts describing how early chronobiology was lumped together with some bad science and some pseudo-science.

All of those early posts were ABOUT chronobiology. I made the transition from theory to practice through a post on methodology. Then, I got into the meat of the field, discussing circadian organization, first from a theoretical perspective, then giving examples of mammals and non-mammalian vertebrates, and finally adding what is known about three individual species: the Japanese quail, the ant-lion, and the human (understandably my most popular post, especially as it is heavily focused on sleep patterns). Since humans are not my "forte", I have also directed you to a website that does a better job on this topic, another one on bipolar disorders, as well as to a blog that covers a specialized topic of time perception in humans. I have also covered some recent research on melanopsin, melatonin, fruitflies, and mammalian clocks, and introduced you to the premier journal in the field.

What comes next is the hardest part of chronobiology - formal analysis of entrainment. This is not covered very clearly in old books and sometimes is not presented well in class either (though I was very fortunate when I took the class to have an exceptionally clear instructor). This is usually the part that pushes students' grades down as it is conceptually difficult. I have started very briefly on the topic earlier on, but within next couple of weeks I will try to present it in a series of short, bite-sized, and hopefully clearly written posts. If you bear with me, and end up understanding how Phase-Response Curves (PRC) are constructed, interpreted, modified and used, you will be able to understand the nitty-gritty physiological research that flows out of it. I may add a post on limit cycles as well, just for fun, but will, for now, avoid topological analysis and more complex mathematical modelling (perhaps I can get a guest-blogger later on to cover those topics).

If you grasp the PRC, you will be able to understand the subsequent topics regarding seasonality: both circannual rhythms and photoperiodism. After that, I will briefly cover the genetics and biochemistry of circadian clocks (including a historical perspective). The next topic involves development, including the embryonic development of the clock, the transfer of circadian (and photoperiodic) information from mother to fetus, and evidence for involvement of the circadian clock in timing of developmental events. The rest of the course is comparatively easy: Continuously Consulted Clocks (as used in spatial orientation), circatidal and circalunar rhythms. So buckle-up, we are ready to take off.

Sunday, March 13, 2005


GENERIC NAME: eszopiclone
BRAND NAME: Lunesta (formerly known as Estorra)
DRUG CLASS AND MECHANISM: Eszopiclone is a non-benzodiazepine, oral, sedative drug ("sleeping pill") that is used for treating insomnia. According to the National Institutes of Health, more than 50 million Americans suffer from insomnia. Symptoms of insomnia include difficulty falling asleep, awakening frequently during the night, waking up too early, an inability to fall back to sleep, or awakening in the morning not feeling refreshed. Most drugs that have been used to treat insomnia are benzodiazepines, for example, flurazepam (Dalmane), lorazepam (Ativan), triazolam (Halcion), and temazepam (Restoril). Zolpidem (Ambien) was the first non-benzodiazepine approved for insomnia in over 20 years. Eszopiclone is unique in that it is the only drug used for insomnia that has been shown to be safe and effective for up to six months. Eszopiclone was approved by the FDA in December, 2004.
PREPARATIONS: Tablets of 1, 2, and 3 mg
STORAGE: Tablets should be stored at room temperature, 15-30 °C (59-86 °F).
PRESCRIBED FOR: Eszopiclone is used for the treatment of insomnia characterized by difficulty falling asleep and/or difficulty maintaining sleep during the night and early morning.
DOSING: The usual dose to improve or maintain sleep in most adults is 2 or 3 mg. Persons over the age of 65 years usually are treated with 1 or 2 mg. Eszopiclone should be taken immediately before going to bed since the onset of sedation may occur as rapidly as 10 minutes. It should be taken only by individuals who intend to sleep for at least 8 hours since its effects may last up to six hours.
DRUG INTERACTIONS: Alcohol (which causes sedation) and drugs that have sedating effects should not be used with eszopiclone since their sedating effects, when added to those of eszopiclone, may cause excessive sedation.
PREGNANCY: Eszopiclone should not be used during pregnancy.
NURSING MOTHERS: It is not known whether eszopiclone is excreted in human breast milk. Because many medicines are excreted in breast milk and because the effect of eszopiclone on infants has not been studied, women should not breast feed while taking eszopiclone.
SIDE EFFECTS: Patients taking eszopiclone or any other sedative drug may develop dependence on the drug for sleep and experience withdrawal symptoms when the drug is discontinued. The most common side effects of eszopiclone are dizziness and loss of coordination.

