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Keywords:

  • cyclooxygenase;
  • gastroduodenal damage;
  • non-steroidal anti-inflammatory drug;
  • safety

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanisms of NSAID-induced gastroduodenal damage
  5. Further explored pathogenic mechanisms related to NSAID toxicity
  6. Potential of novel therapeutic compounds to reduce NSAID-induced gastroduodenal damage
  7. Perspective and future directions
  8. Acknowledgment
  9. References

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs worldwide, which attests to their efficacy as analgesic, antipyretic and anti-inflammatory agents as well as anticancer drugs. However, NSAID use also carries a risk of major gastroduodenal events, including symptomatic ulcers and their serious complications that can lead to fatal outcomes. The development of “coxibs” (selective cyclooxygenase-2 [COX-2] inhibitors) offered similar efficacy with reduced toxicity, but this promise of gastroduodenal safety has only partially been fulfilled, and is now dented with associated risks of cardiovascular or intestinal complications. Recent advances in basic science and biotechnology have given insights into molecular mechanisms of NSAID-induced gastroduodenal damage beyond COX-2 inhibition. The emergence of newer kinds of NSAIDs should alleviate gastroduodenal toxicity without compromising innate drug efficacy. In this review, novel strategies for avoiding NSAID-associated gastroduodenal damage will be described.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanisms of NSAID-induced gastroduodenal damage
  5. Further explored pathogenic mechanisms related to NSAID toxicity
  6. Potential of novel therapeutic compounds to reduce NSAID-induced gastroduodenal damage
  7. Perspective and future directions
  8. Acknowledgment
  9. References

For many years, non-steroidal anti-inflammatory drugs (NSAIDs) have been used for analgesic, anti-inflammatory and antithrombotic actions, the latter against vascular disease, and more recently for cancer prevention through cyclooxygenase (COX)-dependent or -independent mechanisms.1–4 In spite of these diverse applications of NSAIDs, numerous studies have suggested an approximately 4–5-fold enhancement of the risk of ulcer bleeding, perforation and death, especially in elderly patients taking NSAIDs. Older patients taking NSAIDs carried a much higher risk, approximately 13-fold (range, 10–17) compared with younger patients taking NSAIDs. Age, previous ulcer history, high NSAID doses, and concomitant use of anticoagulants or corticosteroids may magnify the risk of bleeding peptic ulcer in patients taking NSAIDs. Further, the indication for NSAID use, sex, smoking and alcohol history, and the status of Helicobacter pylori infection appear to be risk modifiers, albeit with some controversy.

The fact that older patients are more likely to develop NSAID-induced gastropathy and serious complications including perforation or bleeding than younger patients could be attributable to the decline of gastric mucosal prostaglandin synthesis with age. There are also apparent reductions of mucosal blood flow, bicarbonate secretion and mucus synthesis in response to injurious challenges in aged persons.5–11

All of these adverse outcomes with NSAID use are closely related to the impairment maintenance of integrity maintenance in the gastroduodenal mucosa, presenting with various degree of gastroduodenal damage (Fig. 1). In this mini-series review, the novel strategies to rescue patients from NSAID-associated gastrointestinal damage will be described, including introduction of potential novel therapeutics. The latter include gas, for instance, nitric oxide (NO) or hydrogen sulfide (H2S), -complexed NSAIDs, NSAIDs possessing dual inhibition of both COX and lipoxygenase (LOX), lipid-modified NSAIDs, and zinc compounds or zinc complexed NSAIDs.

image

Figure 1. (a) Endoscopic photos showing non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy. Active bleeding gastric ulcer, perforated gastric ulcer, and duodenal ulcer perforated or vessel exposure case are serious complications associated with NSAIDs, leading to mortality. (b) Biosynthesis of eicosanoids from arachidonic acid. Prostaglandin (PG)E2 and prostacyclins are important for the gastroduodenal mucosal integrity, whereas PGF2α and thromboxens are responsible for weakening gastroduodenal defense. Moreover, leukotrienes are also notorious for inflammation.

