The Corpus Callosum

Those of us who watch the drug development pipeline have been pining
for a nonaddictive anti-anxiety drug.  Occasionally there are
glimmers of hope.  One candidate is href="http://en.wikipedia.org/wiki/Emapunil">emapunil, aka XBD-173
or AC-5216.  In 2004, there was an article in the British
Journal of Pharmacology
about this.  That article described
promising findings, in rats and mice.  Now, there is an article in
Science that finally show some findings in humans.

href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1575165/">Antianxiety
and antidepressant-like effects of AC-5216, a novel mitochondrial
benzodiazepine receptor ligand

Br J Pharmacol. 2004 August; 142(7): 1059-1072.

  1. We investigated the ability of
    N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide
    (AC-5216), a novel mitochondrial benzodiazepine receptor (MBR) ligand,
    to produce anti-anxiety and antidepressant-like effects in various
    animal models.
  2. AC-5216 showed high affinity for MBRs prepared from rat whole
    brain (Ki 0.297 nM), rat glioma cells (IC50 3.04 nM) and human glioma
    cells (IC50 2.73 nM), but only negligible affinity for the other main
    receptors including central benzodiazepine receptors.
  3. AC-5216 produced anti-anxiety effects in the Vogel-type
    conflict test in rats, and in the light/dark box and social interaction
    tests in mice at 0.1-3, 0.003-0.01 and 0.01-0.3 mg kg−1, p.o.,
    respectively. These effects of AC-5216 were antagonized by PK11195, an
    MBR antagonist. In the forced swimming test in rats, AC-5216 (3-30 mg
    kg−1, p.o.) reduced the immobility time, and this effect was blocked by
    PK11195.
  4. AC-5216 had no myorelaxant effects, did not affect the memory
    or prolong hexobarbitone-induced sleep in mice, even at doses as high
    as 1000 mg kg−1, p.o. Although it did slightly prolong the
    ethanol-induced sleep time at 1000 mg kg−1, AC-5216 (1-100 mg kg−1,
    p.o.) produced no distinct change in the rat electroencephalogram.
  5. These results indicate that AC-5216 produces anti-anxiety
    and antidepressant-like effects that are mediated by MBR, but does not
    cause the side effects normally associated with conventional
    benzodiazepines.
    Hence, AC-5216 shows potential for the treatment
    of stress-related disorders including anxiety and depression. [emphasis
    added]

Benzodiazepines (BZDs) comprise a family of drugs that exert sedative,
anti-anxiety, muscle-relaxing, and anti-seizure properties. 
Examples are Ativan, Xanax, Klonopin, Valium, and Librium.  They
were developed in response to the toxicity of older sedatives, such as
barbiturates.  Barbiturates and similar drugs are dangerous in
overdose.  BZDs are not very dangerous in overdoses
situations. 

When BZDs were first introduced, they were prescribed, by some
practitioners, with little regard for any potential danger.  They
were thought to be entirely safe.  Unfortunately, quite a few
persons developed physical and/or psychological dependence upon the
BZDs.  That is what this is all about: doctors and patients really
really want an effective anti-anxiety drug that does not have
any potential for abuse or dependence.  If it does not cause any
sedation or cognitive impairment, that would be a nice bonus.

Most drugs that enter the drug development pipeline never make it to
the pharmacy shelf.  Quite a few never even make it to human
trials.  So it is significant that emapunil now has been given to
at least some humans.  It doesn’t mean that it will even make it
to a store near you, but it is a good sign.

The abstract of the Science article follows (full text is not openly
available)…

href="http://www.sciencemag.org/cgi/content/abstract/sci;325/5939/490">Translocator
Protein (18 kD) as Target for Anxiolytics Without Benzodiazepine-Like
Side Effects

Science 24 July 2009: Vol. 325. no. 5939, pp. 490 – 493

Most antianxiety drugs (anxiolytics) work by modulating
neurotransmitters in the brain. Benzodiazepines are fast and effective
anxiolytic drugs; however, their long-term use is limited by the
development of tolerance and withdrawal symptoms. Ligands of the
translocator protein [18 kilodaltons (kD)] may promote the synthesis of
endogenous neurosteroids, which also exert anxiolytic effects in animal
models. Here, we found that the translocator protein (18 kD) ligand
XBD173 enhanced {gamma}-aminobutyric acid-mediated neurotransmission
and counteracted induced panic attacks in rodents in the absence of
sedation and tolerance development. XBD173 also exerted antipanic
activity in humans and, in contrast to benzodiazepines, did not cause
sedation or withdrawal symptoms. Thus, translocator protein (18 kD)
ligands are promising candidates for fast-acting anxiolytic drugs with
less severe side effects than benzodiazepines.

