1991: Study finds albuterol works just as well as epinephrine

In my quest to write a little history of Sus-phrine (epinephrine) I finally found an article I'd been looking for for quite some time. The article was regarding a study comparing the long-acting version of epinephrine with Ventolin (albuterl). It was a breakthrough study. It's basically why we give albuterol breathing treatments for asthma instead of epinephrine injections.

Before I delve into the study, I think a little background is pertinent here. Epinephrine was established as a very effective treatment for asthma during the first few decades of the 19th century. So, if you suffered from severe asthma and went to your doctor with an asthma attack, there's a good chance you were given an epinephrine injection.

Epinephrine was great because it opened airways within only a few short minutes. The down side was that it only lasted 3-4 hours. This often meant that repeated injections were needed to keep airways open long-term. This problem was solved in the 1970's with the introduction of Sus-phrine, which was essentially a long-acting epinephrine: it lasted 6-8 hours.

During the 1970's and 80's if you went to your doctor for severe asthma, you might be given a Sus-phrine shot instead of the traditional epinephrine. My mom kept track of this kind of stuff for me when I was a kid, and I know I was given Sus-hrine in the early 1970's. In 1976, when I was only six-years-old and my family wanted to travel from Michigan to California, my doctor wrote a note saying that if this boy has a severe asthma episode, Sus-phrine works great.

I was initially given these shots in the doctor's office. However, later on I had to go to the hospital. It got to the point that, by 1980, I was literally asking for "the shot." An I got it every time. This came to an end in 1991. This year I went to the emergency room and I asked for "the shot." But, the doctor had never heard of what I was asking for. I said, "It's called Sus-phrine."

After talking with the pharmacist he was able to find one. He gave me the shot. This was the last time I was ever given a Sus-phrine shot. A few months later I had another asthma attack and went to the emergency room. This time I was given a bunch of albuterol breathing treatments. They worked just as well as the shot at opening me up. And, as a bonus, I didn't feel like doing laps when I was done; my heart didn't feel like it was going to explode.

This probably wasn't the only such study, but a 1991 study published in Pediatric Emergency Care tiled, "Effect of injected long-acting epinephrine in addition to aerosolized albuterol in the treatment of acute asthma in children." The study basically showed that Sus-phrine was no better than albuterol at opening airways and ending asthma attacks. 

Considering side effects of albuterol are essentially negligible, and the fact that doctor's generally feel comfortable giving high doses of it in the emergency room when needed, the study was a breakthrough study. It pretty much removed epinephrine as a top-line treatment for severe asthma attacks and moved albuterol up to the top. 

As anyone who works as a respiratory therapist knows, albuterol has remained at the top ever since. In fact, albuterol is considered so safe by the medical community. that it's given indiscriminately to anyone who comes into the emergency room with shortness of breath or wheezes regardless of the cause. If it works, great. If it doesn't work, it was worth a try. 

References and further reading:

1. Kornberg AE, Zuckerman S, Welliver JR, et al. Effect of injected long-acting epinephrine in addition to aerosolized albuterol in the treatment of acute asthma in children. Pediatr Emerg Care 1991; 7:1-3.
2. Asthma History: 1981: Sus-Phrine: The greatest asthma medicine ever

1981: Sus-Phrine: The greatest asthma medicine ever

"When we vacationed to California in 1976.
Dr. Gunderson gave us this to take along." Mom wrote

I think that the world's greatest medicine was Sus-Phrine (brand of epinephrine). It was actually a long acting version of epinephrine. It gave you your breath back within five minutes. I was given this medicine many times in the emergency room. It was a lifesaver.

A few years ago, as I began my quest to learn more about this medicine, a doctor told me that he liked it because a person would come in with status asthmaticus (asthma non-responsive to treatment), and he would prescribe a Sus-Phrine shot followed by a shot of a systemic corticosteroid.

