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The Beat Goes On: The Story of Five Ageless Cardiac Drugs
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S0002-9629(18)30164-2 https://doi.org/10.1016/j.amjms.2018.04.011 AMJMS659
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The Beat Goes On: The Story of Five Ageless Cardiac Drugs Short title – Five Ageless Cardiac Drugs by
Harold Smulyan M.D. Department of Medicine Cardiology Division Upstate Medical University State University of New York 90 Presidential Plaza Syracuse, New York 13208 [email protected]
Corresponding Author Harold Smulyan M.D. Upstate Medical University Department of Medicine Cardiology Division 90 Presidential Plaza Syracuse, NY 13208 Tel 315-464-4535 [email protected]
The author has no conflict of interest and no funding source
Key Words – Aspirin, Atropine, Digitalis, Nitroglycerine, Quinidine
Abstract This paper traces the history of 5 cardiac drugs – Aspirin, Atropine, Digitalis, Nitroglycerine, and Quinidine - that have been in continuous use for centuries and some for longer. Four of the 5 started life as botanicals and 4 have as also served widely varied functions far removed from their current purposes. Collectively, they have played a role in the history of royalty, religious leaders, assassinations and military campaigns in addition to their place in medical therapy.
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Their present clinical status has evolved from long term clinical observation without the need for controlled clinical trials, detailed statistical analyses or FDA approvals. This review of their background illustrates the varied means by which markedly different substances from widely separated sources can come together to participate in the management of circulatory disorders.
Introduction
As long as there has been an awareness of heart disease, there have been efforts at treatment. Five cardiac drugs have been in continuous use for hundreds of years and indeed a few for thousands of years. Many of these agents in the past have led double lives far removed from cardiology - as assassin poisons, nerve gas antidotes, explosives, cosmetics, antipyretics and as a treatment of malaria. The histories of these 5 drugs, from their origins to their present therapeutic positions provide astonishing tales that could never have been predicted. To avoid any implication of their present clinical importance, they are presented in chronologic order beginning with the oldest: Aspirin, Atropine, Digitalis, Nitroglycerine and Quinidine.
Aspirin – from Headaches to Hearts The bark of the willow tree (Salix in Latin) offered one of the most ancient of remedies (fig 1). The willow bark has an abundant watery sap containing salicin that is metabolized in the body to salicylic acid 1,2. Evidence for the use of extracts from the bark and leaves of the willow have been found from clay tablets left by the Assyrians and Babylonians 4000 years ago. The use of these extracts for the treatment of pain, fever and inflammation was also recorded in Egypt
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(1300 BC) and used in the Chinese and Greek civilizations. Our own Hippocrates (460 – 370 BC) recommended the chewing of the willow bark for the treatment of fever and pain and the famed Roman physician and anatomist Galen (circa 200 to 216 AD) also used the leaves of the willow 3. Descriptions of the beneficial effects of the willow continued over the centuries but the first modern clinical description of its use is attributed to the Reverend Edward Stone of Chipping-Norton in Oxfordshire England in a letter to the Right Honorable George Earl of Macclesfield, President of the Royal Society in 1763 3,4 (fig 2). In this letter, Stone described the relief of fever in 50 patients - many probably from malaria. Identification of the bark substance did not begin until the early 1800’s. Initial efforts by Buchner at the University of Munich in 1828 finally led to a relatively pure yellowish substance that he named salicin after the Latin name for the tree. The crystalline form of salicin was finally obtained in 1829 by the French pharmacist Henri Leroux 3. A definition of the chemical structure of salicin took many more years and for the interested reader the sequence of events is described in detail in the review by Mahdi 3. The chemical synthesis of salicylic acid on a small scale was achieved by Kolb and Lautemann in 1860 but they later developed a large scale method that led to commercial production by the Heyden Chemical Company in Germany. The drug was sold for analgesic and antipyretic purposes, but salicylic acid was a gastric irritant and in large doses caused gastric bleeding 3. The potential for an improved compound was recognized by the Bayer company who therefore sought chemical analogues that might be better tolerated. Here, the narrative becomes controversial 5.
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In the Bayer account Felix Hoffman, a chemist at Bayer, was directed by the company (and encouraged by his rheumatic father) to develop a compound with fewer side effects than sodium salicylate. At Hoffmann’s direction Heinrich Dreser, head of the experimental pharmacology laboratory, investigated several derivatives of salicylic acid including the acetylated form 6. Believing that the new drug was of little value and had an “enfeebling” action on the heart, Dreser set the drug aside with no further testing for 18 months 7. However when subsequent clinical trials showed benefit, Bayer in 1899 registered the product under the name of Aspirin and began to distribute the white powder to hospitals and clinics. Bayer published its own history in 1934 and there gave credit for the development of the drug to Hoffmann. Fifteen years later in 1949 Arthur Eichengrün, a former colleague of Hoffman, published an alternative account in the journal Pharmazie. Eichengrün claimed that it was he who instructed Hoffmann to synthesize acetylsalicylic acid, it was he who was convinced that it was superior to the other derivatives and it was he who should have been credited for the drug’s development 6. Dreser’s initial decision to shelve acetylsalicylic acid may have been due to his preoccupation with the sales potential of a new Bayer cough remedy synthesized in 1897 called Heroin 7. At the time, Eichengrün tested the drug on himself and then surreptitiously provided it to clinicians whose reports were encouraging. The drug was then sent by the company to several clinics who confirmed its clinical success. Dreser was then instructed to write a favorable report on the drug and the drug was marketed 6. Why did Eichengrün wait so long to challenge the official history by Bayer? After a productive career there, Eichengrün left Bayer in 1908 to form his own company where he became an affluent industrialist. But he was a Jew and in 1934 when the Bayer history was published, he 4
feared putting his success at risk and instead kept a low profile. The Nazis eventually took over his business and in 1944, at the age of 76, he was sent to Theresienstadt concentration camp where he stayed for 14 months until liberated by the soviet army. He died in 1949 shortly after his account of aspirin development at Bayer was published. Who was most responsible for the introduction of aspirin may never be surely known but after an extensive review, the evidence tilts toward Eichengrün. Bayer made aspirin available in tablet form in 1900 and the ease of administration and increasing clinical recognition of its benefits led to widespread use. But there have been a few problems with its use. The flu epidemic of 1918 had an unexpectedly high mortality that has never been fully explained 8. The virus itself was highly pathogenic and had a predisposition to infect the lungs. But the death rate was spotty, higher in some areas than in others suggesting mitigating factors other than the virus itself. The metabolism of aspirin was not well understood at that time and aspirin was often administered for extended periods in high doses, now believed to be excessive. Non-cardiac pulmonary edema, a feature of aspirin toxicity, may have been a contributing factor to the excessively wet lungs seen at autopsy in patients with influenzal pneumonia 8. Aspirin is now also known to be a contributing factor in Reye’s syndrome in children but the mechanism of this association remains obscure 9. In 1950, a California family practitioner Lawrence Craven observed that daily aspirin ingestion in his patients dramatically reduced the risk of myocardial infarction. In 3 subsequent publications he described his one man clinical trial of 8000 patients on daily aspirin with no definite myocardial infarcts or strokes. Craven was well aware of the limitations of his study
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design and conclusions but felt that his observations were worthy of further better designed studies. His reports, though prescient, were published in non-prestigious journals and went largely unnoticed 7. In the late 1960’s and early 1970’s a series of basic scientific observations led to clinical interest into whether or not aspirin could be useful in the prevention of cardiovascular disease. Weiss demonstrated that aspirin impaired platelet aggregation and this impairment was permanent for the life of the platelet 7. Interference with the clotting mechanism raised the possibility that aspirin could prevent the thrombotic aspects of atherosclerotic complications. But the mechanism for the effect on platelets awaited the findings of Sir John Vane and his graduate student Priscilla Piper who, at about the same time, were studying the effects of aspirin on the biosynthesis of prostaglandins 5,7. The enzyme cyclooxygenase-1 (COX-1) is necessary for the formation of both prostaglandins and thromboxane A2 that are in turn responsible for the pain and fever of inflammation as well as the adhesion of platelets. Aspirin’s effect in the laboratory, later confirmed in human platelets, was due the inhibition of COX-1, thus reducing the formation of prostaglandins and their multiple effects. In 1982, Vane became a Nobel laureate for his contributions to the field 5. By 1988, a group of collaborators from the University of Oxford summarized the results of anti-platelet therapy in 25 randomized trials involving some 29,000 patients for the prevention of vascular complications in the heart and brain 10. The results showed a reduction of about 25 % of serious vascular events in this wide range of patients at risk of atherosclerotic occlusive vascular disease. That same year a large trial (ISIS-2) of 17,187 patients with suspected myocardial infarction from 417 hospitals in 16 countries led by Peter Sleight also from the University of Oxford showed significant reductions 6
in vascular mortality, non-fatal re-infarction and non-fatal stroke 11. Six years later in 1994, the Trialists Collaboration confirmed these results in an overview of 145 randomized trials of antiplatelet therapy 12. After thousands of years and many thousands of patients, the present place of aspirin as an antipyretic, analgesic and in the prevention of vascular disease of the heart seems assured.
