Open access peer-reviewed chapter

Interaction of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Reactive Oxygen Species (ROS): Possible Biomedical Implications

By Norman A. García, Mabel Bregliani and Adriana Pajares

Submitted: June 2nd 2016Reviewed: October 22nd 2016Published: May 24th 2017

DOI: 10.5772/66478

Downloaded: 643

Abstract

The present chapter deals on the interaction of nonsteroidal anti-inflammatory drugs (NSAIDs), diflunisal, indomethacin, meloxicam, tenoxicam and piroxicam with reactive oxygen species (ROS) photogenerated in aqueous solution by the vitamin riboflavin employed as a dye sensitizer. Simple techniques as substrate and oxygen consumption and more sophisticated time-resolved spectroscopic methods were employed for the kinetic and mechanistic evaluation of the deactivation of the in situ generated ROS singlet molecular oxygen (O2(Δ1g)), superoxide radical anion (O2·− ) and hydrogen peroxide (H2O2)  by the mentioned NSAIDs. Results could be prudently extrapolated to a possible action of NSAIDs in the retardation or inhibition of neuroinflammatory disorders, in which oxidative agents such as ROS were found to be upregulated. Despite the potential benefit, some adverse effects in humans reported in relation with high doses of NSAIDs alert about the cares that have to be taken about their use.

Keywords

  • antioxidants
  • NSAIDs
  • photosensitization
  • riboflavin
  • ROS

1. Introduction

In the last decades, it has been a widespread use of an increasing number of chemical compounds with analgesic, antipyretic, and anti-inflammatory properties. In order to remark their differences with other group of medicines which presents known bad side effects, they were labeled as nonsteroidal anti-inflammatory drugs with the acronym NSAIDs [13].

At the same time, many neuroinflammatory mediators, including oxidative agents such as reactive oxygen species (ROS), were found to be upregulated in neurodegenerative disorders (ND) that affect human brain areas [4, 5]. This fact immediately allows the proposal of some kind of cause-effect link between the presence of ROS, oxidation processes, neuroinflammation, and ND pathogenesis [4, 5].

Oxidative stress is a process that occurs in early stages of ND and is considered an identifier mark for their detection as could be evaluated by DNA, RNA, lipids, and protein oxidation levels [68]. Simultaneously, several studies have observed an inverse correspondence between prolonged NSAID administration and the development of some ND in humans, (for review, see Ref. [9]). So, it is now accepted that NSAIDs could play a protective role on many ND and one of the reasons of the great interest for getting more insight into the elucidation of the pathways and mechanisms of the oxidative processes in which several NSAIDs and different ROS take part.

The present chapter will analyze the results presented in two relatively recent papers that have been dedicated to evaluate the possible action of some NSAIDs as protectors against ROS-mediated oxidation/deterioration of biological targets [10, 11]. Those research works are focused on NSAIDs from different chemical structure classes, one salicylic acid derivative, diflunisal (DFN), an indolic acid derivative, indomethacin (IMT) (Figure 1) and the enolic acid derivatives, oxicams, represented by meloxicam (MEL), tenoxicam (TEN) and piroxicam (PIR) (Figure 2).

Figure 1.

Chemical structures of a: 2′,4′-difluoro-4-hydroxyphenyl-3-carboxylic acid, diflunisal (DFN) and b: 2-{1′-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl} acetic acid, indomethacin (IMT).

Figure 2.

Chemical structures of a: [4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1 dioxide], meloxicam (MEL), b: [4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-thieno(2,3-e)-1,2 thiazine-3-carboxamide 1,1-dioxide], tenoxicam (TEN) and c: [4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide], piroxicam (PIR).

2. Oxidation processes

Many compounds in the presence of oxygen and any electron donor can generate different ROS—by energy and/or electron transfer processes—like singlet molecular oxygen, O2(Δ1g), superoxide radical anion (O2· ) or hydrogen peroxide (H2O2) among others. An interesting example of those compounds is vitamin B2, riboflavin (Rf), a naturally occurring endogenous compound of singular importance, present in practically all living organisms. Rf absorbs energy in the wavelength range of visible light, being a well-known photosensitizer for oxidative processes [12, 13]. Upon selective absorption of energy, Rf is promoted from its ground state to electronically excited singlet state (R1f*) (Eq. (1)).