The steroid would take 1-2 hours to reduce airway inflammation. In the meantime, the Sus-Phrine started working within minutes, and would last up from 6-10 hours. So, he said, the Sus-Phrine would keep airways open long enough for the steroid to take effect. Patients would have to stay in the hospital at least an hour after the shot so they could be monitored for potential side effects. Then they'd be sent home feeling good.

I would surely be feeling good. I would be wired. Sus-Phrine was essentially adrenaline. It's a medicine that essentially mimics the sympathetic (flight or fight) nervous system (sympathomimetic). It narrowed blood vessels to speed up the flow of blood to increase blood pressure. It increased the rate and speed of your heart. It caused palpitations. It made you excited. It made you jittery. It kept you awake for hours. But you didn't care, because it felt so good to be able to breathe.

Since 1901, epinephrine was available to be used for asthma. It started working in 3-5 minutes, but only lasted a few hours. This meant that repeat shots were often needed. It had to be given into the muscles, and this was most frequently the gluteal muscle (the butt). It also had to be given with a very large needle, which made the butt a good spot for injection. And kids were not keen to seeing a large needle, let alone having to drop their drawer and getting poked in the butt.

An An ampule of Sus-Phrine (1)

Sus-Phrine was first introduced to the market in the 1950s. Apparently, according to Emergency Medicine PharmD, it was the first medicine that didn't have to be given by intramuscular injection with a large needle. It was available in a concentration of 1:1200 (aqueous solution), which (if you are a nurse and I am not) can be delivered with any gauge needle and introduced to the body subcutaneously (meaning into the fat), meaning you could just get the shot in the arm with a small needle.

I only mention this because I started getting this shot in the mid-1970s and early 1980s when I would have been 5-10 range. Even though they would always assure me they had seen many naked butts before, it was always better to pull down my sleeve than to pull down my drawers. I'm sure this is the same for any kid.

Sus-Phrine (8)

Sus-Phrine became standard for asthmatics who presented to the emergency room during the 1970s to about the mid-1980s. This would have been about the time albuterol entered the mainstream of asthma treatments. It must have been discovered about this time that albuterol was just as effective as epinephrine in opening airways and ending asthma attacks. Giving 2-3 albuterol breathing treatments would also prove to offer the patient fewer side effects as a bonus.

I must have been given Sus-Phrine many times early on in my life. I know this, because, in 1976, my parents decided to take us to California. It was a three day car ride. This would have occurred just after I finished Kindergarten in June. My mom had my doctor write a note to any random doctor who might have to take care of me in case my asthma acted up. The note, written on a prescription pad, said:

Sus-Phrine (8)

"This boy is a known asthmatic undergoing hypersensitization program. If he has severe asthmatic attack without a fever he will respond well to 0.2cc Susphrine sub-q. Stat & observe 20 minutes."

By the late 1980s, and particularly between 1981 and January 1985, I made regular trips to the emergency room. I remember sitting on the hospital bed. I remember my dad saying, "In five minutes you will feel better."

Of course, they always had to give me an Alupent nebulizer treatment first. After a while I knew this wasn't going to work, but they always did it. As I inhaled the mist, I watched as a nurse would prepare the shot. When the treatment neared completion, the shot was given to me on my left or right arm.

Then I watched the clock. It was an oval clock on the wall right in front of me. It was 8 p.m.  I watched the red second hand go round and round as my shoulders dug deep into the mattress I was sitting on. I'd concentrate on my breathing. At first my breath would only go in half way. My chest was tight. I must have been near panic, or I wouldn't have asked mom or dad to take me.

Five minutes would go slow. But, right on cue: at the five minute mark my breath would start coming back. Each subsequent breath would go in deeper and deeper. Then I'd take in a deep breath and it would be easy. Then I'd take several deep breaths just because I could.

I can tell you with complete honesty that there is nothing better than all of a sudden being able to breathe after several hours of struggling to do so. It is just a great feeling. In fact, it usually created a feeling of euphoria. And, quite frankly, in retrospect, I'm not sure if that euphoria was the result of all of a sudden being able to breathe, or a side effect of the medicine. I imagine it was a little of both.

