NSAID

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Biochemical Pharmacology 180 (2020) 114147
Contents lists available at ScienceDirect
Biochemical Pharmacology
journal homepage: www.elsevier.com/locate/biochempharm
Perspective
Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A T

current perspective
⁎
Samik Bindua, Somnath Mazumderb,1, Uday Bandyopadhyayb,c,
a
Department of Zoology, Cooch Behar Panchanan Barma University, Cooch Behar, West Bengal 736101 India
b
Division of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India
c
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Rd, Scheme VIIM, Kankurgachi, Kolkata, West Bengal 700054 India
A R T I C LE I N FO A B S T R A C T
Keywords: Owing to the efficacy in reducing pain and inflammation, non-steroidal anti-inflammatory drugs (NSAIDs) are
NSAID amongst the most popularly used medicines confirming their position in the WHO’s Model List of Essential
Cyclooxygenase Medicines. With escalating musculoskeletal complications, as evident from 2016 Global Burden of Disease data,
Prostaglandin NSAID usage is evidently unavoidable. Apart from analgesic, anti-inflammatory and antipyretic efficacies,
Inflammation
NSAIDs are further documented to offer protection against diverse critical disorders including cancer and heart
Mitochondria
attacks. However, data from multiple placebo-controlled trials and meta-analyses studies alarmingly signify the
Organ damage
Apoptosis adverse effects of NSAIDs in gastrointestinal, cardiovascular, hepatic, renal, cerebral and pulmonary compli-
Gastropathy cations. Although extensive research has elucidated the mechanisms underlying the clinical hazards of NSAIDs,
no review has extensively collated the outcomes on various multiorgan toxicities of these drugs together. In this
regard, the present review provides a comprehensive insight of the existing knowledge and recent developments
on NSAID-induced organ damage. It precisely encompasses the current understanding of structure, classification
and mode of action of NSAIDs while reiterating on the emerging instances of NSAID drug repurposing along with
pharmacophore modification aimed at safer usage of NSAIDs where toxic effects are tamed without compro-
mising the clinical benefits. The review does not intend to vilify these ‘wonder drugs’; rather provides a careful
understanding of their side-effects which would be beneficial in evaluating the risk–benefit threshold while
rationally using NSAIDs at safer dose and duration.
1. Introduction the pharmaceutical industry [1]. In around 500 BCE, even before
conceptualization of clinical trials and scientific knowledge, Hippo-
Since the isolation of salicyclate from willow bark in around 1830s, crates, wrote about the potential of willow bark and leaves in curing
followed by the discovery of aspirin (acetyl salicyclate) by Felix pain and fever. Thereafter, generations of scientists, chemists and sci-
Hoffman of Bayer industry, Germany, in 1897, non steroidal anti-in- ence enthusiasts have extensively worked and ushered the development
flammatory drugs (NSAIDs) have been enjoying a blockbuster status in of these ‘wonder drugs’. At present, NSAIDs are among the most
Abbreviations: NSAID, Non-steroidal anti-inflammatory drug; PGHS, Prostaglandin-endoperoxide synthase; PG, Prostaglandin; FDA, US Food and Drug
Administration; IC, Inhibitory concentration; P450, Cytochromes P450; PLA, Phospholipase; Tx, Thromboxane; LTE, Leukotriene; MOS, Mitochondrial oxidative
stress; ETC, Electron transport chain; O2.-, Superoxide; CVD, Cardiovascular disease; TNF-α, Tumor necrosis factor-alpha; NF-κB, Nuclear factor kappa-light-chain-
enhancer of activated B cells; ICAM-1, Intercellular adhesion molecule 1; MAPK, Mitogen activated protein kinase; PKC, Protein kinase C; DRP1, Dynamin-related
protein 1; LPS, Lipopolysaccharide; HMGB1, High mobility group box 1; DAMP, Damage associated molecular pattern; MEDAL, Multinational Etoricoxib and
Diclofenac Arthritis Long-term trial; GI, Gastrointestinal; MI, Myocardial infarction; HF, Heart failure; VIGOR, Vioxx Gastrointestinal Outcomes Research; APPROVe,
Adenomatous Polyp PRevention On Vioxx trial; PRECISION, Prospective Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen; NANSAIDs, Non
aspirin NSAIDs; ADMA, Asymmetric dimethyl arginine; eNOS, Endothelial nitric oxide synthase; CKD, Chronic kidney disease; AKI, Acute kidney injury; GFR,
Glomerular filtration rate; PPAR, Peroxisome proliferator-activated receptor; CRESCENT, Celecoxib Rofecoxib Efficiency and Safety in Cormorbidities Evaluation
Trial; ICH, Intracerebral haemorrhage; AERD, Aspirin-exacerbated respiratory disease; CAP, Community Acquired Pneumonia; Cys-LTEs, Cysteinyl leukotrienes
⁎
Corresponding author: Dr. Uday Bandyopadhyay Division of Molecular Medicine, Bose Institute, P-1/12, CIT Road, Scheme VIIM, Kankurgachi, Kolkata West
Bengal 700054, India.
E-mail address: [email protected] (U. Bandyopadhyay).
1
Present address: National Institute of Biomedical Genomics, P.O.: N.S.S., Kalyani, West Bengal 741251 India
https://doi.org/10.1016/j.bcp.2020.114147
Received 27 April 2020; Received in revised form 3 July 2020; Accepted 7 July 2020
Available online 10 July 2020
0006-2952/ © 2020 Elsevier Inc. All rights reserved.
S. Bindu, et al. Biochemical Pharmacology 180 (2020) 114147
popular over-the-counter drugs across the world, constituting 5% of all strengthened its foothold as an independent pathway of NSAID-induced
the prescribed medicines [2]. Traditionally NSAIDs were classified on cytopathology [24]. Other than gastrointestinal and cardiovascular
the basis of their chemical characteristics wherein most of the popular complications, habitual use of NSAIDs are also associated with ne-
NSAIDs are categorized as major derivatives of salicylic acid, acetic phrotoxicity and eventual renal failure [25] together with other tran-
acid, enolic acid, anthranilic acid or propionic acid. However, with the sient effects on water and electrolyte balance. In addition, idiosyncratic
advancement of scientific knowledge the classification has also been drug toxicity by NSAIDs has also been significantly attributed to mul-
shifted based on their selectivity for inhibiting cyclooxygenase/pros- tiple incidences of hepatotoxicity [26]. However, the exact mechanism
taglandin-endoperoxide synthase (PGHS) enzymes which are the major involved in inflicting these adverse effects by NSAIDs is still elusive. All
targets of these drugs. In addition, a classification system has also been these data together eventually challenge the long-standing reputation
formulated to categorize NSAIDs on the basis of their half-life. Never- of these ‘wonder drugs’ in relation to their rampant medicinal use.
theless, despite the interclass diversity, their functions are relatively Since, in the current context, NSAID use has become almost unavoid-
similar. NSAIDs are mostly used for the treatment of patients suffering able, a relatively safe usage of these drugs is the need of time which can
from pain and inflammatory conditions such as chronic pain, osteoar- avert the risk of organ failure. To this end, precise understanding of the
thritis, rheumatoid arthritis, postoperative surgical conditions, men- molecular mechanism and signaling pathways involved in NSAID
strual cramps and even used extensively as analgesics and anti-pyretics therapy is quintessential. In addition, chemical modification of FDA
[3–4]. Moreover, the superiority of typical NSAIDs (with potent anti- approved NSAIDs, by pharmacophore modification, aimed at reducing
inflammatory action) over acetaminophen (atypical NSAID devoid of their toxic effects and improving their bioavailability without com-
any anti-inflammatory action, but with weak, non-specific cycloox- promising the therapeutic effects is strongly advocated. Extensive stu-
ygenase/PGHS-inhibitory and antipyretic action) [5–6] and other an- dies have been already undertaken to analyse the effects of NSAIDs at
tipyretic analgesics like opioids has already been established. Blinde- the molecular level besides designing new combinatorial formulations
d, randomized control trials have demonstrated the efficacy of NSAIDs in the form of NSAID-prodrugs with enhanced efficacy. Although there
over acetaminophen [7]. Several opioid-addiction problems actually are discrete individual reports of organ-specific impact of these drugs
initiate with the therapeutic use of opioid-based painkillers. Therefore, where both PGHS/PG-dependent as well as independent effects of
opiods are far more dangerous than NSAIDs owing to the non-addictive NSAIDs have been implicated in their cytotoxic actions, till date no
nature of the latter drugs [8]. Regarding other effects, a recent study on comprehensive document is available which encompasses and accounts
amyloid beta-induced experimental Alzheimer’s disease (AD) in mice the outcome of different randomized trials, meta-analyses, systemic
has shown that mefenamic acid, a fenamate NSAID used to relieve reviews along with the mode of action of NSAIDs and its effects on
period pain, could offer protection by suppressing neuroinflammation multiple organs in a coherent manner. In this article, we have tried to
and memory loss [9]. However, incidents of cognitive impairment in provide an overall idea about the structure and function of NSAIDs with
aspirin users and risk of dementia in elderly people also warn about the special emphasis on organ damage as well as indicated the possible
safety concerns and plausible neurotoxic effects of NSAIDs in AD pa- strategies of using these drugs in a safer approach by discussing the
tients [10–11]. Notably, the protective role of NSAIDs has been sig- previous contributions concurrent with recent understanding of the
nificantly implicated in various cancers [12]. In addition, there are field.
some speculations regarding the use of NSAIDs against coronavirus
[13]. In spite of this extensive therapeutic utility, the NSAIDs are in- 2. Chemistry and classification of NSAIDs
famous for multiple severe side effects including gastrointestinal toxi-
cities, cardiovascular risks, renal injuries, and hepatotoxicity as well as NSAIDs encompass a large class of drugs with extreme structural
hypertension and other minor disorders [14–17]. The general mode of and functional diversity. These are mostly weak organic acids (com-
action of NSAIDs involves the inhibition of cyclooxygenase/pros- prising of an acidic moiety along with an aromatic functional group). In
taglandin-endoperoxide synthase (PGHS-1 and PGHS-2), regulatory terms of functional diversity, isoform-specific selectivity for PGHS in-
enzymes, involved in the biosynthesis of prostaglandin (PG) which is hibition forms the basis of differentiation; while a third classification
strongly implicated in inflammation. PGHS-1 is believed to be a takes into account the bioavailability of the NSAIDs in the serum, ac-
housekeeping gene engaged in multiple biological functions including counting for the pharmacokinetic aspects of NSAID action in the sys-
protection of gastric mucosa while PGHS-2 is responsible for in- temic context. In the following section, a brief description about the
flammation. Some NSAIDs are non-specific inhibitors of both the en- classification of NSAIDs is presented.
zymes while others are specific, notably “coxibs” that specifically in-
hibit PGHS-2. Previously it was believed that PGHS-1 inhibitors, by 2.1. Classification of NSAIDs based on structure
inhibiting PG synthesis in gastric mucosa, can indulge in gastro-
intestinal complications. However, contrary to this, a substantial Based on their chemical structure, NSAIDs can be broadly classified
amount of evidence has emerged in recent years [18–21]. At one point into salicylates, aryl and heteroarylacetic acid derivatives, indole/in-
of time, a shift to coxibs was thought to be effective. Since PGHS-2 is dene acetic acid derivatives, anthranilates and oxicams (enol acids)
inducible and is not directly related to gastric mucosal defence, rather (Fig. 1) [27]. The general structure of a typical NSAID consists of an
engaged in inflammation, inhibition of PGHS-2 by coxibs were sup- acidic moiety (carboxylic acid, enols) attached to a planar aromatic
posed to be rather safe and devoid of gastrointestinal and other com- functional group. Salicylates were the first identified NSAIDs following
plications [22]. But emerging evidences have challenged this theory extraction of salicylic acid from willow bark [1]. They are actually the
too. In line with that, in 2000–03 several reports began to emerge re- derivatives of 2-hydroxybenzoic acid (salicylic acid) [28]. Initially,
garding the cardiovascular adverse effects of PGHS-2 inhibitors and salicylic acid was used medicinally in the form of sodium salt; later, this
subsequent placebo controlled trials also showed that those inhibitors compound got replaced therapeutically by the acetylated derivative,
were linked to increased risk of atherothrombotic vascular events acetylsalicylic acid (ASA) or aspirin. Therapeutic utility was enhanced
[15–16,23]. Moreover, meta-analyses and randomized trials have fur- by the esterification of the phenolic hydroxyl group, as in aspirin, or
ther confirmed these findings which led to the withdrawal of several substitution of a hydrophobic/lipophilic group at C-5 as in diflunisal
PGHS-2 inhibitors by US Food and Drug Administration (FDA) [15]. [28]. After salicylates, aryl or heteroaryl acetic acid derivatives con-
Concurrently with the evolution and establishment of PGHS/PG-de- stitute an important class of NSAIDs. Ibuprofen, fenoprofen, naproxen
pendent mode of NSAID toxicity, a second school of opinions ad- and oxaprozin are some structural derivatives of aryl or heteroaryl
vocating the direct effect of NSAIDs on mitochondria followed by acetic acid which comprise some of the most popular NSAIDs. The next
generation of cellular oxidative stress and apoptosis has also category of NSAIDs is indole or indene acetic acid which includes
2
Fig. 1. Classification of non steroidal anti-inflammatory drugs (NSAIDs) based on structure.
popular pain killers including indomethacin and sulindac. Moving inhibited by the concerned NSAID, if the ratio is less than 1, it means
further, anthranilates are another class of NSAIDs which are N-aryl that the concerned NSAID is less selective for PGHS-2 compared to
substituted derivatives of anthranilic acid. Diclofenac, the derivative of PGHS-1 and in case of ratio greater than 1, the NSAID is preferentially
2-arylacetic acid, is the most widely used anthranilate NSAID found in selective towards PGHS-2 [29–32]. It is presumed that side effects of
diverse formulations including pain killer tablets, injections, topical NSAIDs (such as GI toxicity) are associated with PGHS-1 inhibition
ointments and fast acting sprays. Mefenamic acid and meclofenamic while therapeutic effect (anti-inflammatory) is correlated with that of
acid are also derived from anthranilic acid. Finally, oxicams, mainly PGHS-2 and often a high level of PG suppression is needed for ther-
consisting of piroxicam and meloxicam comprise the last structural apeutic relevance; however this simplistic view has been questioned
category of NSAIDs, characterized by the presence of 4-hydro- recently [29]. In general, NSAIDs are therapeutically employed at doses
xybenzothiazine heterocycle [28]. In addition to the structural classi- that generate more than 50% reduction of PG production. In this con-
fication, NSAIDs have been also categorized based on their PGHS-spe- text, it would be important to check the extent to which PGHS-1 gets
cific inhibitory activity as well as half life in serum. inhibited at the same concentration of NSAID that is required for in-
hibiting 80% of PGHS-2 activity. However, in case of diclofenac, the
concentration which inhibits 80% of PGHS-2 activity can also inhibit
2.2. Classification of NSAIDs based on the type of PGHS interaction and
almost 70% of PGHS-1 activity at the same time. So, therapeutic dose
selectivity
(80% inhibition of PGHS-2) can even lead to toxicity (70% inhibition of
PGHS-1). Hence, in this scenario, when relative selectivity varies within
Bioconversion of arachidonic acid (AA) into inflammatory prosta-
a narrow range, other variables including consumed dose and plasma
noids (prostaglandins and prostacyclin), is mediated by PGHS enzymes;
half-life should be considered. For example, piroxicam which has long
mainly PGHS-1 and PGHS-2 which are inhibited by NSAIDs. The po-
plasma half life and correlated with GI toxicity in vivo, did not show
tency of NSAIDs in inhibiting PGHS-1 and PGHS-2 are often compared
notable PGHS-1 selectivity in the in vitro assay [29]. So, it is clear that
on the basis of their IC50 values (the concentration of NSAIDs that in-
the relative potency of NSAIDs vary with their dose, concentration,
hibits 50% activity of the enzyme) in the in vitro assay system. Of all the
plasma half life. Therefore, IC80 value seems to be clinically more re-
assay systems that have been documented, human whole blood assay is
levant in comparing NSAIDs’ inhibitory potencies against PGHS-1 and
the most widely accepted [29–30]. Here, it is worthwhile to mention
PGHS-2. Now, on the basis of the potencies to inhibit PGHS isoforms,
that almost all the NSAIDs variably inhibit both the PGHS isoforms at
NSAIDs can be divided into four main categories (Table 1): (i) non-
their therapeutic doses. Thus, on the basis of PGHS selectivity, an in-
selective, complete inhibitors of both PGHS-1 and PGHS-2 (ii) complete
hibitory ratio is determined which allows a classification of NSAIDs.
inhibitors of PGHS-1 and PGHS-2, although with specific preference for
The inhibitory ratio is based on the PGHS-1 IC50/ PGHS-2 IC50
PGHS-2 (iii) strong inhibitors of PGHS-2, although with weak inhibiting
[29,31–32]. If the ratio is 1, then both the PGHS enzymes are equally
3
Table 1
Categorization of NSAIDs based on PGHS-selective inhibitory action.
Categories PGHS isoform selectivity Representative NSAIDs
Category 1 PGHS-1 and PGHS-2 Indomethacin, Aspirin, Diclofenac, Naproxen, Ibuprofen