LUNESTA™ (eszopiclone) TABLETS 1 mg, 2 mg, 3 mg
LUNESTA (eszopiclone) is a nonbenzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class. The chemical name of eszopiclone is (+)-(5S)-6-(chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b] pyrazin-5-yl 4-methyl- piperazine-1-carboxylate. Its molecular weight is 388.81, and its empirical formula is C17H17ClN6O3.
Eszopiclone has a single chiral center with an (S)-configuration. It has the following chemical structure:

Eszopiclone is a white to light-yellow crystalline solid. Eszopiclone is very slightly soluble in water, slightly soluble in ethanol, and soluble in phosphate buffer (pH 3.2).
Eszopiclone is formulated as film-coated tablets for oral administration. LUNESTA tablets contain 1 mg, 2 mg, or 3 mg eszopiclone and the following inactive ingredients: calcium phosphate, colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, titanium dioxide, and triacetin. In addition, both the 1 mg and 3 mg tablets contain FD&C Blue #2.

eszopiclone (ezz sop e clone)
What is the most important information I should know about Lunesta?

Use caution when driving, operating machinery, or performing other hazardous activities. Lunesta will cause drowsiness and may cause dizziness. If you experience drowsiness or dizziness, avoid these activities. Lunesta should be taken just before bedtime. You may experience some carryover effects the next day.

Do not drink alcohol while taking Lunesta. Alcohol will increase drowsiness and may increase dizziness while you are taking Lunesta, which could be dangerous.

Do not stop taking Lunesta suddenly if you have been taking it for more than 1 or 2 weeks. This may cause withdrawal symptoms and make you uncomfortable. Talk to your doctor if you need to stop treatment with Lunesta.
What is Lunesta?

Lunesta is in a class of drugs called sedative/hypnotics or sleep medications. Lunesta affects chemicals in your brain that may affect sleep.

Lunesta induces sleep and causes relaxation. It is used to treat insomnia.

Lunesta may also be used for purposes other than those listed in this medication guide.
What should I discuss with my healthcare provider before taking Lunesta?

Before taking this medication, tell your doctor if you

have liver disease;

have asthma, bronchitis, emphysema, or another respiratory disease; or

are depressed or have suicidal thoughts.

You may not be able to take Lunesta, or you may require a lower dose or special monitoring during treatment if you have any of the conditions listed above.

Lunesta may cause memory loss or "amnesia" where a person may not remember what has happened for several hours after taking the medication. Since Lunesta is typically taken just prior to falling asleep for the night, this is generally not a problem. However, this could be a problem if Lunesta is taken while traveling, such as during an airplane flight, and the person wakes up before the effects of the medication are gone. Lunesta should only be taken if you are able to get a full night's sleep (8 or more hours) before you must be active again.

Be aware that you may have more sleeping problems the first night or two after you stop taking Lunesta.

Lunesta is in the FDA pregnancy category C. This means that it is unknown whether Lunesta will harm an unborn baby. Do not take Lunesta without first talking to your doctor if you are pregnant.

Lunesta passes into breast milk and may affect a nursing baby. Do not take this medication without first talking to your doctor if you are breast-feeding a baby.

If you are over 65 years of age, you may be more likely to experience side effects from Lunesta. You may require a lower dose of this medication.
How should I take Lunesta?

Take Lunesta exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you.

Take each dose with a full glass of water.

