Nitroglycerin

Nitroglycerin - Nitroglycerin synthesis has been performed in 1844 by Antoine Jérôme Balard (Montpellier, France) who observed the collapse of animals few minutes after the administration of the drug. The vasodilatating effect of the drug was exploited by Ascani Sobrero (Torino, Italy) following work with Theophile-Jules Pelouze (1847) in Paris. Two years later, Konstantin Hering and Johann Friedrich Albers, developing the sublingual administration of nitroglycerin, observed the violent headache caused by the drug. Alfred Nobel, later founder of Nobel Prize, joined Pelouze in 1851 and recognized the potential of this yellow liquid with explosive interest. 55 He began manufacturing nitroglycerin in Sweden, overcoming handling problems with his patent detonator. 

Pictures of Nitroglycerin

Nitroglycerin Structural Formulae

Nitroglycerin 2,5 mg ER cap major Pharmaceuticals

Nobel suffered acutely from angina but refused what he considered as a chemical for a treatment. When the English physician Thomas Lauder Brunton succeeded to relieve severe recurrent angina pain in refractive patients except by bleeding, he realized that phlebotomy provided relief by lowering arterial blood pressure. This gave birth to the concept that reduced cardiac after load and work were benefi cial. When administering amyl nitrite, a potent vasodilatator, by inhalation, 

Brunton noticed, in 1867, that coronary pain was transiently relieved within 30–60 s. 56 In 1876, William Murrell (Westminster Hospital London) proved that the action of nitroglycerin mimicked that of amyl nitrite, and he established the use of sublingual nitroglycerin for relief of the acute angina attack and as a prophylactic agent to be taken prior physical exercise. Almost a century later, research in the nitric oxide (NO) fi eld explaining the mode of action of nitroglycerin, has dramatically extended. In 1977, Ferid Murad (Houston, USA) discovered the release of NO from nitroglycerin and its action on vascular smooth muscle.Robert Furchgott ( Figure 1.11 ) and John Zawadski (New York, USA) recognized the importance of the endothelium in acetylcholine-induced vaso-relaxation (in 1980) and Louis Ignarro (Figure 1.11) and Salvador Moncada (London, UK) ( Figure 1.10 ) identifi ed endothelial-derived relaxing factor (EDRF) as NO (in 1987). 57 Today, glycerol trinitrate remains the treatment of choice for relieving angina; other organic esters and inorganic nitrates are also used, but the rapid action of nitroglycerin and its established effi cacy make it the mainstay of angina pectoris relief.

The role of NO in cellular signaling has become one of the most rapidly growing areas in biology during the past two decades. As a gas and free radical with an unshared electron, NO participates in various biological processes. NO is formed from the amino acid l -arginine by a family of enzymes, the NO synthases, and plays a role in many physiological functions. Its formation in vascular endothelial cells, in response to chemical stimuli and to physical stimuli such as shear stress, maintains a vasodilator tone that is essential for the regulation of blood fl ow and pressure. NO also inhibits platelet aggregation and adhesion, inhibits leukocyte adhesion and modulates smooth muscle cell proliferation. NO is also synthesized in neurons of the central nervous system (CNS), where it acts as a neuromediator with many physiological functions, including the formation of memory, coordination between neuronal activity and blood fl ow, and modulation of pain. In the peripheral nervous system, NO is now known to be the mediator released by a widespread network of nerves.

Digitalis

Digitalis - In the second half of 18th century, William Withering, an English physician, heard that the local population was able to cure dropsy using a complex plant decoction. After having tested the various herbs on dropsy, digitalis leaf remained the most active and probably contained a substance increasing the ability of the weakened heart to improve pumping blood ( Figure 1.9 ). In 1775, Withering published a pamphlet in which he reported his discovery, meticulously describing how the extract of the digitalis should be prepared, and giving precise instructions on dosage, including warnings about side effects and overdose from the experience learnt from 163 patients.

Digitalis purpurea Candy Mountain

Fleur Digitale abeille digitaline champs

The only but not least problem was a dreadful continuous vomiting and diarrhea during the treatment that was caused by the fact that the boundary between the therapeutic dose and poisoning was exceedingly narrow. It was therefore evident and absolutely necessary to purify the active substance in order to fi x the effective and non-toxic dosage.