The text includes mention of the human trial:

…Out of 85 subjects, 71 healthy volunteers were
randomized to treatment for seven consecutive days with placebo, 10,
30, or 90 mg/day XBD173 or 2 mg/day alprazolam before undergoing a
second CCK-4 challenge. 70 subjects completed the study…

…One way ANCOVA revealed a significant difference from placebo in
attenuating CCK-4 induced anxiety following both alprazolam and the
highest dose of XBD173 (Fig. 3). The number of side effects reported
with XBD173 was comparable to the incidence in the placebo group. In
contrast, a much higher incidence was reported by the alprazolam
treated group, in particular dizziness and somnolence…

…While 57% of the subjects treated with alprazolam complained of
withdrawal symptoms such as sleep disturbances or restlessness, these
were almost absent in the XBD173 treated groups (table S3B). No serious
adverse event occurred during the entire study and there was no need
for treatment of withdrawal symptoms. Thus, this placebo controlled
parallel group study indicates both anxiolytic properties and clearly
less side effects compared to benzodiazepines for XBD173 also in
humans…

To clarify: CCK-4 is a molecule that is use in experiments to induce
panic attacks.  Alprazolam
is the generic name for Xanax.  A few points deserve
mention.  For one, 2mg/day of alprazolam is a medium dose. 
Most people would not start at 2mg/day.  Thus, the high incidence
of adverse effects that was seen in the alprazolam group does not
necessarily reflect what would be seen in routine clinical
practice.  Second, the absence of signs of dependency in the
XBD173 group does not mean that there is no risk of abuse of dependence
with XBD173.  The history of medicine is punctuated with high
hopes for an absence of such risks, followed by nasty surprises. 
(see the href="http://www3.interscience.wiley.com/journal/118582212/abstract">Stadol
story
for an example).  Third, the absence of the adverse effects that
we worry about ahead of time, does not imply an overall absence of
adverse effects. 

The Science paper reports on a small, short-term, unreplicated
study.  There is absolutely no way to know at this point whether
there is a meaningful potential for adverse effects in a larger
population, over a longer time period.  There also is no way to
know if the drug really works. 

If it, or a related molecule, makes it to the marketplace, it will be
interesting to see if if works in persons who have a history of BZD
tolerance.  Another nonaddicting anxiolytic, buspirone (BuSpar),
does not work very well for persons who have already taken BZDs. 
Something about exposure to BZDs makes a subsequent trial with BuSpar
less likely to work.  But unlike XBD173, BuSpar does not have
antipanic effects; it only works for generalized anxiety.  So the
BuSpar experience might not indicate anything about what will happen
with XBD173.

Note: after I write posts like this one, I always get comments, asking
where the drug can be gotten, or when it will be available.  The
answers are: you can’t get it now, and I have no idea when, or if, it
will be available.  I can, however, tell you that it will be too
expensive. 

Comments

  1. #1 Robert
    January 11, 2010

    How does one define non-addictive? Some type of physiological dependence on a substance is measured how exactly?

  2. #2 Michael
    January 11, 2010

    Interesting topic.

    I suffered from severe panic attacks which presented themselves mostly in a feeling of not getting enough air – suffocating – and a feeling of a constricted chest – angina – which of course made me panic, or rather – feel like I was about to die.

    I’ve been taking venlafaxine, and haven’t suffered from anything similar ever since.

    The psychiatrist/neurologist I was consulting told me it was entirely non-addictive. I have some knowledge of various neurosciences, and have read various papers on venlafaxine as well as reports of people who have taken it and tried to stop.

    The fact that the post-synaptic neurons will adapt to the increased presence of serotonine/noradrenaline in the synaptic cleft by becoming less sensitive to them is one aspect that makes me think “non-addictive” is not really correct.

    Once you stop taking it, or even miss your dose by as few as 4-8 hours, you (that is, many people, including me) begin experiencing ‘electroshock-like sensations’ in the brain – in my case it’s like having dozed-off and being suddenly startled, but it occurs whenever I shift my attention or shift from a non-attentive to an attentive state. With that comes irritability, a feeling of unease and generally being unwell. It’s really unpleasant.

    I realize this is why most prescribing physicians recommend tapering the dose. But all of this makes me think that simply because animals in trials with free access do not increase their dose of venlafaxine, it’s not rational to call it “non-addictive”, seeing as attempts at discontinuation have severe negative consequences, and seeing as the adaptation of synapses to the increased presence of serotonine/noradrenalin leads to a relative lack of same neurotransmitters upon discontinuation.

  3. #3 Will
    January 12, 2010

    I’d like to see a comparison with Rolipram.

  4. #4 Kristy
    January 12, 2010

    BuSpar actually *gave* me panic attacks whenever I took it, bizarrely. Xanax, even 1.25 mg cut in half, makes me terribly tired. Nice to see that there may be another option available at some point.

  5. #5 Ian
    July 10, 2010

    I contacted a researcher at the Max Plank institute about this drug and was told that the patent is held by a Japanese pharma company and they do not have any plans to develop this drug further (much to the frustration of the researchers).

    Here’s hoping a related molecule makes it to trials sometime in the future

  6. #6 Cliff
    December 6, 2010

    Does anyone know if the chemical in Emapunil is in any food? I saw that it was a naturally occurring molecule.

    Thanks

  7. #7 hortalored
    April 16, 2011

    DOĞAL YAŞAMIN SIRRI bitkisel organik sarayı ürünü Complex 41 solüsyon ve Bitkisel Şampuan ile Saç problemine yardımcı , saçlarınızın tekrar eski güzelligine kavuşmasında lider, ayrıca düzenli kullanım sonucunda dökülmeyi engellemeye gözle görülür yardımcı oldugu , saçların çıkmasını ve hızlı bir şekilde tekrar uzamayı hızlandırmaya yardımcı oldığunu göreceksiniz