337 [10] ensic Medicine, -nitrophenol, p [4,8] ology, National Board of ¨ oping, Sweden Drug Testing Drug Analysis and 2011 John Wiley & Sons, Ltd. [8] c tional Board of For ayne Jones, Department of Forensic ¨ urner (1783–1841). While working ¨ oping, Sweden. E-mail: [email protected] [11–13] netics and Forensic Toxic ne, Artillerigatan 12, SE-58758 Link 2011 John Wiley & Sons, Ltd. The word ‘toxicology’ derives from the Greek word c th century, the first of the family of drugs [9] which literally referred to a bow for shooting arrows. Correspondence to: ProfessorGenetics Alan and W ForensicArtillerigatan 12, SE-58758 Toxicology, Link Na Department of Forensic Ge Forensic Medici The first hunters learnt the trick of spiking their darts and arrows The isolation and characterization of the active principles in ed from the distillation of coal (coal-tar). The first analgesics as much more palatable. This was acetylsalicylic acid, better ∗ sources and existed in the form of herbs, plants, roots, vines with plant toxins (poisons), suchanimals. as curare to kill or stupefy wild medicinal plants representedchemists a and major apothecaries challenge ofplant the for isolated in time. a analytical pure Morphinenamed state Friedrich was by Willhelm a the 23-year-old Sert apothecary first as an apprentice to a pharmacy in Einback, Germany, in 1805, became more organized, as evidence by Greek, Roman,cultures, and as Indian well as traditional Chinese medicine. Nature’s pharmaceuticals Examples of pharmacologically activeplants substances include derived from from tobacco opium plant, cannabinoids poppy, from nicotine cannabistea from leaves, and caffeine the from coffee, cardiacwoolly foxglove, glycosides quinine (digoxin from andfrom the the digitoxin) cinchona bark tree, of from the and white salicylates willow tree. Other psychoactive substances knownwhich were since popular in certain ancient cultures included times cocaineleaves, from and coca psilocybin from mushrooms,cactus, mescaline to name from just a the few. peyote toxikos, n white willow, salicin or salicylic acid, had a bitter taste and ould not be complete without some knowledge of the history ompanies were spin-offs from the textiles and synthetic dye vered in 1869 and introduced as a -; it is still m the bark of the white willow tree had been used for centuries he events leading to the development and introduction of new [1] [5–7] nilide, were simple chemical derivatives of aniline and Indeed, the )datingfrom [1] papyrus described Ebers both of which refer to dry , a 20-metre-long, 110-page droog, ∗ papaver somniferum Ebers papyrus , 337–344 Copyright 3 , referring to a type of powder. , the first blockbuster drug. At the start of the twentie  ¨ og, 2011 dr or the Dutch word 1500 BC. These were prepared by mixing together Biosynthesis of these natural toxins functioned as ; analgesics; ; drugs; discovery; plants; natural products; ∼ Crude extracts from wild plants and shrubs constituted

[2,3] [4] drogue

Nature has provided a rich source of pharmacologically active Perhaps the earliest written record of medical therapeutics is 3000 BC that contained the all powerful painkiller, morphine. first pharmaceuticals were obtained from theas vegetable kingdom the driedWikipedia, parts the of etymology plants, ofword the herbs, word and ‘drug’barrels shrubs. is containing herbs. According the Old to French chemical substances producedreptiles. by plants, fungi, insects, and the first herbal medicinesand suffering, that to were heal used wounds,Foremost and for among to the these treat natural relief all typesfrom products of of was the pain maladies. the opium juice poppy obtained plant ( Drug Test. Analysis These recipes andof concoctions medicines represented in the theinfluence earliest on ancient later generations record world when knowledge of and herbal products must have had a strong The word ‘drug’ is probablyOld of Arabic German origin as and first appeared in Introduction