Category 2 5-50 fold selectivity for PGHS-2 Meloxicam, Celecoxib, Nimesulide, Etodolac
Category 3 Greater than 50 fold selectivity for PGHS-2 NS-398
Category 4 Poor selectivity for PGHS-1 and PGHS-2 Sulfasalazine, Sodium salicyclate, Nabumetone,
action against PGHS-1 (iv) weak inhibitors of both PGHS-1 and PGHS-2 concentrations, CYP3A4 catalyzes 2-hydroxylation for systemic clear-
[29]. However, in terms of kinetics, NSAID interactions with both the ance while 3-OH-ibuprofen (formed by CYP2C9) gets further trans-
PGHS isoforms can be also used for their classification which is as formed to carboxy-ibuprofen by cytosolic dehydrogenases [37]. Thus,
follows: freely reversible interaction (ibuprofen), slowly reversible in- NSAIDs may undergo either CYP-mediated phase I followed by UGT-
teraction (indomethacin, diclofenac, celecoxib) and irreversible inter- mediated phase II metabolism or direct UGT-mediated glucuronidation
action (aspirin) [32]. (phase II metabolism) [5] before ultimate renal excretion mediated by
efflux transporters. Around 10–15% of absorbed ibuprofen is glucur-
onidated directly to ibuprofen-acyl glucuronide by multiple UGTs in-
2.3. Classification of NSAIDs on the basis of plasma half-life (t½)
cluding UGT1A9, UGT2B17, UGT1A3 and UGT2B7 [42]. Although
binding to plasma proteins hinder the ready passage of NSAIDs to the
NSAIDs can also be divided into short-acting (plasma half-life less
interstitial and transcellular fluids from the plasma, the same aspect
than 6 h) such as aspirin, diclofenac and ibuprofen and long-acting
facilitates their penetrance and persistence in the inflammatory exu-
(half-life approximately greater than 10 h) such as naproxen, celecoxib.
dates, thereby allowing for anti-inflammatory actions. Inherent differ-
Those with short half-life, like ibuprofen, exhibit quick onset of action
ences in the pharmacokinetic properties of NSAIDs with chiral centers
and thus suitable for acute pain. While NSAID like naproxen has a
in their structure (including arylpropionates and etodolac) further de-
longer half-life and effective for treating chronic conditions [33].
mand specific attention before prescribing a suitable dosage for ad-
ministration. This is due to the structural and hence pharmacokinetic
3. Pharmacology of NSAIDs differences between the enantiomers of same NSAIDs along with their
potential conversion from R(-) to S(+) form or vice versa, in vivo, that
More than 90% of the NSAIDS are highly bound to plasma proteins. ultimately dictate their specificities in terms of systemic clearance,
These drugs normally exhibit considerably well bioavailability in elimination half lives and distribution volumes of a particular en-
monogastric species upon oral, subcutaneous and intramuscular ad- antiomer in the circulation [34]. PGHS inhibition predominantly ac-
ministration due to their moderate to high lipid solubility (an aspect counts for the pharmacodynamic and toxicodynamic actions of NSAIDs
that also allows their penetration of blood–brain barrier) [34]. Direct [34]; although mitochondrial toxicity and adverse drug-drug interac-
urinary excretion of the parent drug is low due to high binding with tions also significantly contribute to NSAID actions on the system.
plasma proteins; hepatic metabolism clears out the NSAIDs from the While PGHS-1 inhibition primarily contributes to the toxic side effects
body as inactive metabolites that are excreted in urine and bile. Drug of these drugs, PGHS-2 inhibition underlies most of the therapeutic
elimination by clearance and terminal half life is highly species specific. effects [34]; although instances of PGHS-2 inhibition associated cardi-
The microsomal enzymes cytochrome P450 (CYP)-containing-mixed- otoxicity strongly warrants the risk of coxib usage.
function-oxidase system is responsible for most of the NSAIDs meta-
bolism wherein CYP2C9 is the most important oxidase primarily re-
sponsible for metabolism of a wide range of NSAIDs including cel- 4. Therapeutic uses and repurposing of NSAIDs
ecoxib, indomethacin, diclofenac, flurbiprofen, ibuprofen, naproxen
and enolic acids like piroxicam and tenoxicam. Notably, allelic varia- With the discovery of aspirin’s mechanism of action by John Vane
tions in this protein (including CYP2C9*2 and CYP2C9*3) affect the (Noble Prize 1982), understanding of NSAIDs increased over the years,
pharmacotherapeutic efficacy of the medicine in patient-specific thereby escalating the abilities to develop novel anti-inflammatory
manner [35]. Hence, pharmacogenomic variability of P450 in a popu- therapeutics. Owing to the analgesic, anti-pyretic, anti-inflammatory
lation also correlates well with varying degree of metabolism of the activities these drugs are extensively used in treating pain, fever and
drugs among individuals or ethnic groups [36]. It has been observed inflammation in rheumatic disorders, osteoarthritis and dysmenorrhoea
that CYP2C9 predominantly contributes to ibuprofen clearance through [36,43–45]. They are also implicated in sports medicine and popular
formation of 3-hydroxyibuprofen and 2-hydroxyibuprofen [37]. Apart among sports persons and soldiers [46–49]. Owing to the increasing
from ibuprofen, the action of CYP2C9 on other target NSAIDs has been demand for repurposing of already FDA-approved cheaper drugs in
reported wherein diclofenac is metabolized to 4′-hydroxydiclofenac, treating new diseases (in addition to the canonical purposes), and
flurbiprofen is metabolized to 4′-hydroxiflurbiprofen and naproxen is considering the multiple effects of NSAIDs, these drugs are now also
metabolized to 6-desmethylnaproxen [35]. Other than CYP2C9, NSAIDs aimed for repurposing against other serious health implications. Use of
are also metabolized by other cytosolic hepatic enzymes of phase I aspirin as a cardioprotective agent for treating atherosclerosis can be
metabolism including CYP3A4, CYP2C19, CYP2C8 through oxidative considered as the oldest and most classical example of using an anti-
transformations. This is followed by phase II conjugation reactions in- inflammatory drug for cardiovascular disease. Exploiting the same ra-
volving glucuronidation by uridine 5′-dipho- tionale of NSAID-induced PGHS inhibition and PG depletion, these
sphoglucuronosyltransferases (including UGT1A1, UGT2B7, UGT1A9 drugs are gaining immense importance as new generation anti-cancer
and UGT2B4) and ultimately biliary excretion of the resultant glucur- agents [50]. Other than PGHS-2 inhibition, induction of tumor cell
onides and reactive metabolites by ABCC2 efflux transporters expressed apoptosis, downregulation of epidermal growth factor receptor, at-
on the apical canalicular membranes of hepatocytes and renal tubular tenuation of neoangiogenesis and protection from DNA damage are
epithelial cells [38–40]. In the aforesaid context, diclofenac metabolism some of the strategies by which coxib and non-coxib NSAIDs like aspirin
by UGT2B7, ABCC2 and CYP2C8 has been also linked with hepato- offer chemo preventive as well as therapeutic effect against various
toxicity due to allelic variations in these enzymes notably, UGT2B7 cancers [51]. Evidences of reduced risk for developing cancers (by long
allele [38,41]. In regards to ibuprofen metabolism, at high term NSAID-users) as well as regression of tumor mass upon treatment
4
with NSAIDs (used in combination chemotherapy regimen) clearly in- user is age-sex matched to non-user with a ratio of 1:2) in Honk Kong
dicate the preventive as well as therapeutic potencies [52–53]. Because, depicted significant reduction of different cancers (liver, stomach, col-
inflammatory microenvironment is highly conducive for survival and orectum, lung, oesophagus, pancreas, leukaemia), except breast cancer,
proliferation of malignant cells along with evasion of anti-tumor im- in long-term aspirin users compared with those who have not been
mune response and resistance to chemotherapeutic drugs, NSAIDs prescribed aspirin [65]. Other systemic reviews and cohort studies are
strike at the base of these evasive strategies by depleting the in- also in agreement with this observation [66–67]. Apart from cancer,
flammatory milieu thereby culling the cancer cells [54]. Several studies NSAIDs have been also repurposed for other clinical complications
have convincingly proved the efficacy of NSAIDs in direct che- which include diflunisal-induced osteoprotection against staphylo-
motherapy, combination chemotherapy and even neoadjuvant che- coccal osteomyelitis [68], mefenamic acid-mediated protection against
motherapy owing to their multiple anticancer actions which include, schistosomiasis [69], aspirin and ibuprofen-mediated cryptococcal cell
but not essentially limited to, blocking cell proliferation of diverse death [70], oxyphenbutazone-induced sensitization of Mycobacterium
cancer cell types, preventing tumor angiogenesis and metastasis, re- tuberculosis to host-derived factors and exogenous antimycobacterial
ducing chemo and radio resistance and of course inducing apoptosis compounds [71] and piroxicam-induced dipeptidyl peptidase-4 inhibi-
[55]. Platelet aggregation and adherence to tumor cells aid in immune tion as an alternative strategy for regulating glucose metabolism in
evasion of malignant cells thereby facilitating metastasis. NSAIDs sig- diabetes mellitus [72]. While observations from drug repurposing stu-
nificantly interfere with these processes. As a novel strategy of potential dies in pre-clinical and research settings are highly encouraging, further
anti-cancer therapy, sulindac, aspirin, naproxen and other NSAIDs have exploration and extensive validations are mandatory before re-
been used to target cancer-associated epigenetic processes and mi- purposing of NSAIDs in clinical settings. Recently, induction of PGHS-2
croRNA (miRNA) expression [56–57]. A system-biological approach has been also linked with seizures and PGHS-2 inhibitors have been
was also used to construct an NSAID-effect model based on the PGHS- proposed as potential therapeutic option, targeting PGHS-2 mediated
pathway to identify miRNA biomarkers relevant to tumors. The out- neuroinflammation during epilepsy [73]. In this regard, mefenamic
come of this study could be important in development of personalized acid has been linked to neuroprotection and prevention of cognitive
medicine [58]. In regards to the PGHS-2 and its impact on cancer, impairment in mice by preventing amyloid beta-induced NLRP3/IL-1β-
coxibs have been found to prevent chemo resistance in breast cancer dependent inflammosome activation, neuroinflammation and memory
cells through blocking PGHS-2-dependent-PGE2 production and in- loss suggesting its putative effect against AD [9,74–75]. In contrast to
flammation-associated carcinogenesis [59–60]. Notably, celecoxib has aforesaid, instances of NSAID-associated cognitive problems and risk of
been found to target breast cancer stem cells, prevent carcinogenic dementia in elderly people raise multiple concerns about the safety
epithelial to mesenchymal transition and block metastasis via PGE2 profiles of NSAIDs for using against AD [10–11,76–77]. The complex
depletion and Wnt signaling downregulation [61]. Although PGHS-2 associations (both positive and negative) of AD with NSAID-use there-
inhibition seems a potential strategy for cancer prevention by coxibs, fore demands precise randomized clinical trials taking into account the
serious concerns regarding the long term cardiovascular safety of coxibs specific NSAIDs used by patients, duration, dose, past history of cog-
used in Adenomatous Polyp Prevention on Vioxx (APPROVe, rofecoxib) nitive defects and other relevant confounders in order to define safety
and Adenoma Prevention with Celecoxib (APC, celecoxib) trials (which profiles of NSAIDs in AD. Despite these complex and contradictory ef-
aimed at testing the preventive effect of coxibs on recurrence of col- fects on cognitivefunctions, NSAIDs have been positively implicated in
orectal polyps) got highlighted. A 2–3 fold elevation in cardiovascular post-surgical complications and in treating burn patients [78–79].
risk among patients taking 25 mg of rofecoxib in the APPROVe trial led Furthermore, in the COVID-19 background, owing to a previous report
to premature termination of the study along with subsequent with- of indomethacin in preventing RNA synthesis of coronavirus, a lot of
drawal of Vioxx from the market [62]. The cardiovascular risk of se- speculations are flying around the therapeutic use of NSAIDs against
lective PGHS-2 inhibitors therefore overshadowed the anti-cancer po- COVID-19 [80]. A schematic representation of the diverse canonical
tency of some of these drugs; although PGHS-2 still remained as a and emerging applications of NSAIDs has been presented (Fig. 2)
potential anti-neoplastic target. In this regard, compared to coxibs, Since, NSAIDs are unfortunately associated with number of serious
aspirin has proved to be a rather safe NSAID with significant efficacy complications making different organs vulnerable to damage, a thor-
against diverse tumors. Aspirin-induced PGHS-1 inhibition and asso- ough understanding about their diverse subcellular effects and mode of
ciated TxA2 depletion blocks platelet aggregation and adherence to action are extremely essential.
tumor cells, thereby increasing chemo sensitivity of tumors. Aspirin,
which has shown promising preclinical results in preventing cancer is
now being investigated in an Add-Aspirin phase III, double-blind, ran- 5. Mode of action of NSAIDs
domized trial with four non-metastatic solid-tumour cohorts (breast,
colorectal, gastro-oesophageal and prostrate) to check the recurrence There are several schools of opinions which tend to categorize the
and survival of the patients with those tumours after standard aspirin NSAID actions based on major subcellular targets. PGHS dependent and
use [63]. The interpretation of the preplanned analysis of feasibility of independent pathways of action are the two most widely accepted
Add-Aspirin Trial indicates well-tolerability of aspirin after radical mechanisms by which NSAIDs are reported to act. While the first mode
radiotherapy [64]. It is noteworthy to mention that despite its anti- relies on the action of NSAIDs on the production and abundance of
cancer effect the risk of serious bleeding due to aspirin persists. This has prostanoids (the major inflammatory mediators of the system) to reg-
been well addressed in the Add-Aspirin study where several special ulate tissue inflammation, the second mode of action is dependent on
strategies were taken to reduce bleeding with aspirin, such as exclusion the toxic action of NSAIDs against the cells specially the subcellular
of subjects susceptible to bleeding, randomization of volunteers with
age above 75 years to 100 mg aspirin or placebo due to their dose and
age dependent vulnerability to bleeding and also use of proton pump
inhibitors (PPI) for participants post partial gastrectomy or oesopha-
gectomy [64]. Another randomized phase III placebo-controlled trial is
also undergoing to check the potential of aspirin (300 mg daily) in
preventing the recurrence of cancer in human epidermal growth factor
receptor 2 (HER2) negative breast cancer patients post chemotherapy,
surgery and/or radiation therapy (ClinicalTrials.gov Identifier:
NCT02927249). In addition, a 10-year population cohort study (aspirin Fig. 2. Classical applications and emerging uses of NSAIDs.
5
bioenergetic work horses, mitochondria. Before delving deeper into the produces prostanoids for housekeeping purposes such as gastric mu-
organ-specific action of these drugs, it is essential to provide a com- cosal protection, regulation of acid secretion, and homeostasis as well
prehensive idea about the two basic mechanisms behind NSAIDs-re- as maintaining renal functions. On the other hand, PGHS-2, induced by
lated organ damage. inflammatory cytokines, mitogens, endotoxins and tumor-promoters,
produces prostanoids during inflammation and cancer [94]. PGHS-2
has been mostly linked with immune cells including leukocytes and
5.1. NSAID-PGHS-prostanoid axis macrophages as well as fibroblasts, chondrocytes, endothelial and me-
sangial cells and notably the ensuing inflammatory sites in the body
Although human beings have been consuming NSAIDs in different [95–96]. However accumulated evidence now clearly suggests that
forms for more than 3,500 years, it was not until John Vane in 1971, PGHS-2 is also constitutively expressed in a number of tissues including
when cyclooxygenase 1 enzyme (PGHS-1) was identified as the mole- brain, gut, lung, thymus and kidney wherein it produces prostanoids
cular target of NSAIDs which proved instrumental in elucidating the [97]. Chemically, prostanoids are bioactive lipid molecules which
molecular mechanism of NSAID action [81–82]. Vane’s pioneering mediate autocrine and paracrine action via high-affinity G protein
work also revealed that these chemically varied drugs, by inhibiting coupled receptors [81]. They are derived from 20 carbon ω-6 fatty acid,
PGHS-1, actually reduced PG formation [81,83–85]. His elucidation AA, by the action of PGHS on AA [98]. Since AA is highly reactive and
was followed twenty years later by the identification of a second cy- sensitive to oxidation, it is not found freely in cells; rather stored in
clooxygenase enzyme named PGHS-2 which is also associated with membrane phospholipids mainly as phosphatidylcholine, phosphati-
prostaglandin synthesis like PGHS-1 [86–87]. Other than PGHS-1 and dylethanolamine and phosphatidylinositol. The phospholipases (PLA2)
2, Chandrasekharan et.al in 2002 described a third distinct cycloox- liberate them from the membrane phospholipids. Subsequently free AA
ygenase isozyme, cyclooxygenase-3, in brain-tissue of dogs, which is a is first oxidized to PGG2 (endoperoxide) by the cyclooxygenase activity
splice variant of PGHS-1 and showed some sensitivity to paracetamol followed by peroxidation to form PGH2 (precursor of prostanoids) by
[88]. Although, this sensitivity has not been properly justified in hu- PGHS enzymes (Fig. 3). PGH2 is the precursor of series-2 prostaglandins
mans [89]. However, in this review the main focus would remain on or inflammatory prostanoids. Notably, PGHS enzymes can also convert
PGHS-1 and PGHS-2, the two main pharmacological targets of NSAIDs. other polyunsaturated fatty acid (PUFA) such as dihomo-γ-linolenic
Both these isoforms reside predominantly in the endoplasmic reticulum acid (DGLA) to series-1 prostaglandin precursor PGH1 (generally con-
and are identical in length with just over 600 amino acids (having 63% sidered as anti-inflammatory PGs), eicosapentaenoic acid (EPA) to
homology). The molecular weights of the enzymes are approximately series-3 prostaglandin precursor PGH3 and linolenic acids to 9- and 13-
71 kDa and they are bisfunctional in catalytic activity having both hydroxyoctadecaienoic acids (HODE) [99]. Other than by PGHS, PUFA
cyclooxygenase and peroxidase functions [90–91]. The active site of such as AA can be further metabolized through lipoxygenase (LOX) or
both the isoforms are at the end of a hydrophobic channel. NSAIDs epoxygenase to form other eicosanoids. The structural and functional
prevent the access of the arachidonic acid (AA), the substrate of PGHS, distinctions of the PGHS isoforms is attributed to expressional di-
to this channel. PGHS-1 and PGHS-2 channels differ with non-selective chotomy of the genes in the physiological and pathological contexts as
NSAIDs having access to both the channels; which is not the case for well as differences in the requirement of substrate concentrations and
PGHS-2 [19]. The principal difference between the isoenzyme is the range of substrate specificity. Notably, PGHS-2 has wider substrate
substitution of isoleucine 523 in PGHS-1 with valine in PGHS-2 [92]. As specificity, with ability to metabolize AA ester and amide derivatives
mentioned earlier, these two isoforms are responsible for catalyzing the and oxygenate diverse PUFAs unlike PGHS-1 [62]. Further, the reten-
rate-limiting step of prostanoid biosynthesis and are negatively regu- tion of AA-oxygenation ability of aspirin-treated PGHS-2 also con-
lated by NSAIDs (Fig. 3). Prostanoids are actually the eicosanoids. The tributes to the difference in PGHS isoform-specific function and holds
major eicosanoids consist of PGs, thromboxanes (Txs), leukotrienes physiological relevance owing to the anti-inflammatory property of
(LTEs) and lipoxins (LXs). Of these PGs and Txs are collectively called polyhydroxylated lipids produced in the process [96]. As already stated,
prostanoids [93]. PGHS-1 is constitutively expressed in most cells, and
Fig. 3. NSAID-PGHS-prostanoid axis. PGHS-1/2

