1968-2010: Mast Cell Stabilizers for asthma

Intal Spinhaler used by asthmatics in the 1970s, 80s and 90s

In the early 1980s, my doctor introduced me to the Intal Spinhaler that crushed a capsule with a medicine called disodium cromoglycate or chromolyn.  It was a white powder that was proven to improve lung function by decreasing inflammation. 

It was also proven to improve exercise related asthma. 
Each month you'll pick up a small white and yellow box from your pharmacist that contained a bunch of small capsules called Spincaps wrapped in tinfoil.  You unwrapped one and set it aside. 

Then you the inhaler and held it so the mouthpiece was facing down.  You unscrewed the cap and
placed  it onto a cup on the propeller, screwed the body back on the mouthpiece, and slide the outer sleeve (the blue part in the picture) down as far as it would go and then back up again.  This pierces the capsule and makes the spinhaler ready for use. (1)

You exhaled as much air as you could (just like using any inhaler), placed your mouth over the mouthpiece, and inhaled.  As you inhaled, the powder would enter your airway, with a good portion going to your air passages.  You could feel the powder as impacted in your upper airways, even taste it when it landed on your tongue. This is how you knew you did it right, I suppose

This was the first mass produced dry powder inhaler that hit the market.  It was a great medicine, and when used with an inhaled corticosteroid it worked great to prevent asthma.

Mast cells are white blood cells that are randomly scattered around your respiratory tract. They are granulocytes, meaning they contain tiny grains. When told to do so, they release their contents, which contain histamine, leukotrienes, cytokines, and chemokines. These are tiny proteins that are responsible for airway inflammation.

Mast cell stabilizers like cromolyn prevent mast cells from releasing their contents, thereby preventing them from causing inflammation. The idea was that this would result in better asthma control.

There are a variety of environmental triggers that might trigger mast cells. One is when you inhale allergens, such as dust mites, pollen, animal dander, cockroach urine, mold spores, and certain foods.  Another is rapidly breathing in air that is not properly warmed and humidified, such as what might occur while you are exercising. This irritates cells lining airways, causing mast cells to release their contents.

So, cromolyn was prescribed for allergy and exercise induced asthma. Back then, these were essentially considered the hallmarks of all or most cases of asthma.

When I was a kid I had what my doctors referred to as high risk asthma. I was allergic to pretty much everything outdoors, and had exercise induced asthma (EIA).  Unless I was in an allergy proof bubble, my asthma was usually acting up.  By the time I entered the 9th grade in September of 1984, I pretty much stopped going to gym class per my doctor's instructions.

By January of 1985, I had made so many trips to the emergency room I was admitted to NJH/NAC in Denver.  Once they managed to get my asthma under control, they did some pulmonary function testing on me to see what medicine might help me with my EIA.

In one test I took no medicine and ran on the treadmill.  My lung function dropped significantly.  A week later I did another PFT, this time taking two puffs of Alupent before I ran on the treadmill.  My lung function once again dropped significantly, indicating Alupent had no effect. 

A week later I used my Intal Spinhaler before exercise, and while my lung function declined it wasn't as steep of a decline, indicating that disodium cromoglycate prevented EIA, at least in me. (You can see my PFT tests here).

Intal Inhaler

I was using this inhaler four times a day (which was a pain in the butt), so there was no need for me to use it prior to every time I exercised.  I think the thought was that it would act as an asthma controller medicine to be used either in conjunction with or (ideally) as a stand alone medicine.

In a way, it worked the same way inhaled steroids worked, yet apparently not as well.  Prior to being at NJH/NAC my doctors had me using my Intal every day all the time, and only using my inhaled steroids as needed.  Yet by the time I left NJH/NAC in July of 1985, I was using both medicines four times every day, along with a ton of other medicines as you can see here.  Yes, this was a lot of medicine.

Yet the Intal Spinhaler was a good medicine for asthmatics since it was introduced to the market in 1968.  The medicine disodium cromoglycate was isolated by Roger Altounyan who had bad asthma himself and decided to test a variety of substances that were already proven to benefit asthma. He was working at Bengers Research Laboratories.  (2)

Cromolyn Nebulizer Solution

Khella was used by local natives living in Eastern Mediterranean countries for quite a few years to treat asthma with some success.  They made various "concoctions" from the seeds of the plant Amni Vasnaga, from which the substance Khellin was extracted in 1879.  (3)

Various studies in the 1940s and 50s showed the medicine relaxed smooth muscles throughout the body, including the muscles surrounding air passages in the lungs.  Yet the bronchodilating effect was less than epinephrine.  The various studies showed the medicine accumulated in your system if used regularly, and was proven effective for both asthma and other lung diseases. (4)

In 1953 The American Journal of Physical Medicine published the results of a study that showed inhaling aerosols of  7mg of Khellin improved lung function.  Perhaps it was studies like this that inspired Altounyan to study this extract.  (5)

Amps of Cromolyn solution

By experiments in the lab Altounyan produced a safer version of khellin called disodium chromoglycate.  While his goal was to improve his own asthma, what he ended up with was a new product.  It was marketed by Fisons and sold as the Intal Spincaps and Intal Spinhaler.  It became yet another option for many asthmatics worldwide suffering from asthma and allergies. 