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Mechanisms of NSAID-induced gastroduodenal damage

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanisms of NSAID-induced gastroduodenal damage
  5. Further explored pathogenic mechanisms related to NSAID toxicity
  6. Potential of novel therapeutic compounds to reduce NSAID-induced gastroduodenal damage
  7. Perspective and future directions
  8. Acknowledgment
  9. References

“Classical’ mechanisms of NSAID toxicity”

Direct toxic effects

Because most NSAIDs are, with a few exceptions, molecules with acidic properties, of which pKa values are around 3–5, these acidic natures of NSAIDs can cause cell dehydration and cell death directly. Moreover, since the stomach gastric mucosa is under an acidic milieu, NSAIDs of pKa value of 4–5 will be became easily ionized, leading to enhanced entry of the drug into the gastric mucosal cells in which they exist predominantly in the non-ionized state because of cytoplasmic pH being neutral. Eventually, intracellular NSAIDs become ionized, less lipid soluble and unable to leave the gastric epithelial cell. Their resultant accumulation within gastric mucosal cells creates a so called ‘chemical greenhouse’ effect.12,13

Effects on the mucus-bicarbonate barrier

A wide range of NSAIDs are capable of inhibiting mucus biosynthesis, reducing mucus glycoprotein production, weakening the surface mucus barrier and lowering bicarbonate secretion. This enhances mucosal permeability by weakening tight junctions. All of these effects facilitate mucosal damage.14,15

Effects on mucosal blood flow

In a study using a chambered segment of canine gastric corpus, local application of NSAIDs induced the appearance of focal mucosal pallor followed by subsequent hemorrhagic foci and ulceration.16 The changes occurred simultaneously with a decrease in mucosal blood flow, after which mucosal damage seemed to be inevitable.17

Epithelial cell renewal

Acute administration of NSAIDs inhibits cell proliferation in the gastric mucosa, while chronic administration stimulates cell proliferation in fundic and duodenal mucosa. This latter stimulatory effect might be a compensatory reaction to acute mucosal injury, and thereby represents one mechanism for adaptation of the gastric and duodenal mucosa to continued NSAID exposure. Even though the precise net outcome of NSAID action on cell proliferation remains unclear, it is generally agreed that NSAIDs might confer inferior mucosal integrity and delay the repair of injury.18,19

Surface-active phospholipids

Chemical association between NSAIDs and gastric surface phospholipids may explain the decline of mucosal hydrophobicity after exposure of the gastric mucosa to acidic derivatives of NSAIDs. This partly explains the loss of one of the key defenses mechanisms in the stomach.20,21

Endogenous eicosanoids

Inhibition of the synthesis of cytoprotective prostaglandins (PG) is regarded as a major factor contributing to gastric damage after NSAIDs (Fig. 1b). COX-1 is a house-keeping enzyme, constitutively expressed in many tissues, while COX-2 is an inducible form of the enzyme. COX-1 produces PG that exert cytoprotective effects, while COX-2 produces PG that contribute to inflammation. Therefore, NSAIDs with weaker activity against COX-2 than COX-1 are expected to cause more gastrointestinal cytotoxicity.22,23 Two ‘coxibs’ drugs have been developed, rofecoxib and celecoxib, both appearing to be effective as much as non-selective NSAIDs. However, rofecoxib has been withdrawn due to serious cardiac adverse effects and paradoxical results have been obtained from experiments using COX-1 knockout mice; these animals do not develop gastrointestinal ulceration at an increased rate, and have some reduced inflammatory response, while COX-2 knockout mice show renal abnormalities and relatively minor changes in the inflammatory response.24 These findings challenge the prospects for relying on COX-2 inhibitors to provide safer alternatives to conventional NSAIDs and new strategies are urgently required to develop more effective and safer NSAIDs in the current era of ‘coxib’ prescribing.

Leukocyte-endothelial interactions

Even though NSAIDs are anti-inflammatory in nature, they paradoxically initiate or exacerbate inflammation in the stomach. This discrepancy is explained by upregulation of adhesion molecules with leukocyte adherence to the vascular endothelium in the gastric microcirculation. Specifically, increased synthesis of tumor necrosis factor-α (TNF-α) and leukotriene (LT) B4, and upregulation of the intracellular adhesion molecule-1 (ICAM-1) are observed in gastric tissue after NSAID administration.25,26

