•    NSAIDs
•    Natural products
•    Interactions
•    Anti-inflammatory
 

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.

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.

NSAIDs: Non Steroidal Anti-Inflammatory Drugs; COX1 : Ciclooxigenase-1; COX2 : Ciclooxigenase-2; NP: Natural Products; AA: Arachidonic Acid; PGE2: Prostaglandin E2; PGJ2: Prostaglandin J2; PGD2: Prostaglandin D2; TNF- α: Tumor Necrosis Factor- α; IL-1β: Interleukin 1 Beta; GI: Gastrointestinal; NO: Nitric Oxide; FKA: Flavokawains A; FKB: Flavokawains B; FKC: Flavokawains C; FKs: Flavokawains; GABAA: γ-Aminobutyric Acid Type A; FDA: Food and Drug Administration; EHE: Ephedra Herb Extract; ADP: Adenosine Diphosphate; EC: Epicatechin; EGC: Epigallocatechin; ECG: EC-3-O-Gallate; EGCG: (−) Epigallocatechin-3-Gallate; IFN-γ: Interferon Gamma; cAMP: Cyclic Adenosinemonophosphate; JAK2: Tyrosine-Protein Kinase; STAT3: Signal Transducer and Activator of Transcription 3; PGC-1α: Peroxisome Proliferator Activated Receptor Gamma Coactivator 1α; AMPK: 5’ -Adenosine Monophosphate--Activated Protein Kinase; UCP2: Mitochondrial Uncoupling Protein 2; PI3K: Phosphatidylinositol 3-Kinase; Nrf2: Nuclear Factor Erythroid Related Factor 2; ERK: Extracellular Signal–Regulated Kinases; MAPK: Mitogen-Activated Protein Kinases; AP-1: Activator Protein 1; ICAM-1:Intercellular Adhesion Molecule 1; MCP-1: Monocyte Chemotactic Protein 1; IL-8: Interleukin 8; IL-6: Interleukin 6; IL-17: Interleukin 17; IL-10: Interleukin 10;NF-κB: Factor Nuclear Kappa B; ROS: Reactive Oxygen Species; SIRT: Silent Mating Type Information Regulation; PPAR: Peroxisome Proliferator Activated Receptor; VEGF: Vascular Endothelial Growth Factor; SOD: Superóxido Dismutase; iNOS: The Inducible Nitric Oxide Synthase; PKC: Protein Kinase C; CYP2E1: Cytochrome P450 2E1; CYP3A1: Cytochrome P450 3A1; CYP1A2: Cytochrome P450 1A2; NASH: Non-Alcoholic Steatohepatitis; NAFL: Nonalcoholic Fatty Liver; LPS: Lipopolysaccharide; CD14: Cluster of Differentiation 14; GSH: Glutathione; PGC-1α: Peroxisome Proliferator Activated Receptor Gamma Coactivator 1α

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common pharmaceuticals class of drugs used in global primary health care [1-4]. The anti-inflammatory activity of NSAIDs’ is attributed to the ability to inhibit of cyclooxygenase enzyme selectively or not [1,5]. The COX1 is found primarily in blood vessels, kidney and stomach, responsible for the physiological stimulus (homeostatic effects - constitutive), and COX2 which is responsible for induction of inflammation, pain and fever [6-8]. Stimulus that increase inflammatory mediators such as bradykinin is able to activate phospholipase A2 that hydrolyzes arachidonic acid (AA) in membrane phospholipids [9-12].

Several reports show the side effects including peptic ulcers, mucosal lesions, intestinal perforation, bleeding, hepatotoxicity and kidney damage by the long-term and overdose of NSAIDs [13-19]. The introduction of selective COX2 NSAIDs (coxibs) into the market did not decrease the non-selective NSAIDs usage. Countries such as India [20] have no coxib available or in Brazil, even the coxibs are under controlled prescription, the non selective NSAIDs are easy to buy without any medical prescription [21-25]. In some specific people field such as in US army, the NSAIDs soldiers users of the entire active duty Army was around 69 % in 2006 and increased to 82 % (857,964 prescriptions), in 2014. The selective COX2 inhibitor celecoxib, accounted for 2.4 % of these NSAIDs prescriptions in 2006 and 7.1 % in 2014 [26]. Also, according to the Agencia Española del Medicamento y Producto Sanitarios (Spain) the NSAIDs consumption increased 26.5 % throughout the 2000-2012 period. Ibuprofen was the first NSAID consumed, followed by diclofenac [27]. This is a matter of concern due the side effects that can evolve to secondary diseases.

The effect of COX2 inhibition by NSAIDs promotes at the kidney, a mitochondrial oxidative phosphorylation inhibition and causes uncontrolled renal vasoconstriction in tubule renal cell decreasing the glomerular filtration and/or efflux from proximal tubule cells, leading to acute tubular necrosis. In addition, the presence of NSAIDs at the renal papillary tip also causes renal papillary necrosis [28].

The literature reports some cases of acute hepatitis and cholestatic hepatitis with celecoxib and rofecoxib. The lumiracoxib showed severe hepatic toxicity and led to withdrawal from the market [29-31]. Increase risk of hospitalization for acute hepatitis or cholestatic hepatitis were reported in Taiwan induced by celecoxib [32].

Also, it was reported the increase of liver damages with the use of others NSAIDs including nimesulide, diclofenac, ibuprofen [32,33].

The prostaglandin E2 (PGE2) act as endogenous ligands responsible for the stimulation of signal transduction pathways involved in liver regeneration, [34-36] and for up-regulation of anti-inflammatory cytokines [37-40]. The COX2 is responsible for the 15-deoxy-Δ12 [29,41] and 14– prostaglandin J2 (PGJ2) production, both are prostaglandin D2’ (PGD2) metabolites, that inhibits the pro-inflammatory cytokines as tumor necrosis factor- α (TNF-α) and interleukin 1β (IL-1β) [37,42]. In addition, the coxib inhibition of prostaglandin synthesis decrease the liver protection against bile acid-induced apoptosis by down regulation of Bcl-2, an anti-apoptotic mitochondrial protein [43]. Bessone and co-workers (2016) proposed that the COX2 inhibition by selective NSAIDs can contribute the loss of the protective mechanism of liver, leading to the progression of its damage [44].

The diclofenac is chemical related to lumiracoxib, a phenylacetic acid. Both compounds can promote the formation of a reactive iminoquinone metabolite (also present in acetaminophen structure) that can react with glutathione and cause hepatotoxicity [45,46].

The most frequent and most important adverse effect of NSAIDs, affecting approximately 20 % of patients is the gastrointestinal mucosal damage caused by inhibition COX1, decreasing prostaglandins, mucous and bicarbonate production on the layer of stomach [47]. In addition, the use of NSAIDs can increase the chance of intestine ulceration and also death by ulcer bleeding in patients with colitis, Crohn’s disease or other inflammatory intestinal diseases [48]. Until now, few drugs are used for this protection (proton pump inhibitors, such omeprazole, esomeprazole, rabeprazole and H2 inhibitors, ranitinide, cimetidine). Even, there are COX2 selective inhibitors the long term use are also associate to gastrointestinal (GI) damage [8,49,50].