Rf+hυR1f*E1

The generated R1f*can decay to the original ground state or produce the electronically excited triplet state (R3f*) (Eq. (2)).

R1f*R3f*E2

The R3f*may react with the ground state oxygen (O2(3Σg)) (Eq. (3)) to form superoxide radical anion (O2· ), with a very low quantum yield (0.009) (Krishna, 1991).

R3f*(3Σg) Rf·++O2·E3

In living organisms, a great number of biomolecules essential to life such as DNA, RNA, lipids, and proteins, can be oxidized by the generated ROS producing oxidative stress [68, 14]. Among other substrates, NSAIDs are compounds that can be oxidized in the presence of Rf-generated ROS and as shown can act as quenchers of electronically excited states of Rf (Eqs. (4) and (5)).

R1f*+NSAIDs Rf +NSAIDs or P(4)    rate constant k1qE4
R3f*+ NSAIDsRf·+ NSAIDs ·+      rate constant k3qE5

The protonation of Rf·at neutral pH can generate the species RfH·(pKa = 8.3), (Eq. (6)).

Rf·+H+RfH·E6

Its bimolecular decay through a disproportionation reaction can yield the ground state of the vitamin and fully reduced Rf (Eq. (7)).

2RfH·Rf+RfH2E7

The last product, in the presence of ground state oxygen, is reoxidized to Rf radical and superoxide radical anion (O2·− ) (Eq. (8)).

RfH2+O2(3Σg)RfH2·++O2·         rate constant k8E8

The electron transfer process, in Eq. (8) is relevant as a source of H2O2(Eq. (9)), another important already-mentioned ROS.

RfH2·++O2·Rf+H2O2E9

In parallel, the generated O2·can chemically react with a substrate, according to Eqs. (10) and (11), respectively, illustrates the processes that occur with NSAIDs.

O2· NSAIDsP(10)     rate constant k10E10
H2O2+NSAIDsP(11)E11

Another possible pathway for R3f*is the energy transfer reaction with O2(3Σg)which generates O2(Δ1g), with reported quantum yield of 0.49 in water [15] (Eq. (12)).

R3f*+O2(3Σg)Rf+O2(Δ1g)         rate constant kETE12

The O2(Δ1g)formed may be physically quenched either by the solvent (Eq. (13)).

O2(Δ1g)O2(3Σg)E13

or by a substrate, as happens in the presence of NSAIDs (Eq. (14)).

O2(Δ1g)+NSAIDsO2(3Σg)+NSAIDs        rate constant kqE14

Finally, Eq. (15) represents the main pathway of substrate disappearance in O2(Δ1g)mediated processes.

O2(Δ1g)+NSAIDsP(15)        rate constant krE15

ktbeing the overall rate constant for physical plus chemical quenching processes (Eq. (16)).

kt=kr+kqE16

In order to get more insight into the behavior of NSAIDs toward Rf-generated ROS several in vitro experiments were performed.

2.1. Stationary photolysis: riboflavin-photosensitization

In complex biological structures, Rf and NSAIDs may occupy the same locations. Kinetic and mechanistic aspects of their mutual interaction constitute the crucial information for understanding the behavior of NSAIDs toward Rf-generated ROS and the potential in vivo consequences.

Using a home-made photolyzer, aerated neutral aqueous solutions of each of the following NSAIDs DFN, IMT, MEL, TEN, and PIR, were irradiated with the light of a 150W quartz-halogen lamp, in the presence of Rf as a sensitizer. All the NSAIDs used as substrates are transparent to visible light. Nevertheless, in order to assure that they do not absorb any incident radiation, a cut-off filter at 400 nm was employed. The processes were followed by the absorption spectra using a diode array spectrophotometer (Hewlett Packard 8452A). The light irradiation induced changes in the absorption spectra of the mixtures 0.05 mM DFN + 0.04 Rf (Figure 3), 0.05 mM IMT + 0.04 mM Rf (Figure 3, inset A) and 0.05 mM MEL + 0.04 mM Rf (Figure 4). The processes could be monitored from the absorbance decay at the respective absorption maxima for each substrate. In this way, the rates of sensitized photoxygenation for each NSAID were determined.