Atropine –cosmetic, poison, antidote and antiarrhythmic. Although still in use for many purposes, atropine has an ancient history. In the distant past it was used by women as a cosmetic and even earlier by assassins as a poison 13. The dark inky poisonous material was first extracted by the ancients from the glossy-coated black berries of the deadly nightshade plant, a member of the Solanacae family (Fig 3). The ancient Greeks named the nightshade plant “Atropos” 14 for the eldest sister of the 3 “Fates” who were goddesses of fate and destiny in Greek mythology. The first sister spun the thread of life, the second measured its length while Atropos ended the life of mortals by cutting the thread with her “abhorrent shears” from which there was no appeal (Fig 4)15. Her name in roman mythology appropriately was “Morta”. As a poison, the nightshade berry was the star of the poisonous plants and a killer of ancient kings – Macbeth, Duncan and the Emperors Claudius and Augustus of Rome. The Roman military created a deadly paste to poison tip their arrows 13,16. Historically, it was the plant of choice for assassins and frequently used during the time of the Roman Empire and the Middle Ages to produce obscure and prolonged illnesses 13. Unintentional poisoning has also occurred
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to unsuspecting children since the shiny berries appear interesting and the juice has a sweet taste 17. As a cosmetic, atropine gained fame when Cleopatra, in the last century B.C., used extracts taken from the Egyptian Black Henbane to dilate her pupils in the belief that she would appear more alluring 13,18. Its popularity as a cosmetic in Italy prompted Linnaeus, the famed Swedish botanist, in 1753 to add “belladonna” or beautiful woman in Italian to complete the name of the plant – Atropa Belladonna 13,18. In 1831, the German pharmacist Heinrich F. G. Mein prepared atropine in pure crystalline form and it was first synthesized by German chemist Richard Willstätter 13. Medical atropine is a racemic mixture of the D and L isomers of hyoscyamine with most of its effects due to L – hyoscyamine. Acetylcholine is the main neurotransmitter of the parasympathetic nervous system and atropine is a competitive antagonist of its muscarinic receptors 19. As a parasympathetic blocker, atropine reduces salivary and bronchial secretions, raises the heart rate, and relaxes the smooth muscle of the urinary bladder, gastro-intestinal tract and bronchial tree 13,20. Since atropine crosses the blood brain barrier, it also causes restlessness, mental excitement and hallucinations 19. Nerve gases used in warfare, such as Sarin, inactivate the enzyme acetylcholinesterase that normally breaks down acetylcholine. The unchecked and prolonged acetycholine activity leads to death by the above effects and to asphyxiation from a loss of control of the respiratory muscles 21. Atropine acts as antidote by competitively antagonizing the acetylcholine receptors. The military now provides single auto-injections of atropine to soldiers in areas where nerve gases may be used 19. Atropine is also the antidote to
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accidental poisoning by the organophosphate insecticides whose actions of toxic acetylcholinesterase inhibition are similar to that of the nerve gases 19. The current use of atropine in medicine is as varied as its colorful history. In diagnostic ophthalmology it was used to dilate the pupil to facilitate examination of the retina. But this effect is long lasting and atropine has been replaced for this purpose by shorter acting agents. As a therapeutic ophthalmologic agent, it relieves the pain of iridocyclitis but is contraindicated in patients with glaucoma, especially in those with narrow angle glaucoma 13,20. Despite its ability to reduce bronchial secretions and bronchospasm, atropine is no longer recommended for the routine treatment of asthma or obstructive pulmonary disease 22. It has been used however to reduce sweating in patients with hyperhidrosis 23. However, it still finds a use in those asthmatics who do not tolerate beta agonists 23. Pre-operatively it has been used to reduce salivation and bronchial secretions attributed to the irritative effects of inhaled anesthetics 20,23. This is less of a problem with current anesthetics as the newer anticholinergic agents such as glycopyrrolate do not cross the blood brain barrier. Of all its multiple applications, atropine is used mostly in heart disease for increasing slow heart rates arising from either the sinus or A-V node or improving A-V conduction in heart block. It is less effective at increasing the heart rate in the elderly with degenerative disease of the sinus node but works well in other circumstances when vagal stimulation slows the rate. This occasionally occurs during the course of infero-posterior myocardial infarction (Bezold-Jarisch Reflex)23. Although atropine is also useful in improving conduction in Type I second degree A-V block (Wenckebach) where the block is high in the A-V transmission system, it is ineffective in 9
restoring A-V conduction in 3rd degree A-V block where the block is below the His bifurcation13,19. It will, however, increase the heart rate if the escape rhythm arises from the AV node above the block. The 2010 American Heart Association Guidelines for Adult Advanced Cardiovascular Life Support removed the routine use of atropine for pulseless electrical activity or asystole for lack of evidence of therapeutic benefit 24. But the same guidelines continue to recommend atropine for the management of symptomatic bradycardia (Class IIa, LOE B). In an interesting sidelight, atropine has little effect on the transplanted heart since the vagus nerves are severed in the transplantation process. Recognizing its many salutary functions, atropine is on the World Health Organization List of Essential Medicines and like many other medications with a long history, atropine is inexpensive 25. A one-milligram vial costs $4.89 26. While atropine has lost its appeal as a cosmetic and poison, it has retained its therapeutic position as an antidote and a modifier of cardiac rate and rhythm.