Nearly all of my ER visits were at West Shore Hospital. I remember going to the emergency room at West Shore Hospital in 1991 for an asthma attack. This was the first time I did this since 1985. I requested Sus-Phrine. The nurse never heard of it. The doctor had a vague memory of it, and consulted the pharmacist. The pharmacist and doctor talked about it for a while, and the pharmacist decided he had a cabinet that might have the medicine I requested.

This was the last time I was given the shot. It was discontinued within the next few years. A study published in 1991 in the Journal of the National Medical Association conclude that "Subcutaneous, long-acting epinephrine (Sus-Phrine) provides no additional benefit to a beta-2 agonist (albuterol) by nebulization for children with acute asthma." (6)

To be honest, I have never been given an epinephrine shot since then either, which spotlights the changing times as far as we asthmatics are concerned.

Further reading and references:

1. Emergency Medicine Pharm D: Throwback Drug Thursday: Sus-Phrine, An Aqueous Formulation of Epinephrine
2. Naterman HL. Ephinephrine base suspended in water with thioglycolate. J Allergy 1953; 24:60.
3. Unger AH, Unger L. Prolonged epinephrine action. Ann Allergy 1952; 10:128-130
4. Ben-Zvi Z, Lam C, Hoffman J, et al. An evaluation of the initial treatment of acute asthma. Pediatrics 1982; 70:348-353.
5. Ben-Zvi Z, Lam C, Spohn WA, et al. An evaluation of repeated injections of epinephrine for the initial treatment of acute asthma. Am Rev Respir Dis 1983; 127:101-105.
6. Kornberg AE, Zuckerman S, Welliver JR, et al. Effect of injected long-acting epinephrine in addition to aerosolized albuterol in the treatment of acute asthma in children. Pediatr Emerg Care 1991; 7:1-3.
7. Jenkens, Charles M, "A Clinical Study of 'Sus-Phrine,' an Aqueous Epinephrine Suspensionfor Sustained Action," Journal of the National Medical Association, March, 1953, 45, pages 120-122
8. Bezzant, John L., "Epinephrine: Comparison of short vs long acting," http://library.med.utah.edu/kw/derm/pages/ni18_3.htm, accessed 3/10/17
9. "Sus-Phrine (brand of epinephrine), Physician's Desk Reference," 1991, page 1006
10. Feldman, B. Robert, "The Complete Book of Children's Alergies: A Guide for Parents," 1986, Times Books
11. Brenner, Barry E., editor, "Emergency Asthma," 1999, New York, Marcel Dekker, Inc., page 322

1873: Lebert creates new asthma theory

Herman Lebert (1813-1878)

In 1873, Herman Lebert came up with an interesting theory about asthma that lasted for several decades, and into the 19th century.  

Lebert was born in Germany, and later became professor of pathology in Paris and Zurich.  As a pathologist he spent hours in a lab investigating tissues under the microscope.  

Steven I. Hajdu, in a 2004 article in Annals of Clinical Laboratory Science, said Lebert was one of the first clinical pathologists who often goes unrecognized by pathologists, when he should be a household name to them.  (1)

Hajdu said he sliced"fresh tissues with a razor-like knife and prepared cell samples (smears) by scraping, washing, or by squeezing the tissue slices. Samples from fluids were placed on glass slides without preservatives. Most microscopic preparations were unstained, but occasionally a drop of iodine was applied as a stain." (1)

It was by this approach that he learned about cancerous tumors.  Hajdu said:

In his text on cancer (1851), Lebert gave concise summaries and organ specific descriptions of all forms of tumors. The book consists of 885 pages and discusses the dietary, surgical, and medical treatment of cancer. In 1857, Lebert published a comprehensive pathology text in two volumes that covered everything that was known at that time about anatomic pathology, as well as discussions on clinical pathology. (1)

Hajdu said it was Lebert's work, along with fellow pathologist Julius Vogel (1814-1880) who developed the "concepts of cellular pathology.  Vogel and Lebert established the solid basis on which Rudolph Virchow, in the 1860s, built his general theory about cells."  (1)

Despite his accomplishments, Hajdu said, Lebert (and Vogel too) does not get the credit he deserves, at least as far as pathologists are concerned.  This is yet another example of how history is not always written fairly.