Along with being the first dry powder inhaler, it was also the first mast cell stabilizer.

A problem with the spinhaler was that it couldn't be used during an asthma attack, and the dry powder entered your airway at such a force it was known to cause reflex bronchospasm, a fit of coughing and, thus, cause some asthma attacks.  I never experienced this problem however.  It was a nice option for me until modern inhaled steroids made it unnecessary.

Tilade inhaler

Nedicromil Sodium was approved by the FDA in 1992 as an alternative to Intal, and was marketed as the Tilade inhaler. (6) Studies showed it was equally effective in treating inflammation and reducing allergy and asthma symptoms as Intal.  I never used Tilade, and I have little clinical experience educating it to patients either.

By 1995, Cromolyn was available as a solution to be nebulized, and this was ultimately a good option for pediatricians to prescribe for kids with asthma.  I have no recollection of ever giving this via aerosol to an adult, and rarely gave it to kids either for that matter.  As of 2010, I believe we were no longer carrying it in our stock. 

The Intal Spinhaler was ultimately phased out in the U.S. and Europe in favor of an inhaler, and the inhaler was ultimately phased out on December 31, 2010.  By a simple Google search, I see it's can still be purchased over the Internet, and may act as a viable alternative to top-line asthma medicines.

Tilade was phased out on June 14, 2010.  Altounyan's product was a great option for many asthmatics for many years, and for that we owe him thanks.  Perhaps some form of this product will make a comeback someday and replace the need for inhaled corticosteroids. 

References: 

1. "Intal Spincaps Powder for Inhalation, Sodium cromoglycate, Consumer Medicine Information, " package insert for the Intal Spinhaler and Intal Spincaps, 2005
2. Jackson, Mark, "Asthma: A biography," 2009, New York, page 187
3.  Kennedy, M.C.S, J.P.P. Stock, "The Bronchodilator Action of Khellin," Thorax, 1952, 7, 43, pages 43-65
4. Kennedy, ibid, page 43
5. Braun, K, E. Eilender, "Khellin Aerosol in Bronchial Asthma," American Journal of Physical Medicine, Dec., 1953, Vol. 32, Issue 6,
6. "Tilade approved by FDA; Fisons Announces Co-Promotion Agreement with Rhone-Poulenc Rorer," Press Release, TheFreeLibrary.com, http://www.thefreelibrary.com/TILADE+APPROVED+BY+FDA%3B+FISONS+ANNOUNCES+CO-PROMOTION+AGREEMENT+WITH...-a013101159

1851-1913: The history of asthma sputum

Ernst Victor von Leyden (1832-1910 discovered
crystals in asthmatic sputum and suspected these
to be the cause of asthma. During his era, he was
the closest supporter of Dr. Robert Bree's
bronchitic theory of asthma. (9, pages 14-15)
He believed these crystals somehow irritated the
"vagus in the mucous membrane of the bronchials,
and hereby caused by reflex action a spasm
of the muscles of the small bronchial tubes."
(10, page 8)

Most people find sputum disgusting, and so will have nothing to do with it. But as far back as 400 B.C., the medical significance of it was observed by ancient Greek physicians, and probably even earlier than that.
If you mention it at the dinner table your mother might smack your hand. But for the sake of gaining a complete grasp on the history of asthma and respiratory disease, we must delve into the topic of sputum.  Sorry, but we must.

It must have been observed at an early date in history that people with breathing issues produce sputum, sometimes consisting of a putrid smell, often consisting of many varied colors such as red, yellow, brown and white.

Yet rather than being petrified by the grossness of the substance, Greek philosophers became fascinated by it. They even gave it its own classification as one of the four humors that, along with determining one's personality, also determined whether was healthy or sick.

Prior to the philosophical medicine of the ancient Greeks, other ancient societies, and the primitive clans and families that roamed the lands before them, believed sputum was the production of some evil spirit, demon or god. When a person expectorated the substance, they were, in essence, expectorating an evil substance that caused the symptoms they were suffering from.

From the ancient world to the scientific revolution there were few changes in the way physicians viewed diseases and treated their patients.  In 1799 Dr. Robert Bree speculated that sputum contained a poison that it was trying to get out of the body, and asthma was the result.  This theory wasn't much different than any idea Hippocrates might have postulated.

