“[From the willow to aspirin]. At the beginning was the willow bark, which was considered as a medicine by Hippocrates, Dioscorides and Plinus. During the XVIIIth century, the Reverend Edward Stone re-discovered the willow for the cure of agues. In 1829, the french pharmacist Pierre Joseph Leroux isolated salicin. Raffaelle Piria was the first to synthesize salicylic acid from salicin (salicoside). Hermann Kolbe prepared salicylic acid from sodium phenate and carbon dioxide. And then acetylsalicylic acid was first prepared by Charles Gerhardt in 1853, but he did not succeed in identifying its structure. Felix Hoffmann, Arthur Eichengrun and Heinrich Dresen from Bayer Laboratories were at the origin of the use of Aspirin as a medicine. In 1971, John Vane showed that aspirin-like drugs inhibited prostaglandine synthesis.” http://www.ncbi.nlm.nih.gov/pubmed/18175528
“[From willow bark to acetylsalicylic acid]. Acetylsalicylic acid is one of the most widely used drugs in the world. Its ancestry the salicylates, including salicin and salicylic acid, are found in the bark and leaves of the willow and poplar trees. The ancient Sumerians and Egyptians, as well as Hippocrates, Celsus, Pliny the Elder, Dioscorides and Galen used these natural products as remedies for pain, fever and inflammation. In the Middle Ages these remedies were used for fever and rheumatism by Hildegard of Bingen and Henrik Harpestreng. The first “clinical trial” was reported by Edward Stone in 1763 with a successful treatment of malarial fever with the willow bark. In 1876 the antirheumatic effect of salicin was described by T. MacLagan, and that of salicylic acid by S. Stricker and L. Riess. Acetylsalicylic acid was synthesized by Charles Gerhardt in 1853 and in 1897 by Felix Hoffmann in the Bayer Company. The beneficial effect of acetylsalicylic acid (Aspirin) on pain and rheumatic fever was recognized by K. Witthauer and J. Wohlgemuth, and the mechanism of action was explained in 1971 by John Vane. Today the antithrombotic effect of acetylsalicylic acid and new aspects of ongoing research demonstrates a still living drug.” http://www.ncbi.nlm.nih.gov/pubmed/20509453
“[Aspirin throughout the ages: a historical review]. Even at the beginning of the next millennium, aspirin will still offer surprises. Its relatively young pharmacological history compares with the early use of salicylate-containing plants since antiquity. The Assyrians and the Egyptians were aware of the analgesic effects of a decoction of myrtle or willow leaves for joint pains. Hippocrates recommended chewing willow leaves for analgesia in childbirth and the Reverend Edward Stones is acknowledged as the first person to scientifically define the beneficial antipyretic effects of willow bark. At the beginning of the 19th century salicin was extracted from willow bark and purified. Although a French chemist, Charles Gerhardt, was the first to synthesize aspirin in a crude form, the compound was ignored, and later studied by Felix Hoffmann. He reportedly tested the rediscovered agent on himself and on his father, who suffered from chronic arthritis–a legend was born and Bayer Laboratories rose to the heights of the pharmacological world. First used for its potent analgesic, antipyretic and anti-inflammatory properties, aspirin was successfully used as an antithrombotic agent. Sir John Vane elucidated aspirin’s active mechanism as an inhibitor of prostaglandin synthetase and received the Nobel Price in Medicine for this work in 1982. Two isoform of cyclooxygenase (COX-1 and COX-2) have now been identified, each possessing similar activities, but differing in characteristic tissue expression. The cox enzyme is now a target of drug interventions against the inflammatory process. After two centuries of evaluation, aspirin remains topical, and new therapeutic indications are increasingly being studied.” http://www.ncbi.nlm.nih.gov/pubmed/10763200
“The historical analysis of aspirin discovery, its relation to the willow tree and antiproliferative and anticancer potential. For several millennia, the willow tree and salicin have been associated with salicylic acid, the key precursor molecule that has contributed to the discovery of acetylsalicylic acid, traded as aspirin. These molecules have been shown to possess phyto- and chemotherapeutic activities as analgesic drugs. In recent decades, aspirin has become the focus of extensive investigation into antiproliferative and anticancer activities. The historical steps that led to the discovery of aspirin, and its antiproliferative and anticancer potential are highlighted in this review.” http://www.ncbi.nlm.nih.gov/pubmed/16542349
“Aspirin: a history, a love story. Most pharmacists know that aspirin’s origins lie with willow bark, but they may be unaware of its role in the development of the pharmaceutical industry. Evolving from salacin (the active ingredient in many plant remedies) to salicylic acid (an analgesic in its own right) to the more effective, less toxic acetylsalicylic acid, this pain reliever cornered the nonsteroidal anti-inflammatory market for more than 70 years. It helped the dye industry branch into pharmaceuticals, and is now used in multiple indications.” http://www.ncbi.nlm.nih.gov/pubmed/22591976