After decades of works, Augustin Eugène Homolle and Théodore Quevenne, two Parisian pharmacists obtained from foxglove leaves an amorphous substance they called “ digitaline, ” keeping the “ ine ” terminology, as they were sure that it was an alkaloid.In fact it was a complex substance containing a specific sugar. It is not until 1867 that another French pharmacist,

Claude Adolphe Nativelle was able to purify foxglove leaves and to produce the effective substance in the form of white crystals 49 that he called “ crystallized digitalin. ” Just a few years, later the German, Oswald Schmiedeberg, managed to produce digitoxin (1875). 50 Shortly thereafter reports began to come in about other medicinal herbs which had the same effect on the heart as the foxglove products. Ethnopharmacy gave birth to ouabain, extracted by Albert Arnaud from Acocanthera roots and bark, and strophantin, extracted from Strophantus . Both of these drugs had previously been used by arrow hunters in Equatorial Africa. One hundred years later, explanation for the cardiotonic properties of digitalis, ouabain and strophantin were given through molecular pharmacology experiments. The story began when Jens Christian Skou (Aarhus, Denmark) ( Figure 1.54 ) studied in the early 1950s the action of local anesthetics.

He thought that membrane protein might be affected by local anesthetics. He therefore had the idea of looking at an enzyme which was embedded in the membrane: ATPase, discovering that it was most active when exposed to the right combination of sodium, potassium and magnesium ions. 51 Only then did he realize that this enzyme might have something to do with the active transport of sodium and potassium across the plasma membrane. Skou left out the term “ sodium-potassium pump” from the title of his publication, continuing his studies on local anesthetics. In 1958, Skou met Robert L. Post (Nashville, USA), who had been studying the pumping of sodium and potassium in red blood cells 52 recently discovered that three sodium ions were pumped out of the cell for every two potassium ions pumped in, 53 his research being made by the use of a substance called ouabain which had recently been shown to inhibit the pump.

Conversations between Post and Skou about ATPase drove Skou to verify if ouabain inhibited the pump. Indeed, it did inhibit the enzyme, thus establishing a link between the enzyme and the sodium–potassium pump. Skou received a Nobel Prize in Chemistry (1997). Julius C. Allen and Arnold Schwartz (Houston, USA) then studied digitalis effect on cardiac contractility (the positive inotropic effect), caused by the drug’s highly specifi c interaction with Na /K -ATPase. It has been established that partial inhibition of the ion pumping function of cardiacNa /K -ATPase by digitalis glycosides led to a modest increase in intracellular Na , which in turn, affected the cardiac sarcolemmal Na /Ca 2 exchanger, causing a signifi cant increase in intracellular Ca 2 and in the force contraction.

New strategies for rheumatoid arthritis

New strategies for rheumatoid arthritis - Drug therapy for rheumatoid arthritis (RA), a chronic infl ammatory and destructive joint disease, rests on two bases: symptomatic treatment with NSAIDs, not interfering with the underlying immuno-infl ammatory and disease-modifying ntirheumatic drugs (DMARDs), “ modifying” the disease process. DMARDs are divided into small-molecule drugs and biological therapies. The initial approach to understanding the pathogenesis of RA and defi ning a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro . In a series of experiments using tissue taken from joints, Marc Feldmann and Ravinder Maini (Kennedy Institute, London) investigated the role of cytokines ( Figure 1.8 ), protein messenger molecules that drive infl ammation, and found that a number of pro-infl ammatory cytokines were indeed present in the infl amed joints.

Picture of the join with rheumatoid arthritis

Rheumatoid arthritis

These investigations suggested that neutralization of tumor necrosis factor-alpha (TNF- ) with antibodies significantly inhibited the generation of other pro-infl ammatory cytokines. Their fi rst clinical trial was performed in 1992 at Charing Cross Hospital and revealed rapid and dramatic improvement of rheumatoid disease activity with anti-TNF therapy. The blockade of a single cytokine, TNF- , had farreaching effects on multiple cytokines and thereby exerted signifi cant anti-infl ammatory and protective effects on cartilage and bone of joints. A chimeric anti-TNF- highaffi nity antibody was initially tested, with substantial and universal benefi t. Then, a randomized placebo-controlled double-blind trial supported the proposition that TNF- was implicated in the pathogenesis of RA and was thus a key therapeutic target. 46 Three TNF inhibitors have been approved since 1998 for the treatment of RA.

First was infliximab (Remicade®), a chimeric (human-murine) IgG1 anti-TNF- antibody, administered intravenously. It binds with high affi nity to soluble and membrane-bound TNF-thus inhibiting it. The two others are Etanercept (Enbrel®) and Adalimumab (Humira®) a recombinant humanized monoclonal anti-TNF- antibody administered subcutaneously. 47 Feldmann and Maini received the Albert Lasker award for their discovery in 2003.