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NSAIDs and Natural Products Interactions: Mechanism and Clinical

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Journal of Immunology & Clinical Research
Review Article *Corresponding author
Cauê Benito Scarim, Department of Drugs and

NSAIDs and Natural Products

Medicines, State University of São Paulo, Brazil,
Email:
Submitted: 29 June 2017

Interactions: Mechanism and Accepted: 29 June 2017

Published: 30 June 2017

Clinical Implications
ISSN: 2333-6714
Copyright
© 2017 Scarim et al.
Cauê Benito Scarim*#, Ednir de Oliveira Vizioli#, Jean Leandro
OPEN ACCESS
dos Santos#, and Chung Man Chin#
Departamento de Fármacos e Medicamentos, Universidade Estadual Paulista “Júlio de Keywords
Mesquita Filho” – UNESP, Brazil • NSAIDs
#
All Both authors contributed equally to the manuscript • Natural products
• Interactions
• Anti-inflammatory
Abstract
Traditional herbal medicines is largely used in folk medicine worldwide and
related to be safe by general population. The non steroidal anti-inflammatory drugs
(NSAIDs) are a class of drugs, including selective or not for inhibition the isoform 2 of
ciclooxigenase (COX) largely used to treat acute or chronic inflammation. Several side
effects are related to long term use of NSAIDs. Despite , its widespread use as well
as the natural products (NP), documented NSAIDs-NP interactions are sparse. The NP
may interfere on the effect of the NSAIDs increasing the anti-inflammatory activity and
also reduce tissue damages. However, NP can also produce changes leading to hepato
or nephrotoxicity. This work reviews the NSAIDs-NP (green tea, resveratrol, curcumin,
kava, ginkgo biloba and ephedra) interaction with an emphasis of the mechanistic and
clinical considerations.

ABBREVIATIONS VEGF: Vascular Endothelial Growth Factor; SOD: Superóxido

Dismutase; iNOS: The Inducible Nitric Oxide Synthase; PKC:
NSAIDs: Non Steroidal Anti-Inflammatory Drugs; COX1: Protein Kinase C; CYP2E1: Cytochrome P450 2E1; CYP3A1:
Ciclooxigenase-1; COX2: Ciclooxigenase-2; NP: Natural Products; Cytochrome P450 3A1; CYP1A2: Cytochrome P450 1A2; NASH:
AA: Arachidonic Acid; PGE2: Prostaglandin E2; PGJ2: Prostaglandin Non-Alcoholic Steatohepatitis; NAFL: Nonalcoholic Fatty Liver;
J2; PGD2: Prostaglandin D2; TNF- α: Tumor Necrosis Factor- α; LPS: Lipopolysaccharide; CD14: Cluster of Differentiation 14;
IL-1β: Interleukin 1 Beta; GI: Gastrointestinal; NO: Nitric Oxide; GSH: Glutathione; PGC-1α: Peroxisome Proliferator Activated
FKA: Flavokawains A; FKB: Flavokawains B; FKC: Flavokawains Receptor Gamma Coactivator 1α
C; FKs: Flavokawains; GABAA: γ-Aminobutyric Acid Type A; FDA:
Food and Drug Administration; EHE: Ephedra Herb Extract; ADP: INTRODUCTION
Adenosine Diphosphate; EC: Epicatechin; EGC: Epigallocatechin;
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of
ECG: EC-3-O-Gallate; EGCG: (−) Epigallocatechin-3-Gallate; IFN-γ:
the most common pharmaceuticals class of drugs used in global
Interferon Gamma; cAMP: Cyclic Adenosinemonophosphate;
primary health care [1-4]. The anti-inflammatory activity of
JAK2: Tyrosine-Protein Kinase; STAT3: Signal Transducer and
NSAIDs’ is attributed to the ability to inhibit of cyclooxygenase
Activator of Transcription 3; PGC-1α: Peroxisome Proliferator
enzyme selectively or not [1,5]. The COX1 is found primarily
Activated Receptor Gamma Coactivator 1α; AMPK: 5’ -Adenosine
in blood vessels, kidney and stomach, responsible for the
Monophosphate--Activated Protein Kinase; UCP2: Mitochondrial
physiological stimulus (homeostatic effects - constitutive), and
Uncoupling Protein 2; PI3K: Phosphatidylinositol 3-Kinase; Nrf2:
COX2 which is responsible for induction of inflammation, pain
Nuclear Factor Erythroid Related Factor 2; ERK: Extracellular
and fever [6-8]. Stimulus that increase inflammatory mediators
Signal–Regulated Kinases; MAPK: Mitogen-Activated Protein
such as bradykinin is able to activate phospholipase A2 that
Kinases; AP-1: Activator Protein 1; ICAM-1:Intercellular
hydrolyzes arachidonic acid (AA) in membrane phospholipids
Adhesion Molecule 1; MCP-1: Monocyte Chemotactic Protein
[9-12].
1; IL-8: Interleukin 8; IL-6: Interleukin 6; IL-17: Interleukin
17; IL-10: Interleukin 10;NF-κB: Factor Nuclear Kappa B; ROS: Several reports show the side effects including peptic ulcers,
Reactive Oxygen Species; SIRT: Silent Mating Type Information mucosal lesions, intestinal perforation, bleeding, hepatotoxicity
Regulation; PPAR: Peroxisome Proliferator Activated Receptor; and kidney damage by the long-term and overdose of NSAIDs