NP have been used in popular medicine as remedy for the treatment or “cure” of diseases since the beginning of civilization [51,52]. Up to now, NP is still largely used as herbal preparations (tea, infusion, extract, capsule) and their active molecules have been also isolated and used in therapeutics to treat several diseases [53-57].

The interaction between NSAIDs and NP can be good or danger, leading to increase of anti-inflammatory activity or increasing several adverse effects [19]. The purpose of this review is to show the mechanism of this interactions and clinical implications for the liver and kidney. The figure 1 shows the mechanism of action of action of NSAIDs and the interference of some NP in this mechanism.

Kava (Piper methysticum)

The root of a Pacific Islanders native pepper plant called kava kava (Piper methysticum) is used to prepare a psychoactive beverage to be drink in religious ritual [58,59]. With this knowledge, the occidental medicine, have been used kava to induce sleep and decrease anxiety disorders [60], reported in clinical trials studies [61,62]. However, it is related to rare but severe cases of hepatotoxicity [63,64]. Several explanations have been postulated for this side effect, however, but none of them were established. Narayanapillai and co-workers (2014) related that Flavokawains A and B (FKA and FKB) present in kava potentiate the induction of hepatotoxicity caused by acetaminophen [65]. Also, it was shown that kavain is the major kava’s component and is responsible to potentiate γ-aminobutyric acid type A (GABAA) receptors [66].

However, kava was banned from US and Europe therapeutics but its use is already used in several countries [67,68]. Food and Drug Administration (FDA) and European regulatory agency warnings have been diffused since 2002 [69,70]. Studies showed different concentration of FKA, B and C in different kava cultivars that can vary around 20 fold that can explain difference amounts of FKA and FKB in the products of the market, and also different final results [71], due to this different concentration, the hepatotoxicity is not a linear effect. The presence of hepatotoxicity compounds FKA and B in kava extract can potentiate the liver damage when co-administrated with NSAIDs (mainly the diclofenac chemical related, that can metabolize to iminoquinone derivatives) The level of the injury depends of FKs amount and patient liver conditions. Drug cirrhosis can be precipitated by NSADs-kava in multiple drugs users’ patients, elderly and alcohol chronic individual.

Ephedra (Ephedra sinica)

Ephedra herb is defined as a terrestrial steam of Ephedra sinica, according to 17Th edition of Japanese Pharmacopoeia [72]. Ephedra was described to have an antiviral or antibacterial role, by the activation of immune system [73,74].

The anti-inflammatory effects and analgesic activity of ephedra were previous reported in literature [75-77]. Hyuga (2017) reported that ephedrine alkaloids-free may be the responsible by the anti-inflammatory and analgesic effects [78]. The same researcher reported the anti-metastatic and antitumor effect of ephedra herb extract (EHE), by the suppression of the hepatocytes growth factor-c-Met signaling pathway through the inhibition of c-Met tyrosine kinase activity. Also, they demonstrated the effect of herbacetin glycosides in EHE, which shows c-Met-inhibitory activity and analgesic action [78]. This NP contains ephedrine alkaloids such as ephedrine and pseudoephedrine as the principal active compounds [75], used mainly in pharmaceutical preparation for upper respiratory disease, in combination with other drugs.

Despite the benefic effect of ephedra, its use have been restrict in some countries due the sympathomimetic effect leading to several alterations of physiological responses, such as increased blood pressure, vasoconstriction, bronchodilation and increasing heart rate [79].

The Ephedra alkaloids inhibits reuptake of catecholamines and acts as antagonist of α-2 adrenergic receptor, the functional adrenergic receptor on the platelets [80,81]. According to Watson and co-workers, the increase of intracerebral hemorrhage incidence using ephedra may be related to elevations in blood pressure and also by reductions in epinephrine-mediated platelet aggregation leading to cerebral bleeding [82]. They showed that ephedrine similarly inhibits Adenosine diphosphate (ADP)-induced platelet aggregation. The use of NSAIDs that can increase blood pressure and decrease platelet aggregation, the co-administration of NSAIDs and ephedra may potentiate the risk of cerebral hemorrhage and GI ulcer bleeding.

In addition, it has been reported that ephedra’ alkaloids may contribute to acute liver injury induced by TNF-α leading to fulminant hepatic failure and necrosis [82-85].

Green Tea (Camellia sinensis)

Camellia sinensis is a species of shrub or small tree native from Asia and India. The leaves and leaf buds are used to produce worldwide used tea, popularly named as Green Tea. The most important polyphenolic compounds isolated from this NP include epicatechin (EC), epigallocatechin (EGC), EC-3-O-gallate (ECG), and EGC-3-O-gallate (EGCG), the major one [86].

Several in vitro and in vivo experiments has been reported the strong antioxidant potential of the catechins [87-90]. EGCG has been reported to present anti-inflammatory [91], antimutagenic [92], anti-cancer [93], anti-obesity [94], anti-diabetic [95], anti-viral [96], anti-bacterial [97], neuroprotector [98] and immunomodulatory effect [86,99-102]. Also, green tea catechin is able to amilorate peridontite inflammation caused by Porphyromonas gingivalis in mice [103]. 

Was demonstrated the decreasing the inflammatory mediators in arthritis murine model[99,104,105] According to Kim and co-workers (2008), the polyphenolics compounds are able to reduce the severity of arthritis inflammation in Lewis rats. was observed the decrease of proinflammatory cytokine interleukin (IL)-17 and the increase of immunoregulatory cytokine IL-10 compared to control [106]. The EGCG regulates inflammation and joint degeneration by modulating MAPKs, Activator protein 1 (AP-1), NF-κB pathway and STAT signaling activated by TNF-α, IL-1β and IFN-γ in various cell types [87,91,92].

The enzyme COX2 is overexpressed in several inflammatory diseases and also its implicated in prostate and gastric cancer conditions [107, 108]. However, the use of NSAIDs is limited by the side effects such as gastric ulceration (by the inhibition of COX1 isoform) and cardiovascular damage (by inhibition of COX2 cardiac constitutive isoform).

The catechins demonstrated the decrease of the overexpression of COX2 without interfere in COX1 , showing no gastric injury by decreasing PGE2 [109]. In therapeutic clinic, the catechins could be benefic in cancer conditions, with the possibility to be used in association with chemotherapeutics and low doses of selective COX2 NSAIDs.

The EGCG is able to interrupt lipid peroxidation chain reaction decreasing liver damage [110,111] and it was reported that is about 25 and 100 times more potent than vitamins E and C, respectively [112].

The diary consume of green tea extract is associated with a lower risk of liver injury, hyperlipidemia, and inflammation [113]. The EGCG ameliorates experimental immune-mediated glomerulonephritis and its beneficial roles in chronic kidney disease [102,114]. However, some authors reported hepatotoxicity with long term use of green tea extract in oral supplementation [115,116]. This finds suggest that other components in the plant may be considering in therapeutics/ hepatotoxicity. So, in this condition, the long term use or high doses of the extract/supplement can increase the potentiality of hepatotoxicity and need to be considered when combined with NSAIDs.

