Regina Botting

Inflammation and the mechanism of action of anti-inflammatory drugs.

Inflammation is caused by release of chemicals from tissues and migrating cells. Most strongly implicated are the prostaglandins (PGs), leukotrienes (LTs), histamine, bradykinin, and, more recently, platelet‐activating factor (PAF) and interleukin‐1. Evidence for their involvement comes from studies with competitive antagonists for their receptors and inhibitors of their synthesis. H1 histamine antagonists are effective for hay fever and some skin allergies such as urticaria, which indicates the importance of histamine in these conditions. Symptoms of rheumatoid arthritis are alleviated by the aspirinlike anti‐inflammatory drugs, which inhibit the cyclo‐oxygenase enzyme and reduce synthesis of prostanoids. Corticosteroids prevent the formation of both PGs and LTs by causing the release of lipocortin, which by inhibition of phospholipase A2 reduces arachidonic acid release. They suppress the inflammation of rheumatoid arthritis and asthma. Currently, high doses of nonsedating H1 antihistamines and PAF antagonists are being tested for the treatment of allergic asthma.—Vane, J.; Botting, R. Inflammation and the mechanism of action of anti‐inflammatory drugs. FASEB J. 1: 89‐96; 1987.

Mechanism of Action of Anti-Inflammatory Drugs

Cyclooxygenase (COX) is the pivotal enzyme in prostaglandin biosynthesis. It exists in two isoforms, constitutive COX-1 (responsible for physiological functions) and inducible COX-2 (involved in inflammation). Inhibition of COX explains both the therapeutic effects (inhibition of COX-2) and side effects (inhibition of COX-1) of non-steroidal anti-inflammatory drugs (NSAIDs). A NSAID which selectively inhibits COX-2 is likely to retain maximal anti-inflammatory efficacy combined with less toxicity. The activity of a number of NSAIDs has been investigated in several test systems, showing that most of those marketed have higher activities against COX-1 or are equipotent against both isoforms. Adverse event data of marketed NSAIDs show a relationship between a poor safety profile and more potent inhibition of COX-1 relative to COX-2. There are several new non-steroidal COX-2 inhibitors in development. The most clinically advanced is meloxicam, which consistently demonstrates higher activity against COX-2 than...

Improved Non-Steroid Anti-Inflammatory Drugs: COX-2 Enzyme Inhibitors

1. Overview - Mechanisms of Action of Anti-Inflammatory Drugs J. Vane, R. Botting. 2. The Three-Dimensional Structure of Cyclooxygenases R.M. Garavito. 3. The Dilemma of Two Cyclooxygenases: Identifying the Roles of COX-1 and COX-2 in Inflammation and Apoptosis D. Simmons, et al. 4. Inducible Enzymes with Special Reference to COX-2 in the Inflammatory Response D. Willoughby, et al. 5. NSAID Mechanism of Action: The Role of Intracellular Pharmacokinetics L. Herbette, et al. 6. Differential Inhibition of COX-1 and COX-2 in vitro and Pharmacological Profile in vivo of NSAIDs M. Pairet, G. Engelhardt. 7. COX-2 Expression and Inhibition in Human Monocytes C. Patrono, et al. 8. Expression and Regulation of COX-2 in Synovial Tissues of Arthritic Patients L. Crofford. 9. An Inhibitor of Injury-Induced COX-2 Transcriptional Activation Elicits Neuroprotection in a Brain Damage Model N. Bazan, G. Allan. 10. COX-2 Expression in Labour P. Bennett, D. Slater. 11. Re-Evaluation of Gut Toxicity of NSAIDs D.N. Bateman. 12. NSAID: Can Renal Side Effects be Avoided? J. Frolich, D. Stichtenoth. 13. Pharmacology, Safety Data and Therapeutics of COX-2 Inhibitors P. Emery.

Pathogenesis and Mechanisms of Inflammation and Pain

Pain is perceived through activation of the endings of nociceptive afferent nerves by pain-producing substances released from tissue. These nerves in turn activate nociceptive nerve cells in the dorsal horn of the spinal cord through the release of excitatory amino acids and neuropeptides. The activation of the nociceptive afferents can be amplified after repetitive stimulation via the production of nitric oxide, which facilitates the release of excitatory amino acid transmitters.Pain is one of the cardinal signs of inflammation, the response of tissue to frank or immune damage or infection. The inflammatory response is characterised by vasodilation, oedema and a marked local accumulation of white blood cells. Many intercellular messengers, or cytokines, are responsible for the various stages of inflammation, but tumour necrosis factor seems to be a significant initiator of the response.The severe pain that accompanies inflammatory disease such as rheumatoid arthritis is caused by the action of pain-producing substances such as kinins on nociceptor neurons sensitised by locally produced prostaglandins, and perhaps sympathomimetics released from sympathetic nerves. The first-line treatment of inflammatory pain is the use of nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the cyclo-oxygenase enzyme (COX) which produces the hyperalgesic prostaglandins from their substrate arachidonic acid. Since prostaglandins produced in inflammation are formed by an induced COX (COX-2), distinct from that which produces the cytoprotective prostaglandins, NSAIDs that selectively inhibit COX-2 may provide effective therapy without gastrotoxicity Further clinical experience is required to establish the most effective therapy for inflammatory pain.

