Showing posts with label steroids. Show all posts
Showing posts with label steroids. Show all posts

Sunday, October 9, 2016

1980s: The first corticosteroid inhalers

By the 1980s, it was evident that corticosteroids helped asthmatics gain control of their disease, although it was also evident that prolonged use of high doses resulted in severe and unwanted side effects. Despite this setback, efforts were ongoing to refine the chemical composition of steroids and to develop a method of delivery suitable and safe for asthmatics. This lead to the introduction of inhaled corticosteroids to the market in 1972.  (7)

This was the year that Allen & Hanbury introduced beclomethasone to the market as Becotide, with the recommended dose of 4 puffs daily of 100 μg per puff, a total of 400 μg per day.  (7)

Ten years later, in 1982, the FDA approved two beclomethasone inhalers in the United States: GlaxoSmithKline's Vanceril and Schering-Plough's Beclovent. Other oversease brand names were Becloforte, and Beconaise.  (You can see a 1979 ad for Beclovent and Ventolin from the Canadian Medical Association Journal here. )

Initial studies confirmed the benefits of daily use of this medicine, although it was usually only initiated by hospital physicians due to ongoing fears that even low dose steroids from inhalers could produce unwanted side effects.  (7)

I can use myself as evidence here. I actually have my discharge instructions from a hospital admission in 1984. A note to my mother says, "Have this boy take 2 puffs of Vanceril 4 times daily until he starts to feel better, then only use it when he feels symptoms."

Taking an inhaler four times daily was not easy for an eleven-year old. I would take it to school with me, and then I'd forget to use it. Or, worse, I would hesitate to use it because I didn't want to use it in front of my peers at school. Either way, for one reason or another, taking it compliantly was not easy.

Of course, when I left the hospital I was probably either recently removed from steroids or still on a Medrol pack. And as soon as I was weaned off of them, I was susceptible to the effects of whatever triggered my symptoms in the first place, which was probably dust mites. Sure I tried to avoid them, but the ubiquitous nature of dust mites makes them very difficult to avoid.

So, at some point, I'd be weaned off systemic steroids, would quit using my inhaled steroid, my symptoms would come back, and I'd end up using my Alupent inhaler with increased frequency. Actually, my asthma was so severe that even if I was taking my Vanceril compliantly I might still have symptoms.

During moderate to severe episodes, which was usually the case with me, I'd go through an Alupent inhaler pretty fast. Sometimes it would last a month, and those were the good times. More likely, it lasted a few weeks, or one week, or a matter of days. I know there were times I'd puff through an inhaler in one day.

And, when you're a boy with anxiety, and a boy who is shy like I was, and a boy who is self conscious and who doesn't like to ask for help, you don't seek help when you need it. So I'd suffer from asthma all day, sometimes praying it would go away and knowing it wouldn't. Usually, by the time I sought help I was beyond quick repair, and required a six day admission in a hospital.

For those of you who are wondering why my parents didn't recognize I was having trouble breathing, they probably did. You have to realize that this was back in the early 1980s, when there wasn't a whole lot of parental education about asthma. And even if my parents did know I was having trouble, I developed quite the skill of staying calm and not giving off the appearance that I was having trouble. So, my parents are off the hook.

And it's not that I didn't know better, because I did. I was very much aware that I needed help. It's just that I knew my parents were busy, and I didn't want to bother them. This was especially true when I had only recently visited the emergency room with one of my parents, and had felt guilty that I was overusing my rescue inhaler.

A side story here, and one for another post, is that I also felt guilty asking my mom to buy me another Alupent inhaler. This was especially true when she JUST bougth me one and it was empty already. So, by the time I got the nerve to tell mom I needed help, I was also nervous that they'd be able to tell I was abusing my Alupent.

However, in retrospect, they never said a word about this; they were just happy that I came in to get help, and they did a very good job of making me aware that they were happy I came in to seek help. The good folks at West Shore Hospital got to know "Little Johnny" really well, and the boy really like them, got to know some of them personally.

But I digress. As far as I knew, I was the only asthmatic who had it this bad in the entire world. Little did I know that I was not alone, and studies showed this. So, perhaps this was why my doctors never bothered me about my high frequency of Alupent use.

In 1982, Flunisolide was introduced to the market by Forest Laboratories as Aerobid. Aerobid was supposedly stronger than Azmacort, requiring fewer puffs daily. Many physicians were prescribing it for their patients, and mine was no exception. I, however, could not stand the taste, and was quick to complain about this to my doctor so I could get back to the better tasting Vanceril. Like beclomethasone, the standard dose was four puffs daily.