Studies in the field of forensic pharmacology and toxicology w of pharmaceutical chemistry Alan Wayne Jones (www.drugtestinganalysis.com) DOI 10.1002/dta.301 Early drug discovery and the rise of drug discovery, thetherapeutic various agents. The personalities first involved, medicinal and drugs came t from natural Historical Received: 15 April 2011 Revised: 28 April 2011 Accepted: 28 April 2011 Published online in Wiley Online Library and fungi. Until the mid-nineteenthsuffering. century The nature’s first pharmaceuticals synthetic were drug, all that hydrate, were was availableindustry and to disco owe much relieve to man’s the rich painand source of and antipyretics, organic chemicals exemplified deriv by phenacetin and aceta available today in some countries. The first pharmaceutical c a chemical self-defence mechanismfrom being and eaten protected by thehave predators. species been Accordingly, around these sincebeings, xenobiotics the in dawn theirhave of continuous experienced the history. quest effects of The these forworse. first substances, for food human better or and for survival, must contained in the famous ∼ both of which were byproducts from coal-tar. Anirritated extract the fro gastric mucosa, but aknown simple as chemical Aspirin modification w to treat various fevers and inflammation. The active principle i entered the pharmacopoeia and the rest, as they say, is history. Copyright Keywords: medical scroll, named after the German Egyptologistwho Georg Ebers, acquired it inhundreds 1872 of (Figure 1). treatments The forEgyptians the many aliments inflicting ancient various herbs, shrubs, leaves, minerals, and animal excreta. ), ), [26] Robert ), eme- He also ), which , 337–344 3 3 [22] [27] [21] , A. W. Jones . These bitter- ), and coniine The complex 2011 One of his many [23] ) was established [14] ergot fungus scopolia carniolica [30] strychnos nux-vomica Phantastica and Alfred Swaine Taylor ), LSD ( Orfila is considered as the castor oil beans [28] [25] Materia Medica has been implicated in murder Drug Test. Analysis ), ( ) strychnine ( [29] ), ricinine ( Another venerable pioneer in pharmacology papaver somniferum [11] ). One notorious alkaloid, strychnine, derived from calabar beans [24] ¨ ohler (1800–1882), famed for the synthesis of urea A contemporary, close friend and sometimes scientific strychnos nux-vomica [20] atropa belladona ¨ ohler was the celebrated Justus von Liebig (1803–1873), [19] cephaelis ipecacuanha Examples of common alkaloids and their botanical plant origin The subject of pharmacology ( A major preoccupation of analytical chemists and early toxi- spotted hemlock Friedrich W ‘without the helpcyanate. of a kidney’ simply by heating ammonium include morphine ( tine ( physostigmine ( ( as a scientificcentury by discipline people such as in Rudolf BuchheimSchmiedeberg (1820–1879), (1838–1921), the Oswald Paul Ehrlich latter (1854–1915),Dale and half (1875–1968). Henry of the nineteenth atropine ( and toxicology was Louis Lewin (1850–1929),founding who was fathers one of of the many psychopharmacology published papers as and evidenced the textbook by his discoveries was the volatile liquid (CHCl chemical structure of alkaloids meant they werefrom difficult body to organs extract and tissue, a daunting taskchemists. for Without the being first able analytical to extract andthe identify a body, poison from itmurder. was not possible to prove itscologists use was in to develop the methods thatof crime allowed of plant the identification alkaloidspoisoning. in Foremost among blood these pioneers and was(1787–1853), Mathieu human JB born Orfila on viscera the Spanish as islandand of Minorca evidence worked but who of in lived Parislater as Dean Professor of of the Medical Medical Faculty. Jurisprudence and rival of W whose chemical discoveries areby legendary. many as Liebig the is founding(Figure considered father 2). of organic and clinical chemistry wrote the first book devoted to adverse drug reactions. The first synthetic drugs The doyen amongthe German nineteenth century organic was chemistsrenowned Justus Professor during von of Liebig Chemistry much in (1803–1872), of Munich. the Many of the first forensiccareers chemists by and visiting toxicologists began andincluded their studying Jean-Servais under Stas Orfila. (1813–1881) These individuals in Belgium, Alkaloids The word ‘alkaloid’ (Figurechemist 3) Carl was F. coined Wilhelm inorganic Meissner compounds 1819 played (1792–1853) by a prominent and a roleof this in German the forensic class development toxicology of as a scientific discipline. father of forensic toxicology aswrote the a first textbook scientific on drugs discipline and