1800-1900: Debunking ancient asthma theories

Today I continue to describe my quest (that we started here) through the 19th century learning as much as I can about asthma.  My guide is a gruffy gentleman with a scruffy beard, offers me a cup of Joe, which is something more up my alley than the cigarette and shot of whisky he offered me earlier.

I lean back in my cozy little chair and put my feet on the ledge by the glass, something my guide has already done.  The time machine already took me back to 400 B.C and where I watched  Hippocrates and his fellow physicians study respiratory disorders and work on defining asthma as a medical term.

We're presently in the year 1816 on a hot and humid day in France.  My guide describes the man I'm watching as Rene Laennec.  The physician is leaning forwardwith his ear pressed on one end of rolled up bundle of papers, with the other end of the tube on the chest of a large, dusky, perspiring lady who's hunched up on the doctor's bed panting for air.

"The object he's using is clearly the first stethoscope," my guide says, "yet on this day he humbly refers to it  as le cylindre.  It will be a few years before Laennec is pressured by his peers into calling his object the stethoscope.  Regardless, this would turn out to be a revolutionary device responsible for the evolution of a term called asthma throughout the rest of the 19th century.  Laennec perhaps had no clue his invention would set off a hunt to redefine asthma, or at least provide the tool for such a task."

My guide continues, as Laennec continues to listen to the ladies lungs using his object.  He sets the end opposite his ear at various points on the ladies chest, both front and back.  The lady sits patiently while she continues to breath heavily.  "Over the ensuing years, which will go by fast in the comfy confines of our time machine, we will see a growing number of physicians using this tool to help them better diagnose and treat their patients.  And it's mainly this tool that sparks a hunt by asthma physicians to redefine asthma so it represents the disease as you know it."  He points at me.  "Yet how this evolution occurs is the purpose of our journey through time."   

Laennec's stethoscope

He says, "Through our travels thus far we've learned the Ancient Greeks used the term asthma to describe any condition that causes dyspnea, or shortness of breath.  So dyspnea could be caused by cardiac asthma (what you call heart failure), or humoral asthma (what you call chronic bronchitis), or kidney asthma (what you call kidney failure).

"William Pepper and Louis Star, in their 1885 book "'A System of Practical Medicine' explain that prior to the 19th century all dyspnea and all that wheezes were designated as asthma."

He continues, "John Floyer was the first to separate asthma from dyspnea, yet it was Rene Laennec who was the first to think of asthma as a term abused by the medical community.  He came up with the idea that many cases of asthma are actually heart disease, chronic bronchitis or kidney disease, not asthma.  So he spent a lot of time studying the signs and symptoms of his patients and comparing them with what he found on autopsy.



He reaches for a cigar, places it between his lips, and pretends to puff on it.  He hands you a book with that title, and opens it for you to page 184, where the following is highlighted using a 20th century marker:

 "These guys wrote about the term as covering such an 'extensive range of territory, it was found necessary to subdivide the disease into a number of varieties, each author classifying them according to his conception of the cause, seat, and nature of the trouble. Some of these -- e.g.a. dispepticum (upset stomach), still find their place in medical literature, but the vast majority of them, having ceased to be of any practical significance, have been discarded, and are now only interesting as examples of the crude and fanciful notions which prevailed in an age during which science rather retrograde than advanced." (1)

He took back that book and handed me one I often refer to at Google Books back home: an 1878  book by J.B. Berkart titled "On Asthma: It's pathology and treatment."   I set the book on my lap, and he says, "Open it to page twelve."

Here, on page 12, the following is highlighted:

"ALL early historical traces of the affection at present called asthma are lost. Although the disease is said to be mentioned in the Bible, and described by Hippocrates, Areteaus, Galen, and Celsus, there is not the least evidence that those remarks apply to the asthma of to-day. For in the former systems of medicine, all cases presenting the same conspicuous symptoms were, regardless of their anatomical differences, considered as of a kindred nature, and grouped into classes according to imaginary types. (2)

Laennec is now standing before the lady after his long assessment of the ladies chest  It appears that he even has a short smirk of joy on his face, knowing, perhaps, he is on to something with his invention here.  "I know these highlighted phrases are almost trivial, although I find it interesting because these physicians, in this era, were privy to the idea that they were taking part in the rapid evolution of the disease they were studying -- asthma.

My guide continues, "In essence, Laennec's discovery sparks a leap through time.  Where 7,000 years of asthma suffering results in little progress in the way of asthma wisdom and treatment, the next 81 years -- part of which we are now observing -- provides for asthmatics more than all those 7,000 years combined. I think that Pepper and Star and Berkart were well aware that this was happening.

"And we learn that between 1816 and 1900 many different theories about what causes asthma are created, and every one of these theories has followers.  Each expert writes his own definition of asthma based on his beliefs about the disease, and his own remedies based on these beliefs."

He explains that this is all done in the process of fine tuning the definition of asthma.  Yet in the end, the two theories that win the day are:

1. Bronchospasm theory of asthma (a.k.a. spasmotic or convulsive)
2. Nervous theory of asthma (a.k.a. it's all in your head)

By the end of the 19th century the ground is set for an even bigger leap through time as far as asthmatics are concerned.  By 1899 adrenaline is isolated, and this sets off a wave of wisdom that greatly improves the lives of asthmatics. Yet for the time being (no pun intended), we find ourselves drifting from cozy doctor's offices in large Victorian homes to laboratories of some of the worlds greatest asthma experts. 

Continue the journey by clicking here.  

Click here for more asthma history.

