WARTIME DRUGS

By Carlo FlaschaContributing WriterDuring war, people from an array of disciplines, including chemists, clinicians, engineers, and pharmacologists, are enlisted to speed production of so-called wartime drugs. A common belief is that war stimulates the advancement of medicine, and justly so, seeing how governments pour billions of dollars into medical research as war increases the amount of individuals in need of healing. War is a chance for medical innovations to prove their worth by doing right (healing) to each wrong (wounding) that war causes. There is a reason why wartime drugs are not just called drugs. They do more than stop coughs; they tackle greater problems, from venereal disease to cancer.Wartime drugs are powerful medical innovations fostered by equally powerful, challenging wars. War does not directly cause medical innovation but provides ideal conditions for its progress. Penicillin was already conceived more than a decade before World War II, but war patroned a project for the drug’s mass production. Nitrates were used in World War I as explosives, propellants, and eventually in medicine. But first, opioids evolved under the American Civil War.Opium continued its millennia of medical use in war, and war helped make morphine the gold standard of analgesics. In 1527, alchemist Paracelsus invented laudanum, a tincture of opium in ethyl alcohol that brought medical innovation to opium’s form. As early as the 1600s, celebrated ‘father of English medicine’ Thomas Sydenham recommended laudanum for diarrhea, pain relief, and sleeplessness. (1) Then in 1817, Friedrich Sertürner published his success at isolating pure morphine from opium after over 13 years of research and one notable, nearly catastrophic trial on himself and three young men. As a medical innovation, morphine marked the first instance of a pharmaceutical isolated from a natural product. (2) Opium became a norm for medical use and remained that way entering the 1800s. Meanwhile, medical professionals often used purified morphine as an analgesic, especially after the arrival of the hypodermic syringe in 1853. (3) Both the American Civil War and the Franco-Prussian War used morphine extensively, but since hypodermic needles were not available at the time, the use of opium tincture and opium pills was more common. During the American Civil War alone, the Union Army used around half a million opium pills and 2.8 million ounces of opium tincture powder. (4) In spite of opium’s addictive nature, there was no better substitute at the time, and its pill and powder forms made it easier to distribute to the needy masses.Successful isolations of morphine and the other main opiates (codeine, thebaine, and papaverine) paved the way for the opioids to come, as chemists experimented with these alkaloids to make improved compounds. In 1874, after experimenting with morphine, British scientist C. R. Alder Wright synthesized the earliest opiate called diacetylmorphine, now known more commonly as heroin. Felix Hoffman rediscovered the drug while working at the Bayer pharmaceutical company in Germany. Bayer erroneously marketed heroin as a non-addictive substitute. In 1900, the Eli Lilly pharmaceutical company began selling heroin over the counter in the United States and marketed the drug as a treatment for cough and flu alongside Aspirin. In World War I, doctors administered heroin intravenously to fatally wounded and anguished soldiers on a normal basis. By the 1920s, heroin’s risks outweighed its benefits, and clinicians pushed for the drug’s recall. Today, heroin prescriptions are still available in some countries like England, where they remarket the product as diamorphine and use it as an analgesic. Heroin tops the list of illegal drugs, but during its time it proved to be a significantly valuable analgesic. (5) Also, heroin’s success and failure instigated the search for non-addictive opioids at smaller and larger potencies.World War II, with its large numbers of wounded soldiers, pushed research even further for a strong, non-addictive painkiller. In 1939, Otto Eisleb under the I. G. Farbenindustrie pharmaceutical company in Germany discovered dolantin, a painkiller less potent than morphine and better known by the name meperidine. By 1944, thanks to war’s positive influence on the research of new medicines, manufacturers produced 1,600 kilograms of meperidine annually. Outside of war, medical professionals used meperidine as an analgesic after operation or during childbirth, but the drug currently faces a decline in use because of unwanted side effects. (6) Meperidine is best in short-term care, as the drug needs to be prescribed in larger amounts after each subsequent use to achieve the same effect. To this day, no drug has been discovered that equals the analgesic effect of opium without also replicating most of its addictive tendencies. Thomas Sydenham once said, “Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.” (Cited by Smith, p. 1855) (7) Opioids are superior for easing pain, but penicillin was greater for curing infectious disease.In 1928, bacteriologist