The Corpus Callosum

Gaboxadol for Insomnia

I’ve written about this href="http://trots.blogspot.com/2005/02/pipeline-update-insomniaimplications.html">before,
but now there is some new information.   href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16368265&query_hl=6&itool=pubmed_docsum"
rel="tag">Gaboxadol (THIP;
4,5,6,7-tetrahydroisoxazolo- [5,4-c] pyridin-3-ol)
is an investigational drug being developed by  title="company website" rel="tag"
href="http://www.lundbeck.com">Lundbeck in
conjunction with href="http://www.merck.com/" rel="tag">Merck.

i-7edb1679296a84e3f15f435605c80376-gaboxadol.png
gaboxadol
structure
(image from ChemBank)

At the 2006 Associated Professional Sleep Societies href="http://www.apss.org/FinalProgram.aspx">Conference
in Salt Lake City, Utah, href="http://www.docguide.com/news/content.nsf/news/852571020057CCF68525717F006BE279">data
were presented from href="http://en.wikipedia.org/wiki/Phase_II_trials#Phase_II"
rel="tag">Phase II trials
of the drug.
 They report that the compound has advanced to Phase III
trials, with the intent of getting the drug approved for treatment of
insomnia.


Results Gaboxadol 20 mg and
zolpidem 10 mg significantly increased total sleep time (TST) with 53
minutes compared to baseline (P <.05 compared to placebo) and
gaboxadol 20 mg significantly reduced wakefulness after sleep onset
(WASO) with 27 minutes compared to baseline (P <.05 compared to
placebo). Both gaboxadol 10 and 20 mg but not zolpidem significantly
reduced number of awakenings by 9 compared to baseline (P >.001
compared to placebo). Neither drug significantly reduced sleep onset
latency. However, gaboxadol 20 mg improved self-reported “quality of
sleep” (P <.05).

Both gaboxadol doses enhanced slow wave sleep in a dose dependent
manner.

Tolerability and next-day residual effects Neither
drug treatment was associated with next day residual effects the
morning after treatment. The majority of adverse events (AE) were mild
or moderate with no serious AEs. Compared to placebo, the incidence and
severity of AEs were higher with gaboxadol 20 mg.

The improvement in slow wave sleep is of particular interest.
 Few other drugs do that.   title="Wikipedia link"
href="http://en.wikipedia.org/wiki/Slow_wave_sleep" rel="tag">Slow
wave sleep generally is considered to be the kind of sleep
that is most restorative.  It is thought to be important for href="http://www.futurepundit.com/archives/001903.html">memory
consolidation.  Deficit of slow-wave sleep is href="http://www.sleepreviewmag.com/article.php?s=SRM/2005/05&p=5">associated
with fibromyalgia.

Gaboxadol is a peculiar CNS drug: it acts at nonsynaptic
receptors.  It has a selective effect on title="Wikipedia link"
href="http://en.wikipedia.org/wiki/Gaba_a_receptor">GABA-A
receptors,
which is not terribly unusual these days, but the demonstration of
activity upon receptors that are not located at a
neuronal synapse is
unusual. 

href="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-489B4M4-1&_user=10&_handle=V-WA-A-W-BC-MsSAYWA-UUW-U-AACBZWVEBZ-AACAWUCDBZ-ECZBWYAYY-BC-U&_fmt=summary&_coverDate=04%2F25%2F2003&_rdoc=6&_orig=browse&_srch=%23toc%234892%232003%23995329998%23418055%21&_cdi=4892&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=9d329d778e7f5aff508c0569dd2c3300">Studies
have shown that the mechanism of action of gaboxadol is distinct from
that of href="http://en.wikipedia.org/wiki/Benzodiazepines" rel="tag">benzodiazepines
(and ethanol).  Although there are many drugs for insomnia on
the market, it won’t really be a “me too” drug.  It is
classified as a selective extrasynaptic GABAA agonist,
thus
giving rise to yet another acronym: SEGA.  

Lundbeck and Merck expect to file for FDA approval in the USA in 2007.
 (Non-disclaimer: I don’t own stock in any drug companies, at
least not directly.)

Comments

  1. #1 Hyperion
    June 23, 2006

    I’m probably displaying a huge level of ignorance with this comment, but have there been many studies on the role of endogenous extrasynaptic GABA? And are these extrasynaptic receptors different from presynaptic axon receptors (such as the PKC receptors involved in reverse uptake)? If so, are they on the axon or the dendrite?

  2. #2 Joseph j7uy5
    June 23, 2006

    No, I would not infer ignorance from those questions. Quite the contrary. But frankly I would have to look some things up before giving an authoritative answer. I’ll take the questions collectively as a suggestion for a future post.

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