poisons and in 1814 he (Figure also 4). Christison (1797–1882) in Scotland, tasting (alkaline) substances producedmore by nature atoms in contain the one molecule anda or are deadly pure poisonous state. in the plant by poisoning in many criminal prosecutions. (1806–1880) from London. ¨ urner 2011 John Wiley & Sons, Ltd. c Sert 100 mg in ∼ [10] Another pioneer Copyright [16] of raw opium (the specific [17,18] an Egyptian medical scroll dating ¨ urner felt that he had discovered The new substance was christened [11] the Greek god of dreams. These toxins were incriminated in crimes Not long afterwards other alkaloids were ¨ oping in Sweden, and made enormous Ebers papyrus [14] [11] ¨ aubende Grundstoff Morpheus ¨ ons Jacob Berzelius (1779–1848), who was born [9,15] When this base was administered to a dog, the animal Page from the 1500 BC, which gives instructions how to prepare hundreds of [11] ∼ ¨ urner isolated meconic acid from raw opium. The following By the mid-1800s, German scientists began to dominate the When available in a pure form, the pharmacological activity Drug Testing Drug Analysis and year he obtainedbase. a substance with the properties of a weak tested the pharmacological effectsfriends on and himself took and some unusuallythree divided young large doses). doses (1.5 grains field of analytical and organic chemistry, with such luminaries as and toxicity of thesewere alkaloids deadly increased poisons. considerably and many isolated from opium, including codeine and papaverine. www.drugtestinganalysis.com Animal chemistry and pharmacology Apothecariesprobablyrepresentthefirstpharmaceuticalchemists charged with mixing and dispensing all kinds ofthe herbal remedies hope in of finding a cure for theirForemost customer’s medical complaints. among theWilhelm Scheele early (1742–1786), apothecaries whohistorians is was of known chemistry the and as admired a Swede veritable by pioneer. all Carl Sert Figure 1. from purported herbal medicines and cures. fell into a deep sleep and Sert narcotic element of opium). der eigentliche bet contributions to the chemical sciences, even writingon the animal first (physiological) book chemistry. in the vicinity of Link chemist was J ‘morphine’ after of murder by poisoningfor and extraction development of andspecimens suitable marked methods identification the beginning of oftoxicology. forensic the pharmacology and poison in biological

338 339 Drug Testing Drug Analysis and www.drugtestinganalysis.com ) in some countries. Indeed, chloral  Henry Dale (1875-1968) (1820-1879) Rudolf Buchheim The parent compound of barbiturates, [31] (1803-1873) (1838-1921) Justus von Liebig Oswald Schmiedeberg studies showed that wasaid a relatively (hypnotic) safe and sleeping enteredand still the exists today pharmacopeia (Noctec as early as 1869 Barbiturates Barbiturates represent a remarkableand class function of as sleeping therapeutic aids,They agents anaesthetics, and entered anticonvulsants. thetwentieth pharmacopoeia century. in the first decade of the hydrate was incriminated in themodel accidental Anna-Nicole death of Smith themixture Playboy (1967–2007), of pharmaceuticals. who Otherhypnotic early overdosed drugs include used on as bromidealthough a sedative- these salts, were ,barbiturate made and class more of urethanes, ortwentieth drugs less century. appeared redundant in when the the first decade of the 2011 John Wiley & Sons, Ltd. c kaloid’ and his reasoning for the choice of this word. Paul Erlich (1800-1882) (1854-1915) Friedrich Wöhler f chemistry, pharmacology, and toxicology. [11] (1850-1929) (1779-1848) Louis Lewin Jöns Jakob Berzelius , 337–344 Copyright 3 , 2011 The results of these investigations were reported [11] Title of Meissner’s article in which he coined the word ‘al Some early scientific luminaries in the field o Administration of chloral hydrate to animals put them into a In 1832, Liebig also prepared chloral hydrate and showed that Early drug discovery and the rise of pharmaceutical chemistry in a classic monograph (Figure 5). deep sleep, but withoutpharmacological loss effects of differed from pain that sensation, of which chloroform. Further meant its Drug Test. Analysis later became important asof chloroform a as general a anestheticScottish volatile physician anesthetic drug. James in The Young surgery Simpson