Iloprost-Induced Nociception: Determination of the Site of Anti-nociceptive Action of Cyclooxygenase Inhibitors and the Involvement of Cyclooxygenase Products in Central Mechanisms of Nociception

The writhing response to acute nociception has been used to test the analgesic activity of drugs in rodents. Dilute acetic acid is the most frequently used irritant to induce writhing behaviour. The administration of acetic acid intraperitoneally activates both peripheral and central mechanisms of nociception. It releases nociceptive mediators such as prostaglandins (PG) E(2)and I(2)at the site of noxious stimulation, the peritoneal cavity, and at central sites such as the dorsal horn of the spinal cord and some brain regions. We have used the PGI(2)mimetic, iloprost, an agonist at the IP receptor, to induce the writhing response in mice. Iloprost activates the IP receptors on peripheral nociceptors directly and thus does not release nociceptive prostaglandins into the peritoneal cavity. However, prostaglandins are still involved in nociceptive transmission at the spinal and supraspinal levels. Using this model of nociception, it is possible to identify the site of action of analgesic drugs which reduce prostaglandin release in central tissues through inhibition of cyclooxygenase. Thus, a drug that inhibits the iloprost-induced writhing response and reduces release of prostaglandins in the central nervous system is likely to be a centrally acting analgesic drug. This chapter compares the iloprost- and acetic acid-induced writhing responses in mice and describes a method for measuring central prostaglandin levels. Part of this work has been published previously.

The discovery of COX-2

For over 3000 years various herbal medicines, such as extracts of willow bark, or dried leaves of myrtle or meadowsweet have been used with apparent anecdotal success for the treatment of the pain and swelling of inflammatory disease. By the middle of the nineteenth century the active constituent of these various herbal remedies was found to be salicylate, and the better tolerated acetylated derivative, acetylsalicylate was introduced to medicine as aspirin over a hundred years ago. The manifest efficacy of aspirin resulted in its wide use as an antipyretic and as an analgesic for the pain associated with inflammatory conditions [1]. However, it soon became apparent that aspirin could cause gastrotoxicity, a fact demonstrated unequivocally in 1938 by the endoscopic studies of Douthwaite who observed erosions and ulcers in the gastric mucosa of patients on long-term aspirin therapy [2].

C14 Non-steroidal anti-inflammatory drugs

Throughout history humans have experimented with herbal remedies to alleviate the symptoms of diseases. The active principles of some of these remedies are of proven value and have become established in modern therapeutics. None, however, has been more widely accepted nor as universally practised as the use of the extracts of certain plants for the treatment of the various symptoms of inflammatory conditions such as pain, swelling and fever.

Endothelin and the Homeostatic Function of the Endothelial Cell

Cultured porcine endothelial cells release a peptide into the culture medium that causes slow, long-lasting contractions of isolated vascular strips.17 This peptide was isolated, characterized, and synthesized in 1988 by Yanagisawa et al.,66 who named it “endothelin.” The endothelin from porcine endothelial cells consists of a chain of 21 amino acids held together by two disulfide bridges and is generated from a precursor molecule by a previously unknown protease. It was subsequently discovered that three isomers of endothelin, expressed by three different genes, are probably present in all mammalian species.22 Endothelin-1 is the only one made by endothelial cells and was first called “porcine” or “human” endothelin. Endothelin-2 is more potent than endothelin-1 and has a longer duration of action on blood pressure. It is not known where it is made except perhaps in kidney cells.27 Endothelin-3, first called “rat” endothelin, may be associated with nervous tissue.67 The structure of endothelin-3 differs from that of endothelin-1 by 6 of the 21 amino acid residues and consists of (Thr2, Phe4, Thr5, Tyr6, Lys7, Tyr14)-substituted endothelin-1. Endothelin-2 differs from endothelin-1 by two amino acids and corresponds to (Trp6, Leu7)-substituted endothelin-1.