Along with his other accomplishments, Lebert also did research on lungs and vessels, and he used this to establish opinions about asthma.

In 1873, he supported both the spasmotic theory of asthma and the diaphragmatic theory of asthma. However, he  believed asthma was caused by dilation of the blood vessels in the lungs. (2, page 45)

In fact, this theory was still believed to be true when epinephrine was later invented in 1900, as the vasoconstricting (vasopressor) component of epinephrine was thought to increase blood flow to the lungs to make breathing easier. (3, page 38)

Lebert also offered an interesting remedy for asthma. Rene Laennec, among other asthma experts of the 19th century, observed asthmatics often developed asthma at night, or in the dark.  Based on this observation, "Lebert advised the use of as many candles as possible in the rooms of asthmatics," said Orville Brown in 1917.(3, page 38)

References: 

1. Hajdu, Steven I, "The first cellular pathologists," Annals of Clinical Laboratory Science, 2004, http://www.annclinlabsci.org/content/34/4/481.full, accessed 3/11/14
2. Berkart, J.B., "On Asthma: It's pathology and treatment," 1878, London, J. & A. Churchill
3. Brown, Orville Harry, "Asthma, presenting an exposition of nonpassive expiration theory," 1917, St. Louis, C.V. Mosby Company

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1900: The discovery of epinephrine (adrenaline)

You can thank this man, Jockichi Takamine (1854-1922),
for the discovery of Adrenaline.  T'he rescue inhalers we
use today are only available because of his discovery.  
This is a painting he did of himself 
(From Therapeutic Notes, Vol. 28-32). 

Throughout our history there were always options for asthmatics. Yet that said, what remedy worked best for an individual patients was basically a crap shoot, and the relief obtained was palliative at best. This left asthmatics wishing for a quick relief medicine, a rescue medicine, or something that would quickly relieve asthma symptoms when they occurred. That journey began in 1901 when Jokichi Takamine (1854-1922) isolated the pure form of adrenaline, also known as epinephrine.

Actually the journey began a few years earlier. By 1895 physicians began experimenting with adrenal extracts. In 1893, George Oliver (1841– 1915), using his own instruments, studied the impact of glycerol extracts on arteries. In one experiment, he had his son swallow sheep adrenal gland, and he observed how his son's vessels became constricted.  (1, page 155)

He then performed experiments on adrenal extracts at the University of London with Edward Schafer, although were unable to isolate the active ingredient. (1, page 55)(6, NCBI)

 In 1899, even though he had yet to isolate it, John Jacob Abel (1857-1938) gave the active ingredient the name epinephrine, and later Wilson referred to it as adrenaline.  (1, page 155)

Figure 1 --1944 ad showing glass epinephrine,
 ampoule,and a glass syringe with hypodermic needle.
The medicine was drawn up using the needle,
stored in the glass syringe, and either injected
into the patient or into a nebulizer cup.

Since this time, the compounds has been referred to as adrenaline in Europe and epinephrine in America. The confusion that ensued later inspired the World Health Organization to create a law banning the use of two names for the same medical compound, although epinephrine/ adrenaline was grandfathered in. I'm just writing this here to explain why both names are proper and both are still used to this day to refer to the same thing.  (1, page 155-156)

Beginning in 1895 adrenaline extracts were used in experiments to study its vasoconstricting abilities, and to see if this offered benefits for various medical conditions, including rhinitis, conjunctivitis, and asthma. Oliver and Schafer showed the effects of adrenal extract on blood pressure. In 1900, Solomon Solis-Cohen (1857-1948) of Philadelphia showed the effects of adrenal extract on asthma and hay fever. He showed that the pill version of the extract benefited asthmatics. And finally, in 1907 the bronchodilator effect of the substance was proven by Khan. (1, page 156)(14, NCBI)

In 1903, Jesse G.M. Bullowa and David M. Kaplan gave an injection of adrenaline to an asthmatic who, within only minutes, was breathing easy. This was the first known report of an asthmatic getting instant relief from a medicine. (1, page 156)(need second reference).

