Monday, January 02, 2012

1900: The discovery of epinephrine (adrenaline) x

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.

*In 1903 adrenaline was injected into an asthmatic who, within only minutes, was breathing easy.  This was the first known report that an asthmatic got instant relief by an asthma rescue medicine. I have lost the reference to this, and therefore have deleted it from the post.

** 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

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