Mechanism of Action of Nonsteroidal Anti-Inflammatory Agents

doi:10.1016/S0002-9343(84)80020-0

The American Journal of Medicine

Volume 77, Issue 1, Part 1, 13 July 1984, Pages 57-64

https://doi.org/10.1016/S0002-9343(84)80020-0 Get rights and content

Recent data from several laboratories, which suggest that generally accepted concepts relating to the mechanism of action of nonsteroidal, anti-inflammatory drugs (NSAIDs) in rheumatoid arthritis may be incorrect, are reviewed. Over the past decade, most researchers have espoused the idea that NSAIDs act by inhibiting cyclooxygenase, thereby removing prostaglandins, which are thought to be responsible for pain and inflammation. Recent studies demonstrating that prostaglandins have important immunomodulating properties and that NSAIDs actually provide partial correction of several immunoregulatory dysfunctions in patients with rheumatoid arthritis are described. In addition, some NSAIDs inhibit migration along with other monocyte and polymorphonuclear leukocyte functions. Data suggest that these actions are not related to inhibition of cyclooxygenase.

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Association between non-steroidal anti-inflammatory drug use and development of age-related macular degeneration—A 10-year retrospective cohort study
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To analyze the associations between development of age-related macular degeneration (AMD) and regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs).
We retrospectively recruited individuals who received ≥28-day prescriptions of aspirin or NA-NSAIDs exclusively between 2008 and 2017 in one tertiary center as regular users. Non-regular users were free from regular use of any anti-inflammatory drugs and were matched to regular users in terms of age, sex, and visit date at a ratio of 1–4:1. The aspirin cohort included 36,771 regular users and 110,808 matched non-regular users, while the NA-NSAID cohort included 59,569 regular users and 179,732 matched non-regular users. Stratified multivariate Cox regression analyses with adjustment for systemic confounding factors were performed for the development of AMD and neovascular AMD.
In the aspirin cohort, the adjusted hazard ratios of aspirin use for AMD in the whole cohort, individuals without cardiovascular diseases (CVDs), and those with CVDs were 0.664, 0.618, and 0.702, respectively (P < 0.0001 for all), while those of aspirin use for neovascular AMD were 0.486, 0.313, and 0.584 (P < 0.05 for all), respectively. In the NA-NSAID cohort, regular use of NA-NSAIDs was associated with a decreased risk of AMD (hazard ratio = 0.823, P < 0.0001) and neovascular AMD (hazard ratio = 0.720, P = 0.040) only in people without arthritis.
Regular use of aspirin or NA-NSAIDs had protective effects on AMD and neovascular AMD. The effect of aspirin was observed in all patients, while the effect of NA-NSAIDs was observed only in people without arthritis.
Amine modified magnetic polystyrene for extraction of drugs from urine samples
2019, Journal of Chromatography A
Citation Excerpt :
COX–2 is a by–product of injured or inflamed joint. Traditional NSAIDs are non–selective and inhibit the action of both COX–1 and COX–2 which is why they can cause stomach upset, bleeding, kidney damage and high blood pressure as side–effects [1,2]. Although there is little evidence indicating any advantages with co–administration of NSAIDs, but these drugs are sometimes prescribed together.
Polystyrene is one of the best candidates as the extracting medium due to its high stability in different media and acceptable extraction capability. However, the hydrophobic nature and low wettability of polystyrene limits its application to non–polar analytes. To resolve this limitation, in this project, amine groups were chemically attached to the surface of magnetic polystyrene. The resulting hydrophilic magnetic particles were expected to be capable of extracting both polar and non–polar analytes. Non–steroidal anti–inflammatory drugs (NSAIDs) were chosen for testing the applicability of modified magnetic polystyrene according to the importance of their analysis and also their wide polarity range. Major parameters associated with the extraction procedure were optimized using central composite design (CCD) method and pH 3, extraction time of 15 min, desorption volume of 350 μL and desorption time of 4 min were chosen as optimized values. Under these conditions, figures of merit were calculated including: linear dynamic range (0.5–1000 μg L⁻¹), linear equation and limits of detection (0.1–3 μg L⁻¹). To investigate the method precision, inter–day, intra–day and synthesis–to–synthesis relative standard deviation (RSD) were studied (<12%). All studies were conducted using blank urine samples spiked with aspirin, salicylic acid, ibuprofen, diclofenac and mefenamic acid. Naproxen was chosen as the internal standard and high–performance liquid chromatography–UV–Vis (HPLC–UV) was employed for the subsequent determination after extraction. To evaluate the applicability of the method for real sample analysis, urine samples from patients under treatment were analyzed and acceptable results were obtained. The aminated magnetic polystyrene revealed superior extraction efficiency, much higher than polystyrene before functionalization. In addition, hospital wastewater sample was tested and acceptable extraction efficiencies were obtained.