Take Lunesta just before you go to bed. It will make you drowsy, and you could fall and hurt yourself if you take your dose before you are ready for sleep.

You can take Lunesta with or without food but for Lunesta to work best, do not take it with or immediately after a high-fat, heavy meal.

Do not crush or chew the tablets. Take each tablet whole.

Take Lunesta only if you are able to get a full night's sleep (8 or more hours) before you must be active again.

Do not take more of this medication than is prescribed for you.

Do not stop taking Lunesta suddenly if you have been taking it for more than 1 or 2 weeks. This may cause withdrawal symptoms and make you uncomfortable. Talk to your doctor if you need to stop treatment with Lunesta.

Store Lunesta at room temperature away from moisture and heat.
What happens if I miss a dose?

Since Lunesta is usually taken only if you need it to help you sleep, missing a dose will not cause any problems. Take the missed dose only if you can be sure that you will get 8 full hours of sleep after the dose. If you do not sleep 8 full hours, you may experience carryover effects from Lunesta after you wake up.
What happens if I overdose?

Seek emergency medical attention.

Symptoms of a Lunesta overdose may include sleepiness, confusion, dizziness, difficult or slow breathing, and unconsciousness.
What should I avoid while taking Lunesta?

Use caution when driving, operating machinery, or performing other hazardous activities. Lunesta will cause drowsiness and may cause dizziness. If you experience drowsiness or dizziness, avoid these activities. Lunesta should be taken just before bedtime. You may experience some carryover effects the next day.

Do not drink alcohol while taking Lunesta. Alcohol will increase drowsiness and may increase dizziness while you are taking Lunesta, which could be dangerous.

Avoid other sedatives, sleeping pills, and tranquilizers, including over-the-counter preparations. They should not be used while you are taking Lunesta unless your doctor directs otherwise.
What are the possible side effects of Lunesta?

If you experience any of the following serious side effects, stop taking Lunesta and seek emergency medical attention:

an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, face, or tongue; hives).

Contact your doctor if you experience

daytime drowsiness, dizziness, or clumsiness;

more outgoing or aggressive behavior than normal;


strange behavior;

memory loss problems;


worsening of depression;

hallucinations; or

new feelings of depression.

Other, less serious side effects may be more likely to occur, such as headache and unpleasant taste. If these become bothersome, contact your doctor.

A problem that may occur when sleep medicines are stopped is known as "rebound insomnia." This means that a person may have more trouble sleeping the first few nights after the medicine is stopped than before starting the medicine. If you should experience rebound insomnia, do not get discouraged. This problem usually goes away on its own after 1 or 2 nights.

Lunesta may be habit forming. Stopping this medication suddenly can cause withdrawal effects if you have taken it continuously for several weeks. Talk to your doctor about the safe use of this medication.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.
What other drugs will affect Lunesta?

Many drugs may affect the way that Lunesta is metabolized ("broken down") in the body, leading to higher or lower than expected levels of the medication in the blood. Talk to your doctor before taking any other medicines during treatment with Lunesta.

Lunesta may increase the effects of other drugs that cause drowsiness, including antidepressants, alcohol, antihistamines, other sedatives (used to treat insomnia), pain relievers, anxiety medicines, and muscle relaxants. Tell your doctor about all medicines that you are taking, and do not take any medicine unless your doctor approves.

Drugs other than those listed here may also interact with Lunesta. Talk to your doctor and pharmacist before taking any prescription or over-the-counter medicines including vitamins, minerals, and herbal products.
Where can I get more information?

Your pharmacist has additional information about Lunesta written for health professionals that you may read.