So, epinephrine was isolated, and then it was synthesized, and this resulted in various epinephrine products. Efforts were then made to refine the compound to obtain the desired effect while minimizing side effects.

Doctors were quick to start prescribing it for their asthmatics, who, as you might imagine, quickly fell in love with the medicine.  Yet the majority of asthmatics continued to stick with their usual asthma remedies, which mainly consisted of asthma cigarettes, powders and incense. Only in an emergency did they seek out a physician, who would give the laboring asthmatic epinephrine, and relief would come within minutes.

The question that remains here is: why did epinephrine give sudden asthma relief? At the turn of the 20th century, asthma experts believed asthma was caused by dilation of the vessels in the lungs (and this resulted in congestion).  So it only made sense that the initial theory was that epinephrine made breathing easier because it constricted vessels in the lungs.  This was also the same reason that cocaine was often used to treat asthmatics.  Many articles report the use of both adrenaline and cocaine. (4, page 854)

Yet another theory, a prominent theory from the 19th century actually, was that asthma resulted from spasming bronchiolar smooth muscles, and in 1907 Khan demonstrated the adrenaline was in fact a bronchodilator. For the next several years both the vasoconstriction and bronchoconstriction theories were believed to contribute to asthma.  (4, page 854)

Adrenaline was initially trialed both orally and subcutaneously, and ultimately it was trialed by injection into the muscles and intravenous.  Various physicians reported the oral route had no effect on asthma, and the muscular route was most effective.  However, there are some reports into the 1910s where physicians continued to debate the best route.

James Adam, in his 1913 book "Asthma and its radical treatment," describes it this way: (7, page 27)

Photo from an advertisement for Adrenaline Ampoules in the 1909-10
edition of"Therapeutic Notes" by Park Davis and Company

Part of the spasm-allaying effect may be due to absorption of the drugs from the nasal mucous membrane or larynx or trachea. But while adrenalin applied to the larynx acts fairly energetically in allaying asthma, applied to the nose it acts much less energetically than when given hypodermically (by injection). However it is given, after arriving at the right ventricle the adrenalin will pass direct to the lungs and there, probably somewhat indirectly, it will have the same effect on the congestion of the bronchi and bronchioles as on nose and larynx. In this way and by its action on the heart it will help to relieve the dyspnoea; but (Brian) Melland  makes a further interesting suggestion. 

Perhaps one first to recommend adrenaline to physicians was Brian Melland.  In the May 21, 1910, issue of Lancet, he "claims marvelous results in the treatment of the paroxysm of asthma by the hypodermic use of preparations from the suprarenal glands. One injection of 10 minims of 1:1000 solution is all that is required, but may be repeated if other attacks supervene." (5)

Melland described some of the experiments he performed on his own patients with severe asthma and hay fever.  One of the case studies is reported on here: (6, page 476)

In the first case, for example, that of a woman 30 years of age, with asthma of 6 years' standing, the first injection of 10 minims of the 1 in 1000 solution caused a paroxysm promptly to disappear and prevented a return of the trouble for seven days, whereas before this spasmodic attacks had been present nightly. After the second injection the effect did not persist so long, and for a time the patient employed every night an injection of (i minims of the solution in order to cut short the spasmodic attacks. After four or five weeks of this, the incidence of the asthma became much less frequent, and the general strength of the patient was greatly improved. The use of adrenalin by the mouth, up to 15 minims of the solution, was also tried in this case, but without result.