References:

1. Pepper, William,  Louis Star, "A System of Practical Medicine," Volume 3, page 184
2. Berkart, J.B., "On Asthma: It's pathology and treatment," 1878, London,  Chapter II, "History of Asthma," page 12

Classic toddler asthma signs easily overlooked

Yes it's true that even your humble RT and lifelong asthmatic can over look the classic signs of asthma.  My 3 YO HM woke at 2:30 in the morning, was agitated, coughing, and was annoying her father.  He even yelled at her, because he thought she was simply caught in that flux between sleep and reality.

He finally set her back in bed and decided she'd eventually fall asleep.  He hopped into his own bed, and his wife said, "Did you give her her pulmicort before bed last night.  Sometimes she has asthma when she doesn't get it."

Bingo!  He could have slapped himself up alongside the head.  He carried the little girl to the living room, set her in the recliner, prepared a breathing treatment with pulmicort and ventolin, and gave it to her by blowby.  Within minutes her breathing was easy and she was sound asleep.  

He set her back in bed and not a peep was heard the rest of the night.  This was a perfect real life example of how even the most expert of asthma experts can overlook the classic signs of asthma.

 It's a also a quintessential example of how important it is that everyone responsible for a child know about the signs of asthma.  When one person misses the signs, perhaps the other will pick up on them.  

I suppose it's also a classic example of the importance of good teamwork.  Regardless, she is doing great today, that little asthma girl.  No longer will we be able to skip a dose of pulmicort.  

2012 Inhaled Corticosteroids on the market

Inhaled corticosteroids continue to be a top line option for treating asthma.  As of January 30, 2012, the following are options available to asthmatics:

• Aerobid
• Azmacort
• Qvar
• Flovent HFA
• Azmanex Twisthaler

According to the FDA.gov, any one of the above will work to control asthma.  An interesting thing to note is that the FDA mentioned that every new inhaled corticosteroid to hit the market since beclomethasone in 1960 was just a little stronger and a little safer than the one before it.  If this is true, Azmanex would be the best inhaled corticosteroid.  It's also available in the combination inhaler Dulera (a medicine similar to Advair and Symbicort).

Another neat thing to mention is that the HFA propellant appears to be finer than the CFC propellant, which means the inhaled corticosteroids may get deeper into the lungs to provide better distribution of the medicine.  This has been proven by some studies.  Some hardluck asthmatics have been experimenting taking a few puffs a day of Qvar to go along with their Advair, or Symbicort, or Dulera.

I believe at the present time there will soon be another inhaled steroid on the market, and I think there are already attempts being made to have it released in a combination inhaler with fluticasone (Flovent).  Fluticasone is presently combined with Salmeterol (Sevevent) in Advair.

1940-2012: The dry powdered inhaler (DPI) rewriting

For almost 8,000 years asthmatics inhaled medicine by smoking it.  This changed in the 1930s with the invention of the electric nebulizer and again in the 1950s with the invention of the metered dose inhaler (MDI).  A third option that has been slowly gaining momentum is the Dry Powder Inhaler (DPI). 

A DPI allows you to inhale the powdered version of a medicine, which comes in the form of a capsule or blister that is cracked open inside the inhaler.  There is no propellant, and instead the medicine is breath actuated.  This means the medicine enters your airway as you inhale.  

There are advantages to DPIs:

1. Since they are breath actuated no propellant is needed
2. Coordination is generally easy
3. They are easier to use than MDIs
4. Dose is easily measured

Of course there are also disadvantages:    

1. The patient must be able to generate enough flow
2. Each company markets its own device, which means there may be many to learn
3. You will have to place the capsule into the device prior to inhaling the medicine
4. The devicess tend to be expensive to manufacture and expensive to purchase

To learn about the history of DPIs we actually have to travel back to before the first MDIs hit the market in the 1950s.  In fact, according to Mark Sanders in his 2007 article, "Inhalation Therapy: an historic review," the first patent for a DPI was made in 1964 by Newton.  The medicine he used was potassium chlorate, a medicine Sanders notes was ultimately determined to be a lung irritant.

However, while Newton's device wasn't a commercial success, "He observed that the powder needed to be finely pulverized and that it had to be kept dry -- principles that still apply to dry powder inhalers today."  (1)

According to A.R. Clark in his 1995 article, "Medical Aerosol Inhalers: Past, Present, and Future, Aerosol Science and Technology , the first DPI was patented in 1939.  I would imagine he's referring to DPIs that resemble what we use today, as opposed to the Newton's device.  

Clark explained that the 1939 inhaler  was not used as an asthma inhaler, though, but to inhale "aluminum dust  for the chelation of inhaled silica.  It was intended for use by miners who suffered from silicosis induced by inhaling dust."  Yet the product never gained popularity and was never marketed.  (2)

By the 1940s pharmaceutical companies learned that systemic injection of asthma medicines like epinephrine and atropine caused significant side effects.  They were in an all out race to develop a device that allowed asthmatics to inhale medicine and, thus, generate an immediate effect with fewer side effects. 

In 1949 the Aerohaler was introduced as the first marketable DPI, and also the first rescue inhaler.    The medicine was Isoprenaline sulphate.  Yet it never gained popularity and was later overshadowed when the first MDIs hit the market in 1957 in the form of the Medihaler Epi and the Medihaler Iso.

For all practical purposes, it was ultimately realized DPIs don't work well with rescue medicine because when the medicine is needed many asthmatics have trouble generating enough flow to suck up the medicine.  While Ventolin is available overseas as a DPI, none are currently approved by the FDA for sale in the U.S.

When the CFC propellant (see lexicon) used in MDIs was determined to harm the environment in the 1990s, DPIs were determined to be a solid delivery device for asthma controller medications, and this is the main reason they have become a common site in asthmatic homes.