Figure 3.

Changes in UV-vis absorption spectra of a pH 7 aqueous solution of 0.05 mM DFN plus 0.04 mM Rf upon photoirradiation taken vs. a 0.04 mM Rf aqueous solution (spectrum a). Cut-off 400 nm interference filter, under air-saturated conditions. Numbers on the spectra represent photoirradiation time in seconds. (Inset A) Changes in UV-vis absorption spectrum of a pH 7 aqueous solution of 0.05 mM IMT plus 0.04 mM Rf upon photoirradiation taken vs. a 0.04 mM Rf aqueous solution (spectrum b). Cut-off 400 nm interference filter, under air-saturated conditions. Numbers on the spectra represent photoirradiation time in seconds. (Inset B) Oxygen consumption vs. photoirradiation time in pH 7 aerated aqueous solutions for the systems: a: Rf (A446 = 0.46) plus DFN (0.4 mM); b: Rf (A446 = 0.46) plus ITM (0.4 mM). Reprinted from Purpora et al. [10], © (2013), with permission from The American Society of Photobiology, a Wiley Company, John Wiley & Sons, Inc.

Figure 4.

Changes in UV-vis absorption spectra of aqueous solution of 0.05 mM MEL plus 0.05 mM Rf upon photoirradiation taken vs. 0.05 mM Rf aqueous solution (spectrum a). Cut-off 450 nm interference filter, under air-saturated conditions. Numbers on the spectra represent photoirradiation time in minutes. (Inset A) Changes in UV-vis absorption spectra of aqueous solution of 0.05 mM MEL plus 0.05 mM RB upon photoirradiation taken vs. 0.05 mM RB aqueous solution (spectrum b). Cut-off 450 nm interference filter, under air-saturated conditions. Numbers on the spectra represent photoirradiation time in minutes. (Inset B) Oxygen consumption vs. photoirradiation time under air saturated conditions for the systems: a: Rf 0.05 mM plus TEN (0.5 mM) in MeOH-H2O (buffer pH 7) 1:1 v/v; b: Rf 0.05 mM plus 0.5 mM PIR in MeOH-H2O (buffer pH 7) 1:1 v/v; c: Rf 0.05 mM plus 0.5 mM MEL in aqueous buffer pH 7. λirr>480 nm, cut-off filter. Reprinted from Ferrari et al. [11], © (2015), with permission from Elsevier B.V.

In parallel experiments, using a specific oxygen electrode (Orion 97-08) the oxygen concentration was measured during irradiation of the same mixtures in aqueous solutions in a closed Pyrex cell [10]. Under these conditions, all the NSAIDs under study showed oxygen consumption. Regarding the oxicams family, TEN and PIR presented the lowest rate of oxygen consumption. It was a little bit higher for MEL (Figure 4, inset B). In the corresponding set for DFN and IMT, the rate of oxygen uptake was significantly higher for the latter (Figure 3, inset B).

From all these preliminary findings, we assume that the transformations in NSAIDs can be attributed to interactions with electronically excited states of Rf with the possible participation of photogenerated ROS.

2.1.1. Kinetics and mechanism

The xantenic dye Rose Bengal (RB) is one of the most frequently employed photosensitizers that exclusively generate O2(Δ1g), with a quantum yield of 0.7 in aqueous media [15, 16]. So, experiments performed in the presence of RB involved possible O2(Δ1g)-mediated oxidation of NSAIDs. In this case, eventual interferences of other ROS that could be generated by Rf were avoided. Comparing the rates of substrate consumption by Rf – photosensitization with those in the presence of RB it was possible to elucidate the relevance of O2(Δ1g)in relation to other ROS also generated by Rf.

The combination of stationary and time-resolved experiments unambiguously demonstrates the participation of O2(Δ1g)in NSAIDs’ photooxidation processes. Using time-resolved phosphorescence detection (TRPD) [17], the overall quenching rate constant of O2(Δ1g)by NSAIDs, kt(Table 1) was determined. Hence, ktin the order of 107M1s1allows the consideration of these substrates as good quenchers of O2(Δ1g). The kr/ktratio accounts for the fraction of the overall quenching of O2(Δ1g)that produces chemical transformation in the substrate (Table 2). Low kr/ktvalues denote that O2(Δ1g)removal will proceed without a significant loss of the present NSAIDs, which act as a scavenger [18, 19].