isoenzyme mediated prostanoid biosynthesis from
arachidonic acid. Arachidonic acid is produced from
phospholipids of the plasma membrane under the
action of phospholipase A2. In addition to pros-
taglandin (PG) and thromboxane (Tx) formation by
PGHS isoforms in a cell and tissue-specific manner,
leukotrienes (LTEs) are other immune mediators
which are produced by the enzyme 5- lipoxygenase
(5-LO). Each prostanoid interacts with its specific
receptor as indicated in the figure.
6
the series-2 prostaglandin precursor, PGH2 gives rise to a number of dying cells. In this way MOS leads to tissue inflammation which oper-
prostanoids, such as PGD2, PGE2 PGF2α, PGI2 and thromboxane A2 ates in a positive feedback loop during chronic insults leading to organ
(TxA2) [94], through tissue-specific isomerisation to produce the di- damage. The cytotoxic actions of NSAID also include arrested cell
verse prostanoids which exert wide range of biological effects upon proliferation, activation of multiple death pathways including extrinsic
interaction with specific G-protein coupled receptors [96]. The role of apoptosis [106–107] and most notably increasing the sensitivity of
these prostanoids is therefore also tissue specific and hence determines cancer cells to apoptosis while overcoming chemo and radioresistance
the pathophysiological outcomes in a context-dependent manner. While along with inhibiting tumor-associated angiogenesis [108–109]. Within
PGD2, PGE2 and PGI2 are potent vasodilators in cardiovascular system, the purview of this NSAID-PGHS-prostanoid axis and NSAID-MOS-
TxA2 exhibit vasoconstriction in the same system. TxA2 plays a sig- apoptosis axis, we can now proceed to discuss the basic mechanism
nificant role in platelet aggregation, whereas PGI2 displays antic- involved in NSAIDs-mediated damage to different organs.
oagulant properties. In airways, TxA2 and PGF2α act as bronchocon-
strictors while PGI2 and PGE2 are bronchodilators. PGE2, PGF2α and 6. NSAIDs and organ damage
PGI2 also give protection to gastric mucosa. Moreover, PGE2 and PGI2
are responsible for renal blood flow and diuresis in compromised kid- With their antinociceptive, anti-inflammatory and anticancer
neys. In relation to inflammatory response of body, PGE2 is the most properties, NSAIDs which are friends in need often become formidable
important PG [81]. Regarding the adverse effects of NSAIDs, it is very foes (owing to their non specific cytotoxic effects), leading to multiple
important to understand the role of the two PGHS isoforms in produ- organ pathologies. Here, we will focus on the detrimental impact of
cing these prostanoids as signaling mediators since the effect of PGHS NSAIDs on 6 major organs whose coordinated functioning is pivotal for
isoforms could be counter intuitive. For example, in kidney while PGI2 maintaining healthy life. A schematic representation summarizing the
produced by PGHS-2 affects renin secretion, PGE2 produced by PGHS-1 underlying cytotoxic effects of NSAIDs on human body is presented
regulates glomerular filtration [85]. Essentially, all the biological ac- (Fig. 5).
tivities of these prostanoids depend on their binding to G protein-cou-
pled cell-surface receptors for example FP, IP, and TP receptors which 6.1. Risk to the gastric mucosal and small bowel injuries
are meant for PGF2, PGI2 and TxA2 respectively [100–101]. The re-
ceptors for PGD2 are DP1 and DP2 or CRTH2 (chemoattractant re- In the treatment of chronic inflammatory conditions by NSAIDs,
ceptor-homologous molecule) receptors [100–101]. On the other hand development of gastric mucosal injury creates the major limitation.
PGE2 has four subtypes of receptors named EP1-EP4 [100–101]. Here, it Prevalence of gastric mucosal lesions has been observed in patients,
is important to note that although, there is structural difference be- with rheumatoid arthritis or pain, who have taken NSAIDs [110–111].
tween PGHS-1 and PGHS-2 the enzymatic steps involved in the con- A prospective, cross-sectional multi-centred study in India, which in-
version of AA to prostanoids by both these isoforms are identical [98]. cluded 8 medical colleges across the country, reported NSAID-related
GI complications in 30.08% cases [112]. In a study performed in Pa-
5.2. NSAIDs, mitochondrial oxidative stress and apoptosis kistan, analysing 820 patients who have undergone upper gastro-
intestinal (GI) endoscopy (1998–2000), it was found that 14.7% pa-
As already mentioned above, despite their clinical relevance, tients reflected NSAIDs-related peptic ulcer. Notably, duodenal ulcer
NSAIDs are cytotoxic compounds. NSAIDs can exert activation of mi- (65.3%) was found more frequently than gastric ulcer (42.3%) [111]. In
tochondrial oxidative stress (MOS), a cytopathological condition char- all the cases the duration and dose of NSAID usage were the major
acterized by severe mitochondrial damage due to activation of detri- determinants of the severity of complications [112]. The risk of GI
mental redox-active chain reactions followed by severe bioenergetic complications by NSAIDs increases by 2.5–5.0% in patients with a
crisis and eventual cell death. Mitochondrial electron transport chain previous history of GI incidents [113]. In United States, in 2000, more
(ETC) complex-I is the major target of NSAIDs (Fig. 4). Notably, di- than 111 million prescriptions were written for NSAIDs with an ap-
clofenac has been found to be most potent among the NSAIDs in in- proximate cost of $4.8 billion [114]. Since these drugs have a wide
hibiting ETC complex I activity, thereby leading to electron leakage range of applications, the US Food and Drug Administration (FDA) is-
from the respiratory chain [102]. The leaked e- causes partial reduction sued a health advisory which stated that NSAIDs should be used at the
of molecular oxygen to form superoxide, O2.-, the progenitor reactive lowest effective dose and for the minimum duration consistent with
oxygen species (ROS) [103]. Intra-mitochondrial O2.-, which is mem- individual patient treatment goals [114]. However, several studies have
brane impermeable, is immediately converted to H2O2 by the mi- linked relatively short-time use of NSAIDs to risk of GI, CVD and renal
tochondrial super oxide dismutase, SOD2, as a protective response complications [114]. Initially, it was believed that traditional NSAIDs
against oxidative stress. However, being membrane permeable, H2O2 inhibit gastroprotective PGHS-1-derived PGE2 and PGI2 thereby in-
escapes the mitochondria (before subsequent neutralization) causing flicting injury in the gastric mucosa [115]. This instigated the devel-
oxidative damage to cellular macromolecules including DNA, protein, opment of PGHS-2 selective NSAIDS [115]. PGHS-2 is generally in-
lipids and carbohydrates, rendering them functionally inactive. While duced during inflammation [116]. So, the idea was, PGHS-2 specific
inside mitochondria, O2.- damages various Fe-S cluster proteins in- NSAIDs would take care of the pain and inflammation while not in-
cluding aconitase and cytochrome c, leading to Fe2+ release which in terfering with PGHS-1 pathway. However, this simplistic view has been
turn reacts with H2O2 via Fenton reaction to produce hydroxyl radical challenged by overwhelming evidence, one of which shows that PGHS-
(.OH), the most damaging ROS [104]. All these events perturb the 2 also plays a significant role in resolving gastric mucosal inflammation
cellular redox homeostasis leading to the activation of intrinsic and healing the ulcers [20]. Subsequently, in a meta-analysis study by
pathway of apoptosis. Elevated ROS also triggers mitochondrial depo- Coxib and traditional NSAID Trialists’ (CNT) Collaboration, which
larization and detrimentally shifts the mitochondrial structural dy- comprised of 124,514 participants, the CNT researchers compared the
namic balance towards hyperfission [105]. NSAIDs further enhance NSAID-induced GI complications among various NSAIDs including na-
ubiquitination-dependent mitochondrial clearance. In course, the da- proxen, diclofenac, ibuprofen and PGHS-2 inhibitors such as rofecoxib,
maged mitochondrial membrane proteins release cytochrome c which lumiracoxib, etoricoxib, valdecoxib, GW40368. They found an in-
moves on to form the apoptosome complex required for activating the creased risk of upper GI complications across all the medicines analyzed
executioner caspases leading to nuclear DNA damage and eventual cell [117]. On top of that, since the beginning of this millennium, a number
death. During these processes, damaged mitochondrial DNA is often of randomized control trials (RCT), aimed at evaluating GI complica-
released from the necrotic cells which act as damage associated mole- tions of NSAIDs, have linked PGHS-2 selective NSAIDs with cardio-
cular patterns to attract immune cells for phagocytic clearance of the vascular diseases (CVD) (detailed in the next section) which led to the
7
Fig. 4. Overview of NSAID-induced mitochondrial reactive oxidants production leading to cellular pathology. NSAID triggers electron leakage from complex I of the
electron transport chain (ETC) leading to incomplete reduction of molecular oxygen followed by superoxide (O2.-) production. O2.- is the precursor of most reactive
oxygen species (ROS); itself rapidly being converted to H2O2 by superoxide dismutase (SOD2). In the presence of transitional metals (such as Fe2+), H2O2 can be
converted to hydroxyl radical (HO·). H2O2 may be scavenged by glutathione peroxidise (GPx) in presence of GSH. The oxidised glutathione (GSSG) is reduced back to
GSH by glutathione reductase (GR) in presence of NADPH. Amplification of ROS causes fall of mitochondrial membrane potential (ΔΨm). Reactive radicals react with
biomolecules like membrane lipids, proteins and mtDNA producing lipid peroxides, protein carbonyls and DNA damage. Cytochrome C gets released from damaged
mitochondrial to cytosol through outer mitochondrial membrane (OMM) permeabilization and activate apoptotic pathway. All these events together contribute to a
wide range of cellular pathologies. Dotted arrows indicate detrimental reactions involving free radicals.
withdrawal of a number of NSAIDs [118–119]. Thus ‘shift-to-PGHS-2’ toxicity. In this regard, recently NSAID-mediated uncoupling of oxida-
strategy did not give expected results. Now, it is really important to tive phosphorylation, MOS and apoptosis has been implicated. Owing
verify the notion whether PGHS-1 inhibition is really the actual per- to ‘ion trapping’ during absorption, micromolar to millimolar con-
petrator. Surprisingly, one study has shown that in PGHS-1 knock-out centration of NSAIDs can uncouple oxidative phosphorylation, thereby
mice, aspirin predominantly induced gastric mucosal injury possibly by destabilizing ATP production in the mitochondria leading to bioener-
a PG-independent mechanism, questioning the previous understanding getic crisis [19]. Electron microscopic studies and sub-cellular organelle
of PGHS-1-mediated gastroprotection [21]. In addition, aspirin in- marker enzyme analysis revealed the uncoupling effect of NSAIDs in
creased gastric mucosal PGE2 expression in PGHS-1 knock-out mice, both in vitro and in vivo [120] pre-clinical settings of experimental
probably through induction of PGHS-2. Now, it is clear that PGHS-1 gastropathy. In a dose dependent manner, NSAIDs were found to inhibit
pathway is not the only pathway underlying NSAID-toxicity in the electron transfer through complex I [102,120]. Furthermore, electron
gastric mucosa. Hence, the question is what is that PG-independent paramagnetic studies using sub-mitochondrial particles, revealed that
mechanism? However, in that study the authors also proposed reduced indomethacin, a very well known non-selective NSAID, could bind to a
surface hydrophobicity as a possible explanation for the damage [21]. site near Complex I and ubiquinone thereby generating radical species
NSAIDs, which are weak acids, have been reported to interact with the [121]. Accumulated evidence has supported this finding by demon-
mucosal cell surface phospholipid bilayer and reduce hydrophobicity in strating amplification of ROS in the gastric mucosa with severe MOS
the gastroduodenal mucosa. This compromises the hydrophobic lining, and apoptosis [104,122–127]. Further studies with antioxidant-therapy
thereby exposing the mucosa to luminal aggressive factors (including have found to ameliorate NSAID-inflicted gastric mucosal complica-
gastric acid). A study has shown that when aspirin was co-administered tions indicating a crucial role of oxidative stress in the pathophysiology
with a phospholipid, there was reduced gastric injury even after [128–130]. In addition to apoptosis and MOS, NSAIDs can also unleash
treatment with otherwise toxic combination of aspirin and a PGHS-2 myriad of pro-inflammatory factors (TNF-α, NF-κB, ICAM-1) in the
selective agent [19]. However, disruption of phospholipid bilayer alone gastric mucosa leading to profound inflammation [115,131–132]. Very
is still not sufficient to explain the severity of NSAID-induced gastric recently, an anti-inflammatory molecule, polydeoxyribonucleotide
8
Fig. 5. Effect of NSAIDs on different target organs. The action of NSAIDs on major organs including stomach, small intestine, heart, liver, kidney, respiratory tract
and brain is mainly mediated through PGHS-dependent prostanoid modulation and alteration of mitochondrial functional integrity leading to mitochondrial oxi-
dative stress (MOS) generation, depolarization of mitochondrial transmembrane potential (ΔΨm) and consequent cell death. However, in heart, low dose aspirin
actually offers cardioprotection through anti-thrombotic effect. Upward arrows indicate upregulation/elevation; downward arrows indicate downregulation/de-
pletion.
(PDRN) has been found to reduce NSAID-induced gastropathy by re- on histamine H2 receptor antagonists, proton pump inhibitors (PPIs)
ducing pro-inflammatory cytokines and apoptosis via MAPK/NF-κB and antacids which predominantly act by suppressing gastric acid se-
signaling pathway [131]. Moreover, due to the inhibition of PGHS cretion and neutralizing luminal acidity respectively [115]. There is
isoforms, AA metabolism probably shifts towards 5-lipoxygenase also evidence that PPIs like omeprazole exert anti-oxidant effect at a