In 1973, budesonide (Pulmicort) was patentted, although it was not used clinically to treat asthma until 1981. A landmark study in 1982 by Wiley and company showed that two puffs daily (once in the morning and once before bed) of budesonide was as effective as four puffs daily of beclomethasone.

 by https://www.ncbi.nlm.nih.gov/pubmed/7037035

In 1984, Triamcinolome (package insert here) was introduced to the market by Abbott Laboratories as Azmacort. It's formula was slightly stronger than beclamethasone. It was a bulky white inhaler that had its own built in spacer. This was nice in that it required use of spacer with the medicine, improving coordination and increasing airway deposition to assure that the ideal dose was inhaled. Like beclomethasone, the standard dose was four puffs daily.

I was introduced to this inhaler in 1984. It was nice in that physicians for years had recommended I use my spacer when taking my inhalers, although spacers were large, bulky, and inconvenient to carry around with you. This made them less than ideal, as it was easier to pick up an inhaler and use it without a spacer. The Azmacort built in spacer was nice, although made it impossible to put into your pocket, pretty much assuring that any dose required during school hours would be missed.

At some point my dose of Azmacort was upped to 4 puffs 4 times a day, and, as you might imagine, this was very difficult to be compliant with, even for the most gallant of asthmatics.

I like to think of asthma similar to doing homework and getting good grades. Every semester I would work hard and try to get all A's. However, as time went by, it became harder and harder to study at night. For instance, there was other things to do, funner things to do, like playing football with my brothers. They would bug me until I gave in and played. Being compliant with my Azmacort was the same. I would get a new one and promise myself to take all my puffs, to be a gallant asthmatic. But soon enough I'd get busy, and forget, and puffs would get missed.

Through all of this I thought my doctor would say something. Through all of the extra puffs of albuterol and missed puffs of my corticosteroid inhaler, I thought my doctors would find out and lecture me. But they never did. Now, as an adult, I understand that they were probably aware of all this, and probably didn't say anything because they knew that they would have a difficult time with it, let alone a boy trying to get through life with severe asthma.

My doctor would review all my medicines with me at each appointment, and he would remind me of when I was supposed to take them. Actually, that didn't happen very often. Still,under it all, I'm sure he was aware that such a task was daunting. I know he empathized with me, otherwise he wouldn't have met mom and me at his office after hours. He did this more than once.

Noting the difficulty of taking four puffs daily, studies, studies, such as one conducted by Williams and company in 1986,  purported to show that 2 daily puffs of 200 μg was as effective as four puffs of 100 μg per dose, with a daily dose of 400 μg either way. 

Such studies were neat, in that during the 1990s most asthmatics were changed to a regular routine of 2 puffs daily for maintenance medicines, and this worked to greatly improve compliance with such inhalers. I know this to be true from personal experience. 

References:
  1. Primary Care Respiratory Journal,"A brief history of inhaled asthma therapy over the last fifty years," Volume 15, Issue 6, December 2006, Pages 326-331
  2. Williams, Hywel, et al., "Twice daily versus four times daily with beclomethasone dipropionate in the control of mild childhood asthma," Thorax, 1986, 41, pages 602-605

Thursday, October 6, 2016

1970s: Steroids for Asthma: Part II


By the 1970s, most drugs that contained cortisol were called corticosteroids, or glucocorticosteroids, or simply steroids. They were mainly prescribed in low doses to end severe asthma episodes, and usually in conjunction with epinephrine, or a longer acting version of epinephrine called susphrine.

And then you were gradually weaned off of them over the course of about a week. This allowed your adrenal cortex time to start gradually producing its own cortisol in order to prevent the risk of sudden onset symptoms that occur when cortisol production is shut off, which includes the risk of dying a sudden death.

Steroids were only used when the short term benefits were determined to outweigh any risks of long term side effects. One such circumstance would be if a physician believed the risk of dying from an asthma attack remained high despite aggressive treatment with the bronchodilators such epinephrine or Isuprel, plus the intravenous application of aminophylline, then the option left on the table intramuscular steroids.

It usually took about an hour for steroids to start working. One doctor explained to me a few years back that this was the reason susphrine became so popular among emergency room physicians. He said an asthmatic would come to the emergency room struggling to breathe, and would be given an intramuscular injection of susprine.

Susphrine was a long acting version of epinephrine that lasted several hours as opposed to just a few. He said it was well liked because it would be given at the same time as an intramuscular steroid. The susphrine would open airways within five minutes, and would last long enough for the steroid to take effect.

He said this was nice because it allowed emergency room physicians to send patients home knowing that they would be breathing easy long enough for the steroid to start working. It was a nice combination of medicine.

I know, because I was given these two medicines nearly every time I entered an emergency room for severe asthma. I remember I'd come into the ER, and I would be given an Alupent breathing treatment. I knew the treatment wasn't going to do any good, but remember politely puffing it while the nurse, respiratory therapist, and doctor waited to see if it would work. But all along I would just wait for the shot -- the susphrine shot.