These are adrenaline amps from a 1909 advertisement in
Therapeutic Notes.  For the first time the medicine was
pre-measured and pre-satitized.  All that was needed was
to snap off the top and draw up the medicine with a
hypodermic needle (11, page 69)

The opinion of Melland was further expounded upon by James Adam in 1913: (7, page 27)

Adrenalin acts as a stimulant to the sympathetic**. He suggests, and gives supporting evidence, that at the same time it tends to inhibit or relax all involuntary muscles supplied by the cranial and sacral outflow of nerves. Now the constrictor muscles of the bronchi belong to this group,and assuming that spasm of these in part accounts for the asthmatic spasm, they would be relaxed by the adrenalin. Whereas, the constrictor fibre of the bronchial arteries which come off the systemic system, and are, like other systemic vessels, under sympathetic control, will be stimulated to contract, and so the congestion is reduced.

The author's of General Medicine words it in a more friendly fashion: (8, page 164)

Melland believes the adrenalin acts by relaxing the muscles supplied by the vagus nerve, and since the bronchial muscles are innervated by that nerve they are relaxed and the spasm ceases.

By the many articles, snippets and editorials about Melland's article, you can tell there must have been quite a bit of excitement among the medical community, and asthmatics, about this new medicine.  Another example of this comes from the following snippet from Therapeutic Notes in 1909:(9)

ADRENALIN IN ASTHMA.
A practitioner of wide repute in one of the Central States sends us these words: "I wish to write you a word or two about the use of Adrenalin in asthma following hay-fever. Last year my wife was suffering so greatly with this affliction that she could scarcely breathe. No ordinary remedies appeared to give her any relief, so in desperation I sprayed about twenty drops of the stock solution up into the nostrils, and in a few minutes the paroxysm was over and did not return. I am not in the habit of writing this kind of a letter, but this experience is bona fide and I think it should be known."

The hypodermic needle is a hollowed out needle that allows for medicine
to be drawn into a glass syringe and injected into a patient.  It was invented
in 1853 by Dr. Alexander Wood to make it easier to give blood tranfusions
to patients.  It is one of the top 10 medical inventions of all time.  Here is
a nice case by Park, Davis & Co. for its glass syringes. (11, page 269)

Yet there were side effects.  The vasoconstricting quality of the medicine caused blood flow to speed up and this increased blood pressure, and increased the force and rate of the heart.  It also caused asthmatics to feel jittery, anxious and hyper. And while it provided instant relief, this relief only lasted about an hour and a half to two hours.

The next revolution occurred in 1909 when Parke, Davis & Co. introduced glass ampules that they marketed  as Glaseptic Ampoules.  Ads and articles claimed this made it so accurate doses of the the companies line of soluble medicine, such as adrenaline, could be easily and quickly drawn up in an emergency using a hypodermic needle and glass syringe.  This was a major revolution because prior to this physicians or nurses had to sterilize the water to mix with the medicine, and they had to make sure they measured the medicine up correctly.  Each Glaseptic Ampoule "contains a definite quantity of medicament, an average dose," according to ads.*** (10, page 68-9)

Adrenaline solution as pictured in the 1924 edition of Therapeutic Notes

Also in 1910 British Chemist George Barger (1878-1939) and British Pharmacologist Henry Dale (1875-1968)  reported the use of adrenaline as an inhalent.  (4, page 854) Various nebulizers were available, with one of the more common ones being the Glaseptic Nebulizer marketed by Park-Davis and Company.

Another  report of adrenaline being administered by an inhaler came from a London medical practitioner in 1929. (4)( (1, page 156) By this time there were improved nebulizers on the market such as the Speiss-Drager (Apneu) Nebulizer.  During the 1930s various nebulizing products were purchased by physicians to use in their offices, and patients to use at home.  The decade also saw the birth of the electric nebulizer, the Pneumovac.  It was often purchased by pharmacists and the patient would visit the pharmacy for treatment.

Also during this time epinephrine was available under a variety of brand names, including Adrenaline, Adrenaline Chloride, and Asthma Nefrin.

