Asthma solution -
between two opposites that
all the hoopla about molecular medicine and new health discoveries,
how much progress has been made
in treating asthma? Not too long ago, the official asthma solution
would fit in a short sentence: "You just have to learn to relax".
Then pharmaceutical companies learned how to, more or less
efficiently, suppress asthma symptoms with drugs.
On the opposite
end, environmental medicine was trying, often successfully, to
find, address and neutralize by far the most significant causative
factors of asthma - body's environmental interactions, including
those diet related.
Pharmaceutical industry is investing heavily
in bio-molecular research, but the main goal is unchanged: creating
pharmaceutical agent that will interrupt biological mechanism
producing symptom of illness, without bothering to find and address
its root cause.
One example is the ongoing research at
Yale University, New Heaven, Connecticut, University of California,
San Francisco, and elsewhere. Its subject is cellular cation channel
TRPA1, belonging to TRP anciryn (or TRPA)
subfamily of the TRP (Transient Receptor Potential) cation channel family, making for about 19% of all
cellular ion channels.
While the TRP family in general - found to
play important role in about everything that we feel, from pain to
the five senses - and TRPA subfamily in particular, are actively
investigated worldwide, this particular research is a part of Hydra
Biosciences' venture into "numerous drug discovery opportunities"
based on interfering with TRP channels functions. Investigating the
possibility to medicate asthma in this manner is only a small part
of the project; the main goal is to take a piece of $20 billion
world market for pain medications.
The TRPA1 ion channel - which is a
single mammalian member of TRPA subfamily - as
the experiments on rodents show, is
among major factors
in the mechanism triggering asthma symptoms.
Various irritants, including cold
temperature, natural and man-made chemical compounds, can activate
TRPA1-regulated ion channels, exciting nerve cells - which may
contribute to involuntary muscle constrictions in the airways and/or
cause neurogenic inflammation -
and/or stimulating pro-inflammatory state within tissue cells
and in their surroundings.
In any instance, according to the Yale
research, mice with the gene initiating production of the TRPA1
ion channels' protein removed or disabled had "greatly diminished inflammation, airway
mucus and bronchoconstriction".
Since manipulating genes at present is not a
viable option for treating humans, the researchers used a
drug, HC-030031, blocking TRPA1 production, and found that it
produces similar beneficial effects (the drug was already known to
inhibit TRPA1-related sense of pain; another TRPA1 channel blocker
drug is AP-18).
So, seems as if everything is gliding smoothly toward this new
type of asthma drug, which would ease asthma symptoms by reducing
TRPA1-mediated response to irritants. Drugs based on blocking
activity of ion channels are not exactly a news: so called
channel blockers, for treating hypertension and angina, or
blockers for treating pain are rather common. In fact, as much as
17% of global pharmaceutical sales goes to the drugs affecting ion
This new class of drugs has a few things in common: they are
considerably more expensive, not necessarily more efficient, but
often with more serious side effects than older drugs.
Leaving its price and efficiency aside for now, how safe this new
type of symptom-suppressing asthma drug can be expected to be?
For one, the exact mechanism of action of this type of drug is
not known. It is stated that HC-030031
"antagonizes formalin-evoked calcium influx" into the cell (formalin
test is a standard in pain-related research), because some studies (Zurborg
et al, 2007, Wang et al, 2008) indicated that TRPA1 ion channels are
activated by calcium binding to the proteins at the channel ending,
resulting in subsequent influx of calcium into the cell. But an
alternative mechanism of their activation is by foreign molecules
capable of binding to cysteine residues at the channel ending -
which is how most of substances that activate TRPA1 ion channels
seems to be detected (Macpherson et al, 2007).
However, some "structurally unrelated compounds" - i.e. not able
to chemically bind to cysteine - have also been found capable of
activating TRPA1 channels. The channels can also be activated by
(Hu et al, 2009) and barium (Wang et al, 2008), as well as by a
variety of primary endogenous activators - compounds released by
cells and tissues as a response to mechanical injury or
inflammatory/oxidative stress or damage.