Aerolator with glass vial containing 3 small epi/ penicillin vials

So, without further adieu, here are your DPIs:

Aerohaler:  Released by Abbot laboratories in 1949 as the first marketed dry powdered inhaler (DPI).  The medicine was Norisodrine, isoprenaline sulphate.  It was the first rescue inhaler. It didn't really get much of a chance to gain the love of asthmatics mainly due to the invention of the metered dose inhaler (MDI) in 1957. Just imagine, if the MDI wasn't invented, asthmatics everywhere would probably have an aerohaler.

A.R. Clark, in a 1995 article for Aerosol Science and Technology, described this inhaler this way:

"The device consisted of 'sifter' cartridges containing the powdered dose out of the cartridge and a mouthpiece through which the aerosol was inhaled.  There was very little control over the delivered dose, other than patient symptoms titration, and there was no dispersion mechanism inside the device to aid aerosol generation." (2, page 382)

Each glass vile contained three smaller vials (sifter cartridges) that were set on the inhaler device.  The patient then inhaled the powder through the nose.  There were some disadvantages to this device, the most significant was the release of the MDI in 1957.

The Aerohaler was also used in the late 1940s and 50s as a means to deliver penicillin.  A modern version of the Aerohaler was remarketed and available in some countries, yet it has little in common with the original.

1971: Spinhaler:

The Intal Spinhaler was introduced by Fison in 1971. It was a neat little contraption. Once a physician prescribed the medicine, the patient received a box of Intal Spincaps and an Intal Spinhaler. The spoinhaler was taken apart and the spincap placed on a holder. The spinhaler was put back together. The blue part (see figure) was clicked forward to crush the capsule and release the powder. The patient then put his mouth over the white mouthpiece to inhale the medicine. If the patient was lucky he did not cough.

Warnings on the packaging warned that the produce may incite a cough and bronchospasm. This occurred as the powder impacted the back of the throat, triggering the cough reflex. This may result in bronchospasm and asthma attack. Warnings also noted that the product must be used daily as an asthma controller medicine, and not as a rescue medicine.

Another problem with the medicine is that the patient had to handle each dose. Proper technique also had to be used in order to assure an adequate dose and to prevent the medicine from triggering a cough. A CFC inhaler was available for Intal, and it was approved by the FDA in 1992.  This provided a more convenient and safer delivery device. It also probably improved compliance.

Chromolyn was very popular during the 1980s and 1990s. The spinhaler was ultimately phased out due to the inhaler. The inhaler was phased out due to the Montreal Protocol. A non-CFC chromolyon was never made. One theory for this was declining sales due to better asthma controller medicines that were on the market by the 2000s. It was set to be phased out by December 31, 2010.

It was also available as a solution to be inhaled by nebulizer. It initially came in a glass vial that had to be snapped open, and was probably mainly used in hospitals. Eventually a plastic vial was available. I do not know if the solution was available for home use, although I would imagine so.

By the time I became a respiratory therapist in 1995 I had not used the medicine in over 10 years. I quit on my own because I didn't feel it did any good. In the hospital setting it was mainly just prescribed for children. A reason for this might have been reluctance to prescribing inhaled steroids for kids.



Intal Spinhaler and Intal Gelcap

Spinhaler:  Fisons introduced this device in 1971 as the mechanism to deliver disodium cromoglycate (sodium cromolyn or simply cromolyn).  It was approved by the FDA in .  The product was marketed as the Intal Spinhaler to be used with the Intal Spincaps, and remedied many of the problems of the Aerohaler.  It was the first commercially successful DPI.  The caps were made of a hard gelatin and guaranteed the same dose with each inhaletion (a metered dose).  They had to be removed from the foil package and placed in the spinhaler by the patient.  The patient then cocks the outer shell of the inhaler and needles inside the device pierce the capsule.  The patient then places his mouth on the mouthpiece and inhales.  The flow generated causes a fan inside the device to rotate, and as this occurs the powder is inhaled.  The Intal Spinhaler was very popular as an asthma controller medicine during the 1980s and 90.  It was ultimately phased out because the powder caused some patients to cough and this caused some asthma attacks.  It was replaced by the Intal inhaler in the late 1990s.  I wrote more about the Spinhaler here.

Ventolin Rotahaler and Rotacaps

3.  Rotahaler:  In the early 1960s Allen and hanbury introduced the Ventolin Rotacap to go along with the Ventolin Rotahaler.  The product was marketed throughout the 1980s and 1990s but was ultimately discontinued because some asthmatics who needed the rescue medicine had trouble generating enough flow to suck in the medicine.  Another problem was that each individual unit dose Rotacap had to be handled by the patient and carefully inserted into the device.  The Ventolin Rotahaler was a failed experiment, and since it was discontinued only asthma controller medicines have been available as DPIs.  The Rotahaler was later refined so it contained a month supply of capsules and re-marketed as the Becotide Rotohaler and the Spiriva Handihaler in 2009.

4.  Turbuhaler:  Astra Zeneca introduced this product as one of the first multi dose DPIs in the early 1990s. The Pulmicort Turbuhaler was approved by the FDA in 1997, and the Symbicort Turbohaler in 2000, according to FDA.gov.  Various other products have been marketed in other countries such as the Bricanyl Turbuhaler (terbutaline) and Formoterol Oxis Turbuhaler.  The Pulmicort DPI has since been discontinued.