Ginkgo biloba

The Ginkgo biloba extracts (ginkgo) have been used for alleviating symptoms associated with cognitive impairment, dementia, Alzheimer’s disease [117], hypertension [118], asthma [119] and tinnitus [120], including the anticancer activity [121].

The active constituents related to ginkgo is the biflavones, terpene trilactones (ginkgolides A, B, C, J, P and Q, and bilobalides), flavonol glycosides (quercetin, catechin) and proanthocyanidins [83,122].

The ginkgo reduces the nitric oxide (NO)-induced oxidative stress, acting as NO scavenger and also decreasing its production in diabetic animal models [123,124], thus protecting the animal from retinopathy and probably from nephropathy too, by the same mechanism [125].

Several reports show that ginkgo is able to inhibit the platelet aggregation via ADP and collagen-induced through cyclic adenosinemonophosphate (cAMP) and also by increasing and the inhibition of thromboxane A2 synthesis [126-128]. The Ginkgo extract, in association with anti-platelet drugs (warfarin) [129,130] and acetylsalicylic acid [131] increase the risk of bleeding (cerebral or/and GI ulcer). The co-administration of Ginkgo and NSAIDs is not recommended [132,133].

Curcumin

Curcumin is a polyphenolic bioactive yellow pigment present in the roots of Curcuma longa L. (turmeric). Its therapeutic acivities have been extensively reported, mainly for cancer and inflammatory diseases’ treatment [134]. Also, it present anti-platelet and potent antioxidant effect interacting with several targets, such as tyrosine-protein kinase (JAK2) / Signal transducer and activator of transcription 3 (STAT3), 5’ -adenosine monophosphate--activated protein kinase (AMPK) / mitochondrial uncoupling protein 2 (UCP2), phosphatidylinositol 3-kinase (PI3K)/Akt / nuclear factor erythroid related factor 2 (Nrf2), extracellular signal–regulated kinases (ERK), mitogenactivated protein kinases (MAPK p38), intercellular adhesion molecule 1 (ICAM-1) and monocyte chemotactic protein 1 (MCP-1) [135-141], reducing inflammatory cytokines such as NF-κB, IL-1β, IL-8, IL-6 and TNF-α [142]. It also reduces levels of xanthine oxidase, superoxide anion and myeloperoxidase lipid peroxidation and elevate enzymatic antioxidant activities of glutathione peroxidase, superoxide dismutase (SOD) and catalase [142,143].

Liver is the main detoxification organ of xenobiotics and drugs. However, some compounds can induce to hepatocytes damage such as the NSAIDs by the production of iminoquinones metabolites and reactive oxygen species (ROS). Reports showed that curcumin is able to decreases liver damage induced by acetaminophen [144-146]. By the beneficial effect of curcumin, it’s suggested that curcumin can potentiate the activity NSAIDs and also protect the liver.

Curcumin present nephroprotective activity and have been associated with the prevention of kidney injury. It is able to increase the level of AMPK, SIRT-1/3 (silent mating type information regulation-1), PPAR α/γ (peroxisome proliferatoractivated receptor) as well as reduce glomerular filtration rate in cardiovascular disease [143].

In addition, curcumin is mediated by the MKP-1-dependent inactivation of p38 and inhibition of NF-kB-mediated transcription, gastric inflammation and gastric cancer via reduced NF-κB p65 expression, decreased vascular endothelial growth factor (VEGF) level, and macromolecular leakage in the gastric mucosa, protecting the gastric mucosal injury induced by NSAIDs [143].

Resveratrol

Resveratrol (3,5,40 -trans-trihydroxystibene) is an antioxidant and anti-inflammatory polyphenol present in red wine, grapes and has been extensively investigated as potential compound for the treatment of several diseases, including the cardiovascular diseases, cancer prevention, modulation of lipid metabolism, and regulation of immune system, cerebrovascular and age-related diseases [147-151].This phytochemical acts mainly under via AMPK/SIRT-1 subsequent peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α) activating phosphorylation, increasing mitochondrial biogenesis as well as oxidative capacity [143], however, it is not totally understood.

Resveratrol upregulates the SOD and decrease ROS production, inhibits phospholipase A2 and COX2 activity, decreasing de PGE2 synthesis. It possess the ability to antagonizes the inflammatory citokines NF-κB , TNF-α, IL-6 and the Inducible nitric oxide synthase (iNOS) activity, and MCP-1, promoting a very potent anti-inflammatory effect [152–154]. In addition, resveratrol is able to modulate the platelet adhesion, secretion and activation signaling preventing platelet activation [155-157]. Furthermore, several studies demonstrated that resveratrol inhibits protein kinase C (PKC) activation and intracellular calcium release, thus blocking phosphoinositide metabolism upstream platelet activation signaling [158].

Resveratrol is able to prevent kidney damage. The nephroprotective effect has been related with the prevention of ROS generation as well as increasing of antioxidant enzymes and decreasing inflammatory citokines. Besides, it is able to level increase AMPK, SIRT-1, PPAR [143]. In septic animals, Wu and co-workers showed the protection of kidney damage by the RES activation of SIRT1/3 in the hyper-inflammatory phase.

It’s known that resveratrol improve glucose uptake and metabolism in animals and is beneficial in individuals with diabetes type 2, in clinical trials [159,160]. The use of NSAIDs in diabetics’ patients is not recommended because the side effects mainly vasoconstriction and kidney damages. With this knowledge we can deduce that the use of resveratrol in Type 2 diabetic patients may be interesting by itself. In addition, this patients could use NSAIDs, once resveratrol can protect the kidney and by its anti-inflammatory effect, reducing the NSAIDs doses [161].

Treatment in mice with resveratrol during acetaminophen induced liver damage showed significant inhibition of cytochrome P450 2E1 (CYP2E1), cytochrome P450 3A1 (CYP3A1), and cytochrome P450 1A2 (CYP1A2) activities, as well as the pretreatment with resveratrol able to protect against mitochondrial injury [162,163].

In other hand, Elgebaly et al. (2017), in a systematic review and meta-analysis showed that there are no evidence of resveratrol improvement in non alcoholic fat liver disease and does not alters liver fibrosis [164]. In other hand, Kessoku and co-workers (2016) reported a study performed with non alcoholic steatohepatitis (NASH)/ nonalcoholic fatty liver (NAFL) mice model, that resveratrol can improve liver inflammation and fibrosis but not steatosis, via inhibition of lipopolysaccharide (LPS) reactivity that is due to cluster of differentiation 14 (CD14) expression in Kupffer cells [165].

Resveratrol preserve antioxidant defenses resulting in reduction of acetaminophen-induced liver injury [166], reduce stress-induced gastric damage [167], and an increase in activity of antioxidizing enzymes SOD and glutathione (GSH) [143].

Figure 2 and 3 shows the effect of NP interacting with the effect of NSAIDs in liver and kidney.

NP are widely used since ancient. Acute inflammation and pain is the most motivation for the high use of NSAIDs worldwide. The concomitant use of NP and NSAIDs can be good or not, depending of the active compound. Ephedra and Ginkgo biloba can increase risk of cerebral hemorrhage and GI ulcer bleeding promoted by the NSAIDs and Green tea, curcumin and resveratrol possess improvement of anti-inflammatory activity and protect kidney and liver from NSAIDs damage. The liver deleterious effect of kava depends of the concentration of FKA and B form kava cultivars. High concentrations of these flavokawains and concomitant use of NSAIDs structurally similar to diclofenac can precipitate or lead to liver failure.

1. Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Pain Res. 2015; 8: 105-118.

2. Rao P, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci. 2008; 11: 81s-110s.

3. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl. 1999; 56: 18-24.

4. Al-Shidhani A, Al-Rawahi N, Al-Rawahi A, Sathiya Murthi P. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Use in Primary Health Care Centers in A’Seeb, Muscat: A Clinical Audit. Oman Med J. 2015; 30: 366-371.

5. Goda Y, Kiuchi F, Shibuya M, Sankawa U. Inhibitors of prostaglandin biosynthesis from Dalbergia odorifera. Chem Pharm Bull (Tokyo). 1992; 2452-2457.

6. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal antiinflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000; 284: 1247-1255.

7. Wallace JL. Selective COX-2 inhibitors: is the water becoming muddy? Trends Pharmacol Sci. 1999; 20: 4-6.

8. Lin X-H, Young S-H, Luo J-C, Peng Y-L, Chen P-H, Lin C-C, et al. Risk Factors for Upper Gastrointestinal Bleeding in Patients Taking Selective COX-2 Inhibitors: A Nationwide Population-Based Cohort Study. Pain Med. 2017.

9. Imig JD. Eicosanoid regulation of the renal vasculature. Am J Physiol Renal Physiol. 2000; 279: F965-81.

10. Kakoki M, Smithies O. The kallikrein-kinin system in health and in diseases of the kidney. Kidney Int. 2009; 75: 1019-30.

11. Ulla CK, Michael ZC, Lori AS, Tomas H. Nitric oxide modulates renal sensory nerve fibers by mechanisms related to substance P receptor activation. Am J Physiol Regul Integr Comp Physiol. 2001; 281: R279- 290.

12. Danelich I, Wright S, Lose J, Tefft B, Cicci J, Reed B. Safety of Nonsteroidal Antiinflammatory Drugs in Patients with Cardiovascular Disease. Pharmacotherapy. 2015; 35: 520-535.

13. Ernst E. Toxic heavy metals and undeclared drugs in Asian herbal medicines. Trends Pharmacol Sci. 2002; 23: 136-139.

14. Fong SYK, Efferth TH, Zuo Z. Modulation of the pharmacokinetics, therapeutic and adverse effects of NSAIDs by Chinese herbal medicines. Expert Opin Drug Metab Toxicol. 2014; 10: 1-29.

15. Moro MG, Sanchez PKV, Gevert MV, Baller EM, Tostes AF, Lupepsa AC, et al. Gastric and renal effects of COX-2 selective and non-selective NSAIDs in rats receiving low-dose aspirin therapy. Braz Oral Res. 2016; 30: 127.

16. Latruffe N. Natural products and inflammation. Molecules. 2017; 22: 15-7. 

17. Raman P., DeWitt DL, Nair MG. Lipid Peroxidation and Cyclooxygenase Enzyme Inhibitory Activities of Acidic Aqueous Extracts of Some Dietary Supplements. Phytother Res. 2008; 22: 204-212.

18. Naqvi R, Mubarak M, Ahmed E, Akhtar F, Naqvi A, Rizvi A. Acute tubulointerstitial nephritis/drug induced acute kidney injury; an experience from a single center in Pakistan. J Ren Inj Prev [Internet]. 2016; 5: 17-20.

19. Abebe W. Herbal medication: potential for adverse interactions with analgesic drugs. J Clin Pharm Ther. 2002; 27: 391-401.

20. Kataria BC, Bhavsar VH, Donga BN. Contemplation on approved drugs in India from 1999 through 2011. Asian J Pharm Clin Res. 2012; 5: 25-29.

21. Béria JU, Victora CG, Barros FC, Teixeira AB LC. Epidemiologia do consumo de medicamentos em crianças no centro urbano da região sul do Brasil. Rev Saúde Pública 27. 1993.

22. Oliveira G. Uso racional de medicamentos: indicadores em um estudo populacional. USP. 1998.

23. Mosegui GB, Rozenfeld S, Veras RP, Vianna CM. [Quality assessment of drug use in the elderly]. Rev Saude Publica. 1999; 33: 437-444.

24. Menezes C, Magalhães S. Qualidade terapêutica de medicamentos adquiridos em drogarias da região central de Belo Horizonte-MG. Rev Ciênc Farm. 2004; 25:149-155.

25. Perini E, Magalhães SM, Noronha V. [Drug use during in-hospital birth delivery stay]. Rev Saude Publica. 2005; 39: 358-365.

26. Walker LA, Zambraski EJ, Williams RF. Widespread Use of Prescription Nonsteroidal Anti-Inflammatory Drugs Among U.S. Army Active Duty Soldiers. Mil Med. 2017; 182: e1709-e1712.

27. Agencia Española del Medicamento y Productos Sanitarios. Utilización de medicamentos antiinflamatorios no esteroides (AINE) en España durante el período 2000–2012.

28. Melgaço S, Saraiva M, Lima T, Júniro G, Daher E. Nefrotoxicidade dos anti-inflamatório não esteroidais. Crit Care Med. 2010; 43: 382-390.

29. Lumiracoxib - suspension of uk licences with immediate effect. Drug safety information - lumiracoxib -. 2007; 21.

30. Primary and Community Care Directorate Pharmacy Division. Lumiracoxib - suspension of UK licences with immediate effect. 2007.

31. Australian adverse drug reaction bulletin. Withdrawal lumiracoxib Aust [Internet]. 2016; 27.

32. Lee C-H, Wang J-D CP-C. Increased risk of hospitalization for acute hepatitis in patients with previous exposure to NSAIDs. Pharmacoepidemiol Drug Saf. 2010; 19: 708-714.

33. Lapeyre-Mestre M, de Castro AM, Bareille MP, Del Pozo JG, Requejo AA, Arias LM, et al. Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting systems. Fundam Clin Pharmacol. 2006; 20: 391-395.

34. Laine L, Goldkind L, Curtis S et al. How common is diclofenacassociated liver injury? Analysis of 17289 arthritis patients in a long term prospective clinical trial. Am J Gastroenterol. 2009; 104: 356- 362.

35. Reilly TP, Brady JN, Marchick MR, Bourdi M, George JW, Radonovich MF, et al. A protective role for cyclooxygenase-2 in drug-induced liver injury in mice. Chem Res Toxicol. 2001; 14: 1620-1628.

36. Casado M, Callejas NA, Rodrigo J, Zhao X, Dey SK, Boscá L, et al. Contribution of cyclooxygenase 2 to liver regeneration after partial hepatectomy. FASEB J. 2001; 15: 2016-2018.

37. Beraza N, Marqués JM, Martínez-Ansó E, Iñiguez M, Prieto J, Bustos M. Interplay among cardiotrophin-1, prostaglandins, and vascular endothelial growth factor in rat liver regeneration. Hepatology. 2005; 41: 460-469.