Digitalis – from Foxglove to Heart Failure Digitalis was known to physicians and used for hundreds of years before William Withering described its use as an effective treatment for “dropsy” in 1775 27. Withering, born in 1741 in a small town in Shropshire, was the son of an apothecary and served as his father’s apprentice starting at about age 17. In 1762, influenced by a physician uncle, he enrolled in the medical school at the University of Edinburgh, one of the leading schools in Britain if not the world at that time 28. Following graduation in 1766, a practice opportunity became available in Stafford, about 20 miles from home, with an appointment at the newly built Stafford Infirmary. As a newcomer, his rural practice was slow to develop and provided only limited income but it afforded leisure time for other pursuits 29. But his major avocation during those years was 10
botany. He was drawn to this subject by some botanist friends and by a young patient, Helena Cooke who was an amateur painter of flowers and who later became his wife 28. Botany became more than a hobby since he later became one of England’s most eminent botanists. Withering began to search for a more profitable practice. In 1775, he was contacted by Erasmus Darwin, the eccentric genius grandfather of Charles Darwin (pioneer of the theory of evolution), about an unexpected opening in Birmingham. Withering applied, acquired the practice and was to work there for the next 17 years. The practice was an immediate success and he was later reputed to be “the best loved, most learned, and busiest physician in provincial England”27 if not the richest 28. Despite financial success, he had strong sympathies for the disadvantaged and at Birmingham General Hospital he held a daily free clinic for the poor 28. This clinic also gave him the opportunity to widely expand his clinical experience 29. In addition to medical practice he studied and published distinguished works in minerology and chemistry. These outside interests embellished his reputation and led to his membership in the Lunar Society of Birmingham. This small, select group of intellectuals dined monthly on the Monday nearest to the full moon, so that the members would have the benefit of some light on their way home. In addition to Withering, other members included Erasmus Darwin, James Watt (inventor of the steam engine), Josiah Wedgewood (pottery) and Joseph Priestly (isolator of oxygen). An occasional visitor was Benjamin Franklin 28,29. Withering became aware of the therapeutic properties of digitalis shortly after his arrival in Birmingham. There are many tales of how this took place. It has been said that an old women had successfully treated a severe case of dropsy with a home brewed tea where Withering and
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others had failed. He persuaded her to disclose the contents and, with his botanical background, deduced that the active ingredient had come from the foxglove leaf. Witherings’s description is probably the most accurate. “In the year 1775 my opinion was asked concerning a family receipt for the cure of the dropsy. I was told that it had long been kept secret by an old woman in Shropshire, who had sometimes made cures after the more regular practitioners had failed…..This medicine was composed of 20 or more different herbs; but it was not very difficult for one conversant in these subjects to perceive, that the active herb could be no other than the Foxglove”27. As seen by Withering, the English “foxglove” is a tall wildflower with attractive purple bells that blooms from June to until the end of July throughout the mid and western counties of England 29 (fig 5). Over the next 10 years, he kept records of his personal observations on the use of digitalis and published the results in 1785 in “An Account of the Foxglove, Some of its Medical Uses with Practical Remarks on Dropsy, and other Diseases” (fig 6) 30. The book contained 207 pages and cost five shillings. There has never been a second edition 28,29. This was a one-man clinical trial that objectively and thoroughly described the good results in some, lack of response in others, dose responses and toxic effects of digitalis in the management of 158 patients, 101 of whom were in congestive heart failure 28. The effective use of digitalis described in the book led to its widespread but predictably ineffective use in 32 other conditions 27,28. His clinical descriptions were the more remarkable considering that they were made without access to a sphygmomanometer to measure the blood pressure or a stethoscope 27. His only tools were his powers of observation and intellect 30. Withering suffered from lung disease with hemoptysis
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and shortness of breath for many years and died in 1799 at age 58 of tuberculosis 31 but his contributions to the salutary effects of digitalis have persisted. Apart from the identification of the vagal effects of digitalis to slow the heart rate, especially in atrial fibrillation, there was little research on the substance for more than the next 100 years. There then followed the identification and purification of the many glycosides in the foxglove leaf and the eventual commercial synthesis and wide spread use of digitoxin and digoxin in heart failure and atrial fibrillation 32. The determination of its chemical structure led to a better understanding of cardiac contractility, the function of the membrane-bound Na/K pump and its inhibition by digitalis 33. The development of digoxin blood levels and the antibody specific (FAB) fragments that bind to digoxin improved both the detection of digitalis toxicity and its treatment 34. During the last 3 decades, digitalis has been edged aside by more powerful alternatives to treat heart failure. These include angiotensin converting enzyme inhibitors, angiotensin receptor blockers, mineralocortoid receptor blockers, beta blockers, diuretics and resynchronization of ventricular contraction by pacemakers 35. Despite being sidelined, digitalis still retains a number of favorable features. It is inexpensive and reduces heart failure related hospitalizations 36. It is the only inotrope known to increase the cardiac output and reduce the pulmonary capillary wedge pressure without increasing heart rate, decreasing the BP or diminishing renal function 33. In low dose, it is still generally advised for heart failure in some quarters 37 but clinical interest has been limited. Its use is currently described in the 2013 Practice Guidelines for the Management of Heart Failure 38. This Class IIa, Evidence B designation recommends digoxin in patients with persistent symptoms despite an otherwise full medical regimen and to slow the ventricular rate in atrial fibrillation. Digitalis over time has 13
made a significant contribution to the understanding and treatment of heart disease and although, despite reduced usage now, it refuses to disappear.
Nitroglycerine – from Explosive to Vasodilator The development of nitroglycerine (NTG) followed 2 nearly simultaneous time paths – one as a medication and the other as an explosive. But during their separate and non-parallel developments, the 2 paths crossed.
Explosive
The story begins with Antonio Sobrero who accomplished the nitration of glycerine. Sobrero was born on Oct 12, 1812 in the small town of Casale Monferrato in the Piedmont region of Italy. He received his formal education in Medicine at the acclaimed University of Turin and then in Chemistry at the University of Bieben. To further his interest in chemistry and through the connections of family and friends, he was accepted in the laboratory of the famous chemist Theophile-Jules Pelouze in Paris where he arrived in 1840. By 1846, he had helped to develop nitrocellulose (guncotton) and then achieved the nitration of mannitol (the explosive nitromannite) and glycerine using a mixture of nitric and sulfuric acids. This last reaction was unstable, highly exothermic and resulted in detonation unless the mixture was cooled during the reaction process. Indeed one of these explosions badly scarred his face. In 1847, Sobrero gave an important lecture to the Accademia della Scienza di Torino where he demonstrated the behavior of NTG by detonating a small amount. He also incidentally published the prescient
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observation that … “for a very minute quantity put upon the tongue produces a violent headache for several hours” 39.
Alfred Nobel’s father Immanuel had a building business in Stockholm that went bankrupt and, to avoid creditors, he moved his family in 1842 to St Petersburg. There, he developed a thriving business that provided steam engines, military equipment and explosive naval mines for the Russian military. In 1850, during these prosperous years, his son Alfred went abroad to study chemistry and engineering. He spent a year in Paris in the same laboratory of Pelouze where he met Sobrero and encountered NTG, synthesized 4 years earlier. Because of the instability of NTG, Sobrero had concluded that it was too dangerous to have any practical use 40. But young Nobel saw its potential as an explosive and took it with him back to Stockholm where his family had returned from Russia. He and his father set about to invent means for its safe transport and detonation 39. Their research led to many patents but also to several serious explosions one of which took the life of Emil, Alfred’s younger brother. Their 2 most consequential inventions were the detonator or blasting cap and the combination of liquid nitroglycerine with diatomaceous earth into a workable paste that would not explode without a detonator 40. This substance, shaped into short sticks that he called dynamite, was a huge commercial success. In an ironic twist, Alfred developed angina pectoris later in life. He was advised by his physicians to take nitroglycerine but he declined 39,41. He died in 1896 at age 63 leaving the majority of his vast wealth to establish 5 Nobel Prizes in Physics, Chemistry, Physiology or Medicine, Literature and Peace 40.
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Medication In 1844, almost at the same time that Sobrero nitrated glycerine, the French chemist Antoine Balard first described amyl nitrite. Amyl nitrite was also studied by Robert Bunsen in Germany who was instrumental in the training of the famous English chemist Frederick Guthrie 39. Guthrie, in turn, was an assistant in chemistry at the University of Edinburgh in 1859 when he described the effects of inhaled amyl nitrite on himself. “……after the lapse of about fifty seconds, a sudden throbbing of the arteries of the neck is felt, immediately followed by a flushing of the neck, temples and forehead and an acceleration of the action of the heart” 42. The first possible medical application of the substance is credited to Benjamin Ward Richardson, a London physician, who presented his findings to the British Association for the Advancement of Science between 1863 and 1865 42. He claimed that amyl nitrite “when inhaled, produced an immediate action on the heart, increasing the action on the organ more powerfully than any other known agent.” To dramatically illustrate its effect, Richardson passed samples of the compound to the audience 42. Shortly afterward and at the same university, Arthur Gamgee recorded the ability of the substance to lower the blood pressure in animals and humans 39. Under Gamgee’s mentorship, a clinician, Thomas L. Brunton, described the effect of amyl nitrite in patients and over the succeeding years spread the word of its effectiveness. Brunton went on to gain fame in the new field of clinical pharmacology as the author of one of its first textbooks 42.
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NTG attracted little medical attention until 1858 when Alfred Field, a British physician, described the relief of intense chest pain by NTG in a 68 year old woman 43. Similar observations from single case reports followed. But the drug came to wide attention after a series of articles published in Lancet by William Murrell in 1879 who described multiple clinical observations of chest pain relief 43. Because the liquid form of the drug used by Murrell was inconvenient, a pharmacist, William Martindale, prepared the drug in tablet form. Out of concern for its reputation as an explosive, he claimed that it “is stable, non-volatile….and perfectly inexplosive – it cannot be detonated” 43. By 1882, Murrell’s essays had been republished as a monograph in Britain and America, and Parke Davis & Company had made the drug available in pill form in 5 different strengths43. Although NTG had gained wide acceptance for the relief of anginal pain, at that time there was little or no understanding of the relationship between NTG or angina pectoris and the coronary arteries.