Lunesta: You May Want to Sleep on It

ImmuneSupport.com01-20-2005 Enter the Next 'Miracle' Drug: a Sleeping Pill You Can Take Long-Term. Ads for Lunesta Won't Likely Give That Theme a Rest. This Time Will Consumers Be More Leery?
By Sandra G. BoodmanWashington Post Staff WriterTuesday, January 18, 2005; Page HE01

It sounds like an insomniac's dream: a sleeping pill that can be taken for weeks or even months at a time, without the risk of addiction or morning-after grogginess.
In the next several weeks consumers will see splashy print and television ads touting the lyrically named Lunesta, which was approved last month by the U.S. Food and Drug Administration (FDA). Unlike other sleeping pills, including market leader Ambien, which are not supposed to be taken for longer than 10 days at a time, Lunesta has no FDA recommended time limit.
Since the drug's official launch last week, Sepracor, its Massachusetts-based manufacturer, has deployed 1,250 salespeople to the offices of primary care physicians -- the doctors most patients consult for sleep problems -- as well as psychiatrists and hospitals. The aim, said David P. Southwell, Sepracor's chief financial officer, is to persuade them of Lunesta's superiority in treating insomnia, an extremely common problem that regularly affects more than half of American adults and that, in Southwell's view, is "under-recognized and under-treated."
Some sleep specialists question the wisdom of using a sleeping pill for weeks or months on end, particularly when it is a new drug approved after six months of testing in 2,700 patients.
They cite the fresh examples of the increased risk of heart attack and stroke from arthritis pain relievers Vioxx, Celebrex and Bextra, the dangers of which emerged after millions of patients started taking them.
Because insomnia is so common -- Ambien is the nation's 12th-best-selling prescription medication, according to IMS Health -- and because Lunesta will be aggressively marketed, some sleep specialists emphasize the importance of non-drug remedies.
"The best thing to do is to avoid getting into a situation where you need a medication long-term," said Northern Virginia neurologist John W. Cochran. For a small group of patients who have been adequately screened to rule out underlying physical or psychiatric problems -- such as depression or anxiety -- that might cause insomnia, long-term use of a sleeping medication may be indicated, he said.
To treat insomnia many sleep specialists, including Cochran, recommend behavioral strategies that fall under the schoolmarmish rubric "sleep hygiene." They include relaxation techniques as well as avoidance of caffeine, alcohol and large meals before bedtime. Sleeping pills are often used short-term, to break the cycle of sleeplessness and the anxiety it causes.
Cochran said he worries that many consumers, eager for a speedy and easy remedy, will get a prescription for Lunesta from a primary care doctor who has neither the time nor the training to suggest behavioral techniques or conduct a comprehensive evaluation.
"That means some doctors will give it to patients who will stay on it forever," he said.
Symptoms of insomnia -- difficulty falling or staying asleep -- are extremely common. A 2002 poll by the National Sleep Foundation found that 58 percent of adults experience them a few times each week and one-third have nightly symptoms. The problem is more common among frequent travelers, shift workers, women and the elderly. Another study found that about half of people with insomnia suffer from an underlying medical problem, such as depression, anxiety or chronic pain.
In about 15 percent of cases, sleep specialists say, chronic insomnia has no apparent underlying cause. Gregg D. Jacobs, a sleep specialist at Beth Israel Deaconess Medical Center in Boston, said that long-term use of a sleeping pill is inappropriate for most patients because cognitive behavioral therapy works better than drugs in overcoming insomnia.
Sleeping pills, Jacobs said, are typically prescribed for brief periods. Some medicines used for sleep are habit-forming, such as a class of drugs known as benzodiazepines, which include Valium and Xanax. Doctors worry that long-term use of non-narcotic medications such as Lunesta can create psychological dependence that results when patients fear they can't fall asleep or stay asleep without them.
The other problem, said Jacobs, an assistant professor of psychiatry at Harvard Medical School, is that the long-term effects of Lunesta are unknown.
"Lunesta is like every drug approved by the FDA," said Jacobs. "We don't know what the long-term side effects are" or all the negative side effects seen during the clinical trials. "The message is: Buyer beware."
Sepracor's Southwell said that the drug, known generically as eszopiclone, is closely related to zopiclone, a sleep drug widely used in Europe and Canada for 20 years. Zopiclone, he said, has a good safety record. "If there were a safety defect, one would think they would have seen it by now," he said.
But Southwell acknowledged that oversight of prescription drugs varies from country to country in Western Europe. And some sleep specialists say that the potential market for Lunesta may be larger in the United States because of the aggressive marketing of drugs to consumers.
In the clinical trials of Lunesta, the most common side effects reported to the FDA were headache, an unpleasant taste and dizziness. When they first start taking the drug users are advised to "use extreme care when doing anything that requires complete alertness" such as driving, piloting an airplane or using heavy machinery.
Terri Bagley said she has been counting the days until Lunesta hit the market so she could call her doctor for a prescription.
Bagley, 43, who operates a housecleaning business in Pelham, N.C., said she has battled chronic insomnia for more than 20 years. She said it routinely takes her two hours to fall asleep at night, and she usually awakens four or five times each night, snagging a total of about four hours sleep and feeling perpetually exhausted during the day. None of the host of prescription or nonprescription drugs she tried made much difference, she said, and doctors ruled out underlying psychiatric or medical problems that might be causing her insomnia.
Then Bagley said, she enrolled in the clinical trial of Lunesta conducted at the Duke University Sleep Disorders Center. She said she is certain she got the drug rather than a placebo.
"I've never in my life slept that well or felt that good," Bagley said, adding that during the three months she took the drug she slept about seven hours per night with fewer and shorter awakenings.
Andrew D. Krystal, director of Duke's sleep center and one of the principal investigators of Lunesta, said that another advantage of the drug is that patients did not build up a tolerance to it. That is a common side effect of benzodiazepines, which typically require progressively larger doses to achieve the same effect.
Krystal, who has worked as a consultant for Sepracor, said while behavioral treatments are effective for some people, others have more intractable insomnia and need medication "which should be taken at the lowest possible dose for the shortest duration."
Whether Lunesta works better than its competitors remains to be seen. Chevy Chase sleep specialist Helene Emsellem said no large studies have compared Lunesta with other drugs.
"I think Lunesta clearly fills a needed niche in selected patients," said Emsellem, an associate clinical professor of neurology at George Washington University School of Medicine, who was involved in the clinical trials of the drug but said she has no other financial relationship with Sepracor. "But it's important for people to realize that insomnia is often a symptom and not a disease, and to sort out the problems."
Source and © 2005 The Washington Post Company.

