Controversies over coxibs

Controversies over coxibs - Another cyclo-oxygenase isoform, so-called type 2 (COX-2) has been discovered in the early 1990s by Daniel Simmons and W. L. Xie,39 chemists at Brigham Young University in Provo, Utah. Simmons immediately understood the importance of his discovery. The same day the enzyme was sequenced, Provo, Utah. Simmons immediately understood the importance of his discovery. The same day the enzyme was sequenced,40 and he kept his notebook notarized as proof of his discovery. Subsequently, a new class of drugs, COX-2 inhibitors was developed after researchers at the University of Rochester discovered the gene in humans that is responsible for producing the COX-2 and revealed the enzyme’s role in causing infl ammation within individual cells. 

The team, lead by Donald Young (University of Rochester Medical Centre), provided the basic understanding of the role of COX-2 in disease showing that selectively blocking the activity of the enzyme would be benefi cial in treating his discovery. Subsequently, a new class of drugs, COX-2 inhibitors was developed after researchers at the University of Rochester discovered the gene in humans that is responsible for producing the COX-2 and revealed the enzyme’s role in causing infl ammation within individual cells. 

The team, lead by Donald Young (University of Rochester Medical Centre), provided the basic understanding of the role of COX-2 in disease showing that selectively blocking the activity of the enzyme would be benefi cial in treating II. Two Hundred Years of Drug Discoveries infl ammation.41 Besides the constitutive COX-1, participating to stomach protection and renal artery vasodilatation, this COX-2 enzyme, induced by infl ammatory phenomena and cytokines stimulation, allowed to design specifi c inhibitors,“ coxibs, ” playing an increasing but controversial role in the struggle against infl ammation. This discovery set in motion a worldwide race among pharmaceutical companies to identify drugs that would restrain the action of the enzyme and, in turn, reduce infl ammation and pain. There may be other forms of COX that could account for some of the remaining discrepancies in action amongst non-steroidal anti-infl ammatory drugs (NSAIDs). this COX-2 enzyme, induced by infl ammatory phenomena and cytokines stimulation, allowed to design specifi c inhibitors,“ coxibs, ” playing an increasing but controversial role in the struggle against infl ammation. This discovery set in motion a worldwide race among pharmaceutical companies to identify drugs that would restrain the action of the enzyme and, in turn, reduce infl ammation and pain. There may be other forms of COX that could account for some of the remaining discrepancies in action amongst non-steroidal anti-infl ammatory drugs (NSAIDs).42 COX-2 inhibitors were apparently safer from a digestive point of view but questionable for their cardiovascular effects. Selective inhibitors of COX-2 cause less endoscopically visualized gastric ulceration in arthritis patients than equi-effi cacious doses of traditional NSAIDs, which coincidentally inhibit COX-1 and COX-2. COX-2 inhibitors suppress substantially platelet inhibitory, vasodilator prostaglandins, such as prostacyclin (PGI but questionable for their cardiovascular effects. Selective inhibitors of COX-2 cause less endoscopically visualized gastric ulceration in arthritis patients than equi-effi cacious doses of traditional NSAIDs, which coincidentally inhibit COX-1 and COX-2. COX-2 inhibitors suppress substantially platelet inhibitory, vasodilator prostaglandins, such as prostacyclin (PGI2 ), without coincidental inhibition of the platelet agonist vasoconstrictor thromboxane (TxA the platelet agonist vasoconstrictor thromboxane (TxA2 ). 

As PGI As PGI2 counters the cardiovascular effects of TxA2 and augments the response to thrombotic stimuli augments the response to thrombotic stimuliin vivo , this affords a plausible mechanism by which COX-2 inhibitors might enhance the risk of thrombosis in otherwise predisposed individuals. After being marketed in 1999 rofecoxib (Vioxx®) has been withdrawn in 2004, because of an excess risk of myocardial infarctions and strokes. Despite the withdrawal, controversies remain. Although the nonselective NSAIDs can cause life-threatening gastric toxicity, the risk for any single patient is fairly low when COX-2 inhibitors are compared with two non-selective NSAIDs. affords a plausible mechanism by which COX-2 inhibitors might enhance the risk of thrombosis in otherwise predisposed individuals. After being marketed in 1999 rofecoxib (Vioxx®) has been withdrawn in 2004, because of an excess risk of myocardial infarctions and strokes. Despite the withdrawal, controversies remain. Although the nonselective NSAIDs can cause life-threatening gastric toxicity, the risk for any single patient is fairly low when COX-2 inhibitors are compared with two non-selective NSAIDs.43

Among those controversies, the question whether selective COX-2 inhibitors are prothrombotic, or not, is not theoretical. Whereas aspirin and traditional NSAIDs inhibit both thromboxane A 2 and prostaglandin I2 , the coxibs leave thromboxane A thromboxane A 2 generation unaffected, refl ecting the absence of COX-2 in platelets. Thus, this single mechanism might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque. absence of COX-2 in platelets. Thus, this single mechanism might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque.44 Clinical observations and studies found that taking common NSAIDs was linked to a lower risk of certain cancers. 