Alexander Fleming first discovered penicillin, the first antibiotic in the history of medicine. (8) First, Fleming noticed that one of his plates had a mold that inhibited bacteria from growing around it. Then he demonstrated that exposing the mold (Penicillium notatum) to healthy bacteria caused cell lysis and death. Later on in the early 1930s, Fleming passed on some Penicillium culture to Howard Florey and Ernst Chain at Oxford University. There, Florey and Chain polished penicillin’s growth and isolation methods to the level that allowed for clinical trials. In 1945, Fleming, Chain, and Florey received the Nobel Prize in Physiology or Medicine for the use of penicillin as a successful antibiotic. (9) The next step towards penicillin’s establishment in medicine was mass production, and science struggled to find effective means for doing so until 1939.When World War II began, many scientists pledged to produce penicillin on a large scale. Frequent aerial bombings in the UK and proximal battle frontlines caused a massive, collaborative Anglo-American Penicillin Project. Leading British and American academic and governmental institutions joined forces with major pharmaceutical companies like Merck, Pfizer, and Abbott. Over 40 independent laboratories and hundreds of chemists took up the task of elucidating penicillin’s structure, while the US Agriculture Department Laboratories in Peoria, Illinois took charge of improving penicillin’s fermentation process. In 1940, Mary Hunt secured a greatly improved yield of penicillin from Penicillium chrysogenum from a moldy cantaloupe melon. Within three years, the Penicillin Project had 29 plants fermenting this high-yield fungal strain to make penicillin in a corn-steep liquid medium. (10) The Penicillin Project successfully conjured a natural biosynthesis that provided an effective and practical supply of the medical innovation.On D-Day, General Dwight Eisenhower launched the invasion of Europe with troops backed by three million doses of penicillin (300 billion units). The year 1944 alone witnessed 1,633 billion units of penicillin produced, treating wounded soldiers and civilians alike who contracted infections. (11) Open fractures had a recovery rate of 94-100%, and soldiers with 1/5 or less of their body surface burned made near complete recoveries. From D-day to Germany’s defeat, penicillin reduced the death rate due to infected wounds to nearly 0%, compared to 15% in World War I. (12) Additionally, British and American armed forces used penicillin to treat sexual transmitted diseases like gonorrhea and syphilis. Penicillin even prevented a syphilis epidemic in 1945 after the war on the European front ended. The drug can also cure pneumonia, rheumatic fever, and gas gangrene in a matter of days. (13) Penicillin only strengthened Great Britain and America’s alliance, and the fact that Germany alone failed to produce the ‘miracle drug’ on a large scale was a major deciding factor in their ultimate defeat. (14) Penicillin opened up a wealth of opportunity for the pharmaceutical industry, a claim that Dr. Kyriacos Nicolaou, an expert on total synthesis at the University of California, San Diego supports:[…] this fortunate event […] revealed to scientists a new treasure trove of biologically active molecules ripe for exploration. Thus, to the forest, which held the key to the development of Aspirin, we now add the kingdom of microbes as a rich hunting ground for molecules endowed with healing powers. Indeed, many such molecules have since been isolated from the soil and other habitats where bacteria and fungi hold sway and, from this bountiful harvest, scientists have derived a host of ‘magic bullets’ and billion dollar drugs […]Nitrates, another wartime drug, are a class of powerful explosives primarily used for construction and demolition that inevitably served their purpose for war. In 1847, Italian chemist Asconio Sobrero nitrated glycerol and ended up with the oily yellow liquid known as nitroglycerin (NG). Unfortunately, he failed to acquire an efficient and safe way to ignite the substance. In 1863, Alfred Nobel invented the means for exploding NG, and even went on to invent dynamite in 1867. Looking back at 1863, German chemist J. Wilbrand invented Trinitrotoluene, or TNT, but it was not until 1900 that TNT production costs dropped, and TNT took priority over dynamite. World War I recognized TNT’s advantages over dynamite from the beginning in 1914; TNT produced shock waves that ruptured steel on armor-plated vehicles. World War II weaponry initiated two new explosives: PETN and RDX, which, following modifications, evolved into Composition Four, or C-4 explosive. With its reputation as a ‘plastic’ material, C-4 is easy to mold and can be attached to armored vehicles, bridge supports, and even hulls of ships. (15)Sobrero noted NG’s medical potential through his discovery that ingestion or close handling of the chemical can cause acute headaches, which showed vasodilation capabilities. In 1867, the ‘father of modern pharmacology’ Lauder Brunton used amyl nitrite, another powerful vasodilator, to