Mediators of Inflammation and Immune Responses in the Human Gastrointestinal TractView this Special Issue
Review Article | Open Access
Current Perspectives in NSAID-Induced Gastropathy
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most highly prescribed drugs in the world. Their analgesic, anti-inflammatory, and antipyretic actions may be beneficial; however, they are associated with severe side effects including gastrointestinal injury and peptic ulceration. Though several approaches for limiting these side effects have been adopted, like the use of COX-2 specific drugs, comedication of acid suppressants like proton pump inhibitors and prostaglandin analogs, these alternatives have limitations in terms of efficacy and side effects. In this paper, the mechanism of action of NSAIDs and their critical gastrointestinal complications have been reviewed. This paper also provides the information on different preventive measures prescribed to minimize such adverse effects and analyses the new suggested strategies for development of novel drugs to maintain the anti-inflammatory functions of NSAIDs along with effective gastrointestinal protection.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most well recognized drugs worldwide for the treatment of pain, inflammation, and fever [1–4]. NSAIDs are commonly administered for treatment against inflammatory diseases, rheumatoid arthritis, osteoarthritis, dysmenorrhea, and ischemic cerebrovascular disorders . Use of these drugs in certain types of cancer treatment has also been reported recently [6, 7]. These drugs inhibit prostaglandin biosynthesis and produce their therapeutic effects . However, long-term administration of NSAIDs causes adverse gastrointestinal (GI) symptoms including mucosal lesions, bleeding, peptic ulcer, and inflammation in intestine leading to perforation, strictures in small and large intestines, leading to chronic problems [9–11]. Some of the adverse effects of NSAIDs may be asymptotic, but in many cases there are reports of life-threatening incidents .
Such rampant use of NSAIDs requires a focused approach to avoid the possible side effects arising from their use. In this regard, several prevention methods have been used. These are based on usage of a new class of NSAIDs which does not inhibit a specific gastroprotective cascade or coprescription with proton pump inhibitors (PPIs) and prostaglandin analogues to suppress acid secretion [12–15]. However, these methods also have limited potency because of their additional cardiovascular effects [16–19].
Several clinical practice guidelines have proposed different approaches for controlling the GI complications associated with NSAIDs. A number of strategies have been recommended by American College of Gastroenterology to decrease NSAID-induced GI damage including use of selective cyclooxygenase-2 inhibitors, coadministration of gastroprotective agents like misoprostol, PPIs, or histamine-2 receptor antagonists . These strategies are based on multiple risk factors associated with NSAID-induced GI complications including age of the patient, simultaneous medications, prior medical history, and Helicobacter pylori infection. The risk of GI bleeding enhances when patients already on antiplatelet therapy using thienopyridines, like clopidogrel, are coprescribed with NSAIDs to reduce adverse cardiovascular events . In 2008, the Clinical Expert Consensus Document prepared by the American College of Cardiology, American College of Gastroenterology and American Heart Association has set the guidelines for reducing GI injury in patients undergoing antiplatelet therapy along with NSAIDs . As per the guidelines, PPIs were recommended for gastroprotective therapy to the patients on thienopyridines and NSAIDs. However, based on some reports suggesting possible interactions between PPIs and thienopyridines [23, 24], the expert guidelines have been further updated in 2010 . The Expert Consensus Report has been prepared taking into account the potential risks and benefits from simultaneous intake of PPIs and thienopyridines. Prescription of PPIs is only recommended for patients on antiplatelet therapy who are at risk for gastrointestinal complications .
Till now, there is no effective treatment yet developed for addressing the NSAID-related gastric damage. Identification of the protective factors for gastrointestinal complications associated with NSAIDs still poses a serious challenge. This paper outlines the mechanism of NSAIDs action with their prevalent side effects and provides an insight into the new advances in rational use of NSAIDs for prevention of possible side effects without any compromise on the analgesic properties of the NSAIDs.
2. Properties of NSAIDs
NSAIDs possess certain common pharmacologic properties. Mostly they are organic acids with pKa in the range of 3–5 . In general, they contain an acidic group mostly carboxylic acids or enols. The acidic moiety is essential for COX inhibitory activity and is linked to a planar, aromatic group. The latter is also connected to a lipophilic part through a polar group. The NSAIDs are classified into different groups based on their chemical structure and mechanism of action (Table 1). NSAIDs are generally chiral molecules (except diclofenac), but mostly a single enantiomer is pharmacologically active .
3. Mechanism of Anti-Inflammatory Action of NSAIDs
The mechanism of action of NSAIDs was first defined in early seventies and is based on inhibition of prostaglandin (PG) synthesis . PG is one of the main mediators of inflammation, pain, and fever and is synthesized from arachidonic acid. The reaction is catalyzed by the enzyme, cyclooxygenase (COX) earlier referred to as PGH synthase . NSAIDs block PG formation by binding and inhibiting COX (Figure 1).