I didn't know this at the time, so the susprine was the only medicine I looked forward to. I would watch the clock, while clutching the edge of the bed with my shoulders high working hard to suck in air, knowing that at the five minute mark I'd be able to take in a deep breath. Oh, what relief that felt like, to finally be able to take in a deep breath after suffering for so long. Lord knows I would never tell my parents to take me to the ER until after I had suffered long and hard, and knew that it wasn't just in my head.

So really, while I thought it was the susphrine that was helping me, it was the combination of both the epinephrine product and the steroid product. One opened my airways short term, and one kept them open long term.

I remember having asthma attacks at home, and mom would walk me to the bathroom, where a medicine that helped me breathe better was kept in the medicine cabinet. I remember it tasted horrible, which makes me think it was probably a steroid solution.

1950: Seroids for asthma

In 1949, a report was published noting the benefits of steroids for rheumatoid arthritis. This inspired researchers to experiment with cortisol and ACTH for other diseases, including asthma and allergies. By 1950, the results of the first studies using steroids for asthma came back positive. (1, 2)

The first study showing the benefits of steroids for asthma and allergies was published in 1950 by Carryer and company. They showed that oral cortisone benefited patients with allergies and asthma induced by ragweed pollen. (1, 3)

In 1951, Maxwell F. Gelfand reported on the benefits of inhaling aerosolized cortisol on the treatment of allergic asthma. This was the first study showing the benefits of inhaled corticosteroids for asthma. (3, 4)

In 1955, the first synthetic version of cortisol was approved by the FDA and entered the market as prednisone under the brand name Meticorten by Schering.
That same year, the first synthetic version of ACTH entered the market as prednisolone under the brand name Delta-Cortef by Upjohn. Subsequent studies confirmed the efficacy of these synthetic steroids for the treatment of asthma. (1, page 18) (need more references)

In 1959, methylprednisolone was approved by the FDA and entered the market as Depo-Medrol. Dexamethasone also entered the market in the 1950s as Decadron by Merck. It was shown to produce greater anti-inflammatory effect with less side effects as the other corticosteroids. (9, 10)

Dexamethasone was actually the first corticosteroid to be marketed as a solution to be nebulized, and this was shown to benefit asthmatics in studies performed in the 1960s.  (8)

In 1956, another study was performed by the Medical Research Council in Britain confirming the benefits of cortisol for the treatment of acute and severe asthma episodes. This and other similar studies showed how well oral or intramuscular cortisol worked to end severe asthma exacerbations.  (3, 5)

These and other similar studies confirmed the benefits of steroids for moderate to severe asthma, and they were prescribed generously, mainly because doctors and patients alike could see their benefits.  Sales of systemic corticosteroids boomed during the late 1950s and early 1960s.

However, it did not take long for the harsh side effects of long-term use to become a concern.

Steroids were learned to cause fluid retention, which results in a moon-face, thinning skin that easily bruises, acne, hypertension and diabetes. It also causes weakened bones, osteoporosis, and increased risk for bone fractions. It was also shown to stunt growth, obesity, and glaucoma.

It also became apparent that the diminished immune response responsible for reducing airway inflammation and controlling asthma also slowed healing, which was particularly concerning for those requiring surgery.

Various subjects died as a result of steroids use, some dying as a result of rapid cessation of the medicine. It was soon learned that when a person was taking steroids, their adrenal cortex stopped making natural cortisol.

By 1960, the systemic side effects were such a grave concern that the medical profession all but shunned the use of them. They went from "miracle cure" to condemnation after less than a decade of use. (6)

In the early 1970s, steroids were prescribed for people with moderate to severe asthma to control moderate to severe asthma. These were still only prescribed when oral and inhaled bronchodilators failed to work. (1)

By the 1980s, low dose steroids were used with regularity to control moderate to severe asthma, although they were used only when absolutely necessary. Inhaled corticosteroids were also an option, and even these were used sparingly due to fears of side effects.

