Thursday, February 17, 2005
Yesterday, I did a CME program (Medscape, free registration required) on insomnia. The program was sponsored by Pfizer and Neurocrine. Neurocrine, as it turns out, is developing a new medication, indiplon, which Pfizer will market. This sort of arrangement is common: a small company develops the drug, and then contracts with a big company to sell it. Often, then, one of them will sponsor educational programs to promote awareness of the drug. Because of FDA restrictions, they cannot actually advertise the drug before it is approved. Therefore, they use the CME (Continuing Medical Education) channel to increase awareness of the product and develop some interest in the medical community.
These things generally are sponsored by unrestricted educational grants, which means that they cannot influence the content of the presentation or program. It is an interesting exercise to look at them and see if any commercial bias is evident. In this case, there wasn't any obvious bias. There was a section on "Newer Compounds" that described four agents that are not on the market yet. One of them, eszopiclone, has been approved in the US, and should be available soon. The other three are in various stages of development. The section on indiplon was a couple of sentences longer than the sections for the other three new products, but it appears to be accurate and objective. Neurocrine has a web page describing the compound, for those who are interested. One unique aspect to the marketing of indiplon is that they have come up with two formulations. One is an immediate-release preparation, to be used for those with early or middle insomnia, but not early morning awakening. They also have a modified-release preparation, for those with early morning awakening. The MR releases some drug right away, to put the person to sleep, then another bolus later in the night. Clever.
That, however, is not what really caught my attention. There is another product in the pipeline, gaboxadol, that is a topic of interest. Gaboxadol is being developed in Europe by a Danish company, Lundbeck.
We've known for a while that the nerve cells in the brain sometimes have receptors in odd locations. For example, some nerve cells that release norepinephrine have presynaptic receptors that are sensitive to serotonin. We have no idea why they are there. It is fortunate that they are; an antidepressant, mirtazapine, acts on those receptors. Investigation of apparent anomalies such as these sometimes leads to important discoveries.
Gaboxadol has another interesting property. From the Medscape article:
Not many drugs increase slow-wave sleep. Slow-wave sleep is important, although frankly, its exact significance is still being investigated. We know that it plays a role in the consolidation of memory, for example. We also know that persons with fibromyalgia tend to have too little slow wave sleep. Sodium oxybate (Xyrem) has been shown to increase slow wave sleep and reduce pain in fibromyalgia patients. Xyrem has a high potential for abuse, so it can be prescribed only under a special program. Gaboxadol probably will have a much lower potential for abuse. If it also helps fibromyalgia patients, that would be an important advance.
Gaboxadol. Another GABA-A receptor agonist, THIP, or gaboxadol, has been given some attention in Europe as a possible treatment for insomnia. Gaboxadol is unique in that it acts at GABA receptors in nonsynaptic locations. These receptors have a high affinity for GABA, and desensitize slowly.[46,78] The pharmacologic and clinical properties of gaboxadol most likely reflect its potent effects at extrasynaptic GABA-A receptors insensitive to benzodiazepines and containing alpha(4)beta(3)delta subunits.[46,78] A study by Krogsgaard-Larsen and associates of the effect of gaboxadol on human sleep patterns showed that the functional consequences of a directly acting agonist are distinctly different from those seen after administration of GABA-A receptor modulators, such as benzodiazepines.
Mathias and colleagues investigated the influence of a single oral dose of 20 mg gaboxadol on postnap sleep (as a model of disturbed nocturnal sleep) in a randomized, placebo-controlled cross-over study in young, healthy subjects. The study authors noted that previous studies have demonstrated that gaboxadol increases both non-REM sleep and EEG delta activity within non-REM sleep in rats and slow-wave sleep (SWS) as well as low-frequency activity in the EEG within non-REM sleep in healthy humans under normal conditions. Compared with the placebo postnap night, gaboxadol tended to shorten sleep latency, significantly reduced intermittent wakefulness, lengthened total sleep time and SWS, enhanced delta and theta activity in the non-REM EEG, and improved subjective sleep quality.
Some persons are interested in the pharmaceutical pipeline, so they can rush out and buy stock in companies that are likely to introduce a successful new drug. Personally, I don't care about that. I wouldn't buy stock on that basis, because it would be a conflict of interest: it could affect my prescribing pattern, which would not be right. Rather, the reason I am interesting in drug development is that it can potentially teach us about how the brain works. Gaboxadol acts on nonsynaptic receptors, and increases slow-wave sleep. Understanding the role of nonsynaptic receptors could lead to a much greater understanding of the functional organization of the brain. Understanding the relationship between sleep patterns and disease could help us understand, not only the brain, but the fundamentals of how various body systems interact in health and disease:
Sleep, cytokines and immune function"The mechanisms remain to be determined." We hear that a lot. I am hopeful, though, that the interplay between basic science research, and applied research by pharmaceutical companies, will lead to: "Now we finally understand the mechanism."
Sleep Med Rev. 1999 Sep;3(3):219-28
Dickstein JB, Moldofsky H.
Bi-directional communication pathways exist between the brain and the cytokine-immune-endocrine systems. The hypothalamic-pituitary axis, the efferent neuronal hypothalamus-autonomic nervous system axis, and the direct drainage of macromolecules from the brain into the blood and the lymphatic system provide a network by which the sleeping/waking brain influence bodily functions. Similarly, changes in cytokine levels in the periphery modulate the central nervous system either directly or via the vagal nerve and influence the sleeping/waking brain. In humans, circadian nocturnal sleep-daytime wakefulness is associated with changes in peripheral cytokines, cellular immune functions, and endocrines. Progesterone levels influence sleep and cellular immune functions during the menstrual cycle. The interaction between the circadian sleeping/waking brain and the cytokine-immune-endocrine system are integral to preserving homeostasis. Disorganization or loss of sleep disrupts the harmonious integration of the circadian cytokine-immune-endocrine system. However, the mechanisms of circadian sleep/wakefulness-related cytokine-immune-endocrine functions in host defence against disease remain to be determined.
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