NSAIDk1q ×1010 (M1s1)k3q ×109 (M1s1)kt ×108 (M1s1)kr ×108 (M1s1)
IMT0.89±0.06(a)1.8±0.32.6±0.22.7±0.2
DFN0.90±0.05(a)2.1±0.51.7±0.30.19±0.1
MEL2.84±0.121.5±0.31.15±0.06(b)0.73±0.04
TEN0.88±0.041.9±0.41.00±0.07(c)
(1.1) (d)
0.50±0.03
(0.61) (d)
PIR2.30±0.061.7±0.30.49±0.05(c)0.48±0.06
(1.6) (e)

Table 1.

Values for the rate constants for the interactions of each NSAID by quenching with electronically excited singlet (k1q), and triplet (k3q) of riboflavin; overall rate constants (kt)and reactive (kr)for the interaction of O2(Δ1g)with each NSAID.

(a) In MeOH; (b) in D2O, pH 7; (c) in MeOH-D2O (pD 7) 1:1 v/v; (d) in dioxane-water (molar fraction of water = 0.91) Source: [18]; (e) in MeCN Source: [19].

NSAIDkr/ktRRRfRRRB
IMT~111
DFN0.110.260.07
MEL0.6311
TEN0.520.480.68
PIR~1.000.470.67

Table 2.

Values for the ratio of the reactive and overall rates kr/kt, and relative rates of each NSAID consumption upon Rf (RRRf) and RB (RRRB) photosensitization.

Source: [10, 11].

2.2. Interaction of NSAIDs with photogenerated ROS

Some compounds that are specific ROS quenchers have been used to elucidate which species are effectively involved in a given oxidative event [20, 21]. Catalase from bovine liver (CAT) reacts with H2O2, so the photodegradation via process in Eq. (11) is inhibited due to the process represented by Eq. (17).

2 H2O2+CAT2H2O+O2(3Σg)E17

The enzyme superoxide dismutase from bovine erythrocytes (SOD) dismutates the species O2·, as shown by Eq. (18).

2O2+2H++SODO2(3Σg)+H2O2E18

Meanwhile, sodium azide (NaN3) is a known physical quencher of O2(Δ1g), with a reported rate constant kqof 4.5 × 108 M−1s−1 in water at pH 7 (Eq. (14) with NaN3 instead of NSAIDs) [22]. Several oxygen consumption experiments of NSAIDs upon Rf-photosensitization were performed adding each of these specific ROS interceptors. With DFN or IMT solutions different extent of decrease in the rates of oxygen consumption were observed upon using any of these three quenchers. This fact confirms a significant participation of O2(Δ1g)in the degradation of the analgesics DFN and IMT, in which also O2· and H2O2take part. Bar diagram of the relative rates illustrates the results obtained with IMT solutions in the presence of each specific quencher (Figure 5); DFN solutions presented similar qualitative results.

Figure 5.

Bar diagrams for the relative rates of oxygen consumption with aqueous solutions pH 7, 0.5 mM IMT plus Rf (A445 = 0.5) as function of photoirradiation time (cut-off 400 nm): ITM: alone; IMT + CAT: in the presence of 1µg mL−1 CAT; IMT + SOD: in the presence of 1µg mL−1 SOD; IMT + NaN3: in the presence of 1 mM NaN3. Reprinted from Purpora et al. [10], © (2013), with permission from The American Society of Photobiology, a Wiley Company, John Wiley & Sons, Inc.

Similar experiments were performed using solutions 0.5 mM of the three oxicams and NaN3NaN3 or SOD. The participation of O2(Δ1g)in the oxidation processes of these NSAIDs was revealed by the lower rates of oxygen uptake (Figure 6). As in the previous cases, for MEL the presence of SOD produced a decrease in the rates of oxygen consumption. Meanwhile for TEN and PIR it was the other way around. This fact can be due to the participation of O2·with different mechanistic roles. The regeneration of O2(3Σg)(Eq. (18)) at expenses of O2·increases the O2(Δ1g)leading to the detected rates increased.

Figure 6.