Since the sputum preceded the asthmatic fit, Bree essentially speculated that asthma was essentially bronchitis, and thus created the bronchitic theory of asthma.  Others, without much more evidence, speculated sputum was the effect of asthma rather than the cause.

Such speculation gradually tapered off, but never really came to an end, during the scientific revolution, and mainly due to the inventions of the microscope, which allowed physicians to see that the human body was made up of substances too small to be seen by the unassisted eye, and the stethoscope, which allowed physicians to hear changes that occurred inside the chest and to diagnose diseases with accuracy prior to autopsy.

The microscope allowed physicians to learn that air passages were surrounded by smooth muscle and that it was capable of spasming when stimulated.  The stethoscope allowed them to hear when sputum accumulated in the chest, and learn that it was the effect and not the cause of asthma.

So, pretty much, prior to the 1850s asthma was basically considered to be a disease of excess sputum, mainly because this was all physicians could observe with the unaided eye and ear.

Yet by the 1850s, it was looking pretty clear that asthma was also a disease associated with spasms of the air passages, particularly by the wheezes heard by air flowing through narrowed air passages, and rhonchi heard as air flowed through sputum lined air passages.  (1, pages 592-595)

In 1851, Dr. Beau, along with his assistant Cozart, observed that fits of asthma usually ended with a wad of sputum being coughed up. Beau used this observation as evidence to support his theory that asthma was a disease of chronic catarrh, and that asthma was caused by increased sputum in the air passages.  (3, page 31)

When this sputum dried out mucus plugs formed that were capable of blocking the air passages, thus resulting in dyspnea and other symptoms of asthma, including the "sonorous and sibilant rhonchi -- their 'rales vibrants' heard upon auscultation with a stethoscope."  (3, page 31)

The fit, therefore, was resolved when mucus plugs were broken up with a fit of coughing.  (3, page 31)

Then, in 1878, at a time when most physicians had accepted the nervous and spasmotic theories,  J.B. Berkart used Beau's research as evidence of the bronchitic theory of asthma.

Berkart said:

With the displacement of the mucous plug into the larger bronchus, or on its expulsion by means of a fit of coughing, the dyspnea ceases, and with it also the rales disappear.  This form of bronchitis is, in their (Beau and Crozant's) opinion, due partly to an idiosyncrasy of the patient, partly to exciting causes, which greatly vary in different individuals."

Tiny crystals were first observed in sputum in 1851 by Jean-Martin Charcot, but it wasn't until 1872 that these crystals were linked to asthma by Ernst Victor von Leyden. So history has given credit for this discovery to both men by calling the crystals Charcot-Leyden crystals.

Leyden, whose asthma theories were similar to Dr. Bree's bronchitic theory, believed Charcot-Leyden crystals caused asthma by irritating...

...the peripheral extremities of the vagus nerve, and produce reflex spasm of the bronchial muscle."  

The asthma attack, as Bree and Beau observed, ended when a wad of sputum was coughed up during a fit of coughing. (4, page 14-15

However, it was the discovery of these Charcot-Leyden crystals that would ultimately put an end to the bronchitis theory of asthma.  This was noted by Dr. John Charles Thorowgood in 1878.  He said that these crystals were found in sputum obtained from patients with "ordinary catarrh and croupus bronchitis."  (4, page 15)

Thorowgood said:

The asthmatic patient while in a fit presents abundance of symptoms distressing enough to endure or to witness; and yet, when things seem to be at their worse, and the patient well-nigh at his last gasp, a remission comes on, the spasm yields, air enters the lungs, and the attack subsides, coincidentally often with access of cough and mucous expectoration." (4, page 16)(9, page 1,2)

In 1879, bacteriologist Paul Erlich discovered the eosinophil, and it was soon discovered that elevated levels of eosinophils (eosinophilia) was commonly found in asthmatics. (5)

In 1882 Heinrich Crushmann observed other spirals in asthma sputum and believed they were associated with causing asthma. He believed since Leyden's crystals didn't cause asthma, perhaps his crystals did. (5)

Later Curshmann's crystals were determined to be fragments of mucus plugs associated with asthma, and Leyden crystals were determined to be fragments of eosinophils. Eosinophils were later learned to be a type of white blood cell that, along with mast cells, are involved in the allergic reaction.

In 1911 Hermann Sahli described eosinophils in asthmatic sputum. Yet Sahli noted another author from 1891 who described eosinophils in the asthmatic blood, and he concluded that these must be pathological with asthma. Yet he also noted that neither the cause of the eosinophils nor their origin was known. (7)

Sahli could isolate the area where the sputum came from based on epithelial cells in it, yet he did not understand the mechanisms of its production as we do today. (7)

Dr. James Adams describes asthma sputum in 1913: (8)

"Asthmatic sputum varies. Often there is none till the end of the attack; then it is in the typical form of small, tough pellets expelled by laborious coughing. The attack may then cease, or it may go on till a more free and profuse expectoration occurs."