By the end of the 19th century, NTG had become an established form of therapy for the relief of angina pain. It also found use in the treatment of heart failure by dilating peripheral veins, inducing venous pooling, reducing venous return and lowing right heart pressures. Although during the next 80 years NTG was recognized as a vasodilator, there was little or no understanding of the mechanism of this effect – the “fallow years” 39. In what appeared to be unrelated at the time (1979, 1980), Murad and Furchgott independently described the role of an “endothelium derived relaxing factor” (EDRF) and its role in vascular regulation. Ignarro later identified this factor as nitric oxide (NO), an activator of soluble guanylate cyclase. NO was also recognized as the EDRF by Moncada two months before Ignarro’s publication. The 17
Nobel Prize in Physiology or Medicine was awarded to Murad, Furchgott and Ignarro In 1998 but, for reasons that were never explained, Moncada was not an awardee 39. Most now agree that NO, is an endothelium independent smooth muscle vasodilator that is provided by the organic nitrates but despite much recent investigation, the exact mechanism of this provision is still under debate. Neither explained is the mechanism for NTG tolerance. Despite this basic science uncertainty, NTG continues to be widely used in chronic stable and unstable angina and decompensated heart failure 44,45. For both good and for ill as a medication or as an explosive, NTG has been with us since 1847 and appears likely to remain.
Quinidine – from Malaria to Arrhythmia The early history of quinidine is preceded by the serendipitous but monumental discovery of quinine as a treatment for malaria – the first chemical compound to treat an infectious disease. Accounts vary, but the story appears to have begun in the 1630’s when Jesuit missionaries in South America used the powdered bark of a tree for the relief of fever - although legend suggests that the native population may have used it even earlier for the same purpose 46. The cinchona tree (fig. 7) was named for the wife of the Spanish Viceroy to Peru, Countess Anna del Chinchon who, while in Peru was cured, probably of malaria, in 1638 46,47. Other sources also introduced the powdered bark to various sites in Europe. Juan de Lugo, a Spanish noble turned Jesuit priest, brought it to Rome while attending the election of a new Pope – Innocent X 47. The mysterious powder also gained acceptance in England when Charles II was cured at the end of the 17th century by an apothecarian Robert Talbor 47,48. This healer of the English king was called, in 1678, to cure the son of King Louis XIV of France, who had contracted malaria in the in the swamps surrounding Versailles 47,48. Quinquina was the name given to the therapeutic 18
substance in the cinchona bark and root and the first alkaloid of quinquina was isolated by a Portuguese doctor, Bernardino Antonio Gomez and called cinchonine. But the more effective second alkaloid was isolated by two French pharmacists, Pierre J. Pelleitier and Joseph B. Caventou, and named quinine 47. In 1853, Pasteur isolated what he thought was an impurity of quinine and called it quinidine 47. Because of malaria, the need for quinine grew over the years as European countries continued to colonize Africa, India and South America. The quinine content of many of the cinchona trees was low but a British collector, Charles Ledger, obtained some seeds of a potent Bolivian species. The British were not interested so he sold the seeds to the Dutch government 49,50. The Dutch planted the seeds in Indonesia and came to monopolize the world’s supply of quinine for close to 100 years. By the 1930’s, the Netherlands produced 97% of the world’s quinine output. During WW II, the Allied powers lost their quinine supply when the Germans invaded the Netherlands (processing plants) and the Japanese took control of Java 49,51. The United States obtained seeds from the Philippines and began to plant trees in South America but the drug came too late and, despite informational programs (fig. 8), thousands of our troops died of malaria in Africa and the South Pacific 52. A quinine substitute, Atabrine, became available in 1942 but synthetic quinine was not developed by American scientists until 1944 49,51,52. The first reference to a cinchona alkaloid used in the treatment of a cardiac arrhythmia was in a two volume work on the heart published by Jean-Baptiste de Sénac in 1749 53,54. In this treatise Sénac described the successful use of quinine in the treatment of “rebellious palplitation” that very likely was atrial fibrillation 53. This observation went unnoticed but was rediscovered years
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later when Karel Frederik Wenkebach (best known for his description of Type 1 second degree atrio-ventricular block) described a patient he saw in 1912 55. At that time in malaria prone countries, quinine’s ability to relieve fever had led to its non-specific everyday use, much as aspirin or other NSAIDs are used today. Wenkebach’s patient, a Dutch merchant, suffered from bouts of paroxysmal atrial fibrillation and noted that incidental use of the drug for fever could stop the arrhythmia. Wenkebach was doubtful, but the patient demonstrated that he could abolish the arrhythmia by taking a gram of “quinin”. Wenkebach had limited success in his patients with oral quinin in the treatment of atrial fibrillation but noted that it worked best in cases when the onset of the arrhythmia was recent and when there was little other heart disease – observations that still stand 55. Winterberg, a colleague in the same clinic, showed that intravenous administration was more often effective than the oral form. Wenkebach went on to describe the further salutary effects of oral quinin in the abolition of “extrasystoles”. Impressed with the anti-arrhythmic effects of the drug, he prompted a colleague Walter von Frey, to investigate other alkaloids of the cinchona bark 55. Frey reported in 1918 that of the 4 tested alkaloids in cinchona bark, “quinidin” was the most effective in abolishing atrial fibrillation 56. Sir Thomas Lewis, in 1909, first recognized atrial fibrillation on the ECG 57 and by 1922 observed that quinidine could restore sinus rhythm in 50% of his cases 58. But because 50% of the patients did not convert and because atrial fibrillation often recurred among those who did, Lewis did not recommend quinidine for general use. Despite Lewis’ reservations, quinidine became widely used for the treatment of most cardiac arrhythmias for the next 40 plus years. In 1964, Selzer and Wray reported 36 attacks of syncope in 8 patients all receiving standard 20
doses of digitalis and quinidine for atrial flutter or fibrillation. In 5 of the cases, recorded ECG’s showed ventricular flutter or fibrillation and the episodes were called “Quinidine Syncope” 59. In 1978, the interaction between quinidine and digoxin was described 60 that later required the digoxin dosage be reduced by 50% when used in conjunction with quinidine 61. It now seems possible that some of the early cases of quinidine syncope were in fact due to digitalis intoxication, unrecognized at the time. Subsequent reviews of quinidine usage in atrial fibrillation demonstrated effectiveness in the maintenance of sinus rhythm but with an increased mortality 61. In addition there was growing evidence of harm when the drug was used in the treatment of ventricular arrhythmias and, not surprisingly, the use of quinidine for the maintenance of sinus rhythm has decreased. Quinidine is primarily a sodium channel blocker 20 and, like many other type I anti-arrhythmic drugs, has pro-arrhythmic effects such as premature ventricular beats, ventricular tachycardia and sudden death. Although it has been largely replaced by more effective/safer agents, it is still listed as therapy for atrial and ventricular arrhythmias in selected patients 62 but no longer mentioned in the American Heart Association guidelines for the treatment of atrial fibrillation 63. Recently, quinidine has made a limited comeback in the prevention of arrhythmias associated with the Brugada Syndrome and the short QT syndrome 61. Quinine for malaria and quinidine for arrhythmias are inextricably connected by their origin from the same botanical source. Although quinine has now been replaced as treatment for malaria, quinidine continues to find limited but possibly increasing use in cardiology.
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Conclusions Today, new drugs are developed by chemical or genetic engineering to attack specific chemical or genetic targets, identified by an increasing understanding of disease mechanisms. Potential agents are tested in the laboratory, in animals and in clinical trials followed by FDA approval and post marketing evaluation. This process is costly and takes years. Present technology was unavailable to our forebears but did not prevent them from developing useful drugs using only their powers of observation coupled with a large dose of serendipity. Their process was simpler, cheaper and without television advertisements, but it took much longer.
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Figure Legends Figure 1. Black Willow Tree - Salix Nigra - Photo and permission from Flickr Figure 2.