38. Bhave VS, Donthamsetty S, Latendresse JR, Muskhelishvili L, Mehendale HM. Secretory phospholipase A2 mediates progression of acute liver injury in the absence of sufficient cyclooxygenase-2. Toxicol Appl Pharmacol. 2008; 228: 225-238.

39. Demeure CE, Yang LP, Desjardins C, Raynauld P, Delespesse G. Prostaglandin E2 primes naive T cells for the production of antiinflammatory cytokines. Eur J Immunol. 1997; 27: 3526-3531.

40. Piraino G, Cook JA, O’Connor M, Hake PW, Burroughs TJ, Teti D, et al. Synergistic effect of peroxisome proliferator activated receptorgamma and liver X receptoralpha in the regulation of inflammation in macrophages. Shock. 2006; 26:146-153.

41. Laine L, White WB, Rostom A, Hochberg M. COX-2 selective inhibitors in the treatment of osteoarthritis. Semin Arthritis Rheum. 2008; 38: 165-187.

42. Harris SG, Padilla J, Koumas L, Ray D, Phipps RP. Prostaglandins as modulators of immunity. Trends Immunol. 2002; 23: 144-150.

43. Mayoral R, Mollá B, Flores JM, Boscá L, Casado M, Martín-Sanz P. Constitutive expression of cyclo-oxygenase 2 transgene in hepatocytes protects against liver injury. Biochem J. 2008; 416:337-346.

44. Bessone F, Hernandez N, Roma MG, Ridruejo E, Mendizabal M, MedinaCálizI, et al. Hepatotoxicity induced by coxibs: how concerned should we be? Expert Opin Drug Saf [Internet]. 2016; 15: 1463-1475.

45. Rostom A, Goldkind LL. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol. 2005; 3: 489-498.

46. Gastrup S, Stage TB, Fruekilde PB, Damkier P. Paracetamol decreases steady-state exposure to lamotrigine by induction of glucuronidation in healthy subjects. Br J Clin Pharmacol. 2016; 81: 735-41.

47. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, et al. ACCF/ACG/AHA 2008 Expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID Use: a report of the American College of Cardiology Foundation task Force on Clinical Expert Consensus Documents. Circulation. 2008; 118: 1894-1909.

48. Dey I, Lejeune M, Chadee K. Prostaglandin E 2 receptor distribution and function in the gastrointestinal tract. Br J Pharmacol [Internet]. 2006; 149: 611-623.

49. Chen WC, Lin KH, Huang YT, Tsai TJ, Sun WC, Chuah SK, et al. The risk of lower gastrointestinal bleeding in low-dose aspirin users. Aliment Pharmacol Ther. 2017; 1-9.

50. Mazumder S, De R, Sarkar S, Siddiqui AA, Saha SJ, Banerjee C, et al. Selective scavenging of intra-mitochondrial superoxide corrects diclofenac-induced mitochondrial dysfunction and gastric injury: A novel gastroprotective mechanism independent of gastric acid suppression. Biochem Pharmacol. 2016; 121: 33-51.

51. Dias DA, Urban S, Roessner U. A Historical Overview of Natural Products in Drug Discovery. Metabolites. 2012; 2: 303-336.

52. Cragg GM, Newman DJ. Biodiversity: A continuing source of novel drug leads. Pure Appl Chem. 2005; 77: 7-24.

53. Balch RJ, Trescot A. Extended-release morphine sulfate in treatment of severe acute and chronic pain. J Pain Res. 2010; 3: 191-200.

54. Criscitiello C, Fumagalli D SK. Tamoxifen in early stage estrogen receptor- positive breast cancer?: overview of clinical use and molecular biomarkers for patient selection. Onco Targets Ther. 2011;4: 1-11. 

55. Fabian CJ. The what, why and how of aromatase inhibitors: hormonal agents for treatment and prevention of breast cancer. Int J Clin Pract. 2007; 61: 2051-2063.

56. Göbel A, Kuhlmann JD, Link T, Wimberger P, Browne AJ, Rauner M, et al. Adjuvant tamoxifen but not aromatase inhibitor therapy decreases serum levels of the Wnt inhibitor dickkopf-1 while not affecting sclerostin in breast cancer patients. Breast Cancer Res Treat. 2017.

57. De Marchi T, Timmermans MA, Sieuwerts AM, Smid M, Look MP, Grebenchtchikov N, et al. Phosphoserine aminotransferase 1 is associated to poor outcome on tamoxifen therapy in recurrent breast cancer. Sci Rep. 2017; 7: 2099.

58. Gounder R. Kava consumption and its health effects. Pac Health Dialog. 2006; 13: 131-5.

59. Global status report on alcohol and health 2014. World Heal Organ. 2014.

60. Singh YN. Kava: an overview. J Ethnopharmacol. 1992; 37: 13-45.

61. Sarris J, Kavanagh D, Byrne G, Bone K, Adams J, Deed G. The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum. Psychopharmacology (Berl). 2009; 205: 399-407.

62. Sarris J, Stough C, Bousman C, Wahid Z, Murray G, Teschke R et al. Kava in the treatment of generalized anxiety disorder: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol. 2013; 33: 643-648.

63. Sarris J, Stough C, Teschke R, Wahid Z, Bousman C, Murray G et al. Kava for the treatment of generalized anxiety disorder RCT: Analysis of adverse Reactions, liver Function, addiction, and sexual effects. Phyther Res. 2013; 27:1723-1728

64. Teschke R, Sarris J, Glass X, Schulze J. Kava, the anxiolytic herb: back to basics to prevent liver injury? Br J Clin Pharmacol. 2011; 71: 445-458.

65. Narayanapillai SC, Leitzman P, O’Sullivan MG, Xing C. Flavokawains A and B in Kava, Not Dihydromethysticin, Potentiate AcetaminophenInduced Hepatotoxicity in C57BL/6 Mice. Chem Res Toxicol. 2014; 27: 1871-1876.

66. Chua H, Christensen E, Hoestgaard-Jensen K, Hartiadi L, Ramzan I, Jensen A, et al. Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism. PLoS One. 2016; 11: e0157700.

67. Teschke R, Wolff A. Kava hepatotoxicity: regulatory data selection and causality assessment. Dig Liver Dis. 2009; 41: 891-901.

68. Carreno I, Laurenza E, Martelloni A, Salas B, Simoes BG, Vergona PR. German court repeals the withdrawal of marketing authorisation of kava-containing medicinal products. Trade Perspect. 2014; 13: 2-5.

69. FDA. Consumer Advisory: Kava-Containing Dietary Supplements May be Associated With Severe Liver Injury. 2017.

70. CDC. Hepatic Toxicity Possibly Associated with Kava-Containing Products --- United States, Germany, and Switzerland, 1999—2002. 2017.

71. Lebot V, Do TK, Legendre L. Detection of flavokavins (A, B, C) in cultivars of kava (Piper methysticum) using high performance thin layer chromatography (HPTLC). 2014; 15: 554-560.

72. Ministry of Health, Labour and Welfare of Japan. The Japanese Pharmacopoeia. 2016; 17th Edn.

73. Walter EJ, Hanna-Jumma S, Carraretto M, Forni L. The pathophysiological basis and consequences of fever. Crit Care. 2016; 20: 200.