LUNESTA is indicated for the treatment of insomnia. In controlled outpatient and sleep laboratory studies, LUNESTA administered at bedtime decreased sleep latency and improved sleep maintenance.
The dose of LUNESTA should be individualized. The recommended starting dose for LUNESTA for most non-elderly adults is 2 mg immediately before bedtime. Dosing can be initiated at or raised to 3 mg if clinically indicated, since 3 mg is more effective for sleep maintenance (see PRECAUTIONS).
The recommended starting dose of LUNESTA for elderly patients whose primary complaint is difficulty falling asleep is 1 mg immediately before bedtime. In these patients, the dose may be increased to 2 mg if clinically indicated. For elderly patients whose primary complaint is difficulty staying asleep, the recommended dose is 2 mg immediately before bedtime (see PRECAUTIONS).
Taking LUNESTA with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of LUNESTA on sleep latency (see Pharmacokinetics under CLINICAL PHARMACOLOGY).
Special Populations
The starting dose of LUNESTA should be 1 mg in patients with severe hepatic impairment. LUNESTA should be used with caution in these patients.
Coadministration With CYP3A4 Inhibitors
The starting dose of LUNESTA should not exceed 1 mg in patients coadministered LUNESTA with potent CYP3A4 inhibitors. If needed, the dose can be raised to 2 mg.
LUNESTA 3 mg tablets are round, dark blue, film-coated, and identified with debossed markings of S193 on one side, and are supplied as:

NDC 63402-193-10
bottle of 100 tablets

NDC 63402-193-09
carton of 90 tablets

LUNESTA 2 mg tablets are round, white, film-coated, and identified with debossed markings of S191 on one side, and are supplied as:

NDC 63402-191-10
bottle of 100 tablets
NDC 63402-191-09
carton of 90 tablets
LUNESTA 1 mg tablets are round, light blue, film-coated, and identified with debossed markings of S190 on one side, and are supplied as:

NDC 63402-190-10
bottle of 100 tablets
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Manufactured for: Sepracor Inc., Marlborough, MA 01752 USA by Patheon Inc., Mississauga, Ontario L5N 7K9 Canada, For customer service, call 1-888-394-7377. To report adverse events, call 1-877-737-7226. For medical information, call 1-800-739-0565., December 2004 IN-5169/S


LUNESTATM (eszopiclone)
On December 15, 2004, the U.S. Food and Drug Administration (FDA) approved the New Drug Application (NDA) for LUNESTATM brand eszopiclone, formerly referred to as ESTORRA, 1 mg, 2 mg, and 3 mg tablets for the treatment of insomnia. LUNESTA brand eszopiclone is expected to be made available by prescription within the first quarter of 2005. Insomnia can include difficulty falling asleep as well as difficulty maintaining sleep through the night. The recommended dosing to improve sleep onset and/or maintenance is 2 mg or 3 mg for adult patients (18 to 64) and 2 mg for older adult patients (ages 65 and older). The 1 mg dose is for sleep onset in older adult patients whose primary complaint is difficulty falling asleep.
The NDA for LUNESTA contained data from 24 clinical trials, which included more than 2,700 adult and elderly patients, and more than 60 preclinical studies. Results of six randomized, placebo-controlled Phase III studies for the treatment of chronic or transient insomnia in both adult and older patients (ages 65 and older) were included as part of the NDA package. Data from a landmark, long-term (six-month), double-blind, placebo-controlled safety and efficacy study in 788 patients were reviewed by the FDA as part of the NDA submission for eszopiclone and served as a basis for the FDA's decision to not limit LUNESTA's indication to short-term use. Sepracor's six-month study was the first of its kind for a prescription non-benzodiazepine for the treatment of insomnia. The results of this study were published in the November 2003 issue of the journal SLEEP.
Clinical data on LUNESTA has been presented at various medical society meetings in 2004, including the annual meetings of the American College of Obstetricians and Gynecologists (ACOG), the American Psychiatric Association (APA), and the Associated Professional Sleep Societies (APSS). For further information about the clinical data presented at medical meetings in 2004, please click here or refer to Sepracor's press releases dated, May 6, May 13, and June 8-10, 2004, located on this web site.
Sepracor continues to study LUNESTA in adult and older adult patients in a comprehensive Phase IIIB/IV program. The preliminary results of a Phase IIIB/IV, 545-patient, double-blind, placebo-controlled, ten-week study evaluating the efficacy and safety of LUNESTA in patients with insomnia and co-existing Major Depressive Disorder (MDD) have been completed. Sepracor has submitted results of this study to be considered by the American Psychiatric Association and the Associated Professional Sleep Societies for presentation at their respective scientific meetings in May and June of 2005.
Additional Phase IIIB/IV studies of LUNESTA are nearing completion. These studies include the evaluation of LUNESTA for the treatment of insomnia in women experiencing the hormonal changes associated with perimenopause, in patients experiencing pain associated with rheumatoid arthritis, and a six-month, double-blind, placebo-controlled study in patients with chronic insomnia.
Sepracor currently anticipates that LUNESTA will be available to patients nationwide within the first quarter of 2005.
An estimated 100 million adult Americans suffer from either chronic or occasional insomnia*. Symptoms of insomnia include difficulty falling asleep, awakening frequently during the night, waking up too early, an inability to fall back to sleep, or awakening feeling unrefreshed. Insomnia can be a serious condition. If left untreated, it may become progressively worse and in turn, potentially affect a person's emotional, mental and physical health.
The U.S. market for prescription sleep products, not including off-label (not indicated for the treatment of insomnia) use of central nervous system (CNS) agents for the treatment of insomnia, was approximately $2.1 billion between November 2003 and October 2004, representing a 20 percent increase over the same period the previous year, according to IMS Health Information.
*Extrapolated to current population from 2000 census based on Ancoli-Israel et al. SLEEP. 1999; 22 (suppl 2):S347-S353.
Important Safety Information
It is important to note that because sleep disturbances may be caused by underlying physical and/or psychiatric disorders, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7-10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Patients should only take LUNESTA when they are prepared to get a full night of sleep. Until they know how they will react to LUNESTA, patients should not drive or operate machinery.