Diskhaler

5.  Diskhaler:  GlaxoSmithKline intruduced the disk in the early 1990s and asked for FDA approval in 1992. The original discus contained 4-8 blisters per cartridge, which made it so the patient didn't have to worry about handling each dose.  The device has since been refined so each discus contains 60 capsules, or two capsules for each day, or one month supply.  The recommended dose is one puff twice daily.  Each disc is equivalent to two puffs of the MDI version of the medicine.  A blister of capsules are stored in a roll, or disc inside the device.  All the patient has to do to prepare a dose is to open the device and pull down a lever.  This moves a new capsule into the delivery chamber and decreases the counter by one so the patient knows how many doses are left. The Serevent Discus was FDA approved in 1997 and the Advair Discus in 2000 according to fda.gov.  The Flovent Discus was approved in 2000 but was never marketed. The Serevent Discus may also be referred to as Seritide, Viani, ForAir, and Foxair in some countries.  Advair is a combination of Serevent and Flovent.  The Advair Discus is currently the most popular asthma controller medicine on the market.  The discus is referred to as the autohaler or diskus in some countries.  Other products available but not approved by the FDA are the Becodisk which contains beclomethasone, and the Ventolin Autohaler

6.  Inhalator:  The device is marketed by Novaris.  I've found various articles that mention studies comparing salmeterol (Serevent) inhaler with the formoterol inhalator (Barotec) from as far back as 1985, although I'm not certain it was actually approved for use in any country at this time.  The inhaler was improved upon by 2001 and renamed the Centihaler.  It was this product that was finally approved by the FDA in 2001 as the Foradil Centihaler.  In 2006 the FDA approved the Foradil Aerolizer which will be under patent until 2019.  (3)  The recommended dose is two puffs of the inhaler twice daily or one puff on the DPI.  As a note here, the FDA seems to have the strictest policy for drug approval.  As a rule of thumb, if the FDA approves a medicine chances are it's been run through the gambit and is proven relatively safe, or at least the benefits far outweigh the disadvantages.  I believe this product was slow to be approved by the FDA due to it being linked to asthma related deaths.  However, many believe it wasn't the medicine so much as poor education that resulted in the deaths, yet it was never proven either way.  A similar problem plagues salmeterol.  The problems was addressed in 2003 with a black box warning on the packaging. 

7.  Cyclohaler:   This is another DPI introduced to the market in the early 1990s.  The medicine is stored in hard gelcaps that are inserted into the cyclohaler with each use.  The mouthpiece is long to optimize drug distribution even if the patient isn't able to generate enough flow. Several puffs were often necessary to get an optimal dose.  The initial product was marketed as the Aerolizer Cyclohaler, and the products available were albuterol and ipatropium bromide.  Since the product wasn't marketed in the U.S. the medicine was referred by it's non-U.S. name, such as the Salbutamol Cyclohaler and Salbutamol Cyclocaps.  The product has since been refined and marketed with other medicines such as  salbutamol (Sultanol), beclomethasone (Becotide), Formoterol (Foradil) and  budesonide (Miflonide).  The latest version is marketed as the cyclohaler 400.

8.  Other:  By 2008 there would be over 20 different DPIs on the market (4), and by 2012 that number would rise to 35.  While many are available for use in Europe, only a select few have been approved by the FDA.  DPIs currently on the market (as of 2012) are (you can view pictures of the various devices here):

• Acu-Breathe (Respirics)
• Aerolizer (Novartis)
• AIR (Civitas/Alkermes)
• Airmax (Teva)
• Aspirair (Vectura)
• Axahaler (S.M.B.)
• Breezhaler (Novartis)
• Clickhaler (Vectura)
• Conix Dry (3M)
• Cricket (Mannkind)
• Cyclohaler (Teva)
• Diskhaler (GlaxoSmithKline)
• Diskus (GlaxoSmithKline)
• Dreamboat (Mannkind)
• Easyhaler (Orion)
• EZ Aer (Aerovance)
• Flexhaler (AstraZeneca) -- Pulmicort
• Genuair (Almirall)
• Gemini (GSK)
• Handihaler (Boehringer Ingelheim)
• MicroDose (MicroDose Therapeutx)
• Next DPI (Chiesi)
• Novolizer (Meda)
• Oximax (Mantecorp)
• Podhaler (Novartis)
• Pulmojet (sanofi-aventis)
• Pulvinal (Chiesi)
• Skyehaler (SKyepharma)
• Solis (Sandoz/Novartis)
• Taifun (Akela)
• Taper Dry (3M)
• Trivair (Trimel Bipharma)
• Twincaps/Flowcaps (Hovione)
• Twisthaler (Schering /Merck)
• Turbuhaler (AstraZeneca) (5)
• Dura Spiros (3M) -- battery powered (introduced in 1990s)

Click here for more asthma history.

References:

1. Sanders, Mark, "Inhalation therapy:  an historic review," Primary Care Respiratory Journal, 2007, 16 (2), pages 71-81
2. Clark, A.R., "Medical Aerosol Inhalers: Past, Present, and Future, Aerosol Science and Technology, 1995, 22:4, 374-91
3. Foradil Aerolizer Briefing Document, Available to the public without redaction, pulmonary drug advisory committee on the safety of long acting beta agonist bronchodilators, fda.gov, http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4148B1_02_01-Novartis-Foradil.pdf, page 9
4. Patterson, Roy, "Patterson's Allergic Diseases," 7th ed., page 610
5. "Dry Powder Inhalation: Technology, Devices, Markets and Opportunities," prnewswire.com, Jan. 19, 2012, New York, http://www.prnewswire.com/news-releases/dry-powder-inhalation-technology-devices-markets-and-opportunities-137656553.html 

x1968-2010: 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. 

Now you grab the inhaler and hold it so the mouthpiece is facing down.  You unscrew the cap and place  it onto a cup on the propeller, screw the body back on the mouthpiece, and slide the outer sleeve (the blue part in the picture) down as far as it will go and then back up again.  This pierces the capsule and makes the spinhaler ready for use. (1)

You exhale as much air as you can, place your mouth over the mouthpiece, and inhale.  As you inhale the powder will enter your airway, with a good portion going to your air passages.  You can feel the powder as it enters, and taste it.  This is how you know you did it right. 

