Pill Pushing©

The Best of Pill Pushing - Aspirin - From Bark to Bayer and Beyond - (9/16/2018)

By Dr. Ron Gasbarro
Society at the time
The year was 1918. World War I – the Great War – had just ended. More than 70 million military personnel, including 60 million Europeans, were mobilized in one of the largest wars in history [Meyer, 2006]. Over 9 million combatants and 7 million civilians died as a result of the war, making it one of the deadliest conflicts in history.  The war paved the way for major political changes, including revolutions in many of the nations involved. By the end of the war, the German Empire, Russian Empire, Austro-Hungarian Empire, and the Ottoman Empire ceased to exist.
 
In 1918, German theoretical physicist Max Planck won the Nobel Prize for his work on quantum theory. The French composer, Claude Debussy, who wrote Clair de Lune, died. American actress Rita Hayworth, a top glamour girl in the 1940s and a pin-up girl for military servicemen, was born. Babe Ruth led the American League in home runs for the first time, hitting 11. Radio was in its infancy and 1918 witnessed the first direct communication by this new medium from Australia to the United Kingdom. 
But for everything that happened in 1918, the year is probably most known for the Spanish flu pandemic. It infected 500 million people across the world, including remote Pacific islands and the Arctic, and resulted in the deaths of 50 to 100 million (3 to 5% of the world's population), making it one of the deadliest natural disasters in human history [Barry, 2004]. Because of a lack of vaccines and antibiotics, many infectious diseases – diphtheria, syphilis, smallpox, cholera, yellow fever – had already greatly limited life expectancy in the early 20th century. A considerable spike in the number of deaths occurred at the time of the pandemic, specifically the year 1918. Life expectancy dropped by about 12 years.
During the deadly Spanish flu pandemic, aspirin secured a reputation as one of the most powerful and effective drugs in the pharmacopeia of the time. Its fever-reducing properties gave many sick patients enough strength to fight through the infection, and aspirin companies earned the loyalty of doctors and the public—when they could manufacture or purchase enough aspirin to meet demand. 
The drug in question 
Aspirin, or acetylsalicylic acid, is a derivative of salicylic acid that is a mild, non-narcotic analgesic and anti-inflammatory useful in the relief of headache, and muscle and joint aches. The drug works by inhibiting the production of prostaglandins, body chemicals that are necessary for blood clotting and which also sensitize nerve endings to pain. 
Aspirin is the active ingredient in white willow bark [U of Maryland, 2015]. The use of white willow bark dates back to the time of Hippocrates (400 BC) when patients were advised to chew the bark to reduce fever and inflammation. White willow bark contains salicin, which is an ingredient very similar to acetylsalicylic acid. Willow bark has also been used throughout the centuries in Europe and China and continues to be used to treat pain – particularly lower back pain and osteoarthritis. However, white willow bark does not work as fast as aspirin, although it may work longer. Neither willow bark supplements, nor aspirin should be given to children under age 19 because of the risk of Reye’s Syndrome. This syndrome is a rare but serious condition that causes swelling in the liver and brain and most often affects children and teenagers recovering from a viral infection, commonly the flu or chickenpox [National Reye's Syndrome Organization, 2013].
Refining the bark into billions
After being used in folk medicine for centuries, in 1829, scientists isolated the active compound, salicin, which was the source of willow bark’s ability to be used medically [Davies, 1999]. In 1838, salicin was further refined into salicylic acid which could also be obtained from the meadowsweet, Spiraea ulmaria. Salicylic acid was a good analgesic and antipyretic. However, the problem was that salicylic acid irritated the mouth and stomach, hence, the search for a means of 'buffering' the compound had begun. The first person to do so was a French chemist named Charles Frederic Gerhardt. In 1853, Gerhardt neutralized the acid by buffering it with sodium (sodium salicylate) and acetyl chloride, creating acetylsalicylic acid. Gerhardt's product worked but he had no desire to market it and abandoned his discovery.
In 1899, a German chemist named Felix Hoffmann, who worked for a German drug company called Bayer Laboratories, rediscovered Gerhardt's formula. Felix Hoffmann converted salicylic acid into acetylsalicylic acid and gave it to his father who was suffering from arthritic pain. The results were good. Felix Hoffmann then convinced Bayer to market the new presumptive wonder drug. Aspirin was patented on February 27, 1900. The folks at Bayer came up with the name Aspirin, taking the “A" in acetyl chloride, the "spir" in Spiraea ulmaria and the 'in' was a then familiar name ending for medicines (e.g., insulin, heroin, penicillin, etc.). The drug became wildly successful and Bayer’s trade name, “Aspirin” became world famous. Around 100 billion aspirin tablets are produced every year and that over 1 trillion aspirin have been consumed in the last 100 years [International Aspirin Foundation, 2016]
The good, the bad and the ugly
Even though the pharmacology of aspirin had not yet been elucidated and phase 1 studies that would determine toxic doses in humans were not yet required, aspirin was used generously by the medical community.
Aspirin misuse may have made the 1918 flu pandemic worse.
The devastation of the 1918-1919 influenza pandemic is well known, but one recent analysis of aspirin’s history suggests a surprising factor in the high death toll: the inadvertent misuse of aspirin [Starko, 2009]. High aspirin dosing levels used to treat patients during the Spanish flu pandemic are now known to cause, in some cases, toxicity and a dangerous buildup of fluid in the lungs, which may have contributed to the incidence and severity of symptoms, bacterial infections, and mortality. Additionally, autopsy reports from 1918 are consistent with what we know today about the dangers of aspirin toxicity, as well as the expected viral causes of death.