pathway producing leukotrienes which can also induce inflammation in dose much lower than their acid suppressing dose [126], thereby in-
the gastric mucosa [18]. Lately, it has been also shown that via PKCζ- dicating a dual effect of PPI-based treatment. However, complications
P38-DRP1 pathway, indomethacin triggered the subcellular activation of excessive gastric acid suppression, like dyspepsia, luminal dysbiosis,
of mitochondrial hyper-fission which is critical in contributing to gas- gastric microfloral imbalance, vitamin B12 deficiency, pernicious an-
tric mucosal injury [105]. Having discussed all these mechanisms, it is emia, osteoarthritis, malabsorption of certain drugs active in the acidic
important to mention that gastric acid secretion along with inhibition of microenvironment and even gastric parietal cell hyperplasia and gastric
PGHS-derived PGs may be attributed to the aggravation of the pa- cancer staunchly warrant against rampant use of PPIs and histamine
thology inflicted by MOS. Conforming to the aforementioned; the most receptor blockers [104]. In fact, a recent study also indicated that PPIs
critical consequence of PGHS-inhibition could be perturbation of mi- can actually exacerbate indomethacin-induced small intestinal damage
crocirculation [19]. Other than PGs, nitric oxide (NO) also plays a by detrimentally altering intestinal microbiome composition [135].
significant role in maintaining intestinal microcirculation. However, a Hence, gastric acid is in no way a physiological evil and opting for anti-
long-term clinical trial did not significantly show any difference be- oxidant-based therapeutic strategy to prevent the gastric mucosa from
tween AZD3582 (PGHS-inhibiting nitric oxide donator) versus NSAID NSAID-induced cytopathies is a rather safer approach than indis-
in osteoarthritis patients [133]. In addition, neutrophil infiltration has criminate usage of acid suppressors.
been also implicated in the mechanically compromised micro vascular In addition to upper gut complications, detrimental impact of
blood flow [19]. However, vascular effects could not be considered as NSAIDs on lower gastrointestinal tract is equally crucial in the risk
the primary event in NSAID-mediated gastric mucosal damage [19]. evaluation of these drugs. In fact, over the past decade hospitalizations
Since gastric mucosal lining is constantly exposed to gastric acid, a role due to NSAID-associated lower gut complications have increased com-
of acid should also be discussed in regard to NSAID-toxicity. The “ion pared to the upper gut pathologies [136], thereby underscoring the
trapping theory” demonstrates that the acidic pH of the gastric lumen relevance of NSAID-enteropathy manifested as iron deficiency anemia,
facilitates passive cellular diffusion of the non-ionized, lipid soluble protein loss and hypoalbuminemia, indigestion, and abdominal pain.
NSAIDs followed by re-conversion into ionized and lipophobic form Severe complications include luminal perforation, occult bleeding, in-
within the neutral cytosolic pH of the gastric mucosal cell where they testinal stricture, obstructions and ulcers [137]. Advent of modern
are assumed to induce subsequent toxicity [24]. In addition, the gastric imaging techniques including capsule endoscopy and double balloon
acid synergistically acts as an aggravating necrotic factor to further endoscopy have eased the detection of myriad enteric lesions including
erode the mucosa thereby worsening the gastric consequences of long erosions, petechiae, varix, reddened folds, loss of villi and ulcers
term NSAIDs-treatment [19]. In relationtomucosalerosion, it is note- [137–138]. Incidentally, enteric injuries are evident in approximately
worthy that NSAIDS also prevent re-epithelialization of the injured 71% of chronic NSAID users [139], while prevalence rate of direct
mucosal layer [134]. As a remedial measure, clinicians mostly depend mucosal breach has been found in around 50% of chronic NSAID users
9
[140]. Mode of NSAID absorption within the enterocytes is more direct annual direct and indirect expenses due to CVD and stroke was $351.2
and different from “trapping theory” applicable in the gastric cells. billion which reconfirms the severity of the disease and the economic
However, both NSAID-mediated PG depletion and mitochondrial pa- burden on society [150]. So, it would be highly relevant to enquire the
thology have been found to be instrumental in the early stage of injury link between one of the leading causes of death globally i.e. CVD and one
leading to impairment of intestinal mucosal barrier function. As a of the most-prescribed-drugs on the planet i.e. NSAIDs. Over the years, a
consequence, the invasion of gram negative enterobacteria initiate the large number of scientific reports have associated NSAIDs with CVD.
inflammatory cascade wherein Toll like receptor-4 (TLR-4)-induced Although, aspirin has been known to be effective in secondary pre-
proinflammatory cytokine upsurge along with NLRP3 inflammosome vention of MI and stroke, it does not depict the actual connection be-
activation attract the neutrophils eventually leading to oxidative burst, tween CVD and NSAIDs. Since traditional NSAIDs including aspirin
chronic inflammation, apoptosis and ultimately intestinal ulceration (targeting PGHS-1, thereby suppressing PGE2 & PGI2 in the GIS tract
[140]. Although, the pathogenesis of enteropathy differs with that of and TxA2 in the platelets) inflict severe gastropathy, it was the ‘gas-
gastropathy in the later stages, uncoupling of mitochondrial oxidative trointestinal safety concern’ which motivated the development of
phosphorylation, ATP deficiency, elevation of cytosolic Ca2+ and Na+/ PGHS-2 specific NSAIDs. Moreover, the analgesic efficacy of NSAIDs
K+ imbalance and consequent induction of apoptosis are some of the was largely attributed to the suppression of PGHS-2 derived PGE2 &
hall mark and common events triggered in both these gut compart- PGI2 [151]. As a result, despite the fact that PGHS-2 also implies some
ments by NSAIDs. As a result the barrier function is severely compro- ‘mucosal defence’, the competition for getting approval of PGHS-2 in-
mised due to osmotic imbalance of enteric epithelial cells leading to hibitors gained momentum [20,152]. With the development of coxibs,
increased permeability and invasion by luminal aggressive and noxious it was thought that now gastric complications could be safely taken care
factors including bile acids, pancreatic secretions, hydrolytic/proteo- off without compromising the analgesic efficacy of NSAIDs. With this
lytic enzymes and gram negative bacteria. Intercellular tight junctions view, after the introduction of the first coxib, a number of RCT were
are severely compromised by the aforesaid events along with ag- arranged to evaluate their gastrointestinal tolerability. However, the
gravation due to apoptotic loss of enterocytes [24] and proteolytic first Trial in 2000, the Vioxx Gastrointestinal Outcomes Research
disruption of intestinal capillaries. Bacterial LPS along with TNF-α and (VIGOR) Trial, showed a link between PGHS-2-specific NSAIDs and
High mobility group box 1 (HMGB1), a DAMP released from necrotic CVD risk. This TRIAL, including 8076 patients with a history of os-
enterocytes [141] are chemotactic signals for macrophage and neu- teoarthritis or rheumatoid arthritis and being treated with rofecoxib or
trophil infiltration to the injured mucosa. Intestinal pathogens and bile naproxen, showed a five fold increase in MI events in patients treated
acids further strengthen inflammation and the process proceeds in a with rofecoxib compared to naproxen. In September 2004, Merck re-
feedback loop leading to severe tissue injury in chronic NSAID users. called rofecoxib (Vioxx) from the market and later US-FDA had to issue
Bile acids are especially instrumental factors that highly aggravate a black box warning against valdecoxib (Bextra) [118–119]. Further,
NSAID-induced damage as there are reports showing that NSAID alone the VIGOR Trail findings got support from Adenomatous Polyp PRe-
can trigger less macroscopic injuries in spite of increasing membrane vention On Vioxx (APPROVe) trial, which was primarily aimed at
permeability and inflammation in bile duct-ligated rats [142]. An in- studying the prevention of intestinal polyps by rofecoxib. This study,
teresting study revealed that insoluble dietary fibers and gliadin (con- where 2586 patients were treated with either rofecoxib or placebo,
tained in wheat gluten) lead to intestinal epithelial injury and increase inferred that long term use of rofecoxib is associated with twice the risk
in intestinal permeability mainly when mucus levels are low due to of heart attack or stroke versus placebo [118–119]. Recently, the results
NSAID usage [143–144]. It was evident from the post hoc analysis of the of PRECISION (Prospective Evaluation of Celecoxib Integrated Safety
data, obtained from Multinational Etoricoxib and Diclofenac Arthritis versus Ibuprofen or Naproxen) Trial, funded by Pfizer, concluded that
Long-term (MEDAL) trial that small intestinal complications accounted in regard to cardiovascular hazards, there exists no significant differ-
for 40% of severe gastrointestinal complications in patients using ence between these three NSAIDs [153]. A number of other trials have
NSAIDs [145]. Regarding the relevance of NSAIDs in inducing entero- also linked the risk of CVD with NSAIDs [118]. Albeit, these RCTs
pathy, it is a noteworthy fact that the difficulty in identifying the pri- seemed to provide ‘gold-standard’ evidence; still their interpretations
mary site of injury in the distal small intestine is one of the major are not beyond the scope of interrogation in the scientific community.
drawbacks in diagnosis of enteropathy. However recently, exfoliated G.A FitzGerald has pointed out a number of issues regarding the in-
cell transcriptome (exfoliome), which closely resembles small intestinal terpretation of PRECISION trial. He suggested a more intense pheno-
mucosal-transcriptome, has been recognized as a promising tool in non- typic study at individual level to identify factors that differentially
invasive scrutinizing of NSAID enteropathy [146]. Having stated the predispose to benefits versus risks, thereby being more precise about
direct action of NSAIDs on gastrointestinal cellular integrity, the role of NSAID usage [154]. Hence, it is clear that whatever be the issues re-
gut microbiota, in indirectly regulating NSAID-induced enteropathy, is garding the nuances of the interpretation of various outcomes of dif-
worth highlighting as a promising field to explore. There are already ferent RCTs, there is no doubt about the link between NSAID-use and
preliminary indications that probiotic treatment can modulate in- compromised cardiovascular health. In line with this, Garcia-Rodriguez
testinal gram negative bacteria-induced pathogenesis wherein protec- et.al, in 2008, reported a positive correlation between increasing PGHS-
tive action of some bacteria like Lactobacillus casei, L. gasseri and Bifi- 2 inhibitory potency with increasing CVD incidents [155]. On the
dobacterium breve Bif195 against NSAIDs is already evident [147–149]; contrary to those trials which used patients with long term use of
although establishing specific and precise patterns of microbial profile NSAIDs, studies have raised doubts on the risk of coronary events due to
among regular NSAID users is yet elusive. All these, demonstrate the NSAID usage at lower doses for short durations which are practically
possible underlying mechanisms by which NSAIDS affect the upper and the case for over the counter use or prescription-based intake of NSAIDs
lower GI tracts thereby warranting effective use of NSAIDs without GI for managing acute pain or fever [156].
complications. At this point it is however noteworthy that, following all the trials,
meta-analyses and cohort studies traditional NSAIDs (nonspecific PGHS
6.2. Risk of cardiovascular disease inhibitors) have also been negatively linked to CVDs other than the
coxibs [157]. Nevertheless, lower doses of aspirin were found to offer
Cardiovascular diseases (CVD), which include events like myo- protective effects through secondary prevention of CVD. Low dose as-
cardial infarction (MI), stroke, hypertension and heart failure, to name pirin (≥30 mg/day) can significantly prevent platelet aggregation
a few, are one of the major causes of morbidity and mortality across the without affecting important endothelial cell functions. It was Dr.
world (2020 Heart Disease and Stroke Statistical Update Fact Sheet At-a- Lawrence Craven who, in the early 20th century, conducted some stu-
Glance). During 2014–15, in the United States, the estimated average dies to prove his hypothesis that aspirin prevents coronary thrombosis
10
[158]. Further studies revealed that antithrombotic effects of aspirin solely for the physiological synthesis of PGI2 in endothelium [98].
were due to acetylation of PGHS-1 at a serine 530 in platelets (the si- Hence, the link between PGHS-2 and CVD is still elusive. Growing
milar acetylation site on PGHS-2 being Ser 516; although platelets only evidence supports the presence of a constitutively expressed PGHS-2 in
express PGHS-1) which prevented the interaction of AA with PGHS-1, the kidney or systemic vascular endothelium which is responsible for
thus limiting the synthesis of TxA2 [158]. On one hand, PGHS-1 is the cardio-protective effect of PGHS-2 [98]. In the context of inter-organ
major source of TxA2 production in platelets leading to proaggregation communication, it is known that response of one organ to the sur-
and vasoconstriction; on the other hand, both PGHS-1 constitutively rounding changes may affect or modulate the performance of other
synthesized in the arterial wall and endothelium, are involved in the organs. In line with that, a kidney-heart link has been proposed. Hence,
production of the vasodilator and anti-aggregant PGI2. A healthy inhibiting renal PGHS-2 by NSAIDs could increase asymmetric dimethyl
equilibrium exists through balanced inhibition of TxA2 and PGI2. In- arginine (ADMA), an endogenous eNOS inhibitor, which eventually