“Willow species and aspirin: different mechanism of actions. Many believe that willow is the natural source of aspirin. However, willow species contain only a low quantity of the prodrug salicin which is metabolized during absorption into various salicylate derivatives. If calculated as salicylic acid, the daily salicin dose is insufficient to produce analgesia. Salicylic acid concentrations following an analgesic dose of aspirin are an order of magnitude higher. Flavonoids and polyphenols contribute to the potent willow bark analgesic and anti-inflammatory effect. The multi-component active principle of willow bark provides a broader mechanism of action than aspirin and is devoid of serious adverse events. In contrast to synthetic aspirin, willow bark does not damage the gastrointestinal mucosa. An extract dose with 240 mg salicin had no major impact on blood clotting. In patients with known aspirin allergy willow bark products are contraindicated.” http://www.ncbi.nlm.nih.gov/pubmed/21226125
“In vitro anti-proliferative effects of the willow bark extract STW 33-I. The well-known anti-inflammatory and analgesic effects of the phytopharmacon willow bark extract have been attributed to the content of salicin; however, pharmacological studies have shown that salicin alone, despite being involved in its therapeutic action, cannot fully explain its clinical efficacy. In addition to reducing inflammation and pain, acetylsalicylic acid (ASA, CAS 50-78-2), like other synthetic non-steroidal anti-inflammatory drugs (NSAIDs), has been shown to exert anti-proliferative effects and to induce apoptosis in a variety of cell lines, e.g., colon, stomach, and prostate cancer cells. To investigate the mechanism of action and possible anti-proliferative and proapoptotic effects of willow bark, a water extract (STW 33-I) and a polyphenol rich fraction (fraction E) have been tested by using the colon-carcinoma cell line HT-29. Both, STW 33-I and its fraction E showed significant anti-proliferative and (1) Introduction The most well-known component of willow bark extract is salicin, which is metabolized in vivo to salicylic acid. The standardized aqueous willow bark extract STW 33-I, which is an effective analgesic and anti-inflammatory drug, contains 23-26% total salicin derivatives and additionally flavonoids, condensed tannins and polyphenols. Typical representatives of the flavonoids are glycosides of naringenin, isosalipurpuroside or eriodictyol. In vitro experiments have demonstrated for pro-apoptotic effects on HT-29 cancer cells. Related to the salicin content of the willow bark extract, a higher dosage of ASA was needed. Furthermore, compared to ASA and to diclofenac (Diclo, CAS 15307-79-6), the COX-1 and COX-2 mRNA expressions were influenced differently by STW 33-I and fraction E. ASA and Diclo inhibited both the COX-1 and COX-2 mRNA expressions, whereas STW 33-I and its fraction E increased the COX-1 mRNA expression. In addition to the already well-known anti-inflammatory and analgesic effects, willow bark extract has been found to possess anti-proliferative and pro-apoptotic effects similar to NSAIDs. The different influence of willow bark on the COX-1 and COX-2 mRNA expressions in comparison to NSAIDs might be relevant, e.g., for prevention of undesirable side effects such as gastric erosions.” http://www.ncbi.nlm.nih.gov/pubmed/20648923
“Herbal Medicine: An Introduction to Its History, Usage, Regulation, Current Trends, and Research Needs. Plants are rich in a variety of compounds. Many are secondary metabolites and include aromatic substances, most of which are phenols or their oxygen-substituted derivatives such as tannins (Hartmann 2007; Jenke-Kodama, Müller, and Dittmann 2008). Many of these compounds have antioxidant properties (see Chapter 2 on antioxidants in herbs and spices). Ethnobotanicals are important for pharmacological research and drug development, not only when plant constituents are used directly as therapeutic agents, but also as starting materials for the synthesis of drugs or as models for pharmacologically active compounds (Li and Vederas 2009). About 200 years ago, the first pharmacologically active pure compound, morphine, was produced from opium extracted from seeds pods of the poppy Papaver somniferum. This discovery showed that drugs from plants can be purified and administered in precise dosages regardless of the source or age of the material (Rousseaux and Schachter 2003; Hartmann 2007). This approach was enhanced by the discovery of penicillin (Li and Vederas 2009). With this continued trend, products from plants and natural sources (such as fungi and marine microorganisms) or analogs inspired by them have contributed greatly to the commercial drug preparations today. Examples include antibiotics (e.g., penicillin, erythromycin); the cardiac stimulant digoxin from foxglove (Digitalis purpurea); salicylic acid, a precursor of aspirin, derived from willow bark (Salix spp.); reserpine, an antipsychotic and antihypertensive drug from Rauwolfia spp.; and antimalarials such as quinine from Cinchona bark and lipid-lowering agents (e.g., lovastatin) from a fungus (Rishton 2008; Schmidt et al. 2008; Li and Vederas 2009). Also, more than 60% of cancer therapeutics on the market or in testing are based on natural products. Of 177 drugs approved worldwide for treatment of cancer, more than 70% are based on natural products or mimetics, many of which are improved with combinatorial chemistry. Cancer therapeutics from plants include paclitaxel, isolated from the Pacific yew tree; camptothecin, derived from the Chinese “happy tree” Camptotheca acuminata and used to prepare irinotecan and topotecan; and combretastatin, derived from the South African bush willow (Brower 2008). It is also estimated that about 25% of the drugs prescribed worldwide are derived from plants, and 121 such active compounds are in use (Sahoo et al. 2010). Between 2005 and 2007, 13 drugs derived from natural products were approved in the United States. More than 100 natural product-based drugs are in clinical studies (Li and Vederas 2009), and of the total 252 drugs in the World Health Organization’s (WHO) essential medicine list, 11% are exclusively of plant origin (Sahoo et al. 2010).” http://www.ncbi.nlm.nih.gov/pubmed/22593939
