1913: Cauterize your nose, cure your asthma

Another interesting concept of Adams is that he denied that most asthmatics had allergies, although he associated abnormalities in the nasal cavity with asthma.  He noted that Henry Hyde Salter cursorily mentioned the relevance of the nose in cases of asthma, when such knowledge was known since 1844 when Herck of Freiburg noted the association of sneezing and asthma. (1, page 89)

Later, Adams noted, Voltolini, in 1872, claimed to have "relieved eleven cases of asthma by removal of nasal polypi.  This idea received further impetus when Lazarus, Brodie and Dixon and others showed that electrical stimulation of the nasal mucosa caused bronchial spasm."

Ernst Schmiegelow explained that Voltini noted that no other asthma physicians prior to him noted the link between nasal polypi and asthma.  And while polypi are not always associated with asthma, there are noted cases where, upon removal of the polypi, the asthma disappeared. Although, if asthma has existed long enough so that it is chronic, removal of the polypi will not make the asthma disappear. Schmiegelow notes that Voltini's opinions were confirmed by Hanisch. (2, page 14)

Schmiegelow notes that "Hanisch thinks that as not all nasal polypes cause asthma, there must be a certain debility of the whole organisation or at least of the organs of breathing. In the nasal polypes themselves he finds sufficient ground for the weakened state of the organisms and lungs, as the insufficient breathing, the restless sleep, the buccal respiration, etc., must be considered capable of causing the general weakness."  (2, page 14)

B. Frankel and Weber also confirmed the findings of Voltini, and they also believed that chronic catarrh could also cause asthma. They believed irritation of the nasal mucous membrane passed a message down the pneumogastric to the pulmonary fibres, causing asthma, and "the result of the reflex was always a bronchospasm.". (2, page 15) Henry Hyde Salter previously mentioned this, and referred to is as reflex asthma.  

Schmiegelow also mentions a Dr. Wilhelm Hack, who "supported by casuistic observations, considered a number of different nervous diseases from the same point of view. Hack's principal object was to show that in the swollen cavernous mucous membrane in the foremost end of the inferior turbinated bones, different nervous states of irritation originate, and these reflex neuroses can be caused experimentally, and they disappear entirely as soon as the places in question are operatively removed. The filling of the cavernous membrane is, according to Hack, the essential in the pathogenesis of these reflex neuroses."

Adams notes that other physicians were so focused on the other theories of asthma, particularly that asthma was neurotic, that they were overlooking the true cause: that there was a problem with the patient's nasal passage causing the asthma, or that there was a toxaemia in the blood causing asthma as I discussed in this post.

Adams emphasises the following: (1, page 89-90)

"I have seen patients with noses absolutely ruined, mere shells of what they should have been—their asthma remaining the same, but promptly clearing up on simple antitoxaemic treatment, except in the case of a poor woman who owed an opium habit to her doctor. Francis cauterises the septal tubercle of all asthmatics—sometimes a valuable temporary procedure; others would also cauterise the lower turbinals—an unnecessary addition. The value of proper nasal treatment cannot be gainsaid; but that it should be subsidiary and ancillary to treatment of the toxaemia I have, where mouth breathing was absent, occasionally and successfully proved by the experiment of carrying out the latter treatment and leaving the nose alone. Apart from the experimental and therapeutical evidence just mentioned, the importance of a nasal factor in asthma can be gauged from several considerations."

Some of the ailments he observed on asthmatics, were:

• Nasal polypi
• Deviated Septum
• Hypertrophied areas in nasal passages
• Pigeon chest (due to laboring for air so frequently)
• Mouth breather
• Expanded shoulders (due to years of laboring for air)
• Expanded chest (due to emphysema if chronic)

References:

1. Adam, James, "Asthma and it's radical treatment," 1913, 
2. Schmiegelow, Ernest, "Asthma, considered specially in relation to nasal disease," 

1909: Pituitrin tried for asthma and hay fever

Pituitrini was an extract of the bovine pituitary gland.  Along with other uses,
it was trialed for asthma by various physicians, and with success, around
1909 and 1910. The medicine was provided by Park-Davis & Co. out
of Detroit, Michigan in one-ounce glass stopper bottles and glaseptic
  ampoules (ready for immediate hypodermic injection) as seen here. (2)

Another medicine that was trialed for asthmatics around the 1910s was a medicine called Pituitrin. It was an extract of bovine pituitary gland containing oxytocin and vasopressin, and being a relatively new medicine it garnered much attention among the medical community. As with other new medicines, it was trialed for various purposes, including asthma. 