Cite this article: Scarim CB, de Oliveira Vizioli E, dos Santos JL, Chin CM (2017) NSAIDs and Natural Products Interactions: Mechanism and Clinical Implica-
tions. J Immunol Clin Res 4(2): 1040.
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[13-19]. The introduction of selective COX2 NSAIDs (coxibs) into on the layer of stomach [47]. In addition, the use of NSAIDs can
the market did not decrease the non-selective NSAIDs usage. increase the chance of intestine ulceration and also death by
Countries such as India [20] have no coxib available or in Brazil, ulcer bleeding in patients with colitis, Crohn’s disease or other
even the coxibs are under controlled prescription, the non inflammatory intestinal diseases [48]. Until now, few drugs
selective NSAIDs are easy to buy without any medical prescription are used for this protection (proton pump inhibitors, such
[21-25]. In some specific people field such as in US army, the omeprazole, esomeprazole, rabeprazole and H2 inhibitors,
NSAIDs soldiers users of the entire active duty Army was around ranitinide, cimetidine). Even, there are COX2 selective inhibitors
69 % in 2006 and increased to 82 % (857,964 prescriptions), the long term use are also associate to gastrointestinal (GI)
in 2014. The selective COX2 inhibitor celecoxib, accounted for damage [8,49,50].
2.4 % of these NSAIDs prescriptions in 2006 and 7.1 % in 2014
[26]. Also, according to the Agencia Española del Medicamento y NP have been used in popular medicine as remedy for the
Producto Sanitarios (Spain) the NSAIDs consumption increased treatment or “cure” of diseases since the beginning of civilization
26.5 % throughout the 2000-2012 period. Ibuprofen was the first [51,52]. Up to now, NP is still largely used as herbal preparations
NSAID consumed, followed by diclofenac [27]. This is a matter (tea, infusion, extract, capsule) and their active molecules have
of concern due the side effects that can evolve to secondary been also isolated and used in therapeutics to treat several
diseases. diseases [53-57].

The effect of COX2 inhibition by NSAIDs promotes at the The interaction between NSAIDs and NP can be good or
kidney, a mitochondrial oxidative phosphorylation inhibition and danger, leading to increase of anti-inflammatory activity or
causes uncontrolled renal vasoconstriction in tubule renal cell increasing several adverse effects [19]. The purpose of this
decreasing the glomerular filtration and/or efflux from proximal review is to show the mechanism of this interactions and clinical
tubule cells, leading to acute tubular necrosis. In addition, the implications for the liver and kidney. The figure 1 shows the
presence of NSAIDs at the renal papillary tip also causes renal mechanism of action of action of NSAIDs and the interference of
papillary necrosis [28]. some NP in this mechanism.