When celecoxib was approved for familial adenomatous polyposis in 1999, there was hope that other COX-2 inhibitors would also prove to be safe and powerful anticancer treatments. This is not the case. Structural differences between celecoxib and rofecoxib could explain this discrepancy. A systematic chemical approach allowed to produce 50 compounds tested for their ability to induce apoptosis in human prostate cancer cells, confi rmed that the structural requirements for the induction of apoptosis are distinct from those that mediate COX-2 inhibition.

Apoptosis induction requires a bulky terminal ring, a heterocyclic system with negative electrostatic potential and a benzenesulfonamide or benzenecarbonamide moiety. Ching Shih Chen found that taking common NSAIDs was linked to a lower risk of certain cancers. When celecoxib was approved for  familial adenomatous polyposis in 1999, there was hope that other COX-2 inhibitors would also prove to be safe and powerful anticancer treatments. This is not the case. Structural differences between celecoxib and rofecoxib could explain this discrepancy. A systematic chemical approach allowed to produce 50 compounds tested for their ability to induce apoptosis in human prostate cancer cells, confi rmed that the structural requirements for the induction of apoptosis are distinct from those that mediate COX-2 inhibition. 

Apoptosis induction requires a bulky terminal ring, a heterocyclic system with negative electrostatic potential and a benzenesulfonamide or benzenecarbonamide moiety. Ching Shih Chenet al. (Columbus, USA) modifi ed the structure of rofecoxib to create compounds that mimicked the surface electrostatic potential of celecoxib, one of which showed a substantial increase in apoptotic activity. of rofecoxib to create compounds that mimicked the surface electrostatic potential of celecoxib, one of which showeda substantial increase in apoptotic activity.45 What a challenge for the future!

Aspirin and NSAIDs

Aspirin and NSAIDs - Another active principle soon extracted from plants was salicylic acid. Salicin, extracted from the willow tree, hasbeen launched in 1876 by a Scottish physician, Thomas John McLogan 31 . It was in extensive competition with Cinchona bark and quinine and never became a very popular treatment for fever or rheumatic symptoms. The Italian chemist Raffaele Piria, after having isolated salicylaldehyde (1839) 32 in Spireae species , prepared salicylic acid from salicin in Dumas’ laboratory in the Sorbonne, Paris. This acid was easier to use and was an ideal step before future syntheses. Its structure was closely related to benzoic acid, an effective preservative useful as an intestinal antiseptic for instance in typhoid fever. Acetylsalicylic acid has been fi rst synthesized by Charles Frederic Gerhardt in1853 33 and then, in a purer form, by Johann Kraut (1869).

Asetilsalsilat

Reaction aspirin and  salicylic cacid 

Acetylsalicylic acid synthesis with carbolic acid and carbon dioxide was improved by Hermann Kolbe in1874, but in fact nobody noticed its pharmacological interest. During the 1880s and 1890s, physicians became intensely interested in the possible adverse effects of fever on the human body and the use of antipyretics became one of the hottest fi elds in therapeutic research. The name of ArthurEichengrün, who performed the research and developmentbased pharmaceutical division where Felix Hoffmann worked, and Heinrich Dreser ( Figure 1.6 ) in charge of testing the drug with Kurt Witthauer and Julius Wohlgemuth are to be memorized for this historical discovery (1897). It is likely that acetylsalicylic acid was synthesized under

Arthur Eichengrün’s direction and that it would not have been introduced in 1899 without his intervention. 34 Dreser carried out comparative studies of aspirin and other salicylates to demonstrate that the former was less noxious and more benefi cial than the latter. 35 Bayer built his fortune upon this drug which received the name of “ Aspirin, ” the most familiar drug name. For the first time, an industrial group illustrated the close relationship between chemistry and practical therapeutics. It was not until the late 1970s that aspirin’s ability to inhibit prostaglandins production by the cyclo-oxygenase enzymes was identifi ed as the basis of its therapeutic activity. Prostaglandins are known as end-products of the so-called arachidonic acid cascade.