So the quest was on to learn more about this medicine, to fine tune it to get rid of side effects, to make it last longer, and to discover better and faster modes of delivery.

** This will be described in the next post in this series, see "How does epinephrine work" below

***The ampoule was invented in 1886 by a French pharmacist names Stanislas Limousin.  It was invented in response to a need by physicians to conserve their stock of injectable solutions that became difficult to transport and also deteriorated rapidly due to development of moulds.

Further reading:

1. 1893-1933:  How does epinephrine (adrenaline) work?
2. 1933-1957: Research leads to asthma rescue medicine
3. 1900-present: The evolution of rescue medicine

Click here for more asthma history.  

References:

1. Sneader, Walter, "Drug Discovery: A History," 2005, Wiley, Great Britain,  page 155-157. (Sneader provides a very thorough history of the discovery of hormone therapy in the later portion of the 19th century.)
2. " Jockichi Takamine ," Encyclopedia Britannica.com,  http://www.britannica.com/EBchecked/topic/581144/Jokichi-Takamine, accessed 3/6/13
3. Jackson, Mark, "Asthma: A Biography," 2009, Great Britain, Oxford University Press
4. Rau, Joseph L., "Inhaled Adrenergic Bronchodilators: Historical Development and Clinical Application," at AARC.org (American Association of Respiratory Care, July, 2000, Vol. 45, number 7), pages 854-62
5. Melland, Brian, "Some Therapeutic Suggestions: Asthma Paroxysms," Therapeutic Notes, volumes 17 and 18, 1909 and 1910, Park Davis and Company (this snippet is from "Therapeutic Notes, who quote it from an New England Medical Monthly, July, 2010.  The original article referred to here was published in Lancet, May 21, 2010, 
6. Euchariste, Chgarles,  de Medici Sajous, John Madison Taylor, John Vietch Shoemaker, editors, "Cyclopedia of Current Literature: Asthma, Spasmotic, Hypodermic Injections of Adrenalin in the treatment of," volume 3, page 476, review of Brian Melland's report from Lancet, May 21, 2010.
7. Adam, James, "Asthma and its Radical Treatment," 1913, page 27 (Adam references from Melland, Lancet, May 21, 2010)
8. Billings, Frank, George Howitt Weaver, J.H. Salisbury, editors, "Asthma: Treatment," General Medicine, Volume 1, The Practical Medicine Series Comprising Ten Volumes On The Year's Progress In Medicine And Surgery, 1911, Chicago, The Year Book Publishers,  page 164
9. "Adrenaline in Asthma," Therapeutic Notes, Volumes 17 and 18, 1909 and 1910, page 6
10. "Already for use, Solutions we now supply in ampules for the convenience of our medical friends,"  Therapeutic Notes, volumes 17 and 18, 1909 and 1910, Park Davis and Company, pages 68 and 69.  Also see ads on page 59 and pages 259, page 69, page 269 (note: you may have to scroll down a few pages to get to the advertisements)
11. Rubin, Ronald P., "A Brief History of Great Discoveries in Pharmacology: In Celebration of teh Centennial Anniversary of the Founding of the American Socieity of Pharmacology and Experimental Therapeutics," Pharmacological Reviews, December, 2007, vol. 59, no. 4, pages 289-359 (This article provides a good history of the discoveries of the sympathetic nervous system, the neuromuscular synapse, and how hormones such as adrenaline work)
12. McFadden, E.R., "A Century of Asthma," American Journal of Respiratory Critical Care, August 1, 2004, volume 170, no. 3, pages 215-221
13. Bennett, Max R., "History of the Synapse," Chapter 4: "The discovery of adrenaline and the concept of autoreceptors and synapses," 2001, Britain,  Harwood Academic Publishers, pages 65-77, also available at the link: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.462.9571&rep=rep1&type=pdf, accessed 4/14/16
14. Barnes, Peter J, "Drugs for Asthma," British Journal of Pharmacology, January, 2006, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760737/, accessed on 4/14/16