This was the first 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.

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 ER I was admitted to NJH/NAC in Denver.  Once they managed to get my asthma under control they did some pulmonary function testing (PFT) 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. (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 anyway), so there was no need for me to use it prior to every time I exercised.  Yet the medicine was proven to reduce inflammation in your air passages so your asthma triggers don't irritate you as much, and don't constrict your air passages as much.

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.  It prevented inflammation by preventing mast cells from releasing the mediators of inflammation (like histamine) which ultimately cause the inflammatory response. 

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 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 Tilate inhaler. (6) It was equally effective in treating inflammation and reducing allergy and asthma symptoms.  I never used Tilade, and I have little clinical experience educating it to patients either.

By 1995 Chromolyn 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.  I believe we no longer carry 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.  I imagine by information I've read on the Internet it's still a viable and cheap option for some asthmatics in 3rd world nations.  Yet here in the U.S. it's an antique. 

Tilate 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

1781-1826: Laennec: The inventor of the stethoscope

Figure 1 --Rene Laennec (1781-1826).  Along with
crediting an old kid's game with giving him the idea of
creating his first stethoscope, he was also skilled with
the flute.  His memory and his musical skill  helped him
come up with the ingenious plan of rolling up paper into
a hollow tube.  He then used this to listen to lung sounds.
He later modestly chimed that he was amazed the device
wasn't invented years ago.  Hippocrates was known for
performing auscultation by placing his ear upon his
patient's chest.  A simple stethoscope would have
greatly benefited the ancient physician. (4, page xxiii)

Before the 19th century the only way for a physician to auscultate (hear) heart and lung sounds was to place his ear upon his patent's chest.  This would change thanks to a brilliant invention by Doctor Rene Laennec.

This method of auscultation was first described by the Hippocratic writers as far back as 400 B.C.  Laennec quotes Hippocrates from De Morbis as writing:

You shall know by this that the chest contains water and not pus, if in applying the ear during a certain time on the side, you perceive a noise like that of boiling vinegar. (4, pages 28-29) 

This method, called mediate auscultation, was never further investigated by the successors of Hippocrates, and therefore never became standard practice. Plus some patients were gross, filthy, and disgusting, mainly because the concept of bathing daily was not a standard practice among the populace.  Or, as Laennec said it, the technique can be disgusting. (4, pages 29)

Plus, for a gentleman doing this to a lady , the experience might be a bit uncomfortable for both the patient and the doctor.  Obesity also posed a problem because fat tissue muffles sound.

When he was 38-years-old on a hot and humid day in 1816, Rene Theophile Hyacinthe Laennec was posed with all of these problems, yet the need to auscultate his patient's heart and lung sounds was essential.  He came up with an ingenious plan that helped him assess his patient, yet which also helped him improve the assessment skills for all physicians.

Who was Rene Laenec? 

Laennec was born on February 17, 1781, to to an a"advocate of the provincial courts, and held some appointments under government, in his native country (France)... Fortunately his son was heir of the more solid parts of his genius; without his wit, but without his volatility.  (1, page xix)

At an early age he was put under the care of his uncle, a clergy man in charge of the parish of Eliam, in the vicinity of Quimper.  However, after the French Revolution broke out his care was transferred to another uncle, Dr. Laennec of Nanates. (1, page xix)

 Dr. Laennec was a man of highest respectability both as to talent and conduct, and directed the studies of his nephew with the interest and affection of a parent. The young scholar did credit to his friends and teachers; having obtained considerable distinction from his fellows at the chief school of the department of the Lower Loire, wither he had been sent by his uncle. Having completed his preparatory studies at this seminary, his thoughts naturally turned towards physic as a profession. He willingly engaged himself as the pupil of his uncle, and entered upon the study of his future profession with the zeal inherent in his character, and with success indicative of his subsequent eminence. Besides the instructions derived from his uncle, who was at that time senior physician of the hospital, and afterwards Professor of Medicine and Materia Medica at Nantes, he attended the courses of anatomy given by the surgeons of the same establishment, and is said, even at this early age, to have shown a decided predilection for morbid anatomy and clinical observation.(1, page xix)

Shown here:  Matthew Baille (1761-1823)
While under the tutelage of Corvisant,
Laennec became good friends with
Matthew Baillie.  Ironically, both were
famous for their studies of diseases of
the lungs, and both were diagnosed with
consumption,and eventually died of this disease.  

In 1800 he attended the medical school of La Charite, which was where he came to tutelage of a well respected and well known physician by the name of Jean Nicolas Corvisant (1755-1821).  He also became good friends at this school with Matthew Baillie, who himself would go on to gain great fame as a physician.  (1, page x)

He had actually gained recognition earlier in his career, for while in school he wrote a history of medicine, and, in the year 1802 at the age of 21, published articles that were well received by his fellow physicians.  (1, page x)

He opened a clinic in and began seeing patients.  In 1816 he was appointed chief physician to the Necker Hospital.  It was here where he was presented with the opportunity whereby he came up with an ingenious plan that changed medical diagnosis forever.  (1, page xxiii)

What was Laennec's ingenious plan? 

So on a hot and humid day in 1816, a 36-year-old physician by the name of Rene Laennec came up with an ingenious plan.

According to Kendall F. Haven in his book "One hundred greatest inventions of all time," Laennec was a "well established doctor and diagnostician of chest and abdominal disorders when he was asked by a fellow physician to assess an obese young woman with breathing difficulties." (2, page 96)

Not that it matters, but for the record the patient's name was Marie-Melanie Basset, and she was only 40.

Haven said:

Laenec's normal technique was to have the woman partially disrobe so he could place his ear against a hanker chief over her chest.  He'd listen to lung sounds over five spots:  the underside of each arm, each side of upper back, and upper breast bone. 