Uncoupling of oxidative phosphorylation

It has been suggested that NSAIDs uncouple oxidative phosphorylation, resulting in depletion of cellular adenosine triphosphate (ATP) and leading to cell death. As much as PG dependent way is responsible for NSAID-induced mucosal damage through inhibiting COX activity, ‘topical’ uncoupled mitochondrial oxidative phosphorylation led to increased permeability and mucosal inflammation without decreasing mucosal prostanoid levels. Taken together, both uncoupling of mitochondrial oxidative phosphorylation and direct COX inhibition seem to be particularly important in NSAID-induced enteropathy.27–29

Gastrointestinal motility

Subcutaneous administration of NSAIDs causes an increase in both amplitude and frequency of gastric contractions. In turn, this causes microvascular permeability and cellular damage.30

Further explored pathogenic mechanisms related to NSAID toxicity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanisms of NSAID-induced gastroduodenal damage
  5. Further explored pathogenic mechanisms related to NSAID toxicity
  6. Potential of novel therapeutic compounds to reduce NSAID-induced gastroduodenal damage
  7. Perspective and future directions
  8. Acknowledgment
  9. References

Endoplasmic reticulum (ER) stress response

Accumulation of unfolded protein in the ER induces the ER stress response, otherwise known as ‘the unfolded protein response’ (UPR). In the mammalian ER stress response, three types of transmembrane proteins are engaged: (i) protein kinase and specific endonuclease 1 including inositol requiring ER-to-nucleus signal kinase 1 (IRE1); (ii) protein kinase R-like ER kinase/pancreatic eukaryotic translation initiation factor 2 kinase (PERK/PEK): and (iii) activating transcription factor 6 (ATF6). In turn, these pathways determine adaptations by which cells survive, or apoptotic death is determined (Fig. 2).31–34 By inducing ER-resident stress proteins such as glucose-regulated protein (GRP)-78 and GRP-94, cells adapt to the accumulation of unfolded proteins to maintain homeostasis in the ER. However, if this adaptation does not prove sufficient, the apoptotic response is initiated by both ATF6 and ATF4-dependent activation of C/EBP homologous transcription factor (CHOP). The primary purpose of an ER stress response is to alleviate the stressful disturbance and restore proper ER homeostasis to the ER. When gastric or intestinal cells are exposed continuously to NSAIDs, NSAIDs induce an ER stress response with induction of both GRP78 and CHOP. This ER stress response also causes activation of ATF6, ATF4 and X-binding protein (XBP). Interestingly, although celecoxib was thought to be safer compared to conventional NSAIDs, it generated increased levels of cytosolic intracellular calcium ([Ca++]i) with subsequent activation of an ER stress response.35–38

image

Figure 2. Mammalian response pathways for endoplasmic reticulum (ER) stress after non-steroidal anti-inflammatory drug (NSAID) administration. The three response pathways (pancreatic eukaryotic translation initiation factor 2 kinase [PERK], activating transcription factor 6 [ATF6], IRE1) regulate the mammalian ER stress response. PERK, a transmembrane kinase, phosphorylates eIF2α to attenuate translation, and to upregulate expression of ATF4, leading to enhanced transcription of target genes such as C/EBP homologous transcription factor (CHOP). ATF6, a transmembrane transcription factor, is translocated to the Golgi apparatus and cleavaged by proteases, leading to enhanced transcription of ER chaperone genes. IRE1, a transmembrane RNase, splices XBP1 pre-mRNA, and pXBP1 translated from mature XBP1 mRNA activates transcription of ER-associated degradation (ERAD) component genes.

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Peroxisome proliferation-activated receptor (PPAR)

Stimulation of PPAR with subsequent inhibition of nuclear factor-κB (NF-κB) and other transcription factors plays an important role in the mechanism of NSAID actions. PPAR are members of the nuclear response family of transcription factors. PPAR-α is highly expressed in the liver, skeletal muscle and heart. PPAR-γ is expressed in adipose tissue, but is also present at high levels in the intestine, breast tissue, and so on. PPAR-β/α is ubiquitously expressed, with the highest levels in skin and skeletal muscle. Generally, PPAR regulate transcription of target genes involved in lipid and lipoprotein metabolism, glucose homeostasis and cell differentiation. In addition, PPAR inhibit the activation of certain inflammatory response genes by acting as trans-repressors. Thus, activated PPAR-α during NSAID administration blocks the production of inflammatory response markers, such endothelin-1, ICAM-1, and vascular cell adhesion molecule-1 in endothelial cells, and tissue factors, including matrix metalloproteinase-3 (MMP-3) and TNF-α in macrophages. These anti-inflammatory actions of PPAR activation are mediated by inhibition of pro-inflammatory transcription pathways, such as NF-κB, activator protein-1 (AP-1), nuclear factor of activated T cells (NFAT) and Ccaat enhancer binding protein (C/EBP) or Smad3.39–41