hibition of PGHS-1 in platelets creates a disruption of the equilibrium in could block eNOS, minimizing the protective effect of NO and thereby
favour of PGI2, with a cardioprotective anti-aggregant effect, mani- increasing hypertension, atherosclerosis and thrombosis [98,166].
fested due to low dose-use of aspirin [85,156,159]. Since the plasma However, contrary to this, in relation to ADMA, another group has
half-life of aspirin is 20 min, the enucleate platelets cannot produce any proposed that this increased level of ADMA is actually a result of PGHS-
new PGHS-1; so the effect of aspirin remains as long as the platelets 2 deletion or inhibition-associated renal dysfunction. No alteration of
survive (10 days) [160]. Unlike platelets, in endothelial cells the PGHS- ADMA was found in the context of normal renal function. Now, in re-
1 is restored within a short period of time after being inhibited by as- lation to NO, initially it was assumed that vascular NO might com-
pirin thus without much affecting the PGI2 production [161]. Since pensate for the reduction in PGI2; but subsequent studies have dis-
enhanced calcium is required for platelet aggregation or vessels to approved this assumption [167]. Surprisingly, it was reported in a
contract, PGI2 exerts it anti-thrombotic effect by activating PKA PGHS-2 depletion study that endothelial NO synthase expression is
through IP receptors which in turn cause profound reduction of in- actually regulated by PGHS-2 mediated PGI2 production [168], which
tracellular calcium in platelets or vascular smooth muscle cells by a in turn likely magnifies the effect of PGHS-2 inhibition [167–168].
mechanism still unknown [98]. However, non-aspirin NSAIDs (NAN- Moreover, PGHS-2 inhibition has also been associated with sodium and
SAIDs) can cause incomplete and reversible inhibition of PGHS-1 in water retention, augmenting heart failure and hypertension as well as
platelets [162]. Hence, effect of aspirin in secondary prevention of CVD adverse ventricular remodelling [157]. So, even after so many years of
is mediated through irreversible inhibition of PGHS-1-derived TxA2 in research, the role of PGHS-2 and its cell specific expression is one of the
platelets and not through PGHS-2 [156]. Regarding primary prevention most enigmatic topics of this field. Other than PGHS-prostanoid
of CVD by aspirin, the current guidelines are very close to what Dr. pathway, MOS has been also implicated in the pathogenesis of CVD
Craven recommended for the primary prevention of CVD by aspirin in [92]. Since cardiac cells are highly active, myocardial energy demand is
males aged between 45 and 65 years [157–158]. A recent meta-analysis predominantly met by the ATP produced in huge amount by the car-
based report has pointed out an insufficient benefit-risk ratio for as- diomyocyte mitochondria. Inhibition of PGHS can lead to accumulation
pirin-mediated primary prevention of CVD [163] which was supported of AA which in turn enhances cardiac mitochondrial dysfunction. In an
by further studies [164]. The risk of ‘bleeding’ such as intracerebral in vitro study with bovine heart mitochondria, AA was found to inhibit
haemorrhage or gastrointestinal bleeding is, however, one of the key complex I and III, thereby generating increased ROS and subsequently
limitations of aspirin use in CVD [163]. Since the efficacy of aspirin releasing cytochrome C, which is the rate limiting event in apoptosis
against MI and ischemic stroke (secondary prevention) is indisputable [165]. In addition, the mitochondrial antioxidant superoxide dismutase
over the years, doctors have to evaluate the risk–benefit balance while (SOD2) has been largely associated with the prevention of athero-
prescribing it. However, very recently G. Ravach et.al mentioned that sclerotic lesion through protecting mtDNA [165]. In another study,
according to European Cardiovascular prevention recommendations, diclofenac was found to induce ROS (detected with increased H2DCFDA
aspirin should be prohibited from prescriptions for the primary pre- fluorescence), decrease proteasomal activity (indicated by reduced β5
vention of CVD [164]. All these issues have made cardiovascular safety proteasome activity, increased polyubiquitination) and enhance apop-
of NSAIDs a highly controversial subject [157]. Although aspirin stands tosis (detected by increased caspase 3 activity) unlike aspirin which did
out alone among other NSAIDs in giving cardio-protection, a number of not show any effect on ROS and cell viability. In the same study, the
pathophysiological mechanisms have been proposed to explain non- generation of ROS has been mechanistically linked to diclofenac-
aspirin NSAID-associated CVD. One key explanation postulated that mediated disruption of mitochondrial complex III, and fall of mi-
inhibition of the endothelial PGI2 which normally prevents thrombosis, tochondrial membrane potential [169]. Recently, diclofenac and cel-
by NSAIDs, could be responsible for the onset of CVDs. Recently it is ecoxib-treated cardiomyocyte microarray analyses revealed differential
believed that, in endothelial cells, primarily, PGHS-1 plays the pivotal gene expression (around 2-fold increase of 32 genes in diclofenac and
role in PGI2 biosynthesis replacing the previous concept of PGHS-2 560 genes in celecoxib while around 2-fold decrease in 424 genes for
mediated PGI2 production in those cells. Therefore, non-specific diclofenac and 1718 genes in celecoxib). Interestingly, genes associated
NSAIDs can block PGHS-1 mediated production of cardio-protective with calcium and potassium signaling were found to be significantly
PGI2 at therapeutic doses [98]. However, it is noteworthy that, while affected by NSAIDs along with involvement of major signaling path-
deletion of TP (TxA2) receptors minimizes atherogenesis, deletion of IP ways including apoptosis [170]. In NSAID-treated cardiomyocytes,
(PGI2) receptors enhances atherogenesis which indicates that selective pathway analyses suggested changes in gene expression pattern in
inhibition of PGHS-2 can also disturb the physiological balance be- major cellular pathways such as apoptotic, signal transduction and
tween PGI2 and TxA2, thereby increasing the risk of CVD [152,165]. transcription [170]. Hence, it indicates as well as essentially warrants
Despite this observation, the role of PGHS-2 in PGI2 production in en- that role of PG-independent pathway, specially MOS in CVD, needs to
dothelial cells is controversial. Then how do PGHS-2 specific NSAIDs be deeply explored in the context of NSAID treatment. Although, hi-
induce CVD? It is important to note that, the previously predominant therto, NSAID-mediated inhibition of PGHS-derived PGI2 is still the
hypothesis of PGHS-2 mediated PGI2 production in endothelial cells, dominant mechanism by which NSAIDs affect cardiac health while
which fitted well with ‘PGHS-2-CVD’ link, was actually based on two contributing to CVD [167].
major observations [98]. First being the decrease in urinary metabolite
of PGI2 (2,3-dinor-6-keto-PGF1α) in subjects treated with PGHS-2 se- 6.3. Risk of renal injury
lective NSAIDs and the second being PGHS-2 gene deletion in en-
dothelial cells of mice causing thrombosis. However, later these ob- In addition to CVD and GI complications, NSAIDs also carry a sig-
servations were challenged by evidence of PGHS-1 being responsible nificant risk of kidney damage [171] which includes multiple
11
nephrological complications like acute kidney injury (AKI), and chronic as a result of acute inflammation and edema of renal interstitium. Both
kidney disease (CKD) encompassing electrolyte imbalance, glomer- PGHS-specific and non-specific NSAIDs are one of the major causes of
ulonephritis, renal papillary necrosis, fluid retention-induced hy- this situation [175]. Minimal Change Disease: In this case, PGHS-in-
pertension, renal tubular acidosis, hyponatremia and hyperkalemia to hibition by NSAIDs favours the conversion of AA to leukotriene which
name a few [172–173]. While high dose of NSAIDs has been associated eventually activates helper T lymphocytes to infiltrate glomeruli
with AKI, long term NSAID-use also severely increase the risk of CKD. causing podocyte injury leading to minimal change disease (MCD)
NSAIDs come next to aminoglycosides as the most common cause of [175]. Papillary necrosis: PGs maintain adequate perfusion and oxy-
nephrotoxicity and acute renal failure [174]. Annually 2.5 million genation in the renal medullary and papillary regions. Inhibition of
Americans suffer from NSAID-related renal complications [175]. Con- PGHS by NSAIDs inflicts ischemia and necrosis in the medullary and
sumption of NSAIDs by individuals suffering from chronic pain, rheu- papillary regions thereby causing renal failure [175]. In addition to the
matoid arthritis, osteoarthritis and other musculoskeletal disorders aforesaid, some of the prominent renal complications associated with
render them more susceptible to nephrotoxicity [171]. Significant risk ionic imbalance, experienced as a side effect of rampant NSAID usage
of renal failure was evaluated in an older study with inpatient mean age essentially deserves special mention. Hyponatremia: The antidiuretic
15.2 ± 2.3 years (ten females and five males) [176]. 15% cases of AKI hormone, ADH, or vasopressin is regulated by PGs. In presence of
have been found associated with NSAID usage, with 25% greater pro- NSAIDs, PG-mediated ADH’s role of free-water clearance is prohibited,
pensity of contraction in patients older than 65 years [175]. In addition, thereby forcing the nephron to absorb free water leading to hypona-
recent reports have documented the risk of over-the-counter NSAID tremia and associated renal pathology [175]. Hyperkalemia: There are
usage in pediatric population leading to acute renal failure [173,177]. two predominant mechanisms regulating NSAID-induced hyperka-
Thus, it reveals the risk of using these drugs even at therapeutic dose. In lemia; either causing reduced secretion of potassium in the principal
a recent histopathological study on rat, meloxicam has been linked to cells of collecting duct or by compromising GFR, thereby resulting in
nephrotoxicity along with hepatotoxicity, and gastric metaplasia [178]. attenuated potassium secretion through sodium–potassium exchanger
Given that kidney is the organ for drug excretion, receiving almost 25% which in turn aggravates the renal complications [175]. Renal Tubular
of the cardiac output, the renal arterioles and glomerular capillaries are Acidosis: Prolonged hyperkalemia is associated with decreased net
significantly vulnerable to NSAIDs [171]. Regarding the mode of ac- renal acid excretion in the distal nephron leading to renal tubular
tion, invariably, PGHS-derived prostanoid inhibition by NSAIDs plays a acidosis type 4 (hyperchloremic metabolic acidosis) and consequent
pivotal role in the progression of nephrotoxicity. PGHS-1 is synthesized nephritis [175]. Hypertension: In a patient with CKD, within 1–2 weeks
constitutively in the collecting ducts and in diverse cells of the Bow- of taking NSAIDs, hypertension may develop leading to heart failure
man’s capsule. On the other hand, medullary interstitial cells of renal (HF). NSAID-mediated inhibition of PGs, causing sodium retention and
papillae, epithelial cell lining of the ascending loop of Henle and cells of vasoconstriction, leads to edema and high blood pressure. Under
macula densa exhibit PGHS-2 expression [175]. PGHS-1 primarily normal condition a healthy kidney can respond to such a situation by
controls the glomerular filtration rate (GFR), while PGHS-2 is important minimizing the clinical side effects thereby maintaining a steady-state
for sodium and water retention. Blocking PGHS enzymes in turn blocks homeostasis. However, in a patient suffering from CKD, the fluid load
PG production, of which PGE2 (tubular) and PGI2 (vascular) are im- will exacerbate the edema and hypertension leading to HF. Another
portant [179]. Notably, PGs and their suppression by selective and non- mechanism involves NSAID-mediated blocking of glucuronidation of
selective PGHS-inhibitors have been also associated with renal devel- aldosterone by human kidney which eventually increases the level of
opment [175]. PGs, with their vasodilatation effect, control pre-glo- circulating aldosterone, ultimately leading to hypertension, edema and
merular resistance, maintain GFR and preserve renal blood flow espe- HF. In the previous section, the role of constitutive PGHS-2 in renal
cially in fluid-depleted state [171,174]. Localized PG synthesis (PGI2, medulla has been mentioned in relation to CVD. This constitutive
PGE2, PGD2) causes vasodilatation of afferent arteriole, increases renal PGHS-2 has been shown to be under transcriptional control of NFAT
perfusion together with redistribution of the cortical flow to the ne- (nuclear factor of activated T cells). It has been proposed that in kidney,
phron in juxta-medullary region [171,174]. PGE2 and PGF2α prevent the constitutive PGHS-2 regulates renal blood flow by PGI2-controlled
sodium and chloride transport in thick ascending limb of the loop of PPAR-β/δ (peroxisome proliferator-activated receptor β/δ)-mediated
Henle and colleting ducts. While PGE1 antagonizes vasopressin, PGI2 vasodilation pathway. NSAIDs prevent this blood flow by blocking
maintains glomerular filtration. During volume depletion, the renin- PGHS-2, thereby inducing hypertension [181]. In a recent study, am-
angiotensin-aldosterone axis is activated, leading to vasoconstriction bulatory blood pressure and GFR were compared for two drugs, diclo-
and increased reabsorption of sodium and chloride along with increased fenac and rofecoxib, wherein it was found that 24-hour systolic blood
sympathetic blood flow, further enhancing the vascular tone [174]. In pressure (BP) was increased and GFR was decreased by diclofenac
this setting of decreased perfusion pressure, PGs are responsible for compared to celecoxib. In the Celecoxib Rofecoxib Efficiency and Safety
vasodilatation of afferent arterioles, thereby maintaining normal GFR. in Cormorbidities Evaluation Trial (CRESCENT), the systolic BP was
This action of PGs is further reinforced by angiotensin II, nor- evaluated for monitoring the effect of NSAIDs in subjects treated with