References:
  1. Brenner, Barry E, editor, "Emergency Asthma," 1999, New York, Marcel Dekker Inc., page 18
  2. Cromptom, Graham K, "A Brief History of Inhaled Asthma Therapy," Primary Care Respiratory Journal, 2006, 15, pages 326-331, https://www.researchgate.net/publication/6704067_A_brief_history_of_inhaled_asthma_therapy_over_the_last_fifty_years
  3. Byrne, Paul M., "Future Trends in the Use of Corticosteroids in Asthma," 2000, pages 120-140, http://link.springer.com/chapter/10.1007%2F978-3-0348-8480-8_7, in the book "Asthma: Epidemiology, Anti-Inflammatory Therapy and Future Trends," edited by Mark A. Giembycz and Brian J. O'Conner, 2000
  4. Gelfand, Maxwell L, "Administration of Cortisone by the Aerosol Method in the Treatment of Bronchial Asthma," New England Journal of Medicine, 1951, August 23, 245: 293-294, http://www.nejm.org/doi/pdf/10.1056/
  5. Jackson, Mark, Asthma: The Biography," 2009, New York, Oxford University Press, page 136
  6. Buer, Jonas Kure, "Origins and Impact of the Term "NSAIDs," inflammopharmacology," July, 2014, file:///home/chronos/u-48b0af7d8a6e832f841243beb1bf56db699d3e12/Downloads/NSAID%20accepted%20version%20for%20self-arch.pdf
  7. Pfeiffer, John E., "How Hormone Team is Saving Lives," Popular Mechanics, pages 97-99, 
  8. Schleimer, Robert P., et el, "Inhaled Steroids in Asthma," vol. 163, 2005, New York, page 5
  9. http://pmj.bmj.com/content/36/411/26.full.pdf
  10. http://archderm.jamanetwork.com/article.aspx?articleid=525922



file:///home/chronos/u-48b0af7d8a6e832f841243beb1bf56db699d3e12/Downloads/NSAID%20accepted%20version%20for%20self-arch.pdf

Monday, October 3, 2016

1950: The discovery of steroids

Now in our quest through the annals of history, we come to steroids. If we consider the discovery of epinephrine the most significant to our asthma history, then the discovery of steroids must be a close second.

While epinephrine was isolated in 1901 from the adrenal medulla, cortisol wasn't isolated until 1936. However, interestingly, the history of both substances can be traced back to 1714, when Eustachius described the adrenal gland.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760737/

However, the story of steroids probably began in 1849, where Thomas Addison, working for Guy's Hospital in Britain, was looking to learn more about diseases and define them for the medical community. This quest lead him to making the link between Addison's Disease and the Adrenal Gland, and then to define the disease that would eventually take his name.

This discovery lead to further research on the adrenal gland. In 1894, researchers isolated a hormone from the adrenal cortex that they referred to as "cortin." In 1900 Solomon Soles-Cohen, working for Jefferson Medical College in Philadelphia, described the benefits of using adrenal extracts in asthmatics.

http://jama.jamanetwork.com/article.aspx?articleid=477214
Jackson, Mark, Asthma: A Biography," 1989,

Then, in 1901, researchers isolated a hormone call epinephrine from the adrenal medulla. The significance of cortin was not immediately recognized. However, the significance of epinephrine was recognized, and it was soon learned to have end asthma attacks, and this spearheaded a quest that lead to our modern understanding of asthma.

So, despite all that, the significant portion of the history of steroids, the part that is most recognized by historians, begins in the mid 1930s. And it did not begin with asthma in mind: it began as part of a quest to find a treatment for rheumatoid arthritis.

It began when Dr. Philip S. Hench, who was working for the Mayo Clinic. During the 1930s he observed that pain symptoms subsided during pregnancy and jaundice. His theory was that this was the result of increased cortisol levels. (1, 2, 3)

Hench believed a "substance x" was produced by the adrenal gland in response to stress, and that it would reduce inflammation in joints that occur in people with rheumatoid arthritis, a disease associated with pain in the joints due to chronic inflammation.

Beginning in 1935, this lead him to performing experiments with Edward C. Kendall at the Mayo Clinic to isolate the compound in the adrenal cortex. (1)

In 1936, Kendall succeeded in isolating compounds from the adrenal gland, and he named them in the sequence they were discovered: compound A through F.  Upon further research, he realized that compound E and substance X were one and the same. Hench named this substance cortisone. (2, 4)

In 1943 they extracted cortisone from the adrenal gland for clinical trials. And in 1944 they injected it into a patient with rheumatoid arthritis. They described how this patient was able to walk up and down stairs without discomfort. (1)

In 1948, Tadeus Reichstein, a Polish born chemist, perfected the method of extracting adrenal hormones, and this opened the door for further research. So Kendall and Reichstein had succeeded in isolating cortisol, and then Adrenocorticotropic hormone (ACTH).

That same year, a man was given cortisol as a treatment for rheumatoid arthritis. This was synthetic cortisol, making the medicine readily available for experimentation.

In 1949, a report was released in Mayo Clinic Proceedings showing the benefits of cortisol for the treatment of arthritis. (2)

It was described as the "miracle cure." In 1950, for their work in this great discovery, Kendall, Hench, and Reichstein were awarded the Nobel Prize for Physiology in Medicine.

This inspired researchers to study the affects of cortisol on various diseases, including asthma and allergies. At the time it was believed inflammation was part of the inflammatory response, although it was not known that some degree of inflammation was chronic. This discovery would not be made for another 30 years of so.

In the meantime, cortisol was hailed as a miracle cure, and was prescribed liberally. This was despite knowledge that it caused side effects, such as fluid retention, moon face, acne, and depression.