This week, Dr. Sydney Spiesel discusses circadian rhythms in relation to a treatment for arthritis and a link to bipolar disorder, a big hike in the price for the inhalers used to treat asthma, and whether the drug Imodium is safe for children.
Circadian rhythms and treating arthritis
Affliction: In common with many diseases caused or characterized by chronic inflammation, rheumatoid arthritis has symptoms that vary strikingly in the course of a day. Joint pain, morning stiffness, and functional disability are particularly bad in the early morning hours and least oppressive in the early evening. The difference can be measured objectively, with an average 27 percent increase in grip strength at 6 p.m. compared with 6 a.m., and a 28 percent reduction in pain at 6 p.m. compared with 8 a.m.
Question: Why should this be so? An exceptional paper by two European physicians has examined the effect on rheumatoid arthritis of circadian rhythms, which tell us when to sleep and when to wake up (and tells children at 4 in the afternoon that the witching hour has arrived).
New findings: Circadian rhythms affect, among other things, the production and release of two different hormones, cortisol and melatonin, which modulate the immune response and many aspects of inflammation. Melatonin, which peaks at night and plays a role in putting us to sleep, seems to increase the inflammatory products of activated immune cells. Cortisol, on the other hand, regulates these cells downward. At night, there's less cortisol, and the decrease results in a release of the things that cause inflammation (leakage of fluid into joint tissue, for instance, makes for morning stiffness). With less cortisol also comes less endorphin, the body's natural pain-blocker, so the pain of inflamed joints (and other pain) is felt more acutely in the night.
Implications: These observations about circadian effects suggest that there is a better time of day (or night) for giving anti-inflammatory treatments. Many of these drugs have harmful side effects, and time-targeted administration might improve both their efficacy and safety. One study showed that giving an oral steroid treatment to rheumatoid arthritis patients at 2 a.m. led to much better outcomes than treatment at 7:30 a.m. Since the effects of circadian rhythms are pervasive, many illnesses may similarly respond favorably to time-targeting.
Circadian rhythms and manic mice
Gene: Speaking of circadian rhythm, another recent paper (subscription required) by Kole Roybal, Coleen McClung, and a number of colleagues explores what happens when the "clock" gene goes mutant. This gene controls circadian rhythms and operates in most of our cells. The gene, or its near relatives, is active in cells of creatures as diverse as fruit flies, fungi, plants, and worms. In humans and other mammals, it does its most important work at a location in the brain called the suprachiasmatic nucleus. That's where messages about ambient light levels, generated from the retina, interact with messages from the clock gene to keep us to our daily 24-hour schedule, changing body functions across day and night and regulating the release of hormones. (See above.)
Question: What happens when the function of the clock gene is badly disrupted? Certain variations in this gene have been associated with bipolar disorder in humans, especially its expression in manic behavior. And bipolar patients almost always have abnormal patterns of sleep, activity, appetite, and physiological functions.
New research: The Roybal team showed that abnormalities in the clock gene of mice lead to similar behavioral changes. Compared to littermates with normal clocks, mice with the gene mutation are hyperactive and sleep less. Bipolar people in a manic state have a propensity toward drug abuse; mice with a defective clock gene are more sensitive to the reward effects of cocaine. Finally, lithium alleviates both the symptoms of mania in humans and the effects of a bad clock gene in mice. One difference: The clock-mutant mice don't appear to cycle between mania and depression like bipolar people do.
Conclusion: It is increasingly clear that there is something very powerful about clock-gene functions, which control systems as diverse as immune response, perception of pain, and mental functioning. Who knows what else we can learn from a deeper understanding of our sleep and waking cycles.
The asthma inhaler dilemma: cost vs. chemicals
Chemical: CFCs are organic chemicals that were used for years as refrigerants, solvents, and aerosol propellants. They are nontoxic and nonflammable, and their great molecular stability preserved them as they leaked (or were sprayed) into the atmosphere. But as they floated higher into the stratosphere, they were exposed to high-energy ultraviolet light that attacked their stability. The CFC molecules broke down in the upper stratosphere and released chlorine. This catalyzed the breakdown of the ozone layer, which when intact protects us by filtering out the ultraviolet light that causes sunburn, cataracts, and skin cancer. As a result, CFC products have been largely phased out everywhere since 1987.
New ingredient: But CFCs continued to be used as a propellant for metered dose inhalers, the "puffers" used to treat wheezing disorders like asthma. In the United States alone, about 52 million inhalers containing albuterol (the most commonly used drug for asthma) have been issued annually. Now CFCs have been banned for this use as well and are being replaced by another propellant (HFA-134a). From a medical standpoint, there seems to be little difference in efficacy or safety. (Here's a fine new review of this topic—article purchase required.)
Price: But there is a major cost difference. When the patent for CFC-driven albuterol inhalers expired in 1989, the product went generic and the price dropped to an average of about $13.50 a unit. For some reason that escapes me, the same old medicine blown out of the can by the new propellant has been patented again—and the $13.50 product will be replaced by one that costs $39.50. The consequence will be that some patients paying out of pocket for medication will be driven to use cheaper but much less effective drugs to control their asthma, with potentially serious—or even deadly—effects.
Consequences: This makes me wonder about the balance of harms—what are the consequences of the CFCs dumped in the atmosphere by 52 million puffers compared with the asthmatics who will no longer able to pay for their medication? I don't know much about the contribution of asthma puffers to the atmospheric burden, but I have strong suspicions about the effects of the financial burden. The hike to $39.50 will cost about $1.35 billion more a year. That could mean less for daily necessities for some people without insurance, and less of other medications or care for some of the insured.
Giving Imodium to children
Treatment: Pediatricians have always been leery of loperamide (Imodium) as a diarrhea treatment for children. First, the medication works by slowing down the physical activity (peristalsis) of the bowel, which allows the liquid stool in the small intestine to travel through the colon more slowly. This gives the cellular "pumps" in the wall of the large intestine more opportunity to reabsorb the water in the liquid stool and convert in into solid material. However, it also means that in cases of infectious diarrhea where the "pumps" are working poorly, the diarrhea is really continuing; we just can't see it. That means the severity of a child's fluid loss might go unnoticed. The other problem is that bacterial toxins in the diarrheal fluid have more time to be absorbed by the body or cause damage to the intestinal wall, which is likely to make the child sicker.
New findings: A recent review examined loperamide's benefits and risks for children under the age of 12. The research team, led by Su-Ting Li of the University of California-Davis, put together the results of a number of studies of diarrhea that compared children treated with loperamide with children treated with placebo. When all of the results were pooled, they showed that loperamide somewhat shortened the course of diarrhea (by a little less than a day, on average). But about 1 percent of the loperamide-treated children experienced problems, ranging from lethargy to temporary paralysis of the bowel to death. The serious adverse effects occurred only in children younger than 3.
Conclusion: The authors urged (and I concur) that this medicine should not be used for children under 3, for dehydrated or malnourished children, or for those with bloody diarrhea or broader illnesses.
And also: Citing this paper allows me to pay tribute to the journal in which it was published: PLoS Medicine, one of several journals published by the Public Library of Science. This is a journal of fine quality founded by people who believe that all readers (you, me, and doctors in poor countries) should have free access to the journal's entire contents—not just the abstracts. Peer review is just as stringent as in traditional journals that charge for online viewing. The PLoS way is the way every medical and scientific journal should be published. I'd love to persuade colleagues to submit their work first to a Public Library of Science journal and to go the limited-access route only if they must.