The literature reports some cases of acute hepatitis NATURAL PRODUCTS AND NSAIDS INTERACTION
and cholestatic hepatitis with celecoxib and rofecoxib. The
Kava (Piper methysticum)
lumiracoxib showed severe hepatic toxicity and led to withdrawal
from the market [29-31]. The root of a Pacific Islanders native pepper plant called
kava kava (Piper methysticum) is used to prepare a psychoactive
Increase risk of hospitalization for acute hepatitis or
beverage to be drink in religious ritual [58,59]. With this
cholestatic hepatitis were reported in Taiwan induced by
knowledge, the occidental medicine, have been used kava to induce
celecoxib [32]. Also, it was reported the increase of liver damages
sleep and decrease anxiety disorders [60], reported in clinical
with the use of others NSAIDs including nimesulide, diclofenac,
trials studies [61,62]. However, it is related to rare but severe
ibuprofen [32,33].
cases of hepatotoxicity [63,64]. Several explanations have been
The prostaglandin E2 (PGE2) act as endogenous ligands postulated for this side effect, however, but none of them were
responsible for the stimulation of signal transduction pathways established. Narayanapillai and co-workers (2014) related that
involved in liver regeneration, [34-36] and for up-regulation of Flavokawains A and B (FKA and FKB) present in kava potentiate
anti-inflammatory cytokines [37-40]. The COX2 is responsible the induction of hepatotoxicity caused by acetaminophen [65].
for the 15-deoxy-Δ12 [29,41] and 14– prostaglandin J2 (PGJ2) Also, it was shown that kavain is the major kava’s component and
production, both are prostaglandin D2’ (PGD2) metabolites, is responsible to potentiate γ-aminobutyric acid type A (GABAA)
that inhibits the pro-inflammatory cytokines as tumor necrosis receptors [66].
factor- α (TNF-α) and interleukin 1β (IL-1β) [37,42]. In addition,
However, kava was banned from US and Europe therapeutics
the coxib inhibition of prostaglandin synthesis decrease the
but its use is already used in several countries [67,68]. Food
liver protection against bile acid-induced apoptosis by down
and Drug Administration (FDA) and European regulatory
regulation of Bcl-2, an anti-apoptotic mitochondrial protein
agency warnings have been diffused since 2002 [69,70]. Studies
[43]. Bessone and co-workers (2016) proposed that the COX2
showed different concentration of FKA, B and C in different kava
inhibition by selective NSAIDs can contribute the loss of the
cultivars that can vary around 20 fold that can explain difference
protective mechanism of liver, leading to the progression of its
amounts of FKA and FKB in the products of the market, and also
damage [44].
different final results [71], due to this different concentration, the
The diclofenac is chemical related to lumiracoxib, a hepatotoxicity is not a linear effect.
phenylacetic acid. Both compounds can promote the formation
The presence of hepatotoxicity compounds FKA and B in kava
of a reactive iminoquinone metabolite (also present in
extract can potentiate the liver damage when co-administrated
acetaminophen structure) that can react with glutathione and
with NSAIDs (mainly the diclofenac chemical related, that can
cause hepatotoxicity [45,46].
metabolize to iminoquinone derivatives) The level of the injury
The most frequent and most important adverse effect depends of FKs amount and patient liver conditions. Drug
of NSAIDs, affecting approximately 20 % of patients is the cirrhosis can be precipitated by NSADs-kava in multiple drugs
gastrointestinal mucosal damage caused by inhibition COX1, users’ patients, elderly and alcohol chronic individual.
decreasing prostaglandins, mucous and bicarbonate production