relieve angina pectoris. Although amyl nitrite is not a nitrate itself, this discovery is significant to the development of nitrates as it motivated pharmaceutical chemist William Murrell in 1876 to use NG for angina relief and lowering blood pressure, while proving that the problematic headaches resulted from overdose. In 1879, he published his findings in The Lancet , and the drug’s widespread use soon followed. The medical field uses the name ‘trinitrin’ or ‘glycerol trinitrate’ (GTN) so that patients do not associate the drug with explosions. GTN remains a medical innovation today as the choice treatment for angina relief. (16) Nitrates contribute to medicine twice over as a drug and as an explosive, as Nobel’s profits from explosives helped set up Nobel Prize, with a specific category in ‘Physiology or Medicine,’ in 1901. Some might argue that NG’s use in war did not promote its use in medicine; its use in medicine was inevitable without war’s influence because amyl nitrite’s use for angina inspired NG’s use for angina. Neville and Alexander Marsh, Professors for the School of Life Sciences at Queensland University of Technology in Australia, think otherwise:It is obvious that we owe a great debt to Sobrero and Nobel [… ] Had not the early workers experienced headaches and flushing, NG may never have entered the pharmaceutical world: it would have remained a useful, if not destructive, material in the hands of the military. It is ironic that NG has been largely replaced as an explosive, partly because of its unstable qualities, whereas the substance remains the drug of choice for the treatment of angina. (318) (17)Wartime drugs provide more than one example when wars foster medical advances. Some drugs in use out of war inexorably get involved in war, like the examples of Opioids and Penicillin. In other cases, organic compounds used for war find medical purposes outside of war, like the example of Nitrates. Ultimately, wartime drugs are medical innovations that stemmed from the battlefield. While interest already existed for better analgesics, infection treatments, and vasodilators, war encouraged the greatest investment in medical innovation.(1) Stephen Harding, Lee A. Oliver, and Olivera Jokic. Victorians and Laudanum [Online]. [cited 13 January 2011]. Available from: .(2) Ryan J. Huxtable and Stephan K. W. Schwartz, ‘The Isolation of Morphine – First Principles in Science and Ethics’, Molecular Interventions, 1 (2001), 189-191[accessed 13 January 2011] (p. 190).(3) Kyriacos C. Nicolaou and Tansyn Montagnon. Molecules That Changed the World (Germany: Wiley-VCH, 2008), p. 70.(4) Paul L. Schiff, ‘Opium and Its Alkaloids’, American Journal of Pharmaceutical Education, 56 (2002), 186-194 [accessed 11 January 2011] (p. 189).(5) Nicolaou and Montagnon, pp. 70-71.(6) Ibid., pp. 71-72.(7) ‘The war on drugs’, British Medical Journal, 311 (1995), 1655 [Accessed 13 January 2011].(8) Milton Wainwright, Miracle Cure: The Story of Penicillin and the Golden Age of Antibiotics (England, Blackwell, 1990), p. 14.(9) Nicolaou and Montagnon, pp. 101-102.(10) Ibid., pp. 102-103.(11) Ibid., p. 103.(12) Wainwright, p. 65.(!3) Robert Bud, Penicillin: Triumph and Tragedy (New York, Oxford University Press, 2007), pp. 54, 58-59.(14) Wainwright, p. 65.(15) Tim Graham, ‘The Explosive History of Nitrogen’, ChemMatters, (2003), 8-10 [accessed 14 January 2011], pp. 8-9.(16) Neville Marsh and Alexander Marsh, ‘A Short History of Nitroglycerine and Nitric Oxide In Pharmacology and Physiology’, Clinical and Experimental Pharmacology and Physiology, 27 (2000), 313-319 [accessed 15 January 2011], pp. 313-314, 316.(17) Ibid.Works Cited:Booth, Martin. Opium: A History (New York: St. Martin’s Press, 1996)Bud, Robert, Penicillin: Triumph and Tragedy (New York, Oxford University Press, 2007)Graham, Tim, ‘The Explosive History of Nitrogen’, ChemMatters, (2003), 8-10 [accessed 14 January 2011]Harding, Stephen, Lee A. Oliver, and Olivera Jokic. Victorians and Laudanum [Online]. [cited 13 January 2011]. Available from:Huxtable, Ryan J., and Stephan K. W. Schwartz, ‘The Isolation of Morphine – First Principles in Science and Ethics’, Molecular Interventions, 1 (2001), 189-191 [accessed 13 January 2011]Marsh, Neville, and Alexander Marsh, ‘A Short History of Nitroglycerine and Nitric Oxide In Pharmacology and Physiology’, Clinical and Experimental Pharmacology and Physiology, 27 (2000), 313-319 [accessed 15 January 2011]Nicolaou, Kyriacos C., and Tansyn Montagnon. Molecules That Changed the World (Germany: Wiley-VCH, 2008)Schiff, Paul L., ‘Opium and Its Alkaloids’, American Journal of Pharmaceutical Education, 56 (2002), 186-194 [accessed 11 January 2011]Schück, Henrik, and Ragnar Sohlman, The life of Alfred Nobel (London: William Heinemann Ltd., 1929)Sir Frederick Augustus Abel’, in Encyclopædia Britannica. [accessed 14 January 2011]Smith, Richard, ‘The war on drugs’, British Medical Journal, 311 (1995), 1655 [Accessed 13 January 2011]Wainwright, Milton, Miracle Cure: The Story of Penicillin and the Golden Age of Antibiotics (England, Blackwell, 1990)Photo Courtesy of VCU Libraries