use demonstrated is (1811–1870). credited the Simpson to benefits a associated of with child birth chloroform and one to ofnone his other first deaden patients than in Queen the 1872 Victoria was of pain England. Figure 3. Figure 2. in alkaline solution it wasacid. converted This into prompted chloroform the andOscar German formic Liebreich physician (1839–1908) and pharmacologist reaction might to occur directly investigate in the blood, whether whichchloral would hydrate the mean might that also same be useful anestheticchloroform. in the same way as , 337–344 3 , A. W. Jones 2011 Whether the name [35] Drug Test. Analysis cid. With a higher pKa (7.9), this [36,37] Laterworkshowedthatbarbituricacidcontaineda6-membered work he had done on synthetic indigo dyes. pyrimidine ring (Figure 6),inactive, owing although to itwas poorly the was absorbed from low pharmacologically the gut. pKa Afterbarbituric the acid chemical of was structure elucidated, of 4.12, the physicianJosef which and pharmacologist von meant Mering thatadjacent (1849–1908) hydrogen atoms it in the had pyrimidine ring with theHe ethyl groups. idea knew from of earlier replacingthe research same that two carbon two atom alkylsynthesized imparted groups diethyl pharmacological bonded barbituric activity to so a he barbituric acid was coinedthat in von honour Baeyer of wasfrom allegedly a St dating Barbara lady the at named patron the saintknow. Barbara of time artillery or officers, we if will it never comes [32] amous 1814 treatise on the general toxicology of poisons. 2011 John Wiley & Sons, Ltd. 1869 monograph on chloral hydrate and its use as a hypnotic. c Copyright and Archibald Scott In 1857–1858, more or [33] [34] , although its chemical structure was unknown at 3 O 2 Portrait of Oscar Liebreich alongside the first page of his Portrait of Mathieu JB Orfila alongside the first page of his f N 4 ´ e (1829–1896) from Germany H 4 The synthesis of barbituric acid was only a very small fraction of Drug Testing Drug Analysis and the many contributions to organicBaeyer chemistry and made he justifiably by received Adolf a Von Nobel Prize in 1905, mainly for less simultaneously, theseideas structural about chemists the published tetravalentability novel to nature self-link into of chains and the ring structures carbon atom and its the time. Thearomatic development and aliphatic of rings,Kekul structural had formulae, to await including the work of August www.drugtestinganalysis.com He reacted uric acid, an(from animal apples) waste to produce product, a with new compound malonic withof acid empirical formula C Figure 5. barbituric acid, was(1835–1917) synthesized in as part 1864 of by research Adolf for von his Baeyer thesis (habilitation). Figure 4. Couper (1831–1892) from Scotland.

340 341 [45] [44] [45] Drug Testing Drug Analysis and [43] www.drugtestinganalysis.com which eventually became more  O 2 . In 1887, the Bayer Company began 2H  + (1852-1919) Emil Fischer -aminophenol (paracetamol), but as a commercial p (fever-reducing). H H On closer inspection it turned out that the pharmacist  O O [45] -acetyl- -nitrophenol, which was easily converted into the ethyl ester N p H N N H The success of Antifebrin prompted the Bayer Company to An example of one of the many aromatic compounds derived hesis of barbituric acid by Adolf von Baeyer in a condensation reaction product this was overlooked in favour of phenacetin. search for other chemicalsworks in for the possible waste use productswas as from pharmaceuticals. the One dye- suchderivative substance of acetanilideproduct (Figure 7) to phenacetin give another commercial extraction, identification, and quantitative analysis of barbiturates in blood and liver tissueof belong analytical to and forensic classic toxicology. procedures in the field from coal-tar was naphthalene,antiseptic which for, among was other things, used the irradiation asa of an worms. patient When intestinal with this conditionfrom a who fever received also naphthalene, happened the fever to wasworms. cured be but not suffering the Another derivative of acetanilide prepared aroundwas the same time The first analgesics and antipyretics The first synthetic drugsindustry and, can be indeed, traced to the the manufacture entire ofdyes, textiles pharmaceutical as and exemplified synthetic by mauveine (mauve),by which a was discovered young British chemistOne William Henry of Perkin (1838–1907). thein first pharmaceuticals was German thein chemical Friedrich 1863, firms Bayer and Company, toLeverkusen). originally The founded black show sticky located mass (tar) an in remainingof after Barmen, distillation interest coal Germany under (todaychemicals, including , in a naphthalene, and aniline. vacuum provided a rich source of aromatic hadmadeamistakeandinsteadofnaphthalene,anotherderivative of coal-tar, acetanilide (Figure 7) had beenBayer prescribed. This Company led the to developsynthetic antipyretic and drug, which market became known acetanilideAntifebrin commercially as as the first successful as an analgesic-antipyretic agent than acetanilide. to manufacture phenacetin O , )   [40] 2011 John Wiley & Sons, Ltd. (1849-1908) c Josef von Mering Among OH OH [41] Synthesis of barbituric acid O O + 2 2 [38] NH NH Moreover, barbiturates [41] O (1835-1917) Adolf von Baeyer The development of methods for [42] Together with his students, Fischer , 337–344 Copyright 3 [39] , 2011 [36–38] The success of as a hypnotic led to the , a mixture of two barbiturates, namely brallobarbital  Scientists credited with the development of barbiturates and the synt [11,40] After prescribing the barbiturate group of drugs on a large- As von Mering was a pharmacologist and not a chemist, The barbiturate family of drugs, without any shadow of a doubt, Early drug discovery and the rise of pharmaceutical chemistry between urea and malonic acid. Drug Test. Analysis Fischer andbarbital von as Mering1903. a also sleeping conducted aid clinical and trials published with their findings in diethyl derivative of barbituric acid was more easilythe absorbed from gut, it hadmore a easily crossed greater the solubility blood-brain barrier. in lipids, which meant that it Figure 6. carry a high abuse potentialand and dependence on some their people . Toxicity develop is tolerance enhancedtogether if taken with other depressant drugs, such as . succeeded in making a morewhich potent derivative he of barbituric patented acid, in 1903 under the trade name Veronal allegedly named after the peaceful Italian city of Verona. synthesis of scoresthe of two other hydrogen derivatives atomsring of on barbituric being the acid replaced 5,5-positionMany with of with of the alkyl, these pyrimidine compounds aryl,pharmaceutical were allyl products, further or developed notable aromatic into useful groups. (Luminal scale, problemsused arose, as with sleepingtherapeutic reports aids; dose there of and was acute a a lethal narrow toxicity dose. margin when between a he contactedauthority Emil in Fischer organicasked (1852–1919), chemistry him in the tothe Germany acknowledged verify new at the compound. the time, structure and and check the purity of other famous names,died the from asphyxia pop after inhalation stara of Jimi night vomit when Hendrix of sedatedVesparax after (1943–1970) heavy drinkingand and , as well the as a prescription small amount of sleeping . aid represented a majorsuch advance as thiopental in an intravenous pharmacotherapy anaestheticpentothal), agent are and (e.g. still sodium in some, use today.cocktail Thiopental is used one of in a three-drug injection connection in several with US states. capital punishment by lethal which appearedanticonvulsant. in 1909 and is still in use today as an .  [46] , 337–344 3 , A. W. Jones genus contain 2011 Spiraea Drug Test. Analysis 3 CH NH O Reverend Stone, who lived in Chipping Norton, t 1900 granted to Bayer’s Felix Hoffmann for the synthesis O 3 [47] CH O O OH The first well-documented clinical trial of salicylates in medicine salicin, a naturally occurringafter hydrolysis glycoside and oxidation of gives salicylic salicyl acid. alcohol, which is credited to an English(1702–1768). clergyman, the Reverend Edward Stone Aspirin - a wonder drug This historical account of earlyand drug discovery antipyretics of would mildacetylsalicylic analgesics not acid, better be known complete around the without world mentioning as Aspirin Many plants, shrubs, and trees of the Oxfordshire, had an inquisitivehealth mind and well-being and of was thewas rural interested well community in aware where of he the the lived. rumourscurative He that properties of circulated extracts for of