He also wrote:  (8)

"The sputum does not readily decompose, and is said to be wonderfully free from microbes; but this is not always so, as I have occasionally found it teeming with them."

The true purpose of sputum is to ball up microbes inside the lungs and haul them out, and in this way, the lungs stay sterile.  Surely asthma can be caused by inhaling a microbe, such as a bacteria, but it's also caused by asthma triggers (dust mites, smoke, fumes, chemicals, pollution, animal dander) that are non-infecting agents.

So this might explain why Adams most often found asthmatic sputum without an infecting agent, and sometimes "teeming with them."

Backing up a moment to 1906, Australian pediatrician Clemons van Pirquet coined the term allergy when he observed that some of his patients were hypersensitive to substances that did not bother other people (what we now refer to as allergens, or asthma triggers).  This was the first time asthma was linked with allergies.

By 1910 Histamine was discovered and found to be a major component in the allergic response.  So some went on to speculate that finding a way to block histamine would cure both allergies and asthma.
In 1937, the first antihistamine was synthesized in a lab, and in 1946 antihistamines hit the market. Within a decade they were among the most commonly prescribed medicines.

Yet as time went by, it was learned that there was more to asthma and allergies than just histamine.  It was learned that asthmatic and allergic immune systems respond irrationally to allergens and asthma triggers by increasing production of eosinophils and this spearheads inflammation of the bronchial muscles.

Another weapon of the immune system is mast cells that line the respiratory tract and eyes, and these were discovered in 1953.  .

In 1967 Immunoglobulin E antibodies (IgE) were discovered.  It was later learned IgE has a significant role in the asthmatic and the allergic response.  The first time asthmatics are exposed to asthma triggers (allergens), say dust mites, their immune systems develop dust mite IgE antibodies that attach to mast cells that line the epithelial layer of the skin or respiratory tract.

The second time that person is exposed to that allergen (dust mites in this case), a mast cell that has a dust mite IgE antibody attached to it explodes and releases its contents:  the mediators of inflammation.  A mediator of inflammation called histamine was discovered in 1910, and others called cytokines and leukotrienes were discovered in the 1970s.

These mediators, when released into the blood stream, cause inflammation of the respiratory tract, thus causing the allergic and asthmatic responses.

In the allergic person, they can also cause inflammation of the upper respiratory tract, which includes the back of the throat and nose.  The offending substance (dust in our case) is recognized by the immune system, trapped in the mucus layer, absorbed by the mucus, balled up by the mucus, and sent on it's way up the respiratory track to be coughed up.

So this would explain what Dr. Bree, Beau, and Berkart observed. While hacking up a wad of sputum may have been related to the fit of asthma, it was not the cause, and had nothing to do with the cure.

Later it was learned that asthmatic lungs tended to produce an abnormal number of goblet cells, this results in an abnormal increase in mucus production during an asthma attack.  While some of this sputum may be coughed up, some becomes trapped in obstructed air passages, dries out to form mucus plugs, and this further blocks the air passages, thus compounding the asthma response.

When the fit ends, when the air passages relax and dilate, which may be a result of time or medications, the asthmatic will probably expectorate this sputum, which will usually be, if no bacteria or virus is balled up within it, white and sterile.  It will also have IgE and eosinophils in it, hence your Charcot-Leyden and Curshmann crystals.

So it's easy to understand how this production of sputum at the end of an attack could easily be misinterpreted as the cause, rather than the effect, of asthma.

References:

1. Lotval, J., "Contractility of Lungs and air tubes: experiments performed in 1840 by Charles J.B. Williams, European Respiratory Journal, 1994, (7) pages 592-595
2. Bree, Robert, "A Practical Inquiry into Disordered Respiration Distinguishing the Species of Convulsive Asthma, their Causes and Indication for a Cure," 4th ed, 1810, London, page pages 117-118
3. Berkart, J.B., "On Asthma: Its Pathology and Treatment," 1878
4. Thorowgood, John C., "Asthma and Chronic Bronchitis: A New Edition of Notes on Asthma and Bronchial Asthma," 1894, London, Bailliere, Tyndall, & Cox
5. Lipkowitz, Myron, Tova Navarra, "Encyclopedia of Allergies," 2001
6. Brenner, Barry E, "Emergency Medicine, 1998, page 10
7. Sahli, Hermann, "A treatise on diagnostic methods of examination," 1911
8. Adams, James, Asthma and it's Radical Treatment, 1913
9. Thorowgood, John C., "Notes on Asthma," 1878, 3rd edition, London, J & A Churchill
10. Shmiegelow, Ernst, "Asthma, considered specially in relation to nasal disease," 1890, London, H.K. Lewis

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