Almost 100 years later, the high death toll, especially among young adults, during the pandemic is just beginning to be understood. Although some deaths showed bacterial pneumonia, early deaths exhibited extremely "wet," sometimes hemorrhagic lungs. Hypothetically, the misuse of aspirin contributed to the incidence and severity of viral pathology, bacterial infection, and death, because physicians of the day were unaware that the enormous regimens used as the time (8.0-31.2 g per day vs. today’s recommended dose of 2.4 g per day) produced levels associated with hyperventilation and pulmonary edema in 33% and 3% of recipients, respectively. Less than 10 years ago, pulmonary edema was found at autopsy in 46% of 26 salicylate-intoxicated adults [Starko, 2009]. Experimentally, salicylates increase lung fluid and protein levels and impair mucociliary clearance which would have allowed patients to expectorate the fluid. In 1918, the US Surgeon General, the US Navy, and the Journal of the American Medical Association recommended the use of aspirin just before the October death spike. If these recommendations were followed, and if pulmonary edema occurred in 3% of persons, a significant proportion of the deaths may be attributable to aspirin [Starko, 2009]. According to the author of the study, “In 1918, physicians did not fully understand either the dosing or pharmacology of aspirin, yet they were willing to recommend it. Its use was promoted by the drug industry, endorsed by doctors wanting to "do something," and accepted by families and institutions desperate for hope.” 
A tragic lesson at the expense of children 
Even after the pandemic, influenza deaths continued to coincide with salicylate mishandling [Starko 1980, Waldman, 1982, Halpin 1982]. From the 1950s to the 1980s, thousands of deaths among children following influenza and other infections (e.g. Reye’s syndrome) were unexplained until studies identified aspirin as the major contributor, and aspirin label warnings were followed by a disappearance of the condition. Reye’s syndrome toxicity (vomiting, hyperventilation, delirium, and coma, with brain swelling and fat in the liver and proximal renal tubules) develops after approximately 4 days of salicylate therapy with reported mean daily doses of 25 mg/kg (55 mg/pound or, for a 100 pound child, 17 adult strength tablets/day). Adults with salicylate toxicity present mainly with abnormal consciousness and respiratory distress. Also, a recent avian influenza A-associated fatality involved Reye’s syndrome and aspirin use, and several autopsies of persons who had avian influenza revealed hemorrhagic lungs, fatty liver changes, and swollen kidneys consistent with salicylate intoxication [To, 2001]. Currently, the American Academy of Family Physicians recommends not giving children aspirin until they are 19 years of age; teenagers should be told about the dangers of aspirin as well.
Impact of the drug on culture 
Aspirin remains the go-to drug for a variety of conditions [FDA, 2015].
Strokes: Aspirin use is recommended in both men and women to treat mini-strokes (transient ischemic attack – TIA) or ischemic stroke to prevent subsequent cardiovascular events or death. 
Heart attacks: Aspirin reduces the risk of death in patients with suspected acute heart attacks (myocardial infarctions), prevents recurrent heart attacks and reduces the risk of heart attacks or sudden death in patients with unstable and chronic stable angina pectoris (chest pain). 
Other coronary conditions: Aspirin can be used to treat patients who have had certain revascularization procedures such as angioplasty, and coronary bypass operations. 
Rheumatologic diseases: Aspirin is indicated for relief of the signs and symptoms of rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, spondylarthropathies, as well as arthritis and pleurisy associated with systemic lupus erythematosus. 
Pain relief: Aspirin is indicated for the temporary relief of minor aches and pains.
Colon cancer: As a 2011 study revealed, taking 600 mg of aspirin daily reduced the risk of colon cancer among people at high risk for colon cancer by 63% [Burn, 2011].
New information on diabetes: Women under 60 and men under 50 who have diabetes but no other major risk factors for heart disease probably should not be on low-dose aspirin (81 mg) therapy. The new recommendations endorsed by the American Diabetes Association are based on close examination of 9 studies that found the risks of some aspirin side effects, such as stomach bleeding, should be better balanced against the possible benefits of using aspirin. These new guidelines suggest low-dose aspirin therapy be used by men over 50 and women over 60 with diabetes who have other risk factors for heart attack and stroke.
How do you know if your aspirin is still potent?
Simply take the cap off the bottle and sniff. If it smells like vinegar, it has decomposed and will not work. Luckily, aspirin is economical enough to replace your expired bottle. 
It has been used as money
During the times of hyperinflation in South America last century, aspirin was used as currency. Reportedly, it was the practice at the time to hand over a few tablets of aspirin as change as it held its value considerably better than the actual currency.
Where the drug is today
Over the last several decades, drugs prescribed for many diseases have changed dramatically [International Aspirin Foundation, 2016]. Our better knowledge of the nature of diseases and their management has led to the replacement of many old remedies by new ones specifically targeted at each illness. For example, peptic ulcers used to involve expensive hospital stays and draconian changes in diet. Today, over-the-counter medicines such as Zantac, Pepcid, and Prilosec can heal peptic ulcers. Other common conditions such as asthma, high blood pressure, depression, infections, and arthritis are now much better treated, with higher cure rates and longer survival. We now have the first effective anti-viral drugs, and many types of cancer that were untreatable only a few years ago, are now brought under control.
To assume that prescribers have always turned to new drugs to keep up with ever-changing medical paradigms would be a mistake. Aspirin – millennia old – has continued to flourish, and has even expanded its uses. It is highly effective, has a very good safety record, and continues to be the most trusted home remedy for pain, worldwide. It is also very cheap. 
Everyone has known for years that aspirin is a fast and reliable painkiller that also reduces inflammation and cools fevers. More recently it has become just as well known as a help to people with heart complaints such as angina, coronary thrombosis and after coronary bypass surgery. It is becoming better known, too, in the prevention of stroke. Among other diseases in which active research about aspirin is showing great promise – and in which it is now being increasingly used – are toxemia of pregnancy, diabetes, bowel cancer, and dementia.
Products often come and go. But aspirin may be around for centuries to come. 
Ron Gasbarro, PharmD is a registered pharmacist, medical writer, and principal at Rx-Press.com. Read more at www.rx-press.com.
 