The medicine "has been somewhat extensively used for the past two or three years," by European physicians for its Oxycontin effect on some pregnant women to help strengthen labor and reduce bleeding.  (1) It does this by constricting blood vessels.  It also is a bronchodilator, and for this reason, it was trialed on asthmatics.

In 1919 the Therapeutic Notes reported the following:

The fact that Pituitrin has an Adrenalin-like action, and the fact that this action is more prolonged than that of the suprarenal active principle, has suggested its utility in the treatment of asthma and hay-fever. It has been tested clinically by leading practitioners, who pronounce it a valuable drug in these diseases. Some opinions are here given:

 "One of my asthmatic patients has experienced great relief from the use of Pituitrin.""I have used Pituitrin in two cases of hay-fever with satisfactory results. While ischemia is accomplished less slowly it seems to last much longer; one patient who experienced great irritation from the use of Adrenalin says that the Pituitrin is almost without any irritating effect.'' 

"I have one case of asthma which was relieved by the use of Pituitrin; it is also of a great deal of use in the treatment of hay-fever." 

"A case of hay-fever treated with Pituitrin in normal salt solution (1:3) showed decided relief. I found that its. action was slower, more prolonged and less irritating than Adrenalin, and no after-congestion resulted as in the case of the latter." 

"I used Pituitrin daily in one case of hay-fever, employing the undiluted solution so as to give the hardest possible test as to its irritation. There was no irritation and the relief was perfect.'
"When used in a 10-per-cent normal saline solution the results were very satisfactory."

 It's very common throughout human history to find a medicine experimented with in this fashion, and this continues to this day.  Also, in the 1970s a medicine called terbutaline was approved for asthma as a rescue medicine, and it was ultimately more commonly used to delay pregnancies.

Probably due to the success of adrenaline, pituitrin never caught on as an asthma medicine.  Yet it provided another option for physicians and asthmatics when such an option was necessary.

References:

1. "Pituitin in difficult parturition," Medial Review, June, 1912, Volume 61, Issue 6, Picture is from an advertisement that follows the article paid for by Park-Davis & Co.
2. "Pituitrin in Hay fever and asthma," Therapeutic Notes, Volumes 17 and 18, Park-Davis & Co., 1909 and 1910, page 70.

Further reading: 

1. article on pollen and hay fever

1898: Interesting remedy for hay fever

One of the first doctors to recommend nasal rinses, or nasal washes, was Dr. William Hollopeter in his 1898 book "Hay-fever and its successful treatment." He believed that by washing the nasal passages you'd also be washing out the exciting factors that might contribute to hay fever or other diseases.

Hollopeter said he conducted a study of the sputum of children waiting treatment for hay fever, and he found the bacteria of: (1, page 103)

• Diphtheria
• Scarlet fever
• Measles 
• Whooping Cough
• Tuberculosis

So he concluded that while these children showed "no constitutional indication of the disease whatever," the following bacteria, or some other substance (such as dust or pollen) may be in the sputum to cause hay fever. So a rational treatment here was washing the nasal passages. (1, page 103)

He said that in order for a disease to occur, some weakness has to occur within the body, such as a decrease in vitality or resistance. So, an "overwhelming exposure" to an "unhygienic environment" would result in hay fever or some other disease.

Hollopeter said:(1, page 104):

Conceded that an external irritant is necessary to cause the disease, to prevent or cure it we must either prevent the irritant from reaching the points of exposure, fortify these vulnerable spots, or remove or render inert the irritant when already lodged. In hay-fever the vulnerable spot is undoubtedly somewhere within the nasopharynx (nose and throat). It is now conceded that the nose and throat are entrances for the bacteria of many infectious diseases; and I feel sure that as I have limited the extension of house-epidemics of scarlet fever, diphtheria, whooping-cough, and measles by a carefully conducted antiseptic toilet of the nose and throat, in the same manner I have prevented the dreaded paroxysms in cases of hay-fever.

