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BLOG: July 2009

Asthma solution -
between two opposites that don't attrac

With 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 calcium channel blockers, for treating hypertension and angina, or sodium channel blockers for treating pain are rather common. In fact, as much as 17% of global pharmaceutical sales goes to the drugs affecting ion channel activity.

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 zinc (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

correcting "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

create 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 immune and 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 exposures?

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 other,
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 shelf...

By the way, TRPA1 ion channels are also inactivated by magnesium (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?

Maybe never, maybe not even then. It is pity, but there's no money in magnesium.



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