References 
Barry JM. The Great Influenza: The Epic Story of the Greatest Plague in History. Viking Penguin: New York, NY.;2004.
Burn J, Gerdes AM, Macrae F, et al; CAPP2 Investigators.Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378:2081-7.
Davies M, Hollman A. Aspirin. Heart. 1999;81:458.
Fuster V, Sweeny JM. Aspirin: A historical and contemporary therapeutic overview. Circulation. 2011;123:768-78.
Halpin TJ, Holtzhauer FJ, Campbell RJ, et al. Reye's syndrome and medication use. JAMA. 1982;248:687-91.
International Aspirin Foundation. The Story of Aspirin. Available at: http://www.aspirin-foundation.com/history-of-aspirin/100-years-of-aspirin/ ; 2016. 
Meyer GJ. A World Undone – the Story of the Great War – 1914 to 1918. Bantam Dell: New York, NY; 2006.
Reye’s Syndrome Organization. Reye’s Syndrome. Available at:  https://reyessyndrome.org ; 2013. 
Starko KM. Salicylates and pandemic influenza mortality, 1918-1919 pharmacology, pathology, and historic evidence. Clin Infect Dis. 2009;49:1405-10.
Starko KM, Ray CG, Dominguez LB, Stromberg WL, Woodall DF. Reye's syndrome and salicylate use. Pediatrics. 1980;66:859-64.
To KF, Chan PK, Chan KF, et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol. 2001;63:242-6.
University of Maryland Medical Center. Willow bark. Available at: http://umm.edu/health/medical/altmed/herb/willow-bark ; 2015.
US Food and Drug Administration. Aspirin: Questions and Answers. Available at: http://www.fda.gov/Drugs/ResourcesForYou/Consumers/QuestionsAnswers/ucm071879.htm#aspirin; 2015.
Waldman RJ, Hall WN, McGee H, Van Amburg G. Aspirin as a risk factor in Reye's syndrome. JAMA. 1982;247:3089-94.
 


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