The two obvious conclusions are:
our knowledge of the TRPA1 ion
channels function is partial at best, and
their function is very complex,
making their inhibition with drugs both unpredictable
side-effect-wise and risky.
This, of course, is rather common in the realm of
prescription drugs, and that is a good part of the reason why so
many users suffer serious adverse health effects each and every day.
The other day, I glimpsed at the news that a novel drug for MS
(multiple sclerosis), natalizumab (Tysabri), has been found
to have unplanned effect of helping the potentially deadly JC virus
to spread from the kidneys - where it lies dormant in about 90% of
the population - into the bloodstream (Koralnik et al, NEJM,
September 2009). Despite establishing that the virus in the blood and
urine of tested patients is showing all signs of being active - thus
capable of spreading to the brain and causing progressive multifocal leukoencephalopathy (PML), a destructive brain disease - neither the
study authors, nor government's agency (FDA) see the need to limit
or stop marketing of this drug.
But that is only a drop in the ocean. It is only their enormous
power and influence that allows pharmaceutical companies to claim
arrogantly that what ion channel blocking drugs do is
"aberrant ion channel activity".
Even assuming that their function is aberrant - and that is
likely a gross oversimplification - no one, including pharmaceutical
companies, knows what would be the correct mode of their function in
the complexity of the body. They are certainly aware of that, and
that predicting many possible consequences of interfering with ion
channel functions is still out of our grasp.
Just like every tiny bit of our bodies, the TRPA1 ion channels
exist for a reason. They are important part of the sensory/reaction
mechanism through which the body protects itself from peripheral
threats and damage. No one knows what other processes they might
be supporting. Inhibiting their function is very likely to
vulnerabilities in body's protective mechanisms.
Moreover, how obstructing the channels could affect cellular processes is
anyone's guess. It is all but certain that TRPA1 channels play role
not only in sensing irritation and damage, but also in cellular
intra- and inter communication. Obstructing their function could
alter a cascade of reactions negatively affecting cellular
homeostasis, resulting in adverse health effects, either short-term
or long-term, or both.
Nevertheless, if premarketing trials shows that this
new drug does have sufficient efficacy, without scores of patients falling
seriously ill - or dropping dead - within relatively short trial
period, the drug will hit the market.
Notorious indirect side effect of prescription drugs is that they
leave the underlying cause unaddressed.
Airway hypersensitivity is
very often aggravated by excessive oxidative damage due to
insufficient level of
antioxidants, and/or inefficient, overburdened
detox system. A recent study on
zebra fish - which has genes similar to humans - hit a surprise
discovery that it is hydrogen peroxide, one of the cell-produced
reactive oxygen species, that communicates to the immune cells the call
for help (Mitchison et al, 2009).
It is very likely that oxidative
damage to the lung cells increases concentration of immune cells in the
airways through a similar mechanism.
Instead of lowering concentration of symptom-causing immune cells
in the lungs by shutting down damage-sensing TRPA1 ion channels - an
important part of body's protective mechanism - isn't it better to
give to the body what it needs for protection from oxidative damage, as well as minimize its toxic
Asthma is a complex disease, with a great variety of possible
causative factors, often working in concert - food, chemical and
mold sensitivities, nutritional deficiencies and imbalances,
leaky gut, low gastric acid, poor,
unbalanced diet, faulty tryptophan
metabolism, and others. These factors need to be addressed not only
because of asthma, but also because
they are likely to cause
seemingly unrelated health problems.
Obstructing TRPA1 ion channels won't do any of that. So if you
are lucky enough that the drug works for you in suppressing asthma
symptoms, chances are, sooner rather than later some other symptom
will surface. And that is another "specialty" of the symptom
treating medicine: much to frustration of its practitioners, the
illness often seems as if morphing from one form into another, never
leaving the body. But, never mind - they have plenty of pills on the
By the way, TRPA1 ion channels are also inactivated by
(Wang et al, 2007). It is known that magnesium injection can stop an
asthma attack. It was thought to be the result of magnesium relaxing
the airway muscles, but there could be more to it. So, when do we
see a study on magnesium as a possible remedy for asthma?
never, maybe not even then. It is pity, but there's no money in