years bark from about thethat the white flourishes willow, a in tree wet orriver damp banks environments and streams and in grows manyextracts close countries to had (Figure 8). been Willow-bark used with great benefit in the treatment of a Aspirin was marketedproduct by as the Bayer a Companyrich in in highly salicylates 1897, enjoy although successful a plantthe much treatment extracts pharmaceutical longer of fevers history and and other were ailments since used ancient for times. C 3 O H Aspirin (1899) Phenacetin (1887) [45] 2011 John Wiley & Sons, Ltd. 3 c CH 3 NH O CH -aminophenol, p Copyright NH O -acetyl- N ), the bark of which is rich in salicylates (left), US paten HO Paracetamol (1887) Acetanilide (1886) This liquid formulation was [45] Salix alba -aminophenol as a new pharmaceutical p -acetyl- N [45] The white willow tree ( Chemical structures of early analgesic and anti-pyretic drugs. In the 1950s, a small US drug firm, McNeil laboratories, began Phenacetin was not without its problems because some Drug Testing Drug Analysis and product, named Tylenol Elixir. better known today(Europe), as which retained acetaminophen the antipyretic (USA) andof analgesic or properties the paracetamol parentside-effect. drug but was lacking the methemoglobinemia to develop patients, after long-term usecondition known of as methemoglobinemia. the The drug, ability ofcells developed red blood a to medical distributeskin oxygen is turns lost ainvestigatedbytwoAmericans,namelyJuliesAxelrod(1912–2004) and blue-purple as a colorand result (cyanosis). Bernard the This B patient’s minor metabolite problem Brodie of phenacetin, (1907–1989) was as the who cause of identified the problem. aniline, a www.drugtestinganalysis.com Another metabolite they identified was of acetylsalicylic acid (middle) and an old bottle of aspirin (right). Figure 8. Figure 7. especially suitable for children and thefor elderly and this was approved purposein by 1955. the Shortly Foodtablet afterwards, and Tylenol form Drug was (500 mg), Administrationover-the-counter also becoming (FDA) and manufactured a found in every in blockbuster home. bathroom drug cabinets available of virtually

342 343 , . 2000 It is by . Cambridge .Pergamon Besides its , 121. 6 , , 189. 1 , 113. 1998 , Sagamore Beach 3 , 155. , 177. , . [49,51] 1 2001 Anesth. Analg. Almqvist & Wiksell: . 37 , , 2001 Dissertation, Uppsala , 353. , 56. 1981 , 377. , 351. 1990 28 Chemistry, Medicine and Drug Testing Drug Analysis and 2010 2009 55 25 , 53 .W.W.Norton&Company: 2007 , Oxford, Oxford University , , . John Wiley & Sons Ltd.: . , 175. 1974 1817 1819 , 153. , 299. 2009 , 857. 78 , the botanical name of the 1997 , 1696. 1 , , , 961. 21 74 Molec. Interv. www.drugtestinganalysis.com Chem. Educator , 49 , , 409. , 50 , Readings in Pharmacology . 35 2001 , 164. , 2009 spiraea 2000 Drug Test. Anal. 1997 Econ. Bot. 43 2003 J. Ethnopharmacol Med. Hist. , 2004 2008 Park Street Press: Rochester, 1991 TIPS . Brown Press: Alcester, 1996 . Annal der Physik J. Chemie. Physik . . . ´ ´ anchez, anchez, A. Nieto-Galan, . Bitter Nemesis – The Intimate History of Strychnine J. Chem. Ed. In Search of a Cure: A History of Pharmaceutical 1963 J. R. Coll. Physicians Edinb. J. Chem. Ed. Clin. Chem. 2006 Drug Discovery, A History Justus von Liebig: The Chemical Gatekeeper. Jac Berzelius: His Life and Work. ¨ Med. Hist. Clin. Chem. Ambix 1966 urner, 2005 . Drug Test. Anal. 2003 1997 Hundreds or even thousands of scientific articles The Untoward Effects of Drugs – A Pharmacological and The Greatest Benefit to Mankind Mutual Favours: The Social and Scientific Practice . Oxford University Press: Oxford, Murder, Magic and Medicine. Phantastica. 