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Ephedra (Ephedra sinica) Was demonstrated the decreasing the inflammatory

mediators in arthritis murine model[99,104,105] According to
Ephedra herb is defined as a terrestrial steam of Ephedra
Kim and co-workers (2008), the polyphenolics compounds are
sinica, according to 17Th edition of Japanese Pharmacopoeia [72].
able to reduce the severity of arthritis inflammation in Lewis
Ephedra was described to have an antiviral or antibacterial role,
rats. was observed the decrease of proinflammatory cytokine
by the activation of immune system [73,74].
interleukin (IL)-17 and the increase of immunoregulatory
The anti-inflammatory effects and analgesic activity of cytokine IL-10 compared to control [106]. The EGCG regulates
ephedra were previous reported in literature [75-77]. Hyuga inflammation and joint degeneration by modulating MAPKs,
(2017) reported that ephedrine alkaloids-free may be the Activator protein 1 (AP-1), NF-κB pathway and STAT signaling
responsible by the anti-inflammatory and analgesic effects [78]. activated by TNF-α, IL-1β and IFN-γ in various cell types
The same researcher reported the anti-metastatic and antitumor [87,91,92].
effect of ephedra herb extract (EHE), by the suppression of the
The enzyme COX2 is overexpressed in several inflammatory
hepatocytes growth factor-c-Met signaling pathway through
diseases and also its implicated in prostate and gastric cancer
the inhibition of c-Met tyrosine kinase activity. Also, they
conditions [107, 108]. However, the use of NSAIDs is limited by
demonstrated the effect of herbacetin glycosides in EHE, which
the side effects such as gastric ulceration (by the inhibition of
shows c-Met-inhibitory activity and analgesic action [78].
COX1 isoform) and cardiovascular damage (by inhibition of COX2
This NP contains ephedrine alkaloids such as ephedrine and
cardiac constitutive isoform).
pseudoephedrine as the principal active compounds [75], used
mainly in pharmaceutical preparation for upper respiratory The catechins demonstrated the decrease of the
disease, in combination with other drugs. overexpression of COX2 without interfere in COX1, showing no
gastric injury by decreasing PGE2 [109]. In therapeutic clinic,
Despite the benefic effect of ephedra, its use have been restrict
the catechins could be benefic in cancer conditions, with the
in some countries due the sympathomimetic effect leading to
possibility to be used in association with chemotherapeutics and
several alterations of physiological responses, such as increased
low doses of selective COX2 NSAIDs.
blood pressure, vasoconstriction, bronchodilation and increasing
heart rate [79]. The EGCG is able to interrupt lipid peroxidation chain
reaction decreasing liver damage [110,111] and it was reported
The Ephedra alkaloids inhibits reuptake of catecholamines
that is about 25 and 100 times more potent than vitamins E and
and acts as antagonist of α-2 adrenergic receptor, the functional
C, respectively [112].
adrenergic receptor on the platelets [80,81]. According to Watson
and co-workers, the increase of intracerebral hemorrhage The diary consume of green tea extract is associated with
incidence using ephedra may be related to elevations in blood a lower risk of liver injury, hyperlipidemia, and inflammation
pressure and also by reductions in epinephrine-mediated [113]. The EGCG ameliorates experimental immune-mediated
platelet aggregation leading to cerebral bleeding [82]. They glomerulonephritis and its beneficial roles in chronic
showed that ephedrine similarly inhibits Adenosine diphosphate kidney disease [102,114]. However, some authors reported
(ADP)-induced platelet aggregation. The use of NSAIDs that can hepatotoxicity with long term use of green tea extract in oral
increase blood pressure and decrease platelet aggregation, the supplementation [115,116]. This finds suggest that other
co-administration of NSAIDs and ephedra may potentiate the risk components in the plant may be considering in therapeutics/
of cerebral hemorrhage and GI ulcer bleeding. hepatotoxicity. So, in this condition, the long term use or high
doses of the extract/supplement can increase the potentiality of
In addition, it has been reported that ephedra’ alkaloids may
hepatotoxicity and need to be considered when combined with
contribute to acute liver injury induced by TNF-α leading to
NSAIDs.
fulminant hepatic failure and necrosis [82-85].
Ginkgo biloba
Green Tea (Camellia sinensis)
The Ginkgo biloba extracts (ginkgo) have been used for
Camellia sinensis is a species of shrub or small tree native
alleviating symptoms associated with cognitive impairment,
from Asia and India. The leaves and leaf buds are used to produce
dementia, Alzheimer’s disease [117], hypertension [118], asthma
worldwide used tea, popularly named as Green Tea. The most
[119] and tinnitus [120], including the anticancer activity [121].
important polyphenolic compounds isolated from this NP include
epicatechin (EC), epigallocatechin (EGC), EC-3-O-gallate (ECG), The active constituents related to ginkgo is the biflavones,
and EGC-3-O-gallate (EGCG), the major one [86]. terpene trilactones (ginkgolides A, B, C, J, P and Q, and bilobalides),
flavonol glycosides (quercetin, catechin) and proanthocyanidins
Several in vitro and in vivo experiments has been reported
[83,122].
the strong antioxidant potential of the catechins [87-90]. EGCG
has been reported to present anti-inflammatory [91], anti- The ginkgo reduces the nitric oxide (NO)-induced oxidative
mutagenic [92], anti-cancer [93], anti-obesity [94], anti-diabetic stress, acting as NO scavenger and also decreasing its production
[95], anti-viral [96], anti-bacterial [97], neuroprotector [98] in diabetic animal models [123,124], thus protecting the animal
and immunomodulatory effect [86,99-102]. Also, green tea from retinopathy and probably from nephropathy too, by the
catechin is able to amilorate peridontite inflammation caused by same mechanism [125].
Porphyromonas gingivalis in mice [103].
Several reports show that ginkgo is able to inhibit the