Gabriel Andral (1797-1876)
He was a French pathologist at the
University of Paris.  He is best known
for his work on blood chemistry.
Andral wrote the comments in
the margins of the 1838 edition
of Laennec's book.

Yet he heard nothing, so he tried percussion, a method useful for diagnosing diseases of the chest that he learned from his teacher, Dr. Corvisant.  It was a method of tapping on the chest, and the resonance heard would indicate the different diseases of the chest. For instance, air trapped in lungs from asthma causes a hollow sound, and fluid in the lungs from pneumonia amplifies sound.

While Leannec suspected the lady had heart failure, he was unable to diagnose her by heart and lung sounds. So, he came up with an ingenious plan.

Thinking off the cuff, Haven said he "grabbed 24 sheets of paper, rolled them tightly into a bundle, and secured them in shape with paste glue," wrote Haven. "He applied one end of this paste roll against the young woman's chest, and the other to his ear." (2, page 97)

Leanecc was "delighted" to learn he could hear the woman's heart and lung sounds better this way than with the unaided ear against her chest.  He was so excited at how simple a device could make this job so much easier that he set out to do a series of experiments to find metals and tubes that would aid his ear in hearing heart and lung sounds.  (2, page 96)

He actually wanted to name the device le cylindre claiming it was frivolous to name such a device.  However, his colleagues thought it should have a name, and they came up with some of their own. Yet once he decided he didn't like any of these names, he decided to call it a stethoscope.  Stethe coming from the Greek term for chest, and scope coming from the Latin term for aim.  (2, page 97)

In the ensuing years the model was adjusted by others, and eventually a stethoscope with two ear pieces (binaural) was invented.  In 1852 George Camman fine tuned the stethoscope so it was similar to the models we use today.

In his book "A treaties on the diseases of the chest, and on mediate auscultation," Laennec recollected a little kid's game, and it was this that gave him an idea.

He wrote:

In 1816, I was consulted by a young woman laboring under general symptoms of diseased heart, and in whose case percussion and the application of the hand were of little avail on account of the great degree of fatness. The other method just mentioned (auscultating with an ear to the chest) being rendered inadmissible by the age and sex of the patient, I happened to recollect a simple and well-known fact in acoustics, and fancied it might be turned to some use on the present occasion. The fact I allude to is the great distinctness with which we hear the scratch of a pin at one end of a piece of wood, on applying our ear to the other. Immediately, on this suggestion, I rolled a quire of paper into a kind of cylinder and applied one end of it to the region of the heart and the other to my ear, and was not a little surprised and pleased, to find that I could thereby perceive the action of the heart in a manner much more clear and distinct than I had ever been able to do by the immediate application of the ear. (4, page 6)

Figure 2 -- Laennec's Monaural Stethoscope (1820).  It was an inch
and a half in diameter and a foot long, perforated longitudinally
by a bore three lines wide, and hollowed out into a funnel shape
at one end to the depth of an inch and a half. A plug of wood
was fitted into this hollowed extremity with a perforation through
it of the same diameter as that of the rest of the tube. The plug
was used in auscultating heart sounds, and discarded in
 stethoscopes made at a later date. It was made in two sections
for convenience of carrying. (6, page 626)  Perhaps it
 provided some solace to Laennec that he was diagnosed with
consumption using a stethoscope similar to this. Photo Copyright
Science Museum/ Science and SocietyPicture Library

So he thereby discovered that his invention was better for hearing sounds inside the human body than the ear alone.  He found it very useful, and would incorporate his new tool as a means of assessing all of his patients.  He likewise used it in his efforts to study many diseases, such as tuberculosis, pneumonia and asthma.

What was the first stethoscope like? 

Laennec described his first stethoscope in his book Mediate Auscultation:

The first instrument which I used was a cylinder of paper, formed of three quires, compactly rolled together, and kept in shape by paste. The longitudinal aperture which is always left in the centre of paper thus rolled, led accidentally in my hands to an important discovery. (4, page 7)

He  also set off on a quest to study and perform experiments using the device, and he fine tuned it until he came up with a better product.  He trialed a variety of materials, lengths, and sizes of aperture, until he came up with the product he thought was idea.

He said:

In consequence of these various experiments I now employ a cylinder of wood, an inch and a half in diameter, and a foot long, perforated longitudinally by a bore three lines wide, and hollowed out into a funnel-shape, to the depth of an inch and a half at one of its extremities. It is divided into two portions, partly for the convenience of carriage, and partly to permit its being used of half the usual length. The instrument in this form—that is, with the funnel-shaped extremity,—is used in exploring the respiration and rhonchus: when applied to the exploration of the heart and the voice, it is converted into a simple tube, with thick sides, by inserting into its excavated extremity a stopper or plug traversed by a small aperture, and accurately adjusted to. the excavation. (See figure 2)  (10, page 7)

He also used his new device to study diseases of the chest. He said:

From this moment I imagined that the circumstance might furnish means for enabling us to ascertain the character, not only of the action of the heart, but of every species of sound produced by the motion of all the thoracic viscera, and, consequently, for the exploration of the respiration, the voice, the rhonchus (the sound of air flowing through diseased air passages), and perhaps even the fluctuation of fluid extravasated (leaked) in the pleura (sack around the lungs) or the pericardium (sack around the heart). (4, page 6)

Figure 3 -- Laennec listens to man with tuberculosis*

He took upon this opportunity to study diseases of the chest at the Necker Hospital where he also received patients at his clinic.  He therefore bravely came into close contact with some of the sickest and contagious people in France at the time, which can be seen in figure 3.  It was this type of dedication to his work whereby he contacted the disease that ended up ending his life.

How was the stethoscope accepted by Laennec's peers? 