Hydrogen sulfide (H2S)

Nitric oxide and carbon monoxide (CO) can be ranked as the first and second gaseous neurotransmitters of interest, while H2S ranks third. It is produced in significant amounts in most tissues, with the highest rates of production in the brain, cardiovascular system, liver, stomach and kidney. H2S exhibits a ‘double-edged’ role in clinical diseases. Thus, it can be detrimental or protective in the central nervous system, exert either pro-inflammatory or anti-inflammatory effects, vaso-relaxation or atherosclerosis. In the gastrointestinal system tract, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), the enzymes responsible for H2S generation, are expressed in the gastric mucosa. Endogenous H2S seems to be a protective factor against mucosal injury, whereas it may contribute pro-inflammatory actions in H. pylori infection. Evidence is accumulating that inhibitors of H2S production, or therapeutic H2S donor compounds, exert significant effects in animal models of inflammation, reperfusion injury and circulatory shock. With respect to NSAIDs, H2S can induce upregulation of anti-inflammatory and cytoprotective genes, including heme oxidase-1 (HO-1), vascular endothelial growth factor, insulin-like growth factor receptor, and several genes associated with the transforming growth factor (TGF)-β receptor signaling pathway. By upregulating HO-1, H2S can trigger the production of CO, another neurotransmitter with well-documented cytoprotective and anti-inflammatory effects exerted by inhibition of NF-κB and inducible nitric oxide synthase (iNOS). Other distinct pharmacological effects of H2S relate to the opening of potassium-opened ATP channels (KAPT channels or KATP) in leukocytes or endothelium, leading to vaso-relaxing and smooth muscle relaxing effects. H2S can also inhibit cellular respiration, at least in part, by acting as an inhibitor of cytochrome c oxidase through an interaction with its copper center. All of these protective roles of H2S have been documented in the following situations; cardioprotection, relieving of inflammation and inflammation-related pain, acceleration of wound healing through angiogenesis, and NSAID-induced gastroenteropathy. Regarding the relationship between NSAID toxicity and leukocyte-endothelial interface, under normal conditions, H2S is synthesized in blood vessels primarily by CSE, which is expressed in endothelial cells and smooth muscle cells. H2S tonically downregulates leukocyte adherence through the activation of KATP on both leukocytes and endothelial cells. However, when synthesis of H2S is suppressed by NSAIDs or β-cyanoalanine, leukocyte rolling and adherence to the vascular endothelium might increase accompanied with a marked increase in endothelial permeability (Fig. 3). Currently, development of H2S as therapeutics in a form of an inhaled gas or parenteral injection is underway as well as modified drugs containing H2S-releasing moieties.42,43

image

Figure 3. Protective effects of hydrogen sulfide (H2S) against non-steroidal anti-inflammatory drugs (NSAIDs)-induced leukocyte-endothelial interaction. H2S synthesized by cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS) genes, expressed in endothelial cells or smooth muscle cells tonically downregulates leukocyte adherence through the activation of potassium adenosine triphosphate (ATP) ion channel (KATP) on neutrophil and endothelium. However, when H2S synthesis is inhibited after NSAID administration, leukocyte adherence to vascular endothelium increased and was accompanied with increases in endothelial permeability, resulting in evagination of leukocyte and uropod formation.