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platelet aggregation via ADP and collagen-induced through and age-related diseases [147-151].This phytochemical acts
cyclic adenosinemonophosphate (cAMP) and also by increasing mainly under via AMPK/SIRT-1 subsequent peroxisome
and the inhibition of thromboxane A2 synthesis [126-128]. The proliferator activated receptor gamma coactivator 1α (PGC-1α)
Ginkgo extract, in association with anti-platelet drugs (warfarin) activating phosphorylation, increasing mitochondrial biogenesis
[129,130] and acetylsalicylic acid [131] increase the risk of as well as oxidative capacity [143], however, it is not totally
bleeding (cerebral or/and GI ulcer). The co-administration of understood.
Ginkgo and NSAIDs is not recommended [132,133].
Resveratrol upregulates the SOD and decrease ROS production,
Curcumin inhibits phospholipase A2 and COX2 activity, decreasing de PGE2
synthesis. It possess the ability to antagonizes the inflammatory
Curcumin is a polyphenolic bioactive yellow pigment present citokines NF-κB , TNF-α, IL-6 and the Inducible nitric oxide
in the roots of Curcuma longa L. (turmeric). Its therapeutic synthase (iNOS) activity, and MCP-1, promoting a very potent
acivities have been extensively reported, mainly for cancer anti-inflammatory effect [152–154]. In addition, resveratrol is
and inflammatory diseases’ treatment [134]. Also, it present able to modulate the platelet adhesion, secretion and activation
anti-platelet and potent antioxidant effect interacting with signaling preventing platelet activation [155-157]. Furthermore,
several targets, such as tyrosine-protein kinase (JAK2) / several studies demonstrated that resveratrol inhibits protein
Signal transducer and activator of transcription 3 (STAT3), 5’ kinase C (PKC) activation and intracellular calcium release,
-adenosine monophosphate--activated protein kinase (AMPK) / thus blocking phosphoinositide metabolism upstream platelet
mitochondrial uncoupling protein 2 (UCP2), phosphatidylinositol activation signaling [158].
3-kinase (PI3K)/Akt / nuclear factor erythroid related factor 2
(Nrf2), extracellular signal–regulated kinases (ERK), mitogen- Resveratrol is able to prevent kidney damage. The
activated protein kinases (MAPK p38), intercellular adhesion nephroprotective effect has been related with the prevention
molecule 1 (ICAM-1) and monocyte chemotactic protein 1 of ROS generation as well as increasing of antioxidant enzymes
(MCP-1) [135-141], reducing inflammatory cytokines such as and decreasing inflammatory citokines. Besides, it is able to level
NF-κB, IL-1β, IL-8, IL-6 and TNF-α [142]. It also reduces levels increase AMPK, SIRT-1, PPAR [143]. In septic animals, Wu and
of xanthine oxidase, superoxide anion and myeloperoxidase co-workers showed the protection of kidney damage by the RES
lipid peroxidation and elevate enzymatic antioxidant activities activation of SIRT1/3 in the hyper-inflammatory phase.
of glutathione peroxidase, superoxide dismutase (SOD) and It’s known that resveratrol improve glucose uptake and
catalase [142,143]. metabolism in animals and is beneficial in individuals with
Liver is the main detoxification organ of xenobiotics and diabetes type 2, in clinical trials [159,160]. The use of NSAIDs
drugs. However, some compounds can induce to hepatocytes in diabetics’ patients is not recommended because the side
damage such as the NSAIDs by the production of iminoquinones effects mainly vasoconstriction and kidney damages. With this
metabolites and reactive oxygen species (ROS). Reports showed knowledge we can deduce that the use of resveratrol in Type 2
that curcumin is able to decreases liver damage induced by diabetic patients may be interesting by itself. In addition, this
acetaminophen [144-146]. By the beneficial effect of curcumin, patients could use NSAIDs, once resveratrol can protect the
it’s suggested that curcumin can potentiate the activity NSAIDs kidney and by its anti-inflammatory effect, reducing the NSAIDs
and also protect the liver. doses [161].