Despite how useful he found this new tool in diagnosing and researching diseases of the chest, it was initially rejected by his peers in the medical community.

"What a ridiculous idea," his colleagues would say.  "We doctors are called upon for our brilliant medical minds.  To say we should carry some frivolous tool around with us is absolutely ridiculous and below us." 

This is a plate of the parts of the Laennec's stethoscope
as it appeared in the first edition of his book in 1819.
(4, pages 783) 

Another doctor wrote, "He that hath ears to hear, let him use his ears and not a stethoscope."

This was yet another example of a dogmatic and proud medical profession refusing to accept anything new or different. For thousands of years physicians rejected any scientific idea that opposed Galen's superstitions, and now they flat out rejected a tool that would allow them to do their jobs better.

Perhaps under the encouragement of Corvisart, Laennec published a book reporting what both he and Corvisart had learned about the diseases of the chest by using their new discoveries of chest percussion, vocal fremitus, and the stethoscope.  The book was published in 1819 and titled "De VAuscultation Mediate, ou Traitt du Diagnostic des Maladies despoumons ct du Cceur, fonde principalement sur ce nouveau moyen." 

The book was well received, and, in 1821, it was translated into English by John Forbes.  Slowly over the next few years his hard work payed off.  So even though he only lived six years after his discovery that was not so well received initially, he was able to see its acceptance before he passed away in 1826.

Perhaps there was no better evidence as to his tool's usefulness than by his own perseverance in studying the various diseases of the chest, a quest which may have ultimately cost him his life.  

Figure 4 -- Painting of Laennec using his stethoscope on a boy.
This picture was taken from a painting by Robert Thom,
copyrighted in 1960.  

Conclusion:

Laennec married in 1824 and had two children. However, he was only able to enjoy his young family for a short time.

He continued to work arduously at his clinic, both seeing physicians and performing research.  He also worked hard in perfecting the book he became famous for, releasing the second edition in 1826.

In the process accomplishing this, along with his other duties as a physician and researcher, he became so exhausted that he was forced to give up his work and return to the home he was born in. Although some say he was simply tired from being ridiculed by his colleagues.

Either way, he was ultimately diagnosed with phthsis pulmonalis, which the Latin form of consumption, or tuberculosis.  He was diagnosed using the very same tool that he invented.  Perhaps this was consolation, proof that the passion of his life's work was finally accepted.

So, despite his ingenious idea originally being rejected by the medical community, Laennec would end up with the last laugh.  By the time he passed away on August 13, 1836, his stethoscope, or some variation of it, was a standard tool to assess and diagnose patients.

References:

1. Forbes, John, The life of the author, translator of "A treaties on the diseases of the chest, and on mediate auscultation," a book written by Rene Theophile Hyacinthe Laennec, 1838, New York, Philadelphia, Samuel S., pages xix-xxiii
2. Haven, Kendall F, "One hundred greatest inventions of all time," 2006, U.S., Greenwood Publishing Group, Inc., pages 96-98
3. "Now I hear:  The history of the stethoscope,"  http://antiquemed.com/, 1998-2011, accessed 12/28/13
4. Laennec, Rene Theophile Hyacinthe, "A treaties on the diseases of the chest, and on mediate auscultation," translated by John Forbes, 1838, New York, Philadelphia, Samuel S. and William Wood, Thomas Cowperthwaite and Company
5.  Barchers,Suzanne, "I've Discovered Sound," Brainworks, 2009, Leopard, page 9
6. Camman, Donald M, "Historical Sketch: Stethoscopes," A Reference Handbook for Medical Sciences, edited by Albert Henry Buck, by various writers, volume VI, 1888, New York, William Wood and Company, 626-628

1800-2012: Evolution of back-door bronchodilator

Anticholinergics are medicines that, once inhaled, sit on receptor sites of the neurostransmitter acetylcysteine to prevent it from causing bronchospasm. Because the medicine is blocking a natural response as opposed to actively causing bronchdilation, it is often referred to as a "back-door bronchodilator."

The first "back-door bronchodilators" used came from the nightshade family of plants called solanaceae, and were often included in ancient recipes for asthma remedies.  Some common plants used were:

• Datura strammonium 
• Atropa belladonna 
• Hyoscyamus niger (henbane) 
• Lobelia inflata.

Ancient physicians learned that the best effect was obtained when the medicine was inhaled, and in this way was used as a topical applied directly to the lungs. Over time there different methods were used for inhaling the medicine, which included:

1.  Burning herbs: Leaves, roots and stems from the herbs belladonna and strammonium were sun-dried and crushed by ancient Egyptians, placed on rocks heated on coals, and the asthmatic would roll up stalks of a reed, place one end up to the crushed herbs and inhale the smoke. Surely this sometimes made asthma worse, yet more often than not the herb offered some relief. This method was first recorded in 4000 BC, yet it was probably done long before this.

2.  Pipes:  The sun-dried products of the herbs were ground, and the powder stuffed into crude pipes, lit, and the medicinal smoke inhaled.  This technique was discovered for the modern world in 1803 for Europe and the U.S. and the asthma cigarette craze began.

3.  Cigarettes: The powder was rolled into small paper and smoked as cigarettes and cigars.  This technique was commonly used in India and was discovered for the modern world in the early 19th century. An asthma cigarette craze began around 1879 and lasted until the middle of the 20th century.

4.  Pills:  During the 19th century the medicine was formed into pills that were taken by mouth.  A popular brand was Potter's Asthma Pills.  These were common from around 1880 to 1950s.