“History as a tool in identifying “new” old drugs. To trace the history of a natural product and its use, it is necessary to identify to correct plant among around a half-million species. One must also know how and when harvest the plant and the morphology of location and extraction. Within the same species plant chemistry varies, depending upon climatic and soil conditions, stage of maturity and even diurnal factors. To all of these variations must be added the diagnostic ability of physicians and native healers (to distinguish between Hippocratically-trained Western physicians and whose knowledge is less formally taught). Seldom was a disease identified as we Know it today, but the constellations of symptoms described, when studied carefully within the framework historical setting of the culture, can be related to modern medicine. It is essential to study the historical contemporary usage data in the language in which those accounts were writTen. Translators are often philologists who are not sensitive to medical nuances. Modern readers of translated historical documents often are unaware of the precision the authors delivered in describing medical afflictions and their treatments. Natural product drugs are truly products of human knowledge. Because so many modern pharmaceuticals are manufactured synthetically we forget that once either the compound or its affinity had a home in a natural product. Over 2,500 years ago man first used a drug obtained from white willow bark, which was aspirin or acetylsalicylic acid. Today’s scientists continue to be bewildered by just what aspirin’s mechanisms of action are, discovering new modes of action, and how they relate to medical diagnostics. Whatever the science of aspirin, an intelligent person today takes it just as our ancestors did fo millennia. Throughout time, explanations continue to vary just as purpose of administration do as well. Nevertheless, aspirin is perceived as being beneficial. Historical in-use data can also be a factor in judging a drug’s safety, since the records of its use provide observations made by intelligent persons over generations of employment Many historical “drugs” have crossed the line from drug to food. A number of them are now common items on our tables: coffee, tea, sugar, lemon, chocolate, pepper, to name a few The example of coffee affords useful insight. It was first employed as a drug (like tobacco), its botany and chemistry are well known, it has been in widespread use for centuries with diverse ethnic populations in a variety of preparations and amounts consumed. Still we are unsure about coffee’s effect on health, the latest assertion being that the caffeine it contains may delay the onset of Alzheimer’s. In contrast, the mercury drugs were in widespread use for a long period of time by many populations and that fact indicates that the toxic tolerance in humans is probably higher than as currently proscribed. The past contains important data for the scientific investigator. Like any field of research, historical investigation requires specialized knowledge, but much of that knowledge is readily accessible and employable. Rediscovery through examination of historical contemporaneous use data can be efficient and relatively easy compared to the travails of original research in pursuit of a discovery only to learn later that our ancestors had already made that discovery through trial and error in human usage. If we had started a search from the clues provided by history, presumably our discoveries would have been earlier, and we would have benefitted. As it is. we learn history but not science or else we learn science, not history. Both taken together the learning can be enhanced.” http://www.ncbi.nlm.nih.gov/pubmed/12083469
“Early drug discovery and the rise of pharmaceutical chemistry. Studies in the field of forensic pharmacology and toxicology would not be complete without some knowledge of the history of drug discovery, the various personalities involved, and the events leading to the development and introduction of new therapeutic agents. The first medicinal drugs came from natural sources and existed in the form of herbs, plants, roots, vines and fungi. Until the mid-nineteenth century nature’s pharmaceuticals were all that were available to relieve man’s pain and suffering. The first synthetic drug, chloral hydrate, was discovered in 1869 and introduced as a sedative-hypnotic; it is still available today in some countries. The first pharmaceutical companies were spin-offs from the textiles and synthetic dye industry and owe much to the rich source of organic chemicals derived from the distillation of coal (coal-tar). The first analgesics and antipyretics, exemplified by phenacetin and acetanilide, were simple chemical derivatives of aniline and p-nitrophenol, both of which were byproducts from coal-tar. An extract from the bark of the white willow tree had been used for centuries to treat various fevers and inflammation. The active principle in white willow, salicin or salicylic acid, had a bitter taste and irritated the gastric mucosa, but a simple chemical modification was much more palatable. This was acetylsalicylic acid, better known as Aspirin®, the first blockbuster drug. At the start of the twentieth century, the first of the barbiturate family of drugs entered the pharmacopoeia and the rest, as they say, is history.” http://www.ncbi.nlm.nih.gov/pubmed/21698778
