Non-steroidal anti-inflammatory drugs (NSAIDs): Physiotherapists' use, knowledge and attitudes (original) (raw)
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Purpose. NSAIDs constitute an important class of drugs with therapeutic applications that have spanned several centuries. Treatment of inflammatory conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) starting from the classic drug aspirin to the recent rise and fall of selective COX-2 inhibitors has provided an enthralling evolution. Efforts to discover an ultimate magic bullet to treat inflammation continues to be an important drug design challenge. This review traces the origins of NSAIDs, their mechanism of action at the molecular level such as cyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects, and some recent developments targeted to the design of effective anti-inflammatory agents with reduced side effects. Methods. Literature data is presented describing important discoveries pertaining to the sequential development of classical NSAIDs and then selective COX-2 inhibitors, their mechanism of action, the structural basis for COX inhibition, and recent discoveries. Results. A brief history of the development of NSAIDs and the market withdrawal of selective COX-2 inhibitors is explained, followed by the description of prostaglandin biosynthesis, COX isoforms, structure and function. The structural basis for COX-1 and COX-2 inhibition is described along with methods used to evaluate COX-1/COX-2 inhibition. This is followed by a section that encompasses the major chemical classes of selective COX-2 inhibitors. The final section describes briefly some of the recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NO-NSAIDs, dual COX/LOX inhibitors and anti-TNF therapy. Conclusions. A great deal of progress has been made toward developing novel anti-inflammatory agents. In spite of the tremendous advances in the last decade, the design and development of a safe, effective and economical therapy for treating inflammatory conditions still presents a major challenge.
Pharmacological reports : PR, 2005
Prostanoids act leading roles in a myriad of physiologic and pathologic processes because these autacoids participate in the amplification of biological responses induced by innumerable stimuli. The formation of prostanoids is operated by two synthases named cyclooxygenase(COX)-1 and COX-2. Traditional nonsteroidal antiinflammatory drugs (tNSAIDs) and COX-2 inhibitors (coxibs) give rise to antipyretic, analgesic, and antiinflammatory actions, through their reversible clogging of the COX channel of COX-2 - apart from aspirin which modifies irreversibly the catalytic activity of COX-2. tNSAIDs and COX-2 inhibitors resulted clinically equivalent for the relief of acute pain and symptoms of arthropathies but they failed to modify disease progression. Clinical evidence of the possible contribution of COX-1 in inflammation and pain in some occasion - as suggested by experimental and pharmacology studies - is orphan because none efficacy trial with COX inhibitors was designed to establish ...
Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy?
2001
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay in the treatment of inflammatory disease and are among the most widely used drugs worldwide. They are anti-inflammatory, antipyretic, and analgesic and are prescribed as first choice for the treatment of rheumatic disorders and, in general, inflammation. The main limitation in using NSAIDs consists in their side-effects, including gastrointestinal ulcerogenic activity and bronchospasm. The mechanism of action of these drugs is attributed to the inhibition of cyclooxygenase (COX), and, consequently, the conversion of arachidonic acid into prostaglandins. It is hypothesized that the undesirable side-effects of NSAIDs are due to the inhibition of COX-1 (constitutive isoform), whereas the beneficial effects are related to the inhibition of COX-2 (inducible isoform). Arachidonic acid can also be converted to leukotrienes (LTs) by the action of 5-lipoxygenase (5-LOX). LTC 4, LTD 4, and LTE 4 are potent bronchoconstrictors, whereas LTB 4 is chemotactic for leukocytes and plays an important role in the development of gastrointestinal ulcers by contributing to the inflammatory process. Thus, developing dual inhibitor compounds that will simultaneously inhibit COX and 5-LOX could enhance their individual anti-inflammatory effects and reduce the undesirable side-effects associated with NSAIDs, especially of the gastrointestinal tract. The most promising COX/5-LOX inhibitor is ML3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid), now in Phase III clinical trials. This new approach will certainly help to unravel the mechanisms at the root of the undesirable effects of NSAIDs and to develop safer NSAIDs.
Proceedings of the National Academy of Sciences, 2000
All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors. This paper was submitted directly (Track II) to the PNAS office.
Cyclooxygenases (COXs) are enzymes that take part in a complex biosynthetic cascade that results in the conversion of polyunsaturated fatty acids (PUFAs) to prostaglandins (PGs) and thromboxanes (TXs). Their main role is to catalyze the transformation of AA into the intermediate PG-H2, which is the procursor of a variety of prostanoids (PTS) with diverse and potent biological actions. COXs have two main isoforms that are called COX-1 and COX-2 (as well as a COX-3). COX-1 is responsible for the synthesis of PG and TX in many types of cells, including the gastro-intestinal tract (GIT) and blood platelets. COX-2 plays a major role in PG biosynthesis in inflammatory cells and in the CNS. PG synthesis in these sites is a key factor in the development of inflammation and hyperalgesia. COX-2 inhibitors have analgesic and anti-inflammatory activity by blocking the transformation of AA into PG-H2 selectively. The impetus for development of selective COX-2 inhibitors was the adverse GIT side-effects of NSAIDs. Soon after the discovery of the mechanism of action of NSAIDs, strong indications emerged for alternative forms of COX. COX enzyme proved to be difficult to purify. The COX-2 enzyme was cloned.