epinephrine, endothelin and vasopressin [175]. During NSAID-medi- antihypertensive therapy. The study documented that a 25 mg daily
ated inhibition of PGHS-derived PG production, normal GFR is com- dose of rofecoxib resulted in 24-hour systolic pressure greater than
promised, eventually leading to ischemic injury and acute tubular 135 mm Hg in 30% patients compared to 16% and 19% of patients
necrosis [175]. PGs in the macula densa cells impose a check on the randomly assigned to celecoxib and naproxen respectively [175,182].
renin secretion which in turn would enhance under PGHS inhibition, Therefore, it is incumbent upon the clinicians to prescribe the selective
eventually intensifying the renin-angiotensin-aldosterone pathway and and non-selective NSAIDs with caution. Since a lower dose of NSAID
ultimately leading to sodium reabsorption, hypertension and oedema can also induce renal failure, there is actually no safer dose of these
[175]. AKI is aggravated when NSAIDs are used in the background of drugs for patients with CKD. Because CKD patients are often on medi-
heart failure, or usage of angiotensin-converting enzyme inhibitors, cations like ACEs, ARBs and diuretics, which in fact can interact with
angiotensin receptor blockers as well as intravascular volume depletion NSAIDS worsening the situation, clinicians should be utterly careful in
to name a few [175,180]. Having said about the mechanistic basis of treating these patients with NSAIDs. Among the patients with CKD, in
NSAID-induced nephrotoxicity, precise mention about some of the ty- primary care, use of NSAIDs is variable and relatively high which es-
pical and prominent nephrological complications is essential to project sentially demand for thorough research specifically aimed at strategies
the cytotoxic spectrum of these drugs in the renal context. Interstitial to reduce NSAID-use in this patient population [183]. Regarding the
Nephritis: Approximately 15% of the cases of acute kidney injury are PGHS-independent mechanism of NSAID-induced renal damage (in-
acute interstitial nephritis which is characterised by poor renal function cluding both AKI and CKD), oxidative stress and inflammation has been
12
associated [161,184]. Cells found in kidney vasculature such as vas- variability of aceclofenac-metabolism amongst donor liver cells [192].
cular smooth muscle cells, endothelial cells, adventitial fibroblast and Studies with isolated rat liver mitochondria or rat hepatocytes have
inflammatory cells are able to produce ROS. NADPH oxidase, along demonstrated that diphenylamine, which is structurally identical with
with MOS, majorly contributes to ROS production in kidney [184]. In NSAIDs, actually acts as an uncoupler of oxidative phosphorylation
an old study, indomethacin was found to inflict mitochondrial ab- thereby disrupting ATP formation leading to hepatocyte bioenergetic
normalities in the proximal tubules with evidence of oxidative stress crisis and death. Mitochondrial swelling, fall of mitochondrial mem-
(lipid peroxidation), mitochondrial dysfunction (fall of respiratory brane potential and diminished cellular ATP were observed after in-
control ratio) and neutrophil infiltration (characterized by increased cubation of mitochondria with diphenylamine, mefenamic acid and
myeloperoxidase activity) [185]. Diclofenac, on the other hand, in- diclofenac [196]. In case of naproxen, ferrous iron (Fe2+) release is
duced oxidative stress, renal cell apoptosis and upregulation of pro- responsible for naproxen-induced lipid peroxidation in rat liver mi-
inflammatory cytokines (NF-κB) in AKI as evident from a recent study crosomes [197]. Diclofenac was found to be more toxic in drug meta-
[186]. bolizing cells (isolated primary hepatocytes) compared to non-meta-
Thus, both PGHS-dependent and independent pathways play sig- bolizing cells (HepG2, FaO). The toxicity may be due to diclofenac-
nificant role in kidney injury. However, it is important to note that, induced mitochondrial impairment along with a pointless and super-
young patients without renal diseases or comorbidities are not under fluous consumption of NADPH during the reduction of N,5-hydro-
great risk of NSAIDs; although, there is no place for complacency. xydiclofenac to 5-hydroxydiclofenac; which is otherwise only oxidized
to N,5-hydroxydiclofenac [197]. Mitochondrial permeability transition
6.4. Risk of hepatotoxicity followed by production of reactive oxygen species (ROS), mitochondrial
swelling, oxidation of NADP, proteins and thiols are also linked to di-
Hepatotoxicity is another serious complication that has been linked clofenac-induced liver injury [198]. Similar to diclofenac, oxidative
to NSAIDs although the incidences are less frequent compared to that of stress is also connected with salicylic acid-induced hepatotoxicity
gastrointestinal damage, CVD and renal insufficiency. In line with that, [199]. Notably, genetic predisposition has been an important factor in
a recent study in Brazil, conducted in the primary health care units, diclofenac-induced idiosyncratic hepatotoxicity [38]. Polymorphism in
inferred drug-induced-liver-injury as a rare event [187]. However, the genes for UGT2B7 and CYP2C8 (which forms reactive diclofenac me-
seriousness of the issue lies elsewhere. Considering the case of USA, tabolites) and in ABCC2 (encoding the transporter MRP2 that helps in
where approximately 30 million Americans take NSAIDs each year, it is biliary excretion) may predispose to the formation and accumulation of
clear that a huge number of individuals are actually exposed to the diclofenac metabolites which are implicated in hepatotoxicity [38]. On
potential threat of NSAID-induced liver injury [188]. Hence, studies on the other hand, sulindac can induce cholestasis by competitively in-
the role of NSAIDs in hepatotoxicity are scientifically pertinent. Since hibiting canalicular bile salt transport [200]. In one study with Wistar
premarketing studies are insufficient, hepatotoxicity is mostly en- rats, naproxen has been linked to increased ROS (indicated by enhanced
countered in the post-marketing studies [189–190]. A number of drugs lipid peroxidation and reduced GSH) and hepatotoxicity. In the same
have been withdrawn from the market due to hepatotoxicity which study, naproxen also induced an adaptive response to ROS by in-
includes NSAIDs like bromfenac (1999) and lumiracoxib (2008) creasing SOD and catalase. Interestingly, this increased ROS was sup-
[189,191]. Liver injury caused by most NSAIDs is likely to be idio- posed to be the underlying cause for significant genotoxic effect and fall
syncratic and clinically apparent liver injury is rare (1–10 cases ap- of liver function exerted by naproxen [201]. Although, less frequent,
proximately per 100,000 prescriptions). Although two NSAIDs, sulindac coxibs may also cause liver damage via PG-dependent pathway. This
and diclofenac, are most commonly linked to hepatotoxicity hypothesis is supported by the proposed mechanism that implies the
[188,191–192], at least in rare cases, virtually all the extensively used inhibition of PGHS-2-derived PGE2, by coxibs, which can then reduce
NSAIDs are clinically linked to apparent drug-induced liver injury the anti-apoptotic mitochondrial protein Bcl-2 (which offers protection
[188–189]. However, in a very recent systemic review, ibuprofen has against bile acid-induced apoptosis), leading to hepatocyte apoptosis
been regarded safe in relation to hepatotoxicity despite a number of [202]. Hence, it can be summarized that increased reporting, surveil-
published reports previously linking it otherwise [193]. Several other lance and awareness of NSAID-related hepatotoxicity will help the
systemic reviews are also available which have evaluated the risk of physicians and hepatologists to precisely assess the hepatotoxic po-
NSAIDs in hepatotoxicity [189,191,194–195]. Notably, PGHS-2 specific tential of NSAIDs during prescription of these unavoidable drugs.
NSAIDs are less frequent in causing hepatotoxicity compared to non-
selective NSAIDs [194]. It is important to realize that NSAIDs can ac- 6.5. Risk of intracerebral haemorrhage
tually lead to two major clinical patterns of hepatotoxicity; first being
acute hepatitis (characterized by jaundice, nausea and fever together Bleeding within brain tissue leads to intracerebral haemorrhage
with elevated serum levels of transaminases) while the other being (ICH), a severe type of stroke (haemorrhagic stroke, HS) [203]. Stroke
chronic active hepatitis (characterized by serological and histopatho- events are characterized as either ischemic (blood supply to brain is
logical abnormalities) [192]. Analyzing the published studies, aspartate blocked) or hemorrhagic (bleeding), of which ischemic strokes (IS) are
transaminase (AST) and alanine transaminase (ALT) could be con- more predominant [204]. A multinational European database study has
sidered as the two most common biomarkers linked with hepatotoxi- shown that IS risk differs among individual NSAIDs and specifically it
city. Nevertheless, serological abnormalities in alkaline phosphatase was found to be higher in patients with a previous history of IS or
and total bilirubin levels are also reported [191]. Regarding the hepa- transient ischemic attack [205]. Since NSAIDs can predominantly cause
totoxic mode of action of NSAIDs, a number of mechanisms have been gastrointestinal bleeding, risk of ICH cannot be excluded. Under-
implicated depending on the concerned drug [189,192]. However, two standing the effect of NSAIDs on platelet-function suggests that NSAIDs
predominant mechanisms have been identified; hypersensitivity and can lead to enhanced risk of ICH via regulation of thrombosis. The
metabolic aberration [192]. Patients who have suffered hepatotoxicity antithrombotic effect of aspirin is linked to irreversible and almost
from one NSAID, often experience the same reaction in case the drug is complete inhibition of platelet PGHS activity which results in a re-
re-initiated or a sister drug with identical structure is given. Hy- duction of thrombotic events, thereby increasing the chances of HS
persensitivity reactions are characterized by elevated anti-nuclear [206]. A relationship between NANSAIDs and HS (including sub-
factor or anti-smooth muscle antibody titres, eosinophilia and lym- arachnoid haemorrhagic stroke and ICH stroke) was explored in a na-
phadenopathy [192]. On the other hand, metabolic aberrations could tionwide multicenter case control study in Korea [206]. In this study
be due to genetic polymorphisms and varied susceptibility to a spec- the potential confounders were adjusted. Within 14 days, proportion of
trum of drugs as evident from in vitro studies which showed phenotypic NANSAIDs exposure was 2.9% for HS patients while 2.0% for controls.
13
Comparing NANSAID-users with nonusers, the adjusted odds ratios of tract infections [212–213]; although NSAIDs have never been found to
stroke was 1.12 for all HS, 1.03 for subarachnoid haemorrhage and 1.19 significantly reduce total symptoms or duration of acute respiratory
for ICH. Thus the study concludes that there is no significant rise of HS infections. A nationwide case cross-over study showed that NSAID use
among NANSAIDs users [206]. The explanation for the probable no- during acute respiratory infection was associated with increased risk of
antithrombotic effect of non-selective NSAIDs, other than aspirin, could MI [213]. In relation to CAP, different surveys and observational stu-
be attributed either to incomplete/reversible inhibition of PGHS-1 in dies have also shown that half of the patients of CAP were treated with
platelets or concomitant prevention of PGHS-2-derived PGI2 synthesis NSAIDs [212]. However, this extensive use of NSAIDs was neither ap-
in endothelial cells; although the latter notion is still yet elusive [162]. proved by medical guidelines or any clinical data in pneumonia pa-
However, Islam et.al in 2018, published a meta-analysis of observational tients. From the mechanistic point of view NSAIDs rather worsen the
studies including articles from 1999 to 2017. The study significantly situation by preventing the recruitment and functioning of poly-
linked NSAIDs-use with higher risk of developing HS [207]. In line with morphonuclear neutrophils [212]. Ibuprofen was found to inhibit TNF-
that, in a recent study in March 2019, L. Ge et.al have demonstrated α and NF-κB transcriptional activity, thereby limiting pro-inflammatory
that long term use of aspirin and clopidogrel (antithrombotic drug) cytokine production [214]. Therefore, it may be presumed that NSAIDs
increases the risk of cerebral microbleeds which is a marker of ICH could enhance pulmonary susceptibility to secondary infection to CAP.
[208]. Later in the same year, Paciaroni et. al. have shown a lower risk However, conflicting results were also obtained when role of NSAIDs
of bleeding event for clopidogrel monotherapy compared to aspirin were evaluated in animal models of pulmonary bacterial infection
[208]. Having said this, it should be mentioned that the advantage of [212]. So, pre-existing medication and conditions should be considered
aspirin in secondary prevention of IS is greater over its risk for ICH before prescribing a drug. In one study, in human airway epithelial cells
[160]. Since a large population is exposed to NSAIDs, these drugs Parainfluenza virus (PIV3) reduced PGE2 generation. However, cel-
should be prescribed judiciously by the clinicians keeping in mind the ecoxib treatment on PIV3-infected airway epithelial cells significantly
risk–benefit thresholds which determine the safety profiles. aggravated the PGE2 reduction along with reduced PGHS-2 expression
[215]. In the current perspective of COVID-19 outbreak, several spec-
6.6. Risk of respiratory tract inflammation and infection ulations are popping up regarding the use of NSAIDs. Although in-
domethacin has been shown previously to block coronavirus RNA
It was until 1922, the correlation between asthma, nasal polyposis synthesis in dogs, in a PGHS-independent pathway, still there are no
and aspirin sensitivity (Samter’s Triad) was not known [209]. Later, it direct data advocating clinical use of NSAIDs against the recent COVID-