Update on pain management for advanced genitourinary cancer
2001, Journal of Urology
Pain is a significant problem in many patients with genitourinary malignancy at all stages of disease. Optimal pain control becomes a primary concern as disease progresses and other therapies are exhausted. The selection of the most appropriate therapy becomes difficult without an understanding of the underlying mechanisms of pain and the available therapies.
A review of the literature regarding the mechanisms and assessment of pain syndromes was performed. All available therapies were investigated with respect to conservative management with opioid medications and adjuvant drugs, and the indications for invasive techniques.
Increased understanding of the mechanisms and classification of pain syndromes has led to improved assessment and treatment. Despite these advances a significant number of patients have inadequate pain control and the education of treating physicians remains an important target for improving this situation.
Opioid medication is the mainstay of therapy in the majority of patients but with the appropriate addition of other adjuvant drugs patients may achieve optimal pain control without unwanted side effects. A few patients benefit from more invasive techniques, including plexus blocks and neuraxial infusion therapy, and the indications for these treatments are discussed. These therapies have largely superseded neuroablative procedures that are more destructive and associated with higher morbidity.
Antidenaturant drugs for cataract and other condensation diseases
2001, Medical Hypotheses
‘Condensation diseases’ are heterogeneous pathological conditions in which the primary pathogenetic step is the loss of solubility of specific substances, resulting in the formation of a condensed phase. Typical examples are cataract, nephrolithiasis, gallstone disease and certain rheumatic conditions in which protein denaturation, aggregation and precipitation may occur. Since the condensing molecules are often proteins, antidenaturant agents should be considered rational drugs for the treatment of these diseases. Surprisingly, however, only a few molecules with these properties are currently available for therapeutic use, including bendazac for cataract.
Does cyclooxygenase-2 inhibitor prevent renal tissue damage in unilateral ureteral obstruction?
2001, Journal of Urology
We determined whether the cyclooxygenase-2 inhibitor etodolac affects renal tubular damage and interstitial fibrosis in unilateral ureteral obstruction.
Etodolac (10 mg./kg.) was administered to rats 1 day before unilateral ureteral obstruction and every day thereafter. Kidneys were harvested at day 14 after unilateral ureteral obstruction. Tissue transforming growth factor-β and prostaglandin E2 were measured by bioassay using mink lung epithelial cells and enzyme linked immunosorbent-sandwich assay. Renal tubular proliferation and apoptosis were detected by immunostaining with proliferating cellular nuclear antigen and by terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling, respectively. Cyclooxygenase-2 expression was detected by immunohistochemistry. Fibrosis was assessed by measuring collagen deposition in trichrome stained slides.
Bioassay showed that in the control group obstructed kidneys contained significantly higher mean transforming growth factor-β1 than unobstructed kidneys (79.1 ± 8.3 versus 33.6 ± 4.2 ng./gm. tissue) and etodolac significantly decrease the mean value in obstructed kidneys (46.2 ± 10.0 ng./gm. tissue). Assay demonstrated that obstructed control kidneys had significantly more mean tubular apoptosis than their unobstructed counterparts (26.6 ± 5.4 versus 2.2 ± 1.4 nuclei per high power field) and etodolac significantly decreased mean renal tubular apoptosis in the obstructed kidneys (16.2 ± 1.9 nuclei per high power field). In addition, immunostaining with proliferating cellular nuclear antigen showed that obstructed kidneys in the control group had significantly more mean renal tubular proliferation than unobstructed kidneys (9.8 ± 3.4 versus 3.9 ± 0.1 per high power field) and etodolac significantly increased mean proliferating renal tubule in the obstructed kidneys (24.9 ± 4.3 per high power field). Control obstructed kidneys had significantly more fibrosis and prostaglandin E2 production, which were also significantly blunted by etodolac.
The cyclooxygenase-2 inhibitor etodolac significantly reduces tissue transforming growth factor-β, resulting in decreased tubular damage and interstitial fibrosis. This finding suggests that etodolac is a promising agent for preventing renal tissue damage in unilateral ureteral obstruction.
Separation of 2-arylpropionic acids on a cellulose based chiral stationary phase by RP-HPLC
1994, Journal of Pharmaceutical and Biomedical Analysis
The enantiomers of eight 2-arylpropionic acids, a group of chiral non steroidal antiinflammatory drugs, were resolved as their benzylamide derivatives on a high-performance liquid chromatographic chiral stationary phase consisting of a covalently bound tris (4-methylbenzoate) cellulose layer on silica gel. The column was used under reversed-phase conditions using methanol as the main mobile phase component, with a perchlorate buffer pH 2.0. A compromise for derivatization with a water soluble carbodiimide and 1-hydroxybenzotriazole of a group of eight analytes was obtained. The derivatives were identified by IR- and MS-spectroscopy.