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Uncoupling of mitochondrial oxidative phosphorylation

The topical toxicity hypothesis proposes that gastrointestinal damage is initiated by the accumulation of NSAIDs by mucosal cells, with subsequent impairment of mitochondrial energy metabolism. This is based on the observation that most NSAIDs uncouple isolated mitochondria and inhibit oxidative phosphorylation. Disruption of mitochondrial energy metabolism reduces ATP synthesis and leads to a breach of gastrointestinal barrier function, with increased mucosal permeability and an inflammatory tissue reaction. Salicylates, the main metabolites of acetylsalicylic acid, are known as classical uncouplers of oxidative phosphorylation. Diclofenac sodium, mefenamic acid and piroxicam are approximately 20–200-fold more potent as uncouplers of oxidative phosphorylation than salicylic acid; they act on the inner mitochondrial membrane as proton ionophores. The importance of elucidating the mechanism of the ‘uncoupled mitochondrial oxidative phosphorylation’ damaging effect of NSAIDs lies in the fact that it may be possible, by chemical modification, to make these agents safer. One strategy in particular is to develop safer NSAIDs through modification of the carboxyl group common to most of them.44,45

HO-1

Heme oxidase-1 is the rate-limiting enzyme of heme catabolism. It catalyzes the breakdown of heme into equimolar amounts of CO, iron and biliverdin. Three isoforms transcribed from separate genes have been characterized, among which HO-2 and HO-3 are primarily constitutive, but HO-1 is highly inducible. HO-1, also known as heat shock protein-32, is a stress-response protein and its substrate, heme and various stressors, such as oxidative stressors, ultraviolet irradiation, inflammatory cytokines, heavy metals and NSAIDs, all induce HO-1 production.46 Because bilirubin and biliverdin are potent antioxidants, and CO has anti-apoptotic activities, upregulation of HO-1 makes cells resistant to apoptosis induced by NSAIDs. Upregulation of HO-1 mediates either anti-inflammatory or anti-oxidative effects through the Rac1/NADPH oxidase (NOX)/reactive oxygen species (ROS)/p38 signaling cascade. It is therefore of interest that certain novel NSAIDs, among which 15-deoxy-Δ-12,14 PGJ2 and NS398 are representative,47 exert these protective effects through upregulating HO-1.

Lipoxin A4 (LXA4)

Lipoxin A4 was first identified as a 5-LOX interaction product of activated leukocytes, but was later identified as a mediator contributing to resolution of the inflammatory state. Aspirin plays a key role in lipoxin biosynthesis because it can acetylate a key serine residue in both COX-1 and COX-2. This inhibits the production of prostanoids from archidonic acid. While aspirin appears to completely inhibit COX-1 activity, residual COX-2 activity can still convert arachidonic acid to 5-hydroxyeicosatetraenoic acid (5-HETE). 5-HETE can be further metabolized through 5-lipoxygenase to 15(R)-epilipoxin A4, an isomer of LXA4. However, LXA4 can also be synthesized independently of aspirin administration, and has the capacity to make an important contribution to mucosal defense. In addition to the resolution of inflammatory actions, LXA4 can inhibit inflammatory pain processing and regulate trans-epithelial electrical resistance (TEER) (Fig. 4). To capture these properties therapeutically, a new class of chemically and metabolically stable lipoxin analogs has been designed.48–51

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Figure 4. Biosynthesis of lipoxins and cell–cell interaction. Lipoxins, nominated from lipoxygenase interaction products, are generated from arachidonic acid through the sequential actions of lipoxygenase and subsequent reactions to give specific trihtdroxytetraene-containing eicosanoids. They are the first recognized eicosanoid chemical mediators that display both potent anti-inflammatory and pro-resolving actions.

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Potential of novel therapeutic compounds to reduce NSAID-induced gastroduodenal damage

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanisms of NSAID-induced gastroduodenal damage
  5. Further explored pathogenic mechanisms related to NSAID toxicity
  6. Potential of novel therapeutic compounds to reduce NSAID-induced gastroduodenal damage
  7. Perspective and future directions
  8. Acknowledgment
  9. References

H2S-releasing NSAIDs

The following facts allow a group of investigators to generate a new class of anti-inflammatory drugs combined with the gaseous component H2S: (i) both aspirin and NSAIDs reduced the CSE expression and decrease H2S production in the gastric mucosa; (ii) sodium hydrogen sulfide (NaHS) can prevent the reduction of mucosal blood flow induced by aspirin and NSAID in rats; (iii) NaHS reduces NSAID-induced leukocyte adherence to vascular endothelium; and (iv) NaHS counters increased expression of TNF-α and ICAM-1, and improves PGE2 synthesis impaired by NSAIDs. The principal actions by which these H2S releasing-NSAIDs ameliorate defective blood flow after NSAID administration are depicted in Figure 3. In animal experiments, there was no change in hematocrit treated with H2S-releasing diclofenac, while diclofenac administration resulted in a decrease in hematocrit of 50%, consistent with widespread bleeding in the gastrointestinal tract. H2S-related pharmacological research is a rapidly emerging field, and is likely to yield a number of therapeutic possibilities; early stage drug candidates are now in development.52–57