Curcumin present nephroprotective activity and have Treatment in mice with resveratrol during acetaminophen
been associated with the prevention of kidney injury. It is induced liver damage showed significant inhibition of cytochrome
able to increase the level of AMPK, SIRT-1/3 (silent mating P450 2E1 (CYP2E1), cytochrome P450 3A1 (CYP3A1), and
type information regulation-1), PPAR α/γ (peroxisome cytochrome P450 1A2 (CYP1A2) activities, as well as the pre-
proliferatoractivated receptor) as well as reduce glomerular treatment with resveratrol able to protect against mitochondrial
filtration rate in cardiovascular disease [143]. injury [162,163].

In addition, curcumin is mediated by the MKP-1-dependent In other hand, Elgebaly et al. (2017), in a systematic
inactivation of p38 and inhibition of NF-kB-mediated review and meta-analysis showed that there are no evidence
transcription, gastric inflammation and gastric cancer via of resveratrol improvement in non alcoholic fat liver disease
reduced NF-κB p65 expression, decreased vascular endothelial and does not alters liver fibrosis [164]. In other hand, Kessoku
growth factor (VEGF) level, and macromolecular leakage in the and co-workers (2016) reported a study performed with non
gastric mucosa, protecting the gastric mucosal injury induced by alcoholic steatohepatitis (NASH)/ nonalcoholic fatty liver (NAFL)
NSAIDs [143]. mice model, that resveratrol can improve liver inflammation and
fibrosis but not steatosis, via inhibition of lipopolysaccharide
Resveratrol (LPS) reactivity that is due to cluster of differentiation 14 (CD14)
Resveratrol (3,5,40 -trans-trihydroxystibene) is an expression in Kupffer cells [165].
antioxidant and anti-inflammatory polyphenol present in red Resveratrol preserve antioxidant defenses resulting in
wine, grapes and has been extensively investigated as potential reduction of acetaminophen-induced liver injury [166], reduce
compound for the treatment of several diseases, including the stress-induced gastric damage [167], and an increase in activity
cardiovascular diseases, cancer prevention, modulation of lipid of antioxidizing enzymes SOD and glutathione (GSH) [143].
metabolism, and regulation of immune system, cerebrovascular

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Figure 1 NSAIDs mechanism of action and natural products (Ginko biloba, Ephedra, Resveratrol, Curcumin, Green Tea). Red line: inhibition; blue
line: activation.

Figure 2 Hepatic damage caused by diclofenac compared to acetaminophen and the protective action of green tea, ginko, ephedra, kava, curcumin,
and resveratrol.

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Figure 3 The nephrotoxicity mechanism of NSAID’s and its protection by green tea, curcumin and resveratrol.

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Cite this article

Scarim CB, de Oliveira Vizioli E, dos Santos JL, Chin CM (2017) NSAIDs and Natural Products Interactions: Mechanism and Clinical Implications. J Immunol Clin
Res 4(2): 1040.

J Immunol Clin Res 4(2): 1040 (2017)

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