So it is for this reason the he tried a daily sterilization of his hay fever patients, and, lo and behold, it was successful. The idea behind daily sterilization is this: (1, page 103)

By a daily sterilization of the nares and postnasal spaces the victims of hay-fever may remain in the city attending to their usual duties, surrounded by dust, or in the country amid blooming flowers, without any fear of the distressing symptoms—a consummation devoutly to be wished for by the great army of hay-fever sufferers.

Therefore, he recommended the following daily treatment:

1. Cleansing the nasopharynx with a hand ball atomizer containing a warm solution of boric acid (10 grains to an ounce of water) or Dorbell's solution. Afterwords, wipe the mucous membrane and apply menthol and liquid cosmolin freely to the parts (this would have to be done by the doctor) (1, page 107)
2. Removal of hypertrophy or polypi he no longer recommended because it causes pain and increased inflammation. He therefore recommended Debell's solution applied first with a hand ball atomizer and then with a curved aluminum applicator or Harrison Allen's cotton carrier. Very carefully swab the whole nasopharynx . Dry membranes with clean cotton, followed by free use of blandine comp. (a solution of menthol in albolene). 
3. Surgery only when absolutely necessary, and always followed by 1 and 2 above

When I first stumbled upon this remedy in this book, I thought it sounded very interesting and odd. However, upon further review, it was't far removed from the nasal washes I was forced to endure daily when I was a kid, and what is still recommended to this day for many sufferers of nasal rhinitis.  

So, he said:  "I believe that acute infective disease, particularly in children, may be prevented by most thorough and repeated sterilization of the nasopharynx, and just as house epidemics are never excusable evils so I claim the same to be true of hay fever." (1, page 106)

Here is a recipe for making a nasal rinse.

---

Dobell's Solution:

•   R. Sodii bicarb
•   Sodii boratis
•   Acidi carbolici
•   Glycerini
•   Aqua? rosae, 25 per cent
•   SlG.—Teaspoonful to one ounce of warm water.

---

If you are so inclined, try it and let us know if it works.
References:  

1. Hollopeter, William Clarence, "Hay-fever and its successful treatment," 1898, Philadelphia, P. Blakiston's Son and Co.

1904: Wompole's Hypno-Bromic Comp will cure your asthma

By 1904 asthma was still a nervous affection, and a notable treatments were medicines to ease the mind. One such remedy was Wompole's Hypno-Bromic Comp.  

According to a 1904 article in the New Albany Medical herald:

"If you want to give your patient relief from asthma, and a good refreshing sleep from which he will wake greatly refreshed, Just try wompole's hypno-Bromic Comp.  It will give quick and satisfactory results. Give this relief to the next case of asthma you are called to treat." (1, page 584)  

Cocaine and morphine were often prescribed to help a nervous person sleep. But, ccording to an 1898 article in Medical Progress, Wompole's Hypno-Bromic Comp. not only worked better, but was safer.  The article mentions a case where morphine was trialed, although after a while it allowed the patient, a female, to "sleep an hour or two.  She was given a teaspoon of Wompoles Hypno-Bromic Comp. each night immediately after she had come out of the bath.  This remedy had a most happy effect."

Two other cases were also described, and the results were essentially the same.  (3)

A recipe for this product can be made in your own kitchen:. Here are the ingredients. 

Chloral hydrate gr. 480
Potassium bromide gr. 240
Extract of henbane gr. 4
Extractofcannabisindica.gr. 4
Morphine sulphate gr. 2
Simple syrup fl. dr. 4
Comp. spirit of orange. fl. dr. 1 Water, enough to make. fl.oz. 4 Make a concentrated solution of the chloral hydrate in water, triturate the extracts with this solution; add the potassium bromide and the morphine each dissolved in water, the spirit and the remainder of the water, and filter clear.(2)

This would have been just another option in the days when there were no ideal treatments for our disease.

References:

1. "Medical Gleanings," New Albany Medical Herald, volume 22, No. 286 October, 1904, New Series Volume 11, Number 157 
2. Hiss, Emil, "Thesaurus of Proprietary A recipe for this product can be found on page 271 of Emil Hiss's 1898 book "Thesaurus of Proprietary Preparations and Pharmaceutical Specialties," 1898, Chicago, G.P. Englehard and Company page 272
3. "Suggestions on the management of nervous trouble," The Medical Progress: A monthly history and medical progress,John S. Moreman, M.D., editor, July 12, 1896, volume 12, new series number 79, old series number 126, pages 248-248

1907: Dr. James Sawyer's Asthma Powder

The following is the recipe for making Dr. James Sawyer's Asthma Powder as per The British Pharmaceutical Codex:

---

PULVIS STRAMONII COMPOSITUS.