Page 1 of the letter from Rev Edmund Stone to the Royal Society. With permission from the Royal Society
Figure 3. Atropa Belladonna - Photo and permission from Flickr Figure 4. Bas relief of Atropos, shears in hand, cutting the thread of life - Wikimedia Commons – photo by Tom Oates https://commons.wikimedia.org/wiki/File%3AAtropos.jpg Figure 5. Digitalis Purpurea (Foxglove) - Permission from Pet Poison Help Line – photo by Tyne Houda
http://www.petpoisonhelpline.com/poison/foxglove/
Figure 6. Front page of Withering’s book “An Account of the Foxglove”. With permission Missouri Botanical Garden – Peter H. Raven Library. Figure 7. Cinchona Pubescens – (Quinine) Makawao Forest Reserve, Maui, Hawaii.,May 30, 2005 . Permission – Starr Environmental - Forest & Kim Starr
Figure 8. Informational campaign to US troops to combat malaria – Collection of the National Library of Medicine - Prints and Photographs - NLM unique ID 101454784
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PII: DOI: Reference:
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The Beat Goes On: The Story of Five Ageless Cardiac Drugs Short title – Five Ageless Cardiac Drugs by
Harold Smulyan M.D. Department of Medicine Cardiology Division Upstate Medical University State University of New York 90 Presidential Plaza Syracuse, New York 13208 [email protected]
Corresponding Author Harold Smulyan M.D. Upstate Medical University Department of Medicine Cardiology Division 90 Presidential Plaza Syracuse, NY 13208 Tel 315-464-4535 [email protected]
The author has no conflict of interest and no funding source
Key Words – Aspirin, Atropine, Digitalis, Nitroglycerine, Quinidine
Abstract This paper traces the history of 5 cardiac drugs – Aspirin, Atropine, Digitalis, Nitroglycerine, and Quinidine - that have been in continuous use for centuries and some for longer. Four of the 5 started life as botanicals and 4 have as also served widely varied functions far removed from their current purposes. Collectively, they have played a role in the history of royalty, religious leaders, assassinations and military campaigns in addition to their place in medical therapy.
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Their present clinical status has evolved from long term clinical observation without the need for controlled clinical trials, detailed statistical analyses or FDA approvals. This review of their background illustrates the varied means by which markedly different substances from widely separated sources can come together to participate in the management of circulatory disorders.
Introduction
As long as there has been an awareness of heart disease, there have been efforts at treatment. Five cardiac drugs have been in continuous use for hundreds of years and indeed a few for thousands of years. Many of these agents in the past have led double lives far removed from cardiology - as assassin poisons, nerve gas antidotes, explosives, cosmetics, antipyretics and as a treatment of malaria. The histories of these 5 drugs, from their origins to their present therapeutic positions provide astonishing tales that could never have been predicted. To avoid any implication of their present clinical importance, they are presented in chronologic order beginning with the oldest: Aspirin, Atropine, Digitalis, Nitroglycerine and Quinidine.
Aspirin – from Headaches to Hearts The bark of the willow tree (Salix in Latin) offered one of the most ancient of remedies (fig 1). The willow bark has an abundant watery sap containing salicin that is metabolized in the body to salicylic acid 1,2. Evidence for the use of extracts from the bark and leaves of the willow have been found from clay tablets left by the Assyrians and Babylonians 4000 years ago. The use of these extracts for the treatment of pain, fever and inflammation was also recorded in Egypt
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(1300 BC) and used in the Chinese and Greek civilizations. Our own Hippocrates (460 – 370 BC) recommended the chewing of the willow bark for the treatment of fever and pain and the famed Roman physician and anatomist Galen (circa 200 to 216 AD) also used the leaves of the willow 3. Descriptions of the beneficial effects of the willow continued over the centuries but the first modern clinical description of its use is attributed to the Reverend Edward Stone of Chipping-Norton in Oxfordshire England in a letter to the Right Honorable George Earl of Macclesfield, President of the Royal Society in 1763 3,4 (fig 2). In this letter, Stone described the relief of fever in 50 patients - many probably from malaria. Identification of the bark substance did not begin until the early 1800’s. Initial efforts by Buchner at the University of Munich in 1828 finally led to a relatively pure yellowish substance that he named salicin after the Latin name for the tree. The crystalline form of salicin was finally obtained in 1829 by the French pharmacist Henri Leroux 3. A definition of the chemical structure of salicin took many more years and for the interested reader the sequence of events is described in detail in the review by Mahdi 3. The chemical synthesis of salicylic acid on a small scale was achieved by Kolb and Lautemann in 1860 but they later developed a large scale method that led to commercial production by the Heyden Chemical Company in Germany. The drug was sold for analgesic and antipyretic purposes, but salicylic acid was a gastric irritant and in large doses caused gastric bleeding 3. The potential for an improved compound was recognized by the Bayer company who therefore sought chemical analogues that might be better tolerated. Here, the narrative becomes controversial 5.
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In the Bayer account Felix Hoffman, a chemist at Bayer, was directed by the company (and encouraged by his rheumatic father) to develop a compound with fewer side effects than sodium salicylate. At Hoffmann’s direction Heinrich Dreser, head of the experimental pharmacology laboratory, investigated several derivatives of salicylic acid including the acetylated form 6. Believing that the new drug was of little value and had an “enfeebling” action on the heart, Dreser set the drug aside with no further testing for 18 months 7. However when subsequent clinical trials showed benefit, Bayer in 1899 registered the product under the name of Aspirin and began to distribute the white powder to hospitals and clinics. Bayer published its own history in 1934 and there gave credit for the development of the drug to Hoffmann. Fifteen years later in 1949 Arthur Eichengrün, a former colleague of Hoffman, published an alternative account in the journal Pharmazie. Eichengrün claimed that it was he who instructed Hoffmann to synthesize acetylsalicylic acid, it was he who was convinced that it was superior to the other derivatives and it was he who should have been credited for the drug’s development 6. Dreser’s initial decision to shelve acetylsalicylic acid may have been due to his preoccupation with the sales potential of a new Bayer cough remedy synthesized in 1897 called Heroin 7. At the time, Eichengrün tested the drug on himself and then surreptitiously provided it to clinicians whose reports were encouraging. The drug was then sent by the company to several clinics who confirmed its clinical success. Dreser was then instructed to write a favorable report on the drug and the drug was marketed 6. Why did Eichengrün wait so long to challenge the official history by Bayer? After a productive career there, Eichengrün left Bayer in 1908 to form his own company where he became an affluent industrialist. But he was a Jew and in 1934 when the Bayer history was published, he 4
feared putting his success at risk and instead kept a low profile. The Nazis eventually took over his business and in 1944, at the age of 76, he was sent to Theresienstadt concentration camp where he stayed for 14 months until liberated by the soviet army. He died in 1949 shortly after his account of aspirin development at Bayer was published. Who was most responsible for the introduction of aspirin may never be surely known but after an extensive review, the evidence tilts toward Eichengrün. Bayer made aspirin available in tablet form in 1900 and the ease of administration and increasing clinical recognition of its benefits led to widespread use. But there have been a few problems with its use. The flu epidemic of 1918 had an unexpectedly high mortality that has never been fully explained 8. The virus itself was highly pathogenic and had a predisposition to infect the lungs. But the death rate was spotty, higher in some areas than in others suggesting mitigating factors other than the virus itself. The metabolism of aspirin was not well understood at that time and aspirin was often administered for extended periods in high doses, now believed to be excessive. Non-cardiac pulmonary edema, a feature of aspirin toxicity, may have been a contributing factor to the excessively wet lungs seen at autopsy in patients with influenzal pneumonia 8. Aspirin is now also known to be a contributing factor in Reye’s syndrome in children but the mechanism of this association remains obscure 9. In 1950, a California family practitioner Lawrence Craven observed that daily aspirin ingestion in his patients dramatically reduced the risk of myocardial infarction. In 3 subsequent publications he described his one man clinical trial of 8000 patients on daily aspirin with no definite myocardial infarcts or strokes. Craven was well aware of the limitations of his study
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design and conclusions but felt that his observations were worthy of further better designed studies. His reports, though prescient, were published in non-prestigious journals and went largely unnoticed 7. In the late 1960’s and early 1970’s a series of basic scientific observations led to clinical interest into whether or not aspirin could be useful in the prevention of cardiovascular disease. Weiss demonstrated that aspirin impaired platelet aggregation and this impairment was permanent for the life of the platelet 7. Interference with the clotting mechanism raised the possibility that aspirin could prevent the thrombotic aspects of atherosclerotic complications. But the mechanism for the effect on platelets awaited the findings of Sir John Vane and his graduate student Priscilla Piper who, at about the same time, were studying the effects of aspirin on the biosynthesis of prostaglandins 5,7. The enzyme cyclooxygenase-1 (COX-1) is necessary for the formation of both prostaglandins and thromboxane A2 that are in turn responsible for the pain and fever of inflammation as well as the adhesion of platelets. Aspirin’s effect in the laboratory, later confirmed in human platelets, was due the inhibition of COX-1, thus reducing the formation of prostaglandins and their multiple effects. In 1982, Vane became a Nobel laureate for his contributions to the field 5. By 1988, a group of collaborators from the University of Oxford summarized the results of anti-platelet therapy in 25 randomized trials involving some 29,000 patients for the prevention of vascular complications in the heart and brain 10. The results showed a reduction of about 25 % of serious vascular events in this wide range of patients at risk of atherosclerotic occlusive vascular disease. That same year a large trial (ISIS-2) of 17,187 patients with suspected myocardial infarction from 417 hospitals in 16 countries led by Peter Sleight also from the University of Oxford showed significant reductions 6
in vascular mortality, non-fatal re-infarction and non-fatal stroke 11. Six years later in 1994, the Trialists Collaboration confirmed these results in an overview of 145 randomized trials of antiplatelet therapy 12. After thousands of years and many thousands of patients, the present place of aspirin as an antipyretic, analgesic and in the prevention of vascular disease of the heart seems assured.