Arachidonic acid is normally stored in membrane-bound phospholipids and released by the action of phospholipases. Enzymatic conversion of released arachidonic acid into biologically active derivatives proceeds through several routes. First, cyclo-oxygenase converts arachidonic acid to unstable cyclic endoperoxides from which prostaglandins, prostacyclin and thromboxanes are derived. 36 Second, the production of the leukotrienes from arachidonic acid is initiated by the action of 5-lipoxygenase producing leukotrienes which are also believed to play an important pathophysiological role in allergic broncho-constriction ofasthma. Through pharmacological intervention in the arachidonic acid cascade various anti-infl ammatory agents have been developed. These include aspirin-like drugs, which inhibit cyclo-oxygenase. Corticosteroids appear to indirectly inhibit phospholipases thus preventing release of arachidonic acid. Future progress in this fi eld is likely to produce drugs which antagonize arachidonic acid derivatives or inhibit the enzymes involved in their synthesis with greater specifi city. 37 Using an ingenious “ real time ” biological assay of bloodstream hormones irrigating an isolated organ, called the “ blood-bathed organ cascade, ” John Vane ( Figure 1.7 ) developed a system for highly sensitive monitoring of several mediators like angiotensin, bradykinin and prostaglandins and discovered prostacyclin, a potent platelet aggregation inhibitor. John Vane explained anti-infl ammatory drugs effects (among which aspirin remains a true leader) through their activity on cyclo-oxygenase and inhibition of prostacyclin and thromboxane production. The impact of aspirin administration at low dose for the prevention of stroke or coronary attack resulted from its effect on enzymes regulating the production of prostaglandins.

Poppy extracts led to brain receptors

Poppy extracts led to brain receptors - The first controversy is to know who discovered morphine. Jean-Francois Derosne, 23 in Paris, prepared a crude extract of opium (with alcohol and water), and obtained, after potassium carbonate precipitation, what he called “ sel de Derosne. ” Derosne’s alkaloidal fraction lacked narcotic properties and was probably largely made of narcotine (also known as noscapine), perhaps mixed with meconic acid. This work, has been presented at the Institute of France in 1804, but only published in 1814. 24 It describes the isolation of a compound, but did not report any animal or human experiment. A young German apothecary from Paderborn (Grmany), Friedrich Sertürner did, in fact, begin publishingon opium in 1805, 25 and claimed to have begun work before a paper on opium by Derosne had appeared in 1804.

Opium  led to brain receptors

Opium poppy red led to brain receptors

This claim has been interpreted to mean that Sertürner began work in 1803. However, Sertürner’s earlier work fi xated on acid constituents of opium. Thus, his 1806 paper 26 is mainly concerned with the constituent we now know as meconic acid. It was only in 1817 that he unequivocally reported the isolation of pure morphine. 27 He prepared it by extracting opium with hot water and precipitating morphine with ammonia. He obtained colorless crystals, poorly soluble in water, but soluble in acids and alcohol. He then established that the crystals carried the pharmacological activity of opium. The name “ morphine” has been coined later. The discovery was received by great perplexity: morphine had an alkaline reaction toward litmus paper. The scientific world was doubtful and Pierre Jean Robiquet performed new experiments in order to check Sertürner results. 

For thefirst time a substance extracted from a plant was not an acid!Gay-Lussac fi nally accepted the revolutionary idea that alkaline drugs could be found in plants. All alkaline substances isolated in plants would be given a name with the suffi x “ -ine ” (Wilhelm Meissner, 1818) in order to remind the basic reaction of all these drugs. Morphine gained wide medical use in the beginning of the 1860s during the American Civil War, but many injured soldiers returned from the war as morphine addicts, victims of the “ soldiers’ disease. ” In 1874, English researcher, C. R. Alder Wright (Saint Mary’s Hospital, London) fi rst synthesized (diacetylmorphine) by boiling morphine acetate over a stove. Twenty years later, Heinrich Dreser working for the Bayer Company of Elberfeld, Germany, found (erroneously) that diluting morphine with acetyls produced a drug without the common morphine side effects. In 1895, Bayer began the production of diacetylmorphine and coined the name “ heroin ” and introduced it, commercially, after another three years ( Figure 1.4 ).

At the beginning of the 20th century, heroin addiction rose to alarming rates driving United Kingdom, United States and France to ban opium and opiate drugs. During next 70 years, morphine will be almost completely withdrawn from medical use, before its “ rehabilitation” that came through the so-called Hospice movement , founded in the United Kingdom in order to alleviate suffering of dying patients within hospitals.

The dawn of the organic chemistry crosses the birth of biology

The dawn of the organic chemistry crosses the birth of biology - A radical turn in the development of new chemicals occurred when charcoal and then oil distillation offered so many opportunities. After the extract of paraffi n, carbon derivatives chemistry knew considerable developments with a lot of industrial consequences during the second third of the century.

Chemistry

organic molecules

The first organic molecules used for their therapeutic properties had acyclic structures: chloroform was discovered in 1831 by three independently working chemists: Eugene Soubeiran of France (1831), 9 Justus Von Liebig of Germany, 10 and Samuel Guthrie of the United States (1832). 11 Von Liebig taught chemistry through books like Organic Chemistry and its Application to Agriculture and Physiology (1840), and Organic Chemistry in its Application to Physiology and Pathology (1842) 12 and editing the journal that was to become the preeminent chemistry publication in Europe: Annalen der Chemie und Pharmazie. 