1992 [52] , 486. University Press: Cambridge, MA, Crime – Mateu JB Orfila (1787–1853)MA, and Science, his Times. Clinical Handbook. CRC Press: Boca Raton, of Eighteenth-Century SwedishUniversity, Chemistry. Stockholm, Discovery 91 Press: London, Press: New York, Chichester, 7 F.W.A.Sert [7] [8] M. Weatherall, [9] J. Mann, [6] R. J. Huxtable, S. K. W. Schwarz, [5] R. J. Miller, P. B. Tran, [1] R. Porter, [2] P. J. Houghton, [4] W. Sneader, [3] W. C. Agosta, The world-famous name Aspirin gets the ‘a’ from acetyl, the [29] N. G. Coley, [27] R. Wennig, [28] J. S. Cameron. [30] W. H. Brock, [26] J. R. Bertomeu-S [25] J. R. Bertomeu-S [24] W. Vycudilik, G. Gmeiner, [23] C. F. W. Meissner, [22] L. Lewin, [21] L. Lewin, [20] L. Rosenfeld, [19] G. B. Kauffman, S. H. Chooljian, [14] J. Buckingham, [15] N. G. Coley, [16] H. Fors, [17] J. E. Jorpes, [18] N. G. Coley, [13] J. C. Bruhn, B. Holmstedt, [12] B. Holmstedt, A. Fredga, [11] B. Holmstedt, G. Liljestrand, [10] H. Askitopoulou, I. A. Ramoutsaki, E. Konsolaki, usefulness for the treatmentfever, of aspirin has rheumatic found pain, many other headaches, medicalan anti-clotting uses, and agent most and notably a prophylactic as treatment for thrombosis and stroke. References Concluding remarks This account of early drugside discovery of has pharmacology highlighted including the theand human various other chemists, scientists physicians involved.chemist To paraphrase and the microbiologist famousreading Louis French what Pasteur discoverers have (1822–1895) donesacred flame that of discovery. we lift and maintain the even filed a patent for the discovery,Germany which and was the granted following in 1899 year in in the USA (Figure 8). ‘spir’ from the Latin genus appear each year dealing with oneits usefulness or in other medicine aspect and of therapeutics. Aspirin and meadowsweet plant richa in common salicin, ending and for the drug names ‘in’ at was the added time. as By [49] 2011 John Wiley & Sons, Ltd. [50] c In 1853, a [48] Legend has it that were Heinrich Dreser [47]  [49,50] An account of the success of ociety of London to inform them of (Figure 9), and this represented the , 337–344 Copyright 3 ) as a herbal medicine. In a clinical trial, he , 2011 Salix alba Hoffmann succeeded in preparing acetylsalicylic acid [49] [50] Title and opening paragraph of the letter sent in 1765 by the Philosophical Transactions Around 1763, Reverend Stone decided to undertake a scientific The Bayer Company, already the manufacturer of phenacetin, During the first decades of the nineteenth century, French, Early drug discovery and the rise of pharmaceutical chemistry 1874, Kolbe, in association with hisbegan student to Fredrich von produce Heyden, salicylicsynthetic acid product on was anwillow bark. much industrial cheaper scale and than this that derived from Drug Test. Analysis However, the chemical structure ofand this acetylsalicylic derivative was acid unknown agent. was A major ignored breakthrough in as research on1860 salicylates a when occurred Hermann in potential Kolbe (1818–1884), therapeutic afirst Professor in of Marburg Chemistry and later in Leipzig,synthesize salicylic discovered acid an also establishing efficient its way correct to structure. experiment to test thewillow efficacy bark and ( curative propertiesgave of extracts of white willow bark to aagues total of (fevers), 50 albeit patients suffering without from verify a control any or beneficial placebo effectscommunicated treatment, for to to the this Royal condition. Societyits The of results London and were published in host of medical complaints, including acheschills. and pains, fevers and Figure 9. Reverend Edward Stone to thethe Royal usefulness S of extracts of willow bark as a cure for various fevers. first peer-reviewed documentation of the medicinalwillow properties bark. of The articlethe was bark entitled of the willow in the cure of agues. French chemist Charles Frederic Gerhardt (1816–1856)extract heated of an willow bark withsucceeded acetyl in chloride and producing, in for this the reaction first he time, acetylsalicylic acid. in a chemically pure form and on behalf of the Bayer Company Hoffmann was inspired toacid because make his an fatherand improved was form often a of long-time complained suffererand salicylic about of the rheumatism the bitterstomach. irritation taste it of caused his medicine to the mucosa surfaces of his was naturally muchacid interested in and thisin its rival the compound sodium development salicylic salt. of Bayer’s Two Aspirin of the movers and shakers (1860–1924), who waschemist Felix head Hoffmann of (1868–1946). pharmacology, and a young Italian, and Germanprinciple contained chemists in willow attempted bark (salicin or tocrude salicylic substances acid), isolate but they the obtained theraw were active not material, much because better of than a the lack of chemical purity. . , 411. 6 , , 337–344 3 , A. 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