Atropine –cosmetic, poison, antidote and antiarrhythmic. Although still in use for many purposes, atropine has an ancient history. In the distant past it was used by women as a cosmetic and even earlier by assassins as a poison 13. The dark inky poisonous material was first extracted by the ancients from the glossy-coated black berries of the deadly nightshade plant, a member of the Solanacae family (Fig 3). The ancient Greeks named the nightshade plant “Atropos” 14 for the eldest sister of the 3 “Fates” who were goddesses of fate and destiny in Greek mythology. The first sister spun the thread of life, the second measured its length while Atropos ended the life of mortals by cutting the thread with her “abhorrent shears” from which there was no appeal (Fig 4)15. Her name in roman mythology appropriately was “Morta”. As a poison, the nightshade berry was the star of the poisonous plants and a killer of ancient kings – Macbeth, Duncan and the Emperors Claudius and Augustus of Rome. The Roman military created a deadly paste to poison tip their arrows 13,16. Historically, it was the plant of choice for assassins and frequently used during the time of the Roman Empire and the Middle Ages to produce obscure and prolonged illnesses 13. Unintentional poisoning has also occurred
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to unsuspecting children since the shiny berries appear interesting and the juice has a sweet taste 17. As a cosmetic, atropine gained fame when Cleopatra, in the last century B.C., used extracts taken from the Egyptian Black Henbane to dilate her pupils in the belief that she would appear more alluring 13,18. Its popularity as a cosmetic in Italy prompted Linnaeus, the famed Swedish botanist, in 1753 to add “belladonna” or beautiful woman in Italian to complete the name of the plant – Atropa Belladonna 13,18. In 1831, the German pharmacist Heinrich F. G. Mein prepared atropine in pure crystalline form and it was first synthesized by German chemist Richard Willstätter 13. Medical atropine is a racemic mixture of the D and L isomers of hyoscyamine with most of its effects due to L – hyoscyamine. Acetylcholine is the main neurotransmitter of the parasympathetic nervous system and atropine is a competitive antagonist of its muscarinic receptors 19. As a parasympathetic blocker, atropine reduces salivary and bronchial secretions, raises the heart rate, and relaxes the smooth muscle of the urinary bladder, gastro-intestinal tract and bronchial tree 13,20. Since atropine crosses the blood brain barrier, it also causes restlessness, mental excitement and hallucinations 19. Nerve gases used in warfare, such as Sarin, inactivate the enzyme acetylcholinesterase that normally breaks down acetylcholine. The unchecked and prolonged acetycholine activity leads to death by the above effects and to asphyxiation from a loss of control of the respiratory muscles 21. Atropine acts as antidote by competitively antagonizing the acetylcholine receptors. The military now provides single auto-injections of atropine to soldiers in areas where nerve gases may be used 19. Atropine is also the antidote to
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accidental poisoning by the organophosphate insecticides whose actions of toxic acetylcholinesterase inhibition are similar to that of the nerve gases 19. The current use of atropine in medicine is as varied as its colorful history. In diagnostic ophthalmology it was used to dilate the pupil to facilitate examination of the retina. But this effect is long lasting and atropine has been replaced for this purpose by shorter acting agents. As a therapeutic ophthalmologic agent, it relieves the pain of iridocyclitis but is contraindicated in patients with glaucoma, especially in those with narrow angle glaucoma 13,20. Despite its ability to reduce bronchial secretions and bronchospasm, atropine is no longer recommended for the routine treatment of asthma or obstructive pulmonary disease 22. It has been used however to reduce sweating in patients with hyperhidrosis 23. However, it still finds a use in those asthmatics who do not tolerate beta agonists 23. Pre-operatively it has been used to reduce salivation and bronchial secretions attributed to the irritative effects of inhaled anesthetics 20,23. This is less of a problem with current anesthetics as the newer anticholinergic agents such as glycopyrrolate do not cross the blood brain barrier. Of all its multiple applications, atropine is used mostly in heart disease for increasing slow heart rates arising from either the sinus or A-V node or improving A-V conduction in heart block. It is less effective at increasing the heart rate in the elderly with degenerative disease of the sinus node but works well in other circumstances when vagal stimulation slows the rate. This occasionally occurs during the course of infero-posterior myocardial infarction (Bezold-Jarisch Reflex)23. Although atropine is also useful in improving conduction in Type I second degree A-V block (Wenckebach) where the block is high in the A-V transmission system, it is ineffective in 9
restoring A-V conduction in 3rd degree A-V block where the block is below the His bifurcation13,19. It will, however, increase the heart rate if the escape rhythm arises from the AV node above the block. The 2010 American Heart Association Guidelines for Adult Advanced Cardiovascular Life Support removed the routine use of atropine for pulseless electrical activity or asystole for lack of evidence of therapeutic benefit 24. But the same guidelines continue to recommend atropine for the management of symptomatic bradycardia (Class IIa, LOE B). In an interesting sidelight, atropine has little effect on the transplanted heart since the vagus nerves are severed in the transplantation process. Recognizing its many salutary functions, atropine is on the World Health Organization List of Essential Medicines and like many other medications with a long history, atropine is inexpensive 25. A one-milligram vial costs $4.89 26. While atropine has lost its appeal as a cosmetic and poison, it has retained its therapeutic position as an antidote and a modifier of cardiac rate and rhythm.