Phosphatidylcholine (PC)-NSAID/membrane fusion-NSAID

Because PC is the major surfactant phospholipid, conferring gastric mucosa surface hydrophobic characteristics, the administration of NSAIDs chemically pre-associated with PC may mitigate NSAID-induced surface injury to the gastroduodenal mucosa.58,59 In practice, PC-ibuprofen appeared significantly safer than ibuprofen, especially in older patients,60 while indomethacin modified to DP-155, a lipid-modified formulation comprised of an indomethacin molecule covalently attached through a linker to PC, lecithin, showed a superior safety prolife than the parent compound.61 This enabled long-term indomethacin-based therapy to prevent Alzheimer's disease. An additional merit of lecithin vesicles containing NSAIDs might be the feasibility of topical application.62,63

Zinc-NSAIDs

Santos et al.64 showed that complex formation of zinc with diclofenac does not change the anti-inflammatory or anti-nociceptive properties of the parent drug, but significantly reduced the severity of gastric lesions induced by diclofenac. Similar beneficial outcomes against NSAID-induced injury were noted with tenoxicam or indomethacin zinc complexes. In addition, to protect against NSAID-injury, NSAID complexed with zinc micromineral conferred significant protection from stress- or cold-induced mucosal injury.65–67 Zinc ions are known to possess both anti-ulcer properties and anti-inflammatory activity, and a significant association between lower zinc levels and high gastritis score has been noted in H. pylori infection. These observations provide an additional rationale for trials of zinc-containing NSAIDs.

Nitric oxide-releasing NSAIDs/sidenafil

Elliott et al.68 first attempted to show that healing of experimental gastric ulcers can be accelerated by NO-releasing (or donating) NSAIDs, or NSAIDs combined with an NO donor. In contrast to standard NSAIDs like diclofenac or indomethacin, which have no effect on ulcer healing, nitrofene accelerated the healing of gastric ulcers. The mechanisms by which NO-releasing NSAIDs promote ulcer healing may be based on the role of NO an important mediator of gastric mucosal defense, modulating mucosal blood flow and mucus secretion. NO-naproxene, another novel gastrointestinal-sparing NSAID derivative with superior analgesic and comparable anti-inflammatory properties to the parent moiety, also showed anti-inflammatory and anti-oxidative actions in addition to maintaining mucus gel thickness and modulating gastrointestinal permeability (Fig. 5).69 Jansson et al.69 also showed that administration of dietary nitrate achieved protection from diclofenac-induced gastric ulcer; this study was based on the finding that dietary nitrate pretreatment dose-dependently and potently reduced NSAID-induced gastric lesions. In a similar way, sidenafil (well-known as Viagra, New York, NY, USA), an inhibitor of phosphodiesterase V, the enzyme responsible for breakdown of cyclic-guanosine monophosphate (cGMP), affords protection against NSAID-induced gastric damage through maintenance of gastric blood flow without inhibiting the effect of the NSAIDs on gastric PGE2 levels.70,71

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Figure 5. Proposed mechanisms of cyclooxygenase inhibitor NO donor (CINOD), hydrogen sulfide (H2S)–non-steroidal anti-inflammatory drug (NSAID), and zinc-NSAID. Non-selective NSAIDs coupled to gaseous components (nitric oxide or H2S) or zinc micromineral imposed significant protection from gastrointestinal damage through vasodilatation, anti-inflammation and some cytoprotective actions.