74. Parsaeimehr A, Sargsyan E, Javidnia K. A Comparative Study of the Antibacterial, Antifungal and Antioxidant Activity and Total Content of Phenolic Compounds of Cell Cultures and Wild Plants of Three Endemic Species of Ephedra. Molecules. 2010; 15: 1668-1678.

75. Wu Z, Kong X, Zhang T, Ye J, Fang Z, Yang X. Pseudoephedrine/ ephedrine shows potent anti-inflammatory activity against TNF- ??-mediated acute liver failure induced by lipopolysaccharide/dgalactosamine. Eur J Pharmacol. 2014; 724: 112-121.

76. Wang C, Cao B, Liu QQ, Zou ZQ, Liang ZA, Gu L, et al. Oseltamivir compared with the Chinese traditional therapy maxingshiganyinqiaosan in the treatment of H1N1 influenza: a randomized trial. Ann Intern Med. 2011; 155: 217-125.

77. Fiebich BL, Collado JA, Stratz C, Valina C, Hochholzer W, Muñoz E, et al. Pseudoephedrine inhibits T-cell activation by targeting NF-κB, NFAT and AP-1 signaling pathways. Immunopharmacol Immunotoxicol. 2012; 34: 98-106.

78. Hyuga S. The Pharmacological Actions of Ephedrine Alkaloids-free Ephreda Herb Extract and Preparation for Clinical Application. Yakugaku Zasshi-Journal Pharm Soc Japan. 2017; 137: 179-186.

79. Hardman JG L LE. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. NYM-H, editor. 2001.

80. Persky AM, Berry NS, Pollack GM, Brouwer KL. Modelling the cardiovascular effects of ephedrine. Br J Clin Pharmacol. 2004; 57: 552-562.

81. Yang J, Wu J, Kowalska MA, Dalvi A, Prevost N, O’Brien PJ et al. Loss of signaling through the G protein, Gz results in abnormal platelet activation and altered responses to psychoactive drugs. Proc Natl Acad Sci U S A. 2000; 97: 9984-9989.

82. Watson R, Woodman R, Lockette W. Ephedra alkaloids inhibit platelet aggregation. Blood Coagul Fibrinolysis. 2010; 21: 266-271.

83. Bajaj J, Knox JF, Komorowski R SK. The irony of herbal hepatitis: Ma-Huang-induced hepatotoxicity associated with compound heterozygosity for hereditary hemochromatosis. Dig Dis Sci,. 2003; 48: 1925-1928.

84. Nadir A, Agrawal S, King PD, Marshall JB. Acute hepatitis associated with the use of a Chinese herbal product, ma-huang. Am J Gastroenterol. 1996; 91: 1436-1438.

85. Seeff LB. Herbal hepatotoxicity. Clin Liver Dis. 2007; 11: 577-596.

86. Bose M, Lambert JD, Ju J, Reuhl KR, Shapses SA, Yang CS. The major green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J Nutr. 2008; 138: 1677-1683.

87. Cabrera C, Giménez R, López MC. Determination of tea components with antioxidant activity. J Agric Food Chem. 2003; 51: 4427-4435.

88. Cabrera C, Artacho R, Gimenez R. Beneficial effects of green tea-A review. J Am Coll Nutr. 2006; 25: 79-99.

89. Frei B, Higdon JV. Antioxidant activity of tea polyphenols in vivo: evidence from animal studies. J Nutr. 2003; 133: 3275S-3284S.

90. Nakagawa T, Yokozawa T. Direct scavenging of nitric oxide and superoxide by green tea. Food Chem Toxicol. 2002; 40: 1745-50.

91. Danesi F, Philpott M, Huebner C, Bordoni A, Ferguson L. Foodderived bioactives as potential regulators of the IL-12/IL-23 pathway implicated in inflammatory bowel diseases. Mutat Res. 2010; 690: 139-144.

92. Cheng KW, Wong CC, Chao J, Lo C, Chen F, Chu IK, et al. Inhibition of mutagenic PhIP formation by epigallocatechin gallate via scavenging of phenylacetaldehyde. Mol Nutr Food Res. 2009; 53: 716-725.

93. Johnson J, Bailey H, Mukhtar H. Green tea polyphenols for prostate cancer chemoprevention: a translational perspective. Phytomedicine. 2010; 17: 3-13.

94. Moon HS, Lee HG, Choi YJ, Kim TG, Cho CS. Proposed mechanisms of (-)-epigallocatechin-3-gallate for anti-obesity. Chem Biol Interact. 2007; 167: 85-98.

95. Zhang Z, Li Q, Liang J, Dai X, Ding Y, Wang J, et al. Epigallocatechin-3- O-gallate (EGCG) protects the insulin sensitivity in rat L6 muscle cells exposed to dexamethasone condition. Phytomedicine. 2010; 17: 148.

96. Xiao X, Yang ZQ, Shi LQ, Liu J, Chen W. [Antiviral effect of epigallocatechin gallate (EGCG) on influenza A virus]. Zhongguo Zhong Yao Za Zhi. 2008; 33: 2678-2682.

97. Osterburg A, Gardner J, Hyon S, Neely A, Babcock G. Highly antibioticresistant Acinetobacter baumannii clinical isolates are killed by the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG). Clin Microbiol Infect. 2009; 15: 341-346.

98. Smith A, Giunta B, Bickford P, Fountain M, Tan J, Shytle R. Nanolipidic particles improve the bioavailability and alpha-secretase inducing ability of epigallocatechin-3-gallate (EGCG) for the treatment of Alzheimer’s disease. Int J Pharmacol. 2010; 389: 207-212.

99. Singh R, Akhtar N, Haqqi TM. Green tea polyphenol epigallocatechin3-gallate: inflammation and arthritis. Life Sci. 2010; 86: 907-918.

100. Wu D, Wang J, Pae M, Meydani SN. Green tea EGCG, T cells, and T cell-mediated autoimmune diseases. Mol Aspects Med. 2012; 33: 107-118.

101. Wang J, Ren Z, Xu Y, Xiao S, Meydani SN WD. Epigallocatechin-3- gallate ameliorates experimental autoimmune encephalomyelitis by altering balance among CD4+ T-cell subsets. Am J Pathol. 2012;180:221-234.

102. Peng A, Ye T, Rakheja D, Tu Y, Wang T, Du Y, et al. The green tea polyphenol (-)-epigallocatechin-3-gallate ameliorates experimental immune-mediated glomerulonephritis. Kidney Int. 2011; 80: 601- 611.

103. Cai Y, Chen Z, Liu H, Xuan Y, Wang X, Luan Q. Green tea epigallocatechin-3-gallate alleviates Porphyromonas gingivalisinduced periodontitis in mice. Int Immunopharmacol. 2015; 29: 839-845.

104. Lee S-Y, Jung YO, Ryu J-G, Oh H-J, Son H-J, Lee SH, et al. Epigallocatechin3-gallate ameliorates autoimmune arthritis by reciprocal regulation of T helper-17 regulatory T cells and inhibition of osteoclastogenesis by inhibiting STAT3 signaling. 2016; 100: 559-568.