was found that about 7% of asthma patients experience bronchospasms 19 situation [13]; even though, the nucleocapsid protein of the SARS
after taking aspirin or other PGHS-1 inhibiting NSAIDs which could be coronavirus, which was responsible for 2003 outbreak, was found to
potentially fatal [210]. This condition, characterised by asthma, interact with PGHS-2 promoter along with up regulating its expression,
chronic rhinitis, nasal polyps and acute respiratory tract reaction, in thereby suggesting a putative role of NSAIDs in virus prevention [216].
response to aspirin and NSAIDs is referred to as aspirin-exacerbated However, use of NSAIDs against COVID-19 is still elusive [217]. It is
respiratory disease (AERD). Recollections of patients have made it clear important to state that in the midst of this topsy-turvy situation, where
that 50% of AERD occurred after viral respiratory tract infections the world is desperately seeking for effective COVID-19 antidote, re-
[210]. In cells, such as mast cells, a precarious balance is maintained cently a warning regarding a probable adverse effect of ibuprofen in
between cysteinyl leukotrienes (Cys-LTEs), product of 5-lipoxygenase aggravating the current coronavirus infection has also come up [80];
pathway, and prostanoids, products of PGHS pathways. NSAID-induced although clinicians have also assured patients from not withdrawing
inhibition of PGHS-1, coupled with excessive production of leukotrienes this drug who are already using it for other reasons just out of the fear
disrupts the physiologic brake and triggers the release of plethora of of increased COVID-19 risk. Nevertheless, it has been also mentioned
proinflammatory cytokines (such as IFN-γ, IL-4) responsible for the that patients suffering from COVID-19 should not be administered
pathophysiology of the AERD [209]. It is important to note that of all NSAIDs, as treatment, unless a strong evidence of NSAIDs against
the leukotrienes (LTEs), elevated cysteinyl LTE4 has been suggested to COVID-19 is obtained, because that might predispose those patients
play a significant role in the pathophysiology of AERD. Presence of with other NSAID-associated comorbidities [80].
LTE4 increases airway responsiveness to histamine, a phenomenon not
observed with LTD4 and LTC4 indicating the presence of specific LTE4 7. Pharmacophore modification
receptor [210]. Regarding the prostanoids, PGE2 generally exerts an
inhibitory effect on mast cells and eosinophils to prevent LTE release. Since NSAIDs are associated with severe toxicities, newer ap-
When PGE2 is prevented by NSAID treatment, the PGE2-inhibitory proaches or alternative strategies were taken for “pharmacophore
control on mast cell gets lost, unleashing histamine and LTEs by mast modification” to tame down the toxic side effects without compro-
cells, a hallmark event in AERD [209–210]. Furthermore, during AERD, mising their beneficial health effects. In this regard, recently, prodrugs
downregulation of anti-inflammatory lipoxins, which normally com- are gaining immense popularity. These are bioreversible derivatives of
pete for Cys-LTEs-receptors and prevent expression of proinflammatory pharmacologically active agents which undergo chemical transforma-
cytokines (IFN-γ, IL-5, IL-6), also contributes to the pathophysiology tion and/or enzymatic cleavage, in vivo, to release the parent drug
[209]. In addition, the role of PGD2, type II inflammation and group 2 which then exhibits the desired pharmacological impact. The non-
innate lymphoid cells are also implicated in AERD [211]. On the other parent moiety may/may not be pharmaceutically active in a context
hand, PGHS-2 specific inhibitors, which are larger molecules and specific manner [218]. Emerging documents on NSAID prodrugs have
cannot fit to PGHS-1 channels, are not responsible for respiratory re- pointed towards a promising field where pharmacological research can
actions in patients with AERD [210]. PGHS-2 inhibitors are therefore be logically channelized. Interestingly, the palatable form of salicyclic
unable to affect the constitutive activity of PGHS-1 and production of acid i.e. acetylsalicyclic acid or aspirin itself acts as a prodrug. In vivo,
PGE2 by mast cells, platelets, basophils and eosinophils [210]. Never- aspirin liberates salicyclic acid to elicit the anti-inflammatory action
theless, meloxicam, which is one of the two PGHS-2 inhibitors available while the acetyl group particularly induces PGHS inactivation. A si-
in US market (other than celecoxib), can cause mild symptoms of re- milar mode of action is actually found in several ‘aspirin like drugs’
spiratory reaction in AERD patients at 15 mg dose, behaving as a partial including indomethacin, ibuprofen and naproxen. Thus, irreversible
PGHS-1 inhibitor [210]. So shifting to PGHS-2 from PGHS-1 could be a acetylation of serine residue in PGHS-1, mediated by the acetyl group,
better strategy; however PGHS-2 is not available without prescriptions is one of the ways aspirin exert its therapeutic effect; although few
[210]. Other than its role in AERD, NSAIDs are known to be frequently complications like GI toxicity, disruption of platelet functions, renal
used in Community Acquired Pneumonia (CAP) or acute respiratory failure still accompany, leaving room for further chemical modification
14
of this unavoidable NSAID into a more potent prodrug to use it effec- toxicity [222]. While the organic nitrate derivatives release NO only
tively. Several aspirin prodrugs have been reported such as aspirin after metabolic reduction, in a NONOate derivative of NO-NSAID, NO is
triglycerides, cyclic aspirin triglycerides, methysulfonylmethyl and released spontaneously in physiological media [220]. Moreover, many
nitro aspirin [218]. On the other hand, non acetylated salicyclates are of the NO-NSAIDs have been progressed through clinical trials for
also another class of prodrugs (salsalate and choline magnesium trisa- evaluating their effect in cardiovascular safety and pain-killing attri-
licyclate), considered as viable options in perioperative conditions bute [133,227]. Other than NO, H2S also plays a significant role in
owing to minimum hemorrhagic effects, negligible PGHS-1 inhibition, mucosal defence by inhibiting leucocyte adherence on vascular en-
no effect on renal blood flow and platelet functions [219]. A furoxan- dothelium, neutralizing gastric acid and enhancing gastric mucosal
containing ester of aspirin was found to show significant anti-in- blood flow. Based on these ideas, researchers have developed a number
flammatory and anti-platelet activity in vivo, although with reduced of H2S-releasing NSAIDs (HS-NSAID) of which a number of molecules
gastric toxicity [220]. In general, for synthesis of NSAID prodrugs, focus have been already progressed to clinical trials such as H2S-releasing
has been laid on masking its acidic functional group or the carboxyl naproxen, ATB-346 [228]. This is supported by a phase-II-B study,
moiety since reports have already linked it to the toxic actions of where subjects with ATB-346 (250 mg once daily) showed lesser ulcers
NSAIDs. For instance, mitochondrial-uncoupling potential of NSAIDs is per subject compared to naproxen (550 mg twice daily) and also lesser
inversely correlated with drug pKa. In this regard, modification of the incidence of large ulcers (≥5 mm diameter) and marked reduction of
carboxyl moiety of flurbiprofen (dimero-flurbiprofen and nitrobutyl GI complication [229]. Interestingly, ATB-337, another HS-NSAID, has
flurbiprofen) led to reduced mitochondrial uncoupling [221]. In addi- been made out of linking DTT to diclofenac where DTT acts as H2S
tion, coupling of sulfonamides with free carboxylic group of NSAIDs donor. HS-NSAIDs including HS-sulindac, HS-ibuprofen and HS-aspirin
(flurbiprofen, ibuprofen, diclofenac) was also found to increase their have also been reported to act as anticancer agents. Moving further,
PGHS-2 selectivity while providing relief in gastric ulceration [222], NBS-1120, which releases H2S, NO and aspirin, simultaneously, has
thereby highlighting avoidance of NSAID-gastrotoxicity. However, over been attributed with the most potent anti-cancer potency [230]. Since
time, designing of NSAID prodrug has evolved from ‘just masking the H2S has been linked to cardiovascular homeostasis and normal phy-
carboxylic group’ to meticulously designed conjugates bearing moieties siology of kidney, H2S prodrugs can be also effective against CVD and
aimed at specific goals, including antioxidant activity, increasing water renal failure [231–232]. Another promising group of NSAID-prodrugs
solubility and dissolution, NO release, hydrogen sulphide (H2S) release, are phospho-NSAIDs, such as phospho-aspirin (MDC-22), phospho-su-
acetylcholine esterase inhibitory (AChEI) activity and site specific de- lindac (OXT-328) and phospho-ibuprofen (MDC-917) which probably
livery [220]. For example, many NSAID prodrugs, synthesized by exert their action via COX-independent pathway [220]. In addition,
coupling an antioxidant moiety through amide linkage, as well as NSAID prodrugs with anticholinergic agents, acetylcholinesterase in-
several mutual prodrugs (both moieties are pharmacologically active) hibitory activity (AChEI-NSAIDs) and chemically stable nitroxides,
made with naturally found phenolic antioxidants including guaiacol, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 4-hydroxy-TEMPO
thymol, eugenol and other alcoholic compounds have yielded gastro- (TEMPOL), have also been designed and tested for their efficacy, albeit
sparing results; although without compromising the typical functions of with reduced toxicity [220]. Most of these NSAID prodrugs are en-
NSAIDs [223]. On the other hand, PGHS-2 inhibiting prodrugs, such as dowed with anti-inflammatory potential as tested in in vitro andinvivo
apricoxib (marketed by Tragara Pharmaceuticals) were made to im- studies and clinical trials; however, the gastro-toxic effect of their re-
prove oral bioavailability or increase water solubility for parenteral use spective parent NSAIDs are rationally bypassed thereby improving their
[220]. The characteristic features of PGHS-2 inhibitors include a para- utility. A schematic representation of some common NSAID prodrugs
sulfonamide (SO2NH2) or a para methanesulfonyl (SO2Me) pharmaco- has been presented (Fig. 6). Other than these few examples, a myriad of
phore on one of the aryl rings which bestow PGHS-2-active-site-speci- other NSAID-associated prodrugs, mutual prodrugs and hybrid mole-
ficity to the drug [224]. Apricoxib, mentioned above is an anticancer cules have been prepared and tested and many more are in the pipeline
NSAID, having 1,2-diphenyl moiety attached to a central 5-membered [218,223]. Hence, it is evident that prodrugs can be useful to manage
pyrrole ring together with a para-SO2NH2 PGHS-2-specific pharmaco- the gruesome challenges of therapeutic handling of NSAIDs. However,
phore [224]. Moving further, it is worth mentioning that owing to the extensive research is strongly advocated to fine tune the actual ther-
importance of NO and H2S as two vital endogenous gaseous signaling apeutic potential of these molecules.
molecules involved in different physiological functions, a group of
NSAID prodrugs have been made which release either NO or H2S or 8. Conclusion
both the gastro-transmitters. These compounds have supposed potential
in treating different complications. A new class of drug called ‘cy- Thus, it is evident that the success of NSAIDs comes with a huge
clooxygenase inhibitor nitric oxide donor’ (CINOD) was developed by cost. NSAIDs are associated with 30% hospital admissions for pre-
adding NO generating group to the parent NSAID with an ester linkage. ventable adverse drug reactions [233]. However, it is not our motto to
Naproxcinod, (the first CINOD), has undergone phase-II and III clinical project NSAIDs in a negative perspective; rather, presenting a com-
trials; but also got disapproved by FDA owing to the lack of long-term prehensive view of the susceptibility of some major organs to an almost
controlled studies [225–226]. Moreover, NCX-4016 (NO-aspirin), al- unavoidable drug rampantly used in the day-to-day life. This would
though forbidden from production (since 2007) due to generating increase the awareness in prudent usage of these drugs. Reports of
mutagenic metabolites, has showed reduced gastro-toxicity in phase-I randomized clinical trials, meta-analysis, cohort studies, systemic re-
trials compared to aspirin [227]. As mentioned above, in a phase-II views and observational studies would lead to understanding the actual
trial, the primary end point of 6 week endoscopic gastroduodenal ulcer drug-related risk while mechanistic details will provide indications
did not reveal significant difference between naproxen and AZD3582 about the potential therapeutic candidates/targets. However, various
(naproxcinod) at doses effective in treating osteoarthritis; however, the aspects of NSAID-induced organ damage still need to be investigated
secondary endpoints favoured AZD3582 [133]. It is worthwhile to note which should also include other organs and systems of the body. A
that often the NO-NSAIDs have intrinsic pharmacological activity number of areas need to be explored from mechanistic point of view,
which may not have been predicted during the prodrug designing such as the link between ROS and PGs, role of PGHS-2 in CVD, role of
[220]. P2026, a NO-diclofenac in which the diclofenac moiety is linked mitochondria and other organelles in NSAID-pathophysiology along
to the –ONO2 (nitrate) group via alkyl spacer, showed no gastric toxi- with genetic polymorphisms plausibly linked with NSAID-suscept-
city. In addition, another NO-releasing diclofenac derivative with a ibility. Population based studies may prove helpful in answering com-
benzofuroxan moiety has been also synthesised, whereupon it was plex gene-driven effects on xenobiotics metabolism in the context of
found to offer anti-inflammatory action devoid of gastrointestinal NSAIDs. With respect to age, older individuals are at a higher baseline
15
Fig. 6. Structural representation of some NSAID prodrugs.
risk of cardiovascular, GI, renal and hepatic complications. So a special Acknowledgements