Monday, March 07, 2005

ClockNews #29: More and more complexity in the SCN

Erik has done it again!

Vasoactive intestinal polypeptide needed by the brain's biological clock to coordinate daily rhythms

Erik Herzog, Ph.D., Washington University assistant professor of Biology in Arts & Sciences, has discovered that VIP is needed by the brain's biological clock to coordinate daily rhythms in behavior and physiology. Neurons in the biological clock, an area called the suprachiasmatic nucleus (SCN), keep 24-hour time and are normally synchronized as a well-oiled marching band coming onto the field at half time. Herzog and graduate student, Sara Aton, found that mice lacking the gene that makes VIP or lacking the receptor molecule for VIP suffer from internal de-synchrony. When they recorded the electrical activity of SCN neurons from these mice, they found that many had lost their beat while others were cycling but unable to synch to each other.

That VIP is the signal between pacemaker cells is exciting discovery in itself, but thet fact that in VIP-less mice, many SCN cells stop cycling altogether is really a novel and disturbing finding.

And that there are a number of subsets of pacemaker cells, each with a different period and different function adds to the complexity:

The circadian clock: Understanding nature's timepiece
Dr. Michael Antle, a neuroscientist in the U of C's Department of Psychology, has conclusively shown that the 20,000 cells are organized in a complex network of groups that perform different functions – contrary to the previously held belief that each cell did the same thing. Antle, an emerging leader in the field, has two new papers on the subject: one is featured on the March cover of the prestigious Trends in Neurosciences, and another is due out in a forthcoming issue of the Journal of Neurosciences.

Sleepiness May Be Associated With Visual Impairment

Latest research shows that people who have optic nerve damage might be at anincreased risk of a sleep disorder. For the study researchers involved 25 people with visual impairment. The participants had their sleep-wakefulness cycles followed for 14 days, and their results were compared with those of 12 young subjects with normal sight. It was discovered that those with optic nerve disease were 20-times more likely to have daytime sleepiness than those with normal sight and people with optic nerve damage were nine-times more likely to suffer sleepiness than even those were blind due to non-optic nerve disease. Recent work has indicated that the retina contains non-visual photoreceptors that communicate with the area of the brain involved in circadian rhythms. Thus researchers say, physicians and other health care professionals should be sensitive to the possibility of daytime sleepiness or insomnia, particularly in patients with severe optic nerve disease. Researchers also add that these findings suggest the need to try to maintain any remaining vision in people with optic nerve damage as it plays a crucial role in health and longevity.

Bill Seeks to Ban Nurses' Overtime

"Instead of hiring more nurses, understaffed hospitals typically . . . order nurses to work back-to-back eight-hour shifts or four extra hours on top of a 12-hour shift, even though it is dangerous for patients and nurses," Kennedy said.
A recent report by Circadian concurs. Focusing on the effects of shiftwork on nurses, the Circadian report found that nearly 20 percent of nurses cited fatigue as one of the top three job-related health and safety risks in their profession. The report also noted that fatigue and short staffing can affect the quality of patient care.

Science & fun cool stuff
Circle of Science Assessment
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