Ad for Ozone Paper
showing endorsement
by Dr. Thorowgood
(1891)

5.  Nitre/ Ozonepaper:  By the 1850s paper was impregnated with potassium nitrate, strammonium, or belladonna and ignited to produce fumes that were inhaled as a treatment for spasmotic asthma.  By 1973 this was a common mode of treatment, and recommended by Dr. John Thorowgood in the British Medical Journal.  (1)  (2)  It may also be referred to as ozone paper.  One advertisement for the product even mentions Dr. Thorowgood's endorsement (see picture to right.

6.  Nebulizers/ Inhalers:  During the 19th century various nebulizers and inhalers were invented to help asthmatics inhale various solutions of the medicine.   Nebulizers, of course were fine tuned in the 1930s, and modern inhalers were fine tuned during the 1950s.

As scientists and pharmaceuticals worked with the plants, they learned the active ingredient inside it was atropine.  From there they learned how to synthesize the medicine to create modern anticholinergics.

These include:

1.  Atropine:  It was derived from the belladonna plant in 1833, and by 1867 it was isolated and determined to be a component alkaloid of the various nightshade plants found in India, Egypt, South America and other rocky, warm climates.

It was first available for asthma cigarettes, but around the turn of the 20th century was available as a solution to be nebulized. It ultimately became a top line treatment for asthma during the 1950s.  The medicine was still prescribed for asthma and COPD during the 1980s, although by the 1990s was phased out due to a synthesized anticholinergic medicine with less side effects. I was prescribed this medicine in 1985 and took it up to four times per day until around 1990.

Atrovent Inhaler

2.  Ipatropium Bromide (Atrovent):  This is a synthesized anticholinergic, and it was first introduced in Germany in 1975, followed by the rest of Europe by the late 70s.  It was available both as a solution to be nebulized and as an inhaler, and it was prescribed four times per day.  An HFA inhaler was approved by the FDA in 2004.  I was prescribed this medicine in 1990 and took it up to four times a day until around 1995.  It was initially a top line asthma medicine, although better medicines have replaced it.  I believe the inhaler was phased out in favor of the new Ipatropium Respimat. (3) (4)

3.  Oxitropium Bromide (Oxiven, Tersigen): This was anther synthesized anticholinergic released along with ipatropium bromide.  It was marketed as both an inhaler and solution.  Because it was available in higher doses, the frequency was only three times per day.  This medicine was never approved by the FDA for sale in the U.S. (6)

Combivent Inhaler

10.  Combivent:  This is a combination of Albuterol and Ipatropium bromide in an inhaler form. It was approved by the FDA in 1996 for the convenience of COPD patients and some asthmatics who don't respond to other top line asthma medications. The medicine was set to be phased out by December 31, 2013, but due to a public outcry a new version of the medicine was introduced to the market as a replacement (see Combivent Respimat)

 11.  Duoneb:  This is a combination of albuterol and ipatropium bromide premixed in plastic amps with 0.3cc of normal saline. It was introduced in the early 1990s and approved by the FDA in 1996.  The medicine was nice because it made for a quicker breathing treatment, as compared to mixing separate amps of albuterol and ipatropium bromide, both with 3cc premixed.  It continues to be a top line treatment for COPD, although is an option for asthmatics.

Spiriva HandiHaler

12.  Tiatropium Bromide (Spiriva Handihaler): This dry powdered inhaler was introduced to the market in Europe in 2002 and the U.S. in 2003. It's the first long-acting back-door bronchodilator, meaning it only needs to be taken once a day.  Studies show it is more effective than ipatropium bromide in improving lung function. It is recommended as a top line treatment for COPD.   (7)

Combivent Respimat

13.  Combivent Respimat: This is the new version of combivent approved by the FDA in 2012. The device has no propellant, is breath actuated, and delivers a dose that is supposed to provide greater lung distribution of the medicine than a metered dose inhaler. The medicine was in demand because a non CFC version of combivent was needed.  (8)

Studies show this type of medicine may produce mild bronchodiliation and mild breathing relief. Personally, I never noticed any difference with the medicine. However, modern evidence suggests the medicine, when used daily, may acts as a preventative medicine, keeping lungs dilated long term.

Modern studies have found that anticholinergics that anticholinergics don't benefit asthmatics as once was suspected, and so, while they remain an option, they are no longer a top-line option.  Spiriva continues to be a top line option for COPD, as studies show it improves lung function.  Atrovent and Combivent are slowly being phased out in favor of the newer medicines.

Duoneb continues to be an option for COPD patients, although even it has seen better days.  Some physicians are phasing this medicine out in favor of long acting medicines that only need to be taken once or twice a day, such as Spiriva, Brovana and Pulmicort.


So what started out as a medicine that was sporadically recommended and inhaled as smoke around a primitive cooking fire, has evolved into a medicine that is taken in the form of simple inhalations that are conveniently and safely delivered as simple inhalations.


References:

1. "Nitre paper," Drugs.com, http://www.drugs.com/dict/niter-paper.html
2. Thorowgood, John, "On Bronchial Asthma," British Medical Journal, 1873, Nov. 22, page 600
3. Sittig, Marshal, "Pharmaceutical Manufacturing Encyclopedia," 1988, vol. 1, New Jersey, page 837
4. Barnes, Peter J., Jeffrey M. Drazen, Stephen I. Rennard, "Asthma and COPD: Basic Mechanisms and Clinical Management," 2008, page 616-17
5. Ipatropium Bromide, package insert, http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.serdocBase=renetnt&folderPath=/Prescribing+Information/PIs/Atrovent+HFA/10003001_US_1.pdfingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Atrovent+HFA/10003001_US_1.pdf
6. Barnes, op cit
7. Barnes, op cit
8. "FDA Approves Combivent Respimat (ipatropium bromide and albuterol sulfate) Inhalation Spray," FDA.gov, http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm274684.htm
9. *Picture with much appreciated permission from Inhalatorium.com