Acetylsalicylic Acid

Karsten Schrör

• Verlag: Wiley-Blackwell
• Jahr: 2016
• ISBN:
  9783527685042
• Auflage: 2
• Thema: Biological Sciences
• Thema: Cell Biology

Written by a leading expert on Aspirin-related research, this is the most comprehensive treatise on the pharmacological effects and clinical applications of one of the most successful drugs ever.
The text is written with a wide audience in mind, and to be readily understandable for clinicians, pharmacists, biomedical researchers and pharmacologists alike.
This second, completely revised edition contains the latest results of clinical and pharmacological research on Acetylsalicylic acid, addressing the multiple pharmacological properties of this famous drug with a balanced view on their translation into clinical practice, including prevention from cardiovascular diseases and colorectal cancer.

1
General Aspects

1. 1.1 History
   1. 1.1.1 From Willow Bark to Salicylic Acid
   2. 1.1.2 Synthesis of Acetylated Salicylic Acid and First Medical Use
   3. 1.1.3 Search for Pharmacological Modes of Action
   4. 1.1.4 Clinical Applications: A Piece of History
   5. 1.1.5 Current Research Topics
2. 1.2 Chemistry
   1. 1.2.1 Structures and Chemical Properties of Salicylates
   2. 1.2.2 Determination of Salicylates

1.1 History

1.1.1 From Willow Bark to Salicylic Acid

1.1.1.1 Anti-Inflammatory and Analgesic Effects of Willow Bark and Leaves

Medical Effects of Willow Bark

Treatment of maladies by plants or extracts thereof is as old as the history of mankind. This is also true for fever and pain, two particularly frequent and inconvenient symptoms of acute illnesses but also typical for osteoarthritis and rheumatism, two examples of chronic painful diseases. Rheumatism was already known in old Egypt as seen from cartilage alterations in Egyptian mummies. The Egyptians were also aware of the pain-relieving effects of potions made from myrtle and willow leaves. Clay tablets from the Sumerian period also contained information about the use of willow leaves as medicines. Hippocrates recommended leaves of the willow tree for medical purposes about 400 BC. Pliny (compilations) and Dioscurides (Materia Medica) also recommended decocts of willow leaves or ash from willow bark for treatment of sciatica (lumbago) and gout at about 100 AC. Outside Europe, it were the Nama (Hottentots) in Southern Africa who had “for a long time” used tea made from bark of willow trees for treatment of rheumatic diseases (cited after Ref. [1]). This comment was made by Dr. Ensor from Cape Town (South Africa) in his reply to a publication of Dr. MacLagan in 1876 [2] describing for the first time positive experience with salicylates at 2 g/day for treatment of rheumatism.

The First Published Clinical Trial

The first known public communication on the medical use of willow bark extracts in modern times came from Reverend Edward Stone [3] from Chipping Norton (Oxfordshire, England). He treated some 50 cases of “aigues, fever, and intermitting disorders” with a redissolved powdered dry bark preparation of willow tree. The doses were about “20 gr(ains) [≈1.3 g] to a dram of water every 4 hours.” On June 2, 1763, he wrote a letter to the Earl of Macclesfield, the then President of the Royal Society in London, entitled “An account of the success of the bark of the willow in the cure of aigues.” In this letter, he summarized his opinion about this treatment as follows:

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…As this tree delights in moist or wet soil where agues chiefly abound, the general maxim, that many natural maladies carry their cure along with them or that their remedies lie not far from their causes, was so very apposite to this particular case, that I could not help applying it; and this might be the intention of providence here, I must own had some little weight with me….

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After claiming to have obtained good results, he concluded:

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…I have no other motives for publishing this valuable specific than that it may have a fair and full trial in all its variety of circumstances and situations, and that the world may reap the benefits accruing from it.

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1.1.1.2 Salicylates as the Active Ingredients of Willow Bark and Other Natural Sources

Detection and Preparation of Salicin from Willow Bark

In 1828, the German pharmacist Johann Andreas Buchner was the first to prepare a yellowish mash with bitter taste from boiled willow bark, which he named Salicin, after the Latin word for willow (salix). He considered salicin as the active antipyretic ingredient of willow bark and recommended its use for treatment of fever. A similar conclusion had earlier been reached by the Italians Brugnatelli and Fontana in 1826 using a less purified preparation of willow bark. They also considered salicin as the active principal component of willow bark (cited after Ref. [4]). In 1830, the Frenchman Henry Leroux was the first to obtain salicin in crystalline form. Only 3 years later, in 1833, the pharmacist Merck in Darmstadt (Germany) announced highly purified salicin from willow bark for use as an antipyretic for half of the price of quinine (cited after Ref. [5]) – at that time a really attractive offer.

Salicin from Natural Sources as Starting Material to Make Salicylic Acid

Salicin is not only the active antipyretic ingredient of willow bark but also the reason for its strong bitter taste and the irritation of stomach mucosa. Both limited its practical use. Salicin hydrolyzes in aqueous media to glucose and salicylic alcohol (saligenin). Saligenin has no bitter taste and can be easily oxidized to salicylic acid. Raffaele Piria, an Italian, was the first to successfully synthesize salicylic acid (acide salicique ou salicylique) from salicin in 1839 and also correctly determined the empirical formula C₇H₆O₃. This led to the possibility of replacing the poorly palatable salicin by salicylic acid, for example, as a good water-soluble sodium salt. This became practically relevant after new and abundant natural sources for salicylates were detected. These included wintergreen oil obtained from the American Evergreen (Gaultheria procumbens) and spireic acid (acidum salicylicum) from the American teaberry (Spiraea ulmaria). Gaultheria oil (wintergreen oil) consists of about 99% of methyl salicylate from which free salicylic acid can easily be obtained. However, production of salicylates by plants is also an important defence mechanism in itself.

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Efficient communication between the pest-colonized and noncolonized plants is vital for timely manifestation of defenses that restrict systemic spread of pests. Airborne signals are involved in these processes. Methyl salicylate is a volatile compound that is made by a number of plants and is suggested to act as a mobile airborne signal in plant defence by activation of systemic acquired resistance. This confers enhanced resistance against a broad spectrum of pathogens (Section 2.2.2) [6].

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1.1.1.3 Chemical Synthesis of Salicylic Acid

The Kolbe–Schmitt Synthesis

The modern pharmaceutical history of salicylates and its derivatives starts with the chemical synthesis of the compound. In 1859, Hermann Kolbe, a German and Professor of Chemistry in...

Inhaltsverzeichnis

• Cover
• Title Page
• Copyright
• Preface
• Chapter 1: General Aspects
• Chapter 2: Pharmacology
• Chapter 3: Toxicity and Drug Safety
• Chapter 4: Clinical Applications of Aspirin
• Appendix 1: Abbreviations
• Appendix 2: Selected Clinical Trials and Their Acronyms – Only Published Trials
• Index
• End User License Agreement