Bar diagrams for the relative rates of oxygen consumption upon photoirradiation as function of photoirration time (cut-off filter 400 nm) in the presence of Rf 0.05 mM with the following solutions: 0.5 mM PIR in MeOH-H2O (buffer pH 7) 1:1 v/v plus 1 µg mL−1 SOD; 0.5 mM PIR in MeOH-H2O (buffer pH 7) 1:1 v/v; 0.5 mM TEN in MeOH-H2O (buffer pH 7) 1:1 v/v plus 1 µg mL−1 SOD; 0.5 mM TEN in MeOH-H2O (buffer pH 7) 1:1 v/v; 0.5 mM MEL plus 1 µg mL−1 SOD in aqueous buffer pH 7; 0.5 mM MEL in aqueous buffer pH 7. Reprinted from Ferrari et al. [11], © (2015), with permission from Elsevier B.V.

3. Photoprotective effect of NSAIDs toward amino acids and peptides oxidation

In order to evaluate an eventual antioxidant/protective effect of NSAIDs towards biologically relevant substrates, amino acids (AA) and peptides may be employed as typical oxidizable targets in a proteinaceous medium.

Tryptophan (Trp) and tyrosine (Tyr) are AAs that can be affected by photo-damages through photodynamic activity [23, 24]. They are known quenchers of R3f*with k3qof 2.5×109 M1s1and 1.0×109 M1s1, respectively [13]. In order to evaluate the eventual protective effect of NSAIDs against photooxidation, Rf-photosensitized experiments were performed using each of these AA and the oxicam PIR. For comparative purposes, the trials were also performed replacing Rf by RB which ensures that the prevalent oxidation process is due to O2(Δ1g). As a measure of the global photooxidative process, the rates of oxygen consumption were determined in each trial monitoring up to 10% conversion of the substrate under study.

PIR and Trp, as isolated substrates, are efficient O2(Δ1g)chemical scavengers. Their krvalues are virtually identical, while the kr/ktrelationship presents also very similar values. For the interaction Trp-O2(Δ1g)it has been reported the rate constant values kt=7.2×107M1s1. and kt=4.7×107M1s1.[13, 25]. Using RB as the sensitizer, the rates of oxygen uptake for the mixture PIR + Trp were approximately equal to the rates of PIR and Trp individually considered, which may be due to the fact that they react through a pure O2(Δ1g)-mediated process (Figure 7). Employing Rf as the photosensitizer, the mixture PIR + Trp presented a rate of oxygen consumption significantly lower than the addition of the respective rates for each substrate. A possible explanation is that both compounds present a high k3q value, so the simultaneous action of them may decrease the O2(Δ1g)concentration leading to the lower rate observed with the presence of the mixture.

Figure 7.

Bar diagrams for the relative rates of oxygen consumption upon RB (A560 = 0.4) photosensitization in pH 7 buffered aqueous solution by: 0.5 mM PIR; 0.5 mM Trp; 0.5 mM PIR plus 0.5 mM Trp. And upon Rf (A445 = 0.5) photosensitization in pH 7 buffered aqueous solution by: 0.5 mM PIR; 0.5 mM Trp; 0.5 mM PIR plus 0.5 mM Trp. Reprinted from Ferrari et al. [11], © (2015), with permission from Elsevier B.V.

In neutral pH, Tyr is present in a very low reactive form. The interaction Tyr with O2(Δ1g)mostly operates by physical deactivation of the ROS with a reported rate constant value kt=1.5×107M1s1[22, 26]. The very low kr/ktmay be due to the clear decrease in the rate of oxygen uptake by the mixture PIR + Tyr as compared to the one for the isolated PIR with RB as the photosensitizer. (Figure 8) With Rf as a sensitizer, the corresponding rates for PIR alone and the one for the mixture are practically equal.

Figure 8.

Bar diagrams for the relative rates of oxygen consumption upon RB (A560 = 0.4) photosensitization in pH 7 buffered aqueous solution by: 0.5 mM PIR; 0.5 mM Tyr; 0.5 mM PIR plus 0.5 mM Tyr. And upon Rf (A445 = 0.5) photosensitization in pH 7 buffered aqueous solution by: 0.5 mM PIR; 0.5 mM Tyr; 0.5 mM PIR plus 0.5 mM Tyr. Reprinted from Ferrari et al. [11], © (2015), with permission from Elsevier B.V.