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Dual inhibitors of COX and LOX

Arachidonic acid is the substrate for both COX-1 and COX-2, oxidation which form not only PG, but also LT, the latter by the action of 5-LOX. LTB4 is a potent chemotactic agent for leukocytes and has been reported to play an important role in the development of NSAID-associated gastroduodenal ulcers. Therefore, developing compounds that can inhibit both COX and 5-LOX could enhance anti-inflammatory effects and reduce undesirable side-effects. As a result, one of the first examples of dual acting anti-inflammatory drug was tepoxalin, followed by the appearance of BF-389, ER-34122, ML3000, RWJ 63556, PGV20229, licofelone, among others. However, as often happens in science, things are never as simple as they appear. Even though the development of dual inhibitors may represent a new promising alternative, inhibition of the COX pathway increases formation of LT through peroxidative cleavage of 5-HETE, while 5-LOX inhibition would attenuate this effect.72–74

Co-therapy with gastroprotectants

Geranylgeranylacetone (GGA), one of the leading anti-ulcer drugs in Japan, stimulates the synthesis of mucus, increases mucosal blood flow and induces heat shock proteins, a novel activity to protect the gastric mucosa against NSAIDs. Ushijima et al.75 proposed a rationale for prescribing GGA against NSAID-injury, based on the membrane-stabilizing action of GGA. GGA suppressed NSAID-induced permeabilization of calcein-loaded liposomes and NSAID-induced stimulation of K+-efflux across the cytoplasmic membranes in cells. Rebamipide is another gastroprotectant with various mechanisms for ulcer healing and prevention of gastric damage induced by NSAIDs. These include induction of PG synthesis through COX-2 expression, and upregulation of growth factors like epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), and anti-inflammatory activities through a free radical scavenging effect, inhibition of neutrophil activation and inhibition of cytokine production from leukocytes. As expected, rebamipide exerted significant protection against both aspirin- and indomethacin-induced gastric injury in humans and animals.76–78

Zinc compounds

Zinc is an essential trace mineral required by many enzymes in different biological systems. Among zinc-dependent enzymes, DNA and RNA polymerases are crucial during tissue repair, as they affect cell proliferation and protein synthesis. Therefore, zinc deficiency delays the process of wound healing in skin, and halts restorative pathways in gastric ulcer repair. From the extended points of view related to zinc in various gastroenterological disorders, zinc compounds conferred protection against radiation-induced cell damage, and attenuated hepatic fibrosis in a mouse model of non-alcoholic steatohepatitis.79,80 Currently, two kinds of zinc compound are available clinically as tools for preventing NSAID-toxicity: zinc carnosine (ZnC) and zinc acexamate (ZnAc).81–95 ZnC is an artificially produced derivative of carnosine, whereby zinc and carnosine are linked in a one-to-one ratio to provide a polymeric structure. ZnAc delivers zinc micromineral complexed with acexamic acid.

Perspective and future directions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanisms of NSAID-induced gastroduodenal damage
  5. Further explored pathogenic mechanisms related to NSAID toxicity
  6. Potential of novel therapeutic compounds to reduce NSAID-induced gastroduodenal damage
  7. Perspective and future directions
  8. Acknowledgment
  9. References

One of the greatest accomplishments of modern medicine might be the prolongation of human longevity. However, this brings with it an incremental requirement for greater prescription of drugs like NSAIDs to mitigate the pains arising from neurodegenerative changes. The large number of victims suffering gastroduodenal damage is witness to this. To date, advances and increasing understanding of mechanisms underlying NSAID-induced gastroduodenal damage have led to the development of potential newer therapeutics, including coxibs, COX and LOX dual-inhibiting NSAIDs, NO-NSAID, H2S-NSAIDs, zinc-NSAIDs, PC-NSAIDs and zinc compounds. Optimism in this field is exuberantly reflected by such running titles from researchers as: ‘Building a better aspirin; gaseous solution to a century-old problem’,56‘Turn to the path of resolving neutrophil’,96‘NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action’.97 In our opinion, it is likely that clinicians will be able to rescue their patients from the assault of NSAID damage in the near future. However, more effort should be paid to documenting the molecular pathogenesis of NSAID-induced damage and to solve the life-threatening questions drawn from the clinic.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Mechanisms of NSAID-induced gastroduodenal damage
  5. Further explored pathogenic mechanisms related to NSAID toxicity
  6. Potential of novel therapeutic compounds to reduce NSAID-induced gastroduodenal damage
  7. Perspective and future directions
  8. Acknowledgment
  9. References