105. Min S-Y, Yan M, Kim SB, Ravikumar S, Kwon S-R, Vanarsa K, et al. Green Tea Epigallocatechin-3-Gallate Suppresses Autoimmune Arthritis Through Indoleamine-2,3- Dioxygenase Expressing Dendritic Cells and the Nuclear Factor, Erythroid 2-Like 2 Antioxidant Pathway. J Inflamm. 2015; 12: 1-15.

106. Kim H, Rajaiah R, Wu Q, Satpute S, Tan M, Simon J, et al. Green tea protects rats against autoimmune arthritis by modulating diseaserelated immune events. J Nutr. 2008; 138: 2111-2116.

107. Fujita H, Koshida K, Keller ET, Takahashi Y, Yoshimito T, Namiki M, et al. Cyclooxygenase-2 promotes prostate cancer progression. Prostate. 2002; 53: 232-240.

108. Wang Z, Chen J, Liu J. COX-2 Inhibitors and Gastric Cancer. Gastroenterol Res Pract. 2014; 2014: 7.

109. Hussain T, Gupta S, Adhami V, Mukhtar H. Green tea constituent epigallocatechin-3-gallate selectively inhibits COX-2 without affecting COX-1 expression in human prostate carcinoma cells. Int J Cancer. 2005; 113: 660-669. 110. Jin X, Zheng RH, Li YM. Green tea consumption and liver disease: a systematic review. Liver Int. 2008; 28: 990-996.

111. Skrzydlewska E, Ostrowska J, Farbiszewski R, Michalak K. Protective effect of green tea against lipid peroxidation in the rat liver, blood serum and the brain. Phytomedicine. 2002; 9: 232-238.

112. Clark J, You M. Chemoprevention of lung cancer by tea. Mol Nutr Food Res. 2006; 50: 144-151.

113. Imai K, Nakachi K. Cross sectional study of effects of drinking green tea on cardiovascular and liver diseases. BMJ. 1995; 310: 693-696.

114. Li J, Sapper TN, Mah E, Rudraiah S, Schill KE, Chitchumroonchokchai C, et al. Green Tea Extract Provides Extensive Nrf2-Independent Protection Against Lipid Accumulation and NF?B Pro- Inflammatory Responses During Nonalcoholic Steatohepatitis In Mice Fed A HighFat Diet. Mol Nutr Food Res. 2016; 60: 858 70.

115. Bonkovsky HL. Hepatotoxicity Associated with Supplements Containing Chinese Green Tea (Camellia sinensis). Ann Intern Med. 2006; 144: 68-71.

116. Stevens T, Qadri A, Zein NN. Two Patients with Acute Liver Injury Associated with Use of the Herbal Weight-Loss Supplement Hydroxycut. Ann Intern Med. 2005; 142: 477-478.

117. Solfrizzi V, Panza F. Plant-based nutraceutical interventions against cognitive impairment and dementia: meta-analytic evidence of efficacy of a standardized Gingko biloba extract. J Alzheimers Dis. 2015; 43: 605-611.

118. Xiong XJ, Liu W, Yang XC, Feng B, Zhang YQ, Li SJ, et al. Ginkgo biloba extract for essential hypertension: a systemic review. Phytomedicine. 2014; 21: 1131-1136.

119. Chu X, Ci X, He J, Wei M, Yang X, Cao Q, et al. A novel anti-inflammatory role for ginkgolide B in asthma via inhibition of the ERK/MAPK signaling pathway. Molecules. 2011; 16: 7634-7648.

120. Hilton MP, Zimmermann EF, Hunt WT. Ginkgo biloba for tinnitus. Cochrane Database Syst Rev. 2013; 3: 3852.

121. Zhou C, Li X, Du W, Feng Y, Kong X, Li Y, et al. Antitumor effects of ginkgolic acid in human cancer cell occur via cell cycle arrest and decrease the Bcl-2/Bax ratio to induce apoptosis. Chemotherapy. 2010; 56: 393-402.

122. Charalampopoulos A, Karatsourakis T, Tsiodra P. Acute hepatitis associated with the use of Mahuang in a young adult. Eur J Intern Med. 2007; 18: 81.

123. Rudge M, Damasceno D, Volpato G, Almeida F, Calderon I, Lemonica I. Effect of Ginkgo biloba on the reproductive outcome and oxidative stress biomarkers of streptozotocin-induced diabetic rats. Braz J Med Biol Res. 2007; 40: 1095-1059.

124. Saini AS, Taliyan R, Sharma PL. Protective effect and mechanism of Ginkgo biloba extract-EGb 761 on STZ-induced diabetic cardiomyopathy in rats. Pharmacogn Mag. 2014; 10: 172-178.

125. Huanga S-Y, Jengb C, Kaoc S-C, Yud JJ-H, Der-Zen Liuc. Improved haemorrheological properties by Ginkgo biloba extract (Egb 761) in type 2 diabetes mellitus complicated with retinopathy. Clin Nutr. 2004; 23: 615-621.

126. Dutta-Roy A, Gordon M, Kelly C et al. Inhibitory effect of Ginkgo biloba extract on human platelet aggregation. Platelets. 1999; 10: 298-305.

127. Kudolo G, Dorsey S, J. B. Effect of the ingestion of Ginkgo biloba extract on platelet aggregation and urinary prostanoid excretion in healthy and type 2 diabetic subjects. Thromb Res. 2002; 108: 151- 160.

128. Kudolo GB, Wang W, Barrientos J, Elrod R, Blodgett J. The ingestion of Ginkgo biloba extract (EGb 761) inhibits arachidonic acid-mediated platelet aggregation and thromboxane B2 production in healthy volunteers. J Herb Pharmacother. 2004; 4: 13-26.

129. Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, et al. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2005; 59: 425-432.

130. Engelsen J, Nielsen JD, Winther K. Effect of coenzyme Q10 and Ginkgo biloba on warfarin dosage in stable, long-term warfarin treated outpatients. A randomised, double blind, placebo-crossover trial variation in relative risk of venous thromboembolism in different cancers. Thromb Haemost. 2002; 87:1075-1076.

131. Gardner C, Zehnder J, Rigby A, Nicholus J, Farquhar J. Effect of Ginkgo biloba (EGb 761) and aspirin on platelet aggregation and platelet function analysis among older adults at risk of cardiovascular disease: a randomized clinical trial. Blood Coagul Fibrinolysis. 2007; 18: 787-793.

132. Abdel-Salam OME, Baiuomy AR, El-batran S, Arbid MS. Evaluation of the anti-inflammatory, anti-nociceptive and gastric effects of Ginkgo biloba in the rat. Pharmacol Res. 2004; 49: 133-142.

133. Vaes LP, Chyka PA. Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: nature of the evidence. Ann Pharmacother. 2000; 34: 1478-82.

134. Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009; 41: 40-59.

135. Duan W, Yang Y, Yan J, Yu S, Liu J, Zhou J, et al. The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway. Basic Res Cardiol. 2012; 107: 263.

136. Pu Y, Zhang H, Wang P, Zhao Y, Li Q, Wei X, et al. Dietary curcumin ameliorates aging-related cerebrovascular dysfunction through the ampk/uncoupling protein 2 pathway . Cell Physiol Biochem. 2013; 32: 1167-1177.