Liebig and Friedrich Wöhler ( Figure 1.3 ) began in 1825 various studies over two substances that had apparently the same composition – cyanic acid and fulminic acid – but very different characteristics. The silver compound of fulminic acid, investigated by Liebig was explosive; whereas Wöhler’s silver cyanate was not. These substances, called “ isomers” by Berzelius, lead chemists to suspect that substances were defi ned not simply by the number and kind of atoms in the molecule but also by the arrangement of those atoms. The most famous creation of an isomeric compound was Wöhler’s “ accidental ” synthesis of urea (1828), when failing to prepare ammonium cyanate. For the fi rst time someone prepared an organic compound by the means of inorganic ones. 13 That “ incident” made Wöhler saying: “ I can no longer, so to speak, hold my chemical water and must tell you that I can make urea without needing a kidney, whether of man or dog; the ammonium salt of cyanic acid is urea ”. 14 Liebig and Wöhler’s original objective was to interpret radicals as organic chemical equivalents of inorganic atoms. It was an early step along the path to structural chemistry. Organic chemistry precipitously entered the medicinal arena in 1856 when the youngster William Perkin, in an unsuccessful attempt to synthesize quinine, stumbled upon mauveine, the fi rst synthetic dye, leading to the development of many other synthetic dyes, which willgive birth few decades later to the fi rst antiseptic and antiinfectious drugs. Indeed, industrial world understood that some of these dyes could have therapeutic effects.

The renewal of chemistry

The renewal of chemistry - The 18th century concluded its progress in chemistry with an enthusiastic environment. Joseph Priestley in the United Kingdom, Carl Wilhelm Scheele in Sweden, Antoine Laurent de Lavoisier in France, 2 gave a precise signifi cation to the chemical reactivity and promoted a large number of substances to the statute of chemical reagents. Scheele and Priestley prepared and studied oxygen. Both of them discovered nitrogen as a constituent of air, carbon monoxide, ammonia, and several other gases ; manganese, barium and chlorine; isolated glycerin and many acids, including tartaric, lactic, uric, prussic, citric, and gallic. Lavoisier is generally considered as the founder of modern chemistry as creating the oxygen theory of combustion. 3 He should be known as one of the most astonishing 18th century “ men of the Enlightenment, ” the founder of modern scientifi experimental methodology. By formulating the principle of the conservation of mass, he gave a clear differentiation between elements and compounds, something so important for pharmaceutical chemistry.

Renewal of Chemistry

The Experiment

Few years later, Antoine François de Fourcroy, Louis Nicolas Vauquelin, Joseph Louis Proust, Jöns Jakob Berzelius, Louis-Joseph Gay-Lussac, and Humphrey Davy introduced new concepts in chemistry. Those scientists integrated the practical advancements of a new generation of experimenters. All these industrial innovations would have their own impact on other developments in industrial and then medicinal chemistry. 4 At the turn of the 19th century, as the result of a scientific approach, drugs are becoming an industrial item. Claude Louis Berthollet began the industrial exploitation of chlorine (1785). Nicolas Leblanc prepared sodium hydroxide (1789) and then, bleach (1796).

Davy performed electrolysis and distinguished between acids and anhydrides. Louis Jacques Thénard prepared hydrogen peroxide and Antoine Jérôme Balard discovered bromide (1826). The growing of therapeutic resources was mainly due to the mastery of chemical or physico-chemical principles  proposed by Gay-Lussac and Justus Von Liebig. 5 This chemists ’ generation, by realizing all these discoveries, established the compost of the therapeutic discoveries of the 19th century. The constitution of chemistry as a scientifi c discipline found a new turn few decades later by crossing the road of biology which included revolutionary works of ClaudeBernard, 6 Rudolph Virchow, 7 and Lo uis  Pasteur. 8 Besides these fundamental sciences, physiology, biochemistry, or microbiology were becoming natural tributaries of the outbreak of pharmacology. Thus, rational treatments were about to be designed on the purpose of new knowledge in various clinical or fundamental fi elds. After a period characterized by extraction and purifi cation from natural materials (mainly plants), drugs would be synthesized in chemical factories or prepared through biotechnology (fermentation or gene technology) after a rational research, design and developmentin research laboratories.

Whereas the purpose was to isolate active molecules from plants during the fi rst half of the 19th century, the birth of organic chemistry following charcoal and oil industries, progressively led chemists and pharmacists toward organic synthesis performed in what would be called “ laboratory ” a new concept created by this generation of scientists. Even when those laboratories hosted discoveries like active principles extracted from plants, progresses in drug compounding and packaging made irreversible industrialization processes. At the same time, the economical dimension of growing pharmaceutical industry transformed drugs as strategic items, mainly when it could interfere with military processes, for instance during colonial expeditions.