Digitalis – from Foxglove to Heart Failure Digitalis was known to physicians and used for hundreds of years before William Withering described its use as an effective treatment for “dropsy” in 1775 27. Withering, born in 1741 in a small town in Shropshire, was the son of an apothecary and served as his father’s apprentice starting at about age 17. In 1762, influenced by a physician uncle, he enrolled in the medical school at the University of Edinburgh, one of the leading schools in Britain if not the world at that time 28. Following graduation in 1766, a practice opportunity became available in Stafford, about 20 miles from home, with an appointment at the newly built Stafford Infirmary. As a newcomer, his rural practice was slow to develop and provided only limited income but it afforded leisure time for other pursuits 29. But his major avocation during those years was 10
botany. He was drawn to this subject by some botanist friends and by a young patient, Helena Cooke who was an amateur painter of flowers and who later became his wife 28. Botany became more than a hobby since he later became one of England’s most eminent botanists. Withering began to search for a more profitable practice. In 1775, he was contacted by Erasmus Darwin, the eccentric genius grandfather of Charles Darwin (pioneer of the theory of evolution), about an unexpected opening in Birmingham. Withering applied, acquired the practice and was to work there for the next 17 years. The practice was an immediate success and he was later reputed to be “the best loved, most learned, and busiest physician in provincial England”27 if not the richest 28. Despite financial success, he had strong sympathies for the disadvantaged and at Birmingham General Hospital he held a daily free clinic for the poor 28. This clinic also gave him the opportunity to widely expand his clinical experience 29. In addition to medical practice he studied and published distinguished works in minerology and chemistry. These outside interests embellished his reputation and led to his membership in the Lunar Society of Birmingham. This small, select group of intellectuals dined monthly on the Monday nearest to the full moon, so that the members would have the benefit of some light on their way home. In addition to Withering, other members included Erasmus Darwin, James Watt (inventor of the steam engine), Josiah Wedgewood (pottery) and Joseph Priestly (isolator of oxygen). An occasional visitor was Benjamin Franklin 28,29. Withering became aware of the therapeutic properties of digitalis shortly after his arrival in Birmingham. There are many tales of how this took place. It has been said that an old women had successfully treated a severe case of dropsy with a home brewed tea where Withering and
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others had failed. He persuaded her to disclose the contents and, with his botanical background, deduced that the active ingredient had come from the foxglove leaf. Witherings’s description is probably the most accurate. “In the year 1775 my opinion was asked concerning a family receipt for the cure of the dropsy. I was told that it had long been kept secret by an old woman in Shropshire, who had sometimes made cures after the more regular practitioners had failed…..This medicine was composed of 20 or more different herbs; but it was not very difficult for one conversant in these subjects to perceive, that the active herb could be no other than the Foxglove”27. As seen by Withering, the English “foxglove” is a tall wildflower with attractive purple bells that blooms from June to until the end of July throughout the mid and western counties of England 29 (fig 5). Over the next 10 years, he kept records of his personal observations on the use of digitalis and published the results in 1785 in “An Account of the Foxglove, Some of its Medical Uses with Practical Remarks on Dropsy, and other Diseases” (fig 6) 30. The book contained 207 pages and cost five shillings. There has never been a second edition 28,29. This was a one-man clinical trial that objectively and thoroughly described the good results in some, lack of response in others, dose responses and toxic effects of digitalis in the management of 158 patients, 101 of whom were in congestive heart failure 28. The effective use of digitalis described in the book led to its widespread but predictably ineffective use in 32 other conditions 27,28. His clinical descriptions were the more remarkable considering that they were made without access to a sphygmomanometer to measure the blood pressure or a stethoscope 27. His only tools were his powers of observation and intellect 30. Withering suffered from lung disease with hemoptysis
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and shortness of breath for many years and died in 1799 at age 58 of tuberculosis 31 but his contributions to the salutary effects of digitalis have persisted. Apart from the identification of the vagal effects of digitalis to slow the heart rate, especially in atrial fibrillation, there was little research on the substance for more than the next 100 years. There then followed the identification and purification of the many glycosides in the foxglove leaf and the eventual commercial synthesis and wide spread use of digitoxin and digoxin in heart failure and atrial fibrillation 32. The determination of its chemical structure led to a better understanding of cardiac contractility, the function of the membrane-bound Na/K pump and its inhibition by digitalis 33. The development of digoxin blood levels and the antibody specific (FAB) fragments that bind to digoxin improved both the detection of digitalis toxicity and its treatment 34. During the last 3 decades, digitalis has been edged aside by more powerful alternatives to treat heart failure. These include angiotensin converting enzyme inhibitors, angiotensin receptor blockers, mineralocortoid receptor blockers, beta blockers, diuretics and resynchronization of ventricular contraction by pacemakers 35. Despite being sidelined, digitalis still retains a number of favorable features. It is inexpensive and reduces heart failure related hospitalizations 36. It is the only inotrope known to increase the cardiac output and reduce the pulmonary capillary wedge pressure without increasing heart rate, decreasing the BP or diminishing renal function 33. In low dose, it is still generally advised for heart failure in some quarters 37 but clinical interest has been limited. Its use is currently described in the 2013 Practice Guidelines for the Management of Heart Failure 38. This Class IIa, Evidence B designation recommends digoxin in patients with persistent symptoms despite an otherwise full medical regimen and to slow the ventricular rate in atrial fibrillation. Digitalis over time has 13
made a significant contribution to the understanding and treatment of heart disease and although, despite reduced usage now, it refuses to disappear.
Nitroglycerine – from Explosive to Vasodilator The development of nitroglycerine (NTG) followed 2 nearly simultaneous time paths – one as a medication and the other as an explosive. But during their separate and non-parallel developments, the 2 paths crossed.
Explosive
The story begins with Antonio Sobrero who accomplished the nitration of glycerine. Sobrero was born on Oct 12, 1812 in the small town of Casale Monferrato in the Piedmont region of Italy. He received his formal education in Medicine at the acclaimed University of Turin and then in Chemistry at the University of Bieben. To further his interest in chemistry and through the connections of family and friends, he was accepted in the laboratory of the famous chemist Theophile-Jules Pelouze in Paris where he arrived in 1840. By 1846, he had helped to develop nitrocellulose (guncotton) and then achieved the nitration of mannitol (the explosive nitromannite) and glycerine using a mixture of nitric and sulfuric acids. This last reaction was unstable, highly exothermic and resulted in detonation unless the mixture was cooled during the reaction process. Indeed one of these explosions badly scarred his face. In 1847, Sobrero gave an important lecture to the Accademia della Scienza di Torino where he demonstrated the behavior of NTG by detonating a small amount. He also incidentally published the prescient
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observation that … “for a very minute quantity put upon the tongue produces a violent headache for several hours” 39.
Alfred Nobel’s father Immanuel had a building business in Stockholm that went bankrupt and, to avoid creditors, he moved his family in 1842 to St Petersburg. There, he developed a thriving business that provided steam engines, military equipment and explosive naval mines for the Russian military. In 1850, during these prosperous years, his son Alfred went abroad to study chemistry and engineering. He spent a year in Paris in the same laboratory of Pelouze where he met Sobrero and encountered NTG, synthesized 4 years earlier. Because of the instability of NTG, Sobrero had concluded that it was too dangerous to have any practical use 40. But young Nobel saw its potential as an explosive and took it with him back to Stockholm where his family had returned from Russia. He and his father set about to invent means for its safe transport and detonation 39. Their research led to many patents but also to several serious explosions one of which took the life of Emil, Alfred’s younger brother. Their 2 most consequential inventions were the detonator or blasting cap and the combination of liquid nitroglycerine with diatomaceous earth into a workable paste that would not explode without a detonator 40. This substance, shaped into short sticks that he called dynamite, was a huge commercial success. In an ironic twist, Alfred developed angina pectoris later in life. He was advised by his physicians to take nitroglycerine but he declined 39,41. He died in 1896 at age 63 leaving the majority of his vast wealth to establish 5 Nobel Prizes in Physics, Chemistry, Physiology or Medicine, Literature and Peace 40.
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Medication In 1844, almost at the same time that Sobrero nitrated glycerine, the French chemist Antoine Balard first described amyl nitrite. Amyl nitrite was also studied by Robert Bunsen in Germany who was instrumental in the training of the famous English chemist Frederick Guthrie 39. Guthrie, in turn, was an assistant in chemistry at the University of Edinburgh in 1859 when he described the effects of inhaled amyl nitrite on himself. “……after the lapse of about fifty seconds, a sudden throbbing of the arteries of the neck is felt, immediately followed by a flushing of the neck, temples and forehead and an acceleration of the action of the heart” 42. The first possible medical application of the substance is credited to Benjamin Ward Richardson, a London physician, who presented his findings to the British Association for the Advancement of Science between 1863 and 1865 42. He claimed that amyl nitrite “when inhaled, produced an immediate action on the heart, increasing the action on the organ more powerfully than any other known agent.” To dramatically illustrate its effect, Richardson passed samples of the compound to the audience 42. Shortly afterward and at the same university, Arthur Gamgee recorded the ability of the substance to lower the blood pressure in animals and humans 39. Under Gamgee’s mentorship, a clinician, Thomas L. Brunton, described the effect of amyl nitrite in patients and over the succeeding years spread the word of its effectiveness. Brunton went on to gain fame in the new field of clinical pharmacology as the author of one of its first textbooks 42.
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NTG attracted little medical attention until 1858 when Alfred Field, a British physician, described the relief of intense chest pain by NTG in a 68 year old woman 43. Similar observations from single case reports followed. But the drug came to wide attention after a series of articles published in Lancet by William Murrell in 1879 who described multiple clinical observations of chest pain relief 43. Because the liquid form of the drug used by Murrell was inconvenient, a pharmacist, William Martindale, prepared the drug in tablet form. Out of concern for its reputation as an explosive, he claimed that it “is stable, non-volatile….and perfectly inexplosive – it cannot be detonated” 43. By 1882, Murrell’s essays had been republished as a monograph in Britain and America, and Parke Davis & Company had made the drug available in pill form in 5 different strengths43. Although NTG had gained wide acceptance for the relief of anginal pain, at that time there was little or no understanding of the relationship between NTG or angina pectoris and the coronary arteries.