Compound Stramonium Powder.

Synonym.—Sir James Sawyer's Asthma Powder.

Stramonium Leaves, in powder ... ... 50.00

Lobelia, in powder ... ... ... ... 6.oo

Anise Fruit, in powder 12.00

Tea Leaves, in powder ... ... ... 6.oo

Oil of Eucalyptus 1.oo

Potassium Nitrate, sufficient to produce ... 100.00 

Mix the oil with the vegetable powders, then add the potassium nitrate.

This powder is used to relieve asthma. About half a teaspoonful is pressed by the fingers into the shape of a cone, which is then lighted at the top; the patient inhales the fumes as the powder burns. The powder is used several times daily, as may be necessary, for asthma. Pulvis Lobeliae Compositus is a similar preparation.

Note.—A simpler form of Sir James Sawyer's Asthma Powder consists of 50 of stramonium leaves in powder, mixed with 25 each of potassium nitrate and anise fruit in powder; it may be distinguished as Pulvis Stramonii Nitratus.

---

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

1978: No antihistamines for this asthmatic

I remember my mom specifically telling me when I was a kid that I can't have antihistamines. She said they may cause bronchospasm, and that doctor said so. What my doctor prescribed for me instead was Tedral and salt water drops. That's it!

I remember many times when my nose was so plugged I couldn't sleep. I remember playing outside and my eyes would basically swell shut. Mom would have me lie on the couch, or on my bed, with a cold, wet rag over my eyes. Obviously, this affected my social life.

It also affected my asthma. 

My doctor, according to a 1978 notes my mom took while talking with my doctor on July 14, 1978, I was supposed to take Tedral three times a day, and rinse my nose with salt water drops four times every day. The medicine tasted terrible, and rinsing out my nose with salt water was torture. I hated both. 

It kind of reminds me of something Teddy Roosevelt wrote in his diary about growing up with asthma in the mid 19th century: "The medicine was often tortuous, and was often worse than the disease." I am paraphrasing it here, but that's pretty much what he was saying. I would have to say, that in the 1970s, asthma treatment wasn't much different. 

I can understand why my doctor would not prescribe for me a medicine that probably would have offered me some relief. It goes back to a myth in medicine during the 1950s and 60s that antihistamines, although they offered relief from allergies, dehydrated your lungs. This, it was believed, would cause bronchospasm and asthma.

I think it would have made more sense if they would have prescribed me an antihistamine, such as Marax (I am told it actually tasted good). I could have trialed it to see if it offered a benefit, If it didn't, or if my asthma got worse while taking it, I could have stopped. But this trial never happened. Instead, based on a myth, I suffered.

Now, by 1976, this myth was on the way out the door. The down side here is that most doctors were educated back in the 1950s, when the myth was taught in medical schools. Unless they kept up to date on their studies about asthma and allergies (and asthma was considered an allergic disease back then), doctors -- such as my doctor -- would have prevented themselves from prescribing antihistamines to asthmatic kids such as myself. 

An article in the January, 1968, edition of the Journal of the National Medical Association makes light of this myth. 

Antihistamines. The use of antihistamines in asthmatic children has been condemned in the past. In theory, they should be valuable in counteracting the effect of one of the principal allergic mediators-histamine. However, they do dry secretions and possibly, aggravate the patient with asthma. Practically speaking, some small children with pollen allergy do respond to antihistamine. But, generally, they are not effective in reversing bronchospasm. (1)

I did not start using antihistamines until I was over 18. They worked great, and have never induced asthma. I suppose I could hate my doctor and parents for not allowing me to have them, but I'm not. This is just one of those life lessons you learn as you grow older. You do the best you can with the wisdom you have today, and as you learn better you do better.

References:

1. LeNoir, Michael A., Lawrence D. Robinson, outpatient management of an asthmatic child, Journal of the National Medical Association, January, 1976, page 46-50, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2609533/pdf/jnma00473-0072.pdf, accessed 2/22/17

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