COX-2-Specific Inhibitors - the Emergence of a New Class of Analgesic and Anti-inflammatory Drugs
Clinical Rheumatology, 2000
The prostaglandin series of bioactive compounds is formed by the interaction of two distinct but related enzymes, cyclo-oxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is a constitutive form which is present mainly in the gastric mucosa, kidney and platelets. COX-2 is mainly an inducible form, although also to some extent present constitutively in the CNS, the juxtaglomerular apparatus of the kidney and in the placenta during late gestation. Both isoforms contribute to the in¯ammatory process, but COX-2 is of considerable therapeutic interest as it is induced, resulting in an enhanced formation of prostaglandins, during acute as well as chronic in¯ammation. Conventional NSAIDs inhibit both isoforms to a similar extent and in an approximately equal dose and concentration range. The two recently developed and clinically available selective COX-2 inhibitors, celecoxib and rofecoxib, are about 100±1000 times more selective on the COX-2 than on the COX-1 isoform. In Europe rofecoxib is today indicated for the symptoms and signs of osteoarthritis, whereas celecoxib is indicated for both osteoarthritis and rheumatoid arthritis. The major clinical interest of these drugs has been related to the lower incidence of gastrointestinal bleeding which, with the conventional COX-1/COX-2 agents has been a source of hospitalisation, disablement and death, especially in the elderly. Clinical trials have convincingly demonstrated that celecoxib and rofecoxib in clinical use induce very few gastrointestinal complications compared to conventional and non-selective NSAIDs. However, the well known contraindications for NSAIDs, such as late pregnancy, aspirin-induced asthma, congestive heart failure and renal dysfunction, will so far apply also to the COX-2 inhibitors. Compared to the traditional and non-selective NSAIDs, COX-2 inhibitors may provide an insight into additional therapeutic areas, such as gastrointestinal cancer and dementia, where the potential relevance to COX-2 mechanisms are currently being explored and clinical trials being performed. With the rapid clinical acceptance of celecoxib and rofecoxib, knowledge about their clinical usefulness in various in¯ammatory disease states and pain disorders is increasing. For the many patients suffering from such conditions, the selective COX-2 inhibitors are likely to become a signi®cant addition to the therapeutic arsenal of analgesic and anti-in¯ammatory drugs.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development
Pharmaceuticals, 2010
This paper reports on a survey regarding physiotherapists' knowledge, use and attitudes to non-steroidal anti-inflammatory drugs (NSAIDs), some of which have recently been re-scheduled to non-prescription dispensing. A written survey instrument was developed and administered to 750 physiotherapists in South Australia, Tasmania and the Australian Capital Territory (50% of the registered physiotherapists). Responses were received from 285 physiotherapists. The survey identified opportunities for patient misuse and misadventures with NSAIDs in conjunction with physiotherapy management. Differences in physiotherapists' understanding of the dosage and actions of oral and topic administrations of NSAIDs were highlighted, as were the moral and ethical responsibilities of physiotherapists to patients considering taking NSAIDs. The study identified the need for regular professional updates on quality use of NSAIDs. [Grimmer K, Kumar S, Gilbert A and Milanese S (2002): Non-steroidal anti-inflammatory drugs (NSAIDs): Physiotherapists' use, knowledge and attitudes. Australian Journal of Physiotherapy 48: 82-92]
An Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs), including both traditional nonselective NSAIDs and the selective cyclooxygenase (COX)-2 inhibitors, are widely used for their anti-inflammatory and analgesic effects. NSAIDs are a necessary choice in pain management because of the integrated role of the COX pathway in the generation of inflammation and in the biochemical recognition of pain. This group of drugs has recently come under scrutiny because of recent focus in the literature on the various adverse effects that can occur when applying NSAIDs.This review will provide an educational update on the current evidence of the efficacy and adverse effects of NSAIDs. It aims to answer the following questions: (1) are there clinically important differences in the efficacy and safety between the different NSAIDs, (2) if there are differences, which are the ones that are more effective and associated with fewer adverse effects, and (3) which are the effective therapeutic approaches that could reduce the adverse effects of NSAIDs. Finally, an algorithm is proposed which delineates a general decision-making tree to select the most appropriate analgesic for an individual patient based on the evidence reviewed.
Clinical Pharmacology of Non-Steroidal Anti-Inflammatory Drugs: A Review
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2012
Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of often chemically unrelated compounds with some common therapeutic actions and side effects. They have potent anti-inflammatory, analgesic and antipyretic activity, and are among the most widely used drugs worldwide. It is generally thought that one of their main mechanisms of action is the inhibition of cyclo-oxygenase (COX), the enzyme responsible for biosynthesing the prostaglandins and thromboxane. NSAIDs are also associated with an increased risk of adverse gastrointestinal, renal and cardiovascular effects. This review describes the clinical pharmacology of NSAIDs, their classification, molecular mechanisms of action and adverse effects, including their possible contribution to neuro-inflammation and carcinogenesis, as well as some recent developments aimed at designing effective anti-inflammatory agents with improved safety and tolerability profiles.