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Limitations of drug concentrations used in cell culture studies for understanding clinical responses of NSAIDs

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Abstract

In this review, the in vitro cellular effects of six nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate, ibuprofen, naproxen, indomethacin, celecoxib and diclofenac, are examined. Inhibition of prostanoid synthesis in vitro generally occurs within the therapeutic range of plasma concentrations that are observed in vivo, consistent with the major action of NSAIDs being inhibition of prostanoid production. An additional probable cellular action of NSAIDs has been discovered recently, viz. decreased oxidation of the endocannabinoids, 2-arachidonoyl glycerol and arachidonyl ethanolamide. Many effects of NSAIDs, other than decreased oxidation of arachidonic acid and endocannabinoids, have been put forward but almost all of these additional processes are observed at supratherapeutic concentrations when the concentration of albumin, the major protein that binds NSAIDs, is taken into account. However, one exception is salicylate, a very potent inhibitor of the neutrophilic enzyme, myeloperoxidase, the inhibition of which leads to reduced production of the inflammatory mediator, hypochlorous acid, and inhibition of the inflammation associated with rheumatoid arthritis.

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Abbreviations

COX:

Cyclooxygenase

NSAID:

Non-steroidal anti-inflammatory drug

2-AG:

2-Arachidonoyl glycerol

AEA:

Arachidonoyl ethanolamide

AA:

Arachidonic acid

FBS:

Foetal bovine serum

RSK-2:

Ribosomal protein S6 kinase alpha-3

PG:

Prostaglandin

PGM:

Prostaglandin M

PGE2 :

Prostaglandin E2

2-PG:

2-Prostaglandin glycerol

PGEA:

Prostaglandin ethanolamide

PMA:

Phorbol myristate acetate

AMPK:

5′ Adenosine monophosphate-activated protein kinase

PPAR:

Peroxisome proliferator-activated receptor

LPS:

Lipopolysaccharide

BAEC:

Bovine aortic endothelial cells

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Acknowledgements

The research assistance of Professors Michael Whitehouse, Richard Day, Kim Rainsford, Peter Sadler and Ken Williams in arthritis research is gratefully acknowledged. The authors also gratefully acknowledge the assistance of Dr Penny Graham and Dr Siiri Iismaa in the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, St Vincent’s Hospital Sydney, Darlinghurst, NSW, 2010, Australia

    Garry G. Graham

  2. School of Medical Sciences, University of New South Wales, Kensington, NSW, 2052, Australia

    Garry G. Graham

  3. School of Medicine, Western Sydney University, Campbelltown, NSW, Australia

    Kieran F. Scott

  4. Ingham Institute of Applied Medical Research, 1 Campbell St, Liverpool, NSW, 2170, Australia

    Kieran F. Scott

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GGG conceived and wrote the manuscript. KFS contributed intellectually to the manuscript, conducted literature searches, interpreted search results, edited and revised manuscript drafts.

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Graham, G.G., Scott, K.F. Limitations of drug concentrations used in cell culture studies for understanding clinical responses of NSAIDs. Inflammopharmacol 29, 1261–1278 (2021). https://doi.org/10.1007/s10787-021-00871-2

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