137. Wu J, Li Q, Wang X, Yu S, Li L, Wu X, et al. Neuroprotection by curcumin in ischemic brain injury involves the Akt/Nrf2 pathway. PLoS One. 2013; 8: 59843.

138. Deng ZH, Liao J, Zhang JY, Hao XH, Liang C, Wang LH, et al. Localized leptin release may be an important mechanism of curcumin action after acute ischemic injuries. J Trauma Acute Care Surg. 2013; 74: 1044-1051.

139. Kim YS, Ahn Y, Hong MH, Joo SY, Kim KH, Sohn IS, et al. Curcumin attenuates inflammatory responses of TNF-alpha-stimulated human endothelial cells. J Cardiovasc Pharmacol. 2007; 50: 41-4 9.

140. Parodi FE, Mao D, Ennis TL, Pagano MB, Thompson WR. Oral administration of diferuloylmethane (curcumin) suppresses proinflammatory cytokines and destructive connective tissue remodeling in experimental abdominal aortic aneurysms. Ann Vasc Surg. 2006; 20: 360-368.

141. Pan Y, Zhu G, Wang Y, Cai L, Cai Y, Hu J, et al. Attenuation of highglucoseinduced inflammatory response by a novel curcumin derivative B06 contributes to its protection from diabetic pathogenic changes in rat kidney and heart. J Nutr Biochem. 2013;24: 146 -155.

142. Manikandan P, Sumitra M, Aishwarya S, Manohar BM, Lokanadam B, Puvanakrishnan R. Curcumin modulates free radical quenching in myocardial ischaemia in rats. Int J Biochem Cell Biol. 2004; 36: 1967 -1980.

143. Pagliaro B, Santolamazza C, Simonelli F, Rubattu S. Phytochemical Compounds and Protection from Cardiovascular Diseases: A State of the Art. Biomed Res Int. 2015; 2015: 1 -17.

144. Soliman MM, Nassan MA, Ismail TA. Immunohistochemical and molecular study on the protective effect of curcumin against hepatic toxicity induced by paracetamol in Wistar rats. BMC Complement Altern Med. 2014; 14: 457.

145. Li G, Chen JB, Wang C, Xu Z, Nie H, Qin XY, et al. Curcumin protects against acetaminophen-induced apoptosis in hepatic injury. World J Gastroenterol. 2013; 19: 7440-7446.

146. Granados-Castro LF, Rodríguez-Rangel DS, Fernández-Rojas B, León-Contreras JC, Hernández-Pando R, Medina-Campos ON et al. Curcumin prevents paracetamol-induced liver mitochondrial alterations. J Pharm Pharmacol. 2016; 68: 245-256.

147. Karuppagounder SS, Pinto JT, Xu H, Chen HL, Beal MF, Gibson GE. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer s disease. Neurochem Int. 2009; 54: 111-118.

148. Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, et al. A randomized, doubleblind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015; 85: 1383-1391.

149. Udenigwe CC, Ramprasath VR, Aluko RE, Jones PJ. Potential of resveratrol in anticancer and anti-inflammatory therapy. Nutr Rev. 2008; 66: 445-454.

150. Wang S, Qian Y, Gong D, Zhang Y, Fan Y. Resveratrol attenuates acute hypoxic injury in cardiomyocytes: Correlation with inhibition of iNOS-NO signaling pathway. Eur J Pharm Sci. 2011; 44: 416-421.

151. Kalantari H, Das DK. Physiological effects of resveratrol. Biofactors. 2010; 36: 401-406.

152. Moreno JJ. Resveratrol modulates arachidonic acid release, prostaglandin synthesis, and 3T6 fibroblast growth. J Pharmacol Exp Ther. 2000; 294: 333-338.

153. Yang L, Zhang J, Yan C, Zhou J, Lin R, Lin Q, et al. SIRT1 regulates CD40 expression induced by TNF-α via NF-?B pathway in endothelial cells. Cell Physiol Biochem. 2012; 30: 1287-1298.

154. Cullen JP, Morrow D, Jin Y, Curley B, Robinson A, Sitzmann JV, et al. Resveratrol, a polyphenolic phytostilbene, inhibits endothelial monocyte chemotactic protein-1 synthesis and secretion. J Vasc Res. 2007; 44: 75-84.

155. Wu CC, Wu CI, Wang WY, Wu YC. Low concentrations of resveratrol potentiate the antiplatelet effect of prostaglandins, . PlantaMedica. 2007; 73: 439-443.

156. Lin KH, Hsiao G, Shih CM, Chou DS, Sheu JR. Mechanisms of resveratrol-induced platelet apoptosis. Cardiovasc Res. 2009; 83: 575-585.

157. Shen MY, Hsiao G, Liu CL, Fong TH, Lin KH, Chou DS, et al. Inhibitory mechanisms of resveratrol in platelet activation: pivotal roles of p38 MAPK and NO/cyclic GMP. Br J Haematol. 2007; 139: 475-485.

158. Olas B, Wachowicz B, Holmsen H, M. H. Fukami. Resveratrol inhibits polyphosphoinositide metabolism in activated platelets. Biochim Biophys Acta Biomembranes. 2005; 1714: 125-133.

159. Jung K, Lee J, Thien QC, Paik J, Oh H, Park J, et al. Resveratrol suppresses cancer cell glucose uptake by targeting reactive oxygen species-mediated hypoxia-inducible factor-1a activation. J Nucl Med. 2013; 54: 2161-2167.

160. Leon D, Uribe E, Zambrano A, Salas M. Implications of resveratrol on glucose uptake and metabolism. Molecules. 2017; 22: 1-11.

161. Xu S, Gao Y, Zhang Q, Wei S, Chen Z, XinguiDai, et al. SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model. Oxid Med Cell Longev. 2016; 2016: 12.

162. McGill, Sharpe M.R, Williams, Taha M, Curry S.C, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest. 2012;122:1574-1583.

163. Reid, A.B, Kurten, R.C, McCullough, S.S, Brock, R.W, Hinson JA. Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes. J Pharmacol Exp Ther. 2005; 312: 509- 516.

164. Elgebaly A, Radwan I, AboElnas M, Ibrahim H, Eltoomy M, Atta A, et al. Resveratrol Supplementation in Patients with Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-analysis. J Gastrointestin Liver Dis. 2017; 26: 59-67.

165. Kessoku T, Imajo K, Honda Y, Kato T, Ogawa Y, Tomeno W, et al. Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Sci Rep. 2016; 6: 22251.

166. Wang Y, Jiang Y, Fan X, Tan H, Zeng H, Wang Y, et al. Hepatoprotective effect of resveratrol against acetaminophen-induced liver injury is associated with inhibition of CYP-mediated bioactivation and regulation of SIRT1-p53 signaling pathways. Toxicol Lett. 2015; 236: 82-89.

167. Konturek S, Brzozowski T, Pajdo R, Konturek P, Kwiecie? S, Sliwowski Z, et al. Gastric preconditioning induced by short ischemia: the role of prostaglandins, nitric oxide and adenosine. Med Sci Monit. 2001; 7:610-621.