A relevant result was that PIR in the presence of Rf showed an interesting degree of protection against Trp or Tyr oxidation by the in situ-photogenerated ROS. This fact has been revealed by the lower rates of oxygen consumption of the mixture oxicam-AA as compared to the ones for the individual substrates.

The dipeptide Trp-Tyr in a 0.5 mM aqueous solution was employed as a biologically relevant model compound, with RB or Rf as photosensitizers and IMT or DFN as potential photo-protective substrates. The O2(Δ1g)- mediated process of Trp-Tyr could be studied using RB alone. Its rate constant value kr=5.9×107M1s1had already been reported [24]. The comparison of the relative rates of oxygen consumption in the presence and in the absence of 0.5 mM IMT showed that the value for the mixture Trp-Tyr + IMT was close to the simple addition of the respective individual rates (Figure 9).

Figure 9.

Bar diagram for the relative rates of oxygen consumption upon RB (A560 = 0.4) photosensitization in pH 7 buffered aqueous solution of: 0.5 mM Trp-Tyr; 0.5 mM IMT; 0.5 mM DFN; 0.5 mM Trp-Tyr plus 0.5 IMT; 0.5 mM Trp-Tyr plus 0.5 DFN. Reprinted from Purpora et al. [10], © (2013), with permission from The American Society of Photobiology, a Wiley Company, John Wiley & Sons, Inc.

Meanwhile, the rate for the mixture Trp-Tyr + DFN decreased more than 50% of the one for the isolated dipeptide. Upon Rf-sensitization, similar results were obtained for DFN and IMT (Figure 10). This fact suggested that the photoxidation occurs mainly by reaction with the Rf-photogenerated O2(Δ1g).

Figure 10.

Bar diagram for the relative rates of oxygen consumption upon Rf (A445 = 0.5) photosensitization in pH 7 buffered aqueous solution of: 0.5 mM Trp-Tyr; 0.5 mM IMT; 0.5 mM DFN; 0.5 mM Trp-Tyr plus 0.5 IMT; 0.5 mM Trp-Tyr plus 0.5 DFN. Reprinted from Purpora et al. [10], © (2013), with permission from The American Society of Photobiology, a Wiley Company, John Wiley & Sons, Inc.

4. Conclusions

The results presented for the NSAIDs under study pointed out their efficiency as quenchers of photogenerated O2(Δ1g). In Rf-photosensitized processes the dominant mechanism is the O2(Δ1g)-mediated, but also other ROS can be intercepted by most of them. The experiments here detailed showed that DFN and IMT can interact with H2O2and O2whereas MEL is an effective quencher for the latter Rf-photogenerated species.

DNF could be considered as an ideal scavenger of O2(Δ1g), as the oxidative process occurs by a physical mechanism without significant self-degradation of this NSAID. In the case of IMT or oxicams, their protective effect decline along the time. The reason is that these scavengers can also be targets of the oxidation ROS-mediated processes. Even though, the in vivo antioxidant effectiveness would be warranted by daily and prolonged intake. Generally, that is the form of administration in which these analgesics are employed in the treatment of serious detrimental inflammatory illness or chronic pains.

Based on the discussed results, the NSAIDs studied herein present, in principle, promising properties for medicinal use as bio-antioxidants against in situ generated ROS. Nevertheless, great care must be taken because at the same time different negative effects in the human body have been reported [27, 28]. The literature on this topic, in most cases, only mentions rare but possible gastrointestinal adverse effects [29]. In the case of DFN, the reported side effects are not so dramatic, but IMT and MEL have been connected to the pathogenesis of gastric and intestinal mucosal lesions with participation of ROS [3032]. Those undesired effects must be thoroughly taken into account mainly because of the relative high doses necessary with some of them in order to guarantee the replenishment, ensuring the antioxidant effectiveness against ROS activity.

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Norman A. García, Mabel Bregliani and Adriana Pajares (May 24th 2017). Interaction of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) with Reactive Oxygen Species (ROS): Possible Biomedical Implications, Pain Relief - From Analgesics to Alternative Therapies, Cecilia Maldonado, IntechOpen, DOI: 10.5772/66478. Available from:

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