strategy should be developed regarding the usage of NSAIDs by the
older people [233]. Answers to these issues will definitely advance the SB acknowledges research grants from Early Career Research
current strategies of NSAID-related risk management, albeit in a more Award, SERB (Department of Science and Technology, Govt. of India)
rationally organised manner while maintaining high safety profiles of and Higher Education, Science & Technology and Biotechnology (Dept.
these unavoidable ‘wonder drugs’ in days to come. of Science and Technology, Govt. of West Bengal). UB acknowledges
J.C. Bose National Fellowship (Department of Science and Technology,
Govt. of India) to perform this work.
CRediT authorship contribution statement
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Since January 2020 Elsevier has created a COVID-19 resource centre with

free information in English and Mandarin on the novel coronavirus COVID-

Elsevier hereby grants permission to make all its COVID-19-related

Contents lists available at ScienceDirect

Non-steroidal anti-inﬂammatory drugs (NSAIDs) and organ damage: A T

Fig. 1. Classiﬁcation of non steroidal anti-inﬂammatory drugs (NSAIDs) based on structure.

Category 1 PGHS-1 and PGHS-2 Indomethacin, Aspirin, Diclofenac, Naproxen, Ibuprofen

Fig. 3. NSAID-PGHS-prostanoid axis. PGHS-1/2

Fig. 6. Structural representation of some NSAID prodrugs.

risk of cardiovascular, GI, renal and hepatic complications. So a special Acknowledgements

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