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Mechanism of Action of Nonsteroidal Anti-Inflammatory Agents

Gastroenterology

Biochem Biophys Res Commun

Clin Immunol Immunopathol

Jap J Pharmacol

Am J Med

Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

Nature New Biol

Hormones, prostaglandins and dysmenorrhea

Topical aspirin plus HCI gastric lesions in the rat: toprotective effect of prostaglandin, cimetidine and probanthine

Gastroenterology

Effect of orally and intravenously administered prostaglandin 15 (R) 15-methyl E2 on gastric secretion in man

Adv Biosci

Endoscopic evaluation of the effects of aspirin, buffered aspirin, and enteric coated aspirin on the gastric and duodenal mucosa

N Engl J Med

Acute effect of systemic aspirin on gastric mucosa in man

Dig Dis Sci

Cytoprotection by prostaglandins

Gastroenterology

Gastroscopic evalution of anti-inflammatory agents

Br Med J

A double-blind randomized placebo controlled gastroscopic study to compare the effects of indomethacin capsules and indomethacin suppositories on the gastric mucosa of human volunteers

J Rheumatol

Prostaglandins and inflammation

Semin Arthritis Rheum

Effects of prostaglandin E, on adjuvant arthritis

Nature

Evolution of ideas on the role of prostaglandins in inflammation

Agents Actions

Inhibition of arachidonic acid cyclo-oxygenase and lipoxygenase activities of leukocytes by indomethacin and compound BW755C

Agents Actions

Novel leukotrienes: products formed by initial oxygenation of arachidonic acid at C-15

Biochem Biophys Res Commun

Effect of novel leukotrienes on neutrophil function

FEBS Letters

Indomethacin in submicromolar concentrations inhibits cyclic AMP-dependent protein kinase

Nature

Prostaglandin regulation of macrophage collagenase production

Proc Natl Acad Sci

Prostaglandin mediation of collagenase-induced bone resorption

Nature

Monocytes regulate osteoclast-activating factor by releasing prostaglandins

J Exp Med

Effect of orally and intravenously administered prostaglandin 15 (R) 15-methyl E² on gastric secretion in man