By the end of the 19th century, NTG had become an established form of therapy for the relief of angina pain. It also found use in the treatment of heart failure by dilating peripheral veins, inducing venous pooling, reducing venous return and lowing right heart pressures. Although during the next 80 years NTG was recognized as a vasodilator, there was little or no understanding of the mechanism of this effect – the “fallow years” 39. In what appeared to be unrelated at the time (1979, 1980), Murad and Furchgott independently described the role of an “endothelium derived relaxing factor” (EDRF) and its role in vascular regulation. Ignarro later identified this factor as nitric oxide (NO), an activator of soluble guanylate cyclase. NO was also recognized as the EDRF by Moncada two months before Ignarro’s publication. The 17
Nobel Prize in Physiology or Medicine was awarded to Murad, Furchgott and Ignarro In 1998 but, for reasons that were never explained, Moncada was not an awardee 39. Most now agree that NO, is an endothelium independent smooth muscle vasodilator that is provided by the organic nitrates but despite much recent investigation, the exact mechanism of this provision is still under debate. Neither explained is the mechanism for NTG tolerance. Despite this basic science uncertainty, NTG continues to be widely used in chronic stable and unstable angina and decompensated heart failure 44,45. For both good and for ill as a medication or as an explosive, NTG has been with us since 1847 and appears likely to remain.
Quinidine – from Malaria to Arrhythmia The early history of quinidine is preceded by the serendipitous but monumental discovery of quinine as a treatment for malaria – the first chemical compound to treat an infectious disease. Accounts vary, but the story appears to have begun in the 1630’s when Jesuit missionaries in South America used the powdered bark of a tree for the relief of fever - although legend suggests that the native population may have used it even earlier for the same purpose 46. The cinchona tree (fig. 7) was named for the wife of the Spanish Viceroy to Peru, Countess Anna del Chinchon who, while in Peru was cured, probably of malaria, in 1638 46,47. Other sources also introduced the powdered bark to various sites in Europe. Juan de Lugo, a Spanish noble turned Jesuit priest, brought it to Rome while attending the election of a new Pope – Innocent X 47. The mysterious powder also gained acceptance in England when Charles II was cured at the end of the 17th century by an apothecarian Robert Talbor 47,48. This healer of the English king was called, in 1678, to cure the son of King Louis XIV of France, who had contracted malaria in the in the swamps surrounding Versailles 47,48. Quinquina was the name given to the therapeutic 18
substance in the cinchona bark and root and the first alkaloid of quinquina was isolated by a Portuguese doctor, Bernardino Antonio Gomez and called cinchonine. But the more effective second alkaloid was isolated by two French pharmacists, Pierre J. Pelleitier and Joseph B. Caventou, and named quinine 47. In 1853, Pasteur isolated what he thought was an impurity of quinine and called it quinidine 47. Because of malaria, the need for quinine grew over the years as European countries continued to colonize Africa, India and South America. The quinine content of many of the cinchona trees was low but a British collector, Charles Ledger, obtained some seeds of a potent Bolivian species. The British were not interested so he sold the seeds to the Dutch government 49,50. The Dutch planted the seeds in Indonesia and came to monopolize the world’s supply of quinine for close to 100 years. By the 1930’s, the Netherlands produced 97% of the world’s quinine output. During WW II, the Allied powers lost their quinine supply when the Germans invaded the Netherlands (processing plants) and the Japanese took control of Java 49,51. The United States obtained seeds from the Philippines and began to plant trees in South America but the drug came too late and, despite informational programs (fig. 8), thousands of our troops died of malaria in Africa and the South Pacific 52. A quinine substitute, Atabrine, became available in 1942 but synthetic quinine was not developed by American scientists until 1944 49,51,52. The first reference to a cinchona alkaloid used in the treatment of a cardiac arrhythmia was in a two volume work on the heart published by Jean-Baptiste de Sénac in 1749 53,54. In this treatise Sénac described the successful use of quinine in the treatment of “rebellious palplitation” that very likely was atrial fibrillation 53. This observation went unnoticed but was rediscovered years
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later when Karel Frederik Wenkebach (best known for his description of Type 1 second degree atrio-ventricular block) described a patient he saw in 1912 55. At that time in malaria prone countries, quinine’s ability to relieve fever had led to its non-specific everyday use, much as aspirin or other NSAIDs are used today. Wenkebach’s patient, a Dutch merchant, suffered from bouts of paroxysmal atrial fibrillation and noted that incidental use of the drug for fever could stop the arrhythmia. Wenkebach was doubtful, but the patient demonstrated that he could abolish the arrhythmia by taking a gram of “quinin”. Wenkebach had limited success in his patients with oral quinin in the treatment of atrial fibrillation but noted that it worked best in cases when the onset of the arrhythmia was recent and when there was little other heart disease – observations that still stand 55. Winterberg, a colleague in the same clinic, showed that intravenous administration was more often effective than the oral form. Wenkebach went on to describe the further salutary effects of oral quinin in the abolition of “extrasystoles”. Impressed with the anti-arrhythmic effects of the drug, he prompted a colleague Walter von Frey, to investigate other alkaloids of the cinchona bark 55. Frey reported in 1918 that of the 4 tested alkaloids in cinchona bark, “quinidin” was the most effective in abolishing atrial fibrillation 56. Sir Thomas Lewis, in 1909, first recognized atrial fibrillation on the ECG 57 and by 1922 observed that quinidine could restore sinus rhythm in 50% of his cases 58. But because 50% of the patients did not convert and because atrial fibrillation often recurred among those who did, Lewis did not recommend quinidine for general use. Despite Lewis’ reservations, quinidine became widely used for the treatment of most cardiac arrhythmias for the next 40 plus years. In 1964, Selzer and Wray reported 36 attacks of syncope in 8 patients all receiving standard 20
doses of digitalis and quinidine for atrial flutter or fibrillation. In 5 of the cases, recorded ECG’s showed ventricular flutter or fibrillation and the episodes were called “Quinidine Syncope” 59. In 1978, the interaction between quinidine and digoxin was described 60 that later required the digoxin dosage be reduced by 50% when used in conjunction with quinidine 61. It now seems possible that some of the early cases of quinidine syncope were in fact due to digitalis intoxication, unrecognized at the time. Subsequent reviews of quinidine usage in atrial fibrillation demonstrated effectiveness in the maintenance of sinus rhythm but with an increased mortality 61. In addition there was growing evidence of harm when the drug was used in the treatment of ventricular arrhythmias and, not surprisingly, the use of quinidine for the maintenance of sinus rhythm has decreased. Quinidine is primarily a sodium channel blocker 20 and, like many other type I anti-arrhythmic drugs, has pro-arrhythmic effects such as premature ventricular beats, ventricular tachycardia and sudden death. Although it has been largely replaced by more effective/safer agents, it is still listed as therapy for atrial and ventricular arrhythmias in selected patients 62 but no longer mentioned in the American Heart Association guidelines for the treatment of atrial fibrillation 63. Recently, quinidine has made a limited comeback in the prevention of arrhythmias associated with the Brugada Syndrome and the short QT syndrome 61. Quinine for malaria and quinidine for arrhythmias are inextricably connected by their origin from the same botanical source. Although quinine has now been replaced as treatment for malaria, quinidine continues to find limited but possibly increasing use in cardiology.
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Conclusions Today, new drugs are developed by chemical or genetic engineering to attack specific chemical or genetic targets, identified by an increasing understanding of disease mechanisms. Potential agents are tested in the laboratory, in animals and in clinical trials followed by FDA approval and post marketing evaluation. This process is costly and takes years. Present technology was unavailable to our forebears but did not prevent them from developing useful drugs using only their powers of observation coupled with a large dose of serendipity. Their process was simpler, cheaper and without television advertisements, but it took much longer.
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Figure Legends Figure 1. Black Willow Tree - Salix Nigra - Photo and permission from Flickr Figure 2.
Page 1 of the letter from Rev Edmund Stone to the Royal Society. With permission from the Royal Society
Figure 3. Atropa Belladonna - Photo and permission from Flickr Figure 4. Bas relief of Atropos, shears in hand, cutting the thread of life - Wikimedia Commons – photo by Tom Oates https://commons.wikimedia.org/wiki/File%3AAtropos.jpg Figure 5. Digitalis Purpurea (Foxglove) - Permission from Pet Poison Help Line – photo by Tyne Houda
http://www.petpoisonhelpline.com/poison/foxglove/
Figure 6. Front page of Withering’s book “An Account of the Foxglove”. With permission Missouri Botanical Garden – Peter H. Raven Library. Figure 7. Cinchona Pubescens – (Quinine) Makawao Forest Reserve, Maui, Hawaii.,May 30, 2005 . Permission – Starr Environmental - Forest & Kim Starr
Figure 8. Informational campaign to US troops to combat malaria – Collection of the National Library of Medicine - Prints and Photographs - NLM unique ID 101454784
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