The analgesic activity of the NSAIDs has been demonstrated to be due to the interference of PGE1 and PGF2 in animal pain models [27, 28]. It has also been observed that NSAIDs are effective against pain because of their ability to inhibit PG-mediated cerebral vascular vasodilation [29, 30]. Several studies have shown that the antipyretic action of NSAIDs is via inhibition of PGE2 synthesis in and near the preoptic hypothalamic area in circumventricular organs [31–33].
4. Mechanism of NSAID-Induced GI Injury
There are mainly three different mechanisms of NSAID-induced GI complications: inhibition of enzyme COX-1 and gastroprotective PG, membrane permeabilization, and production of additional proinflammatory mediators (Figure 2).
4.1. Inhibition of COX-1 and Gastroprotective PG
There are two isoforms of COX, COX-1 and COX-2, which have different functions . COX-1 is constitutively expressed and is responsible for the normal physiological protection of gastric mucosa. It is responsible for the synthesis of prostaglandins, which protects the stomach lining from the secreted acid, maintains blood flow in gastric mucosa, and produces bicarbonate [35, 36]. The other isoform, COX-2, is triggered by cell damage, various proinflammatory cytokines, and tumor-derived factors [37, 38]. NSAID-induced gastropathy is caused mainly by inhibition of COX-1 by NSAIDs [39–41].
4.2. Membrane Permeabilization
NSAIDs also have a direct cytotoxic effect on gastric mucosal cell causing lesions and injury [42, 43]. Some studies have shown that direct cytotoxicity is independent of the inhibition of COX activity . Topical damage of this kind has been observed in the case of acidic NSAIDs like aspirin resulting in accumulation of ionized NSAID, a phenomenon called “ion trapping” . It is suggested that NSAIDs cause membrane permeabilization leading to disruption of epithelial barrier . NSAIDs were also able to induce both necrosis and apoptosis in gastric mucosal cells .
4.3. Production of Additional Proinflammatory Mediators
Inhibition of PG synthesis by NSAIDs leads to simultaneous activation of the lipoxygenase pathway and increased synthesis of leukotrienes (Figure 1) [48–50]. Leukotrienes cause inflammation and tissue ischaemia leading to gastric mucosal injury [51, 52]. Along with this, there is also enhanced production of proinflammatory mediators such as tumour necrosis factors . This further leads to occlusion of gastric microvessels leading to reduced gastric blood flow and release of oxygen-derived-free radicals . Free oxygen radicals react with poly unsaturated fatty acids of the mucosa leading to lipid peroxidation and tissue damage .
5. Current Therapies for Prevention of Gastric Damage
Several approaches have been adopted for addressing the prevention and cure of the possible side-effects produced by the NSAIDs in the gut. Some of these strategies are routinely prescribed to the patients administering NSAIDs. Presently, the most common protective strategies adopted are (1) combination therapy of NSAIDs with gastroprotective agents and (2) use of selective COX-2 inhibitors (Table 2).
5.1. Combination Therapy of NSAIDs with Gastroprotective Agents
5.1.1. PG Analogues
PG analogues are prescribed with NSAIDs for replenishment of PG which is inhibited by NSAIDs. Misoprostol, a widely used PG analogue, was found to reduce NSAID-induced gastroduodenal ulceration considerably . However, it fails to prevent the reduction of dyspepsia and other GI adverse effects and hence has a limited efficiency [55, 56]. Recently it has been reported that the single-tablet formulations of diclofenac and misoprostol which have been found to be effective in arthritis and in reducing the NSAID-induced gastropathy .
5.1.2. Acid Suppressants
Acid increases NSAID-induced mucosal injury and gastric absorption of acidic NSAIDs. H2-receptor antagonists and proton pump inhibitors (PPIs) are most commonly used because they not only reduce acid secretion but also enhance gastric pH and have a role in scavenging-free radicals [58, 59].
H2-receptor antagonists were the first drugs to be used as a prevention mechanism against NSAID-induced peptic ulcers . They were found to be effective against gastric ulceration to a considerable extent . However, no signs of improvement were observed in cases of gastric bleeding,  and hence, these drugs are no longer recommended presently.
PPIs are effective in terms of acid suppression and prevention of peptic ulcers when coadministered with the NSAIDs. PPIs are generally prescribed for long-term use since they do not show any significant risk of any associated effects [63, 64]. Omeprazole, a PPI widely prescribed with NSAIDs, can specifically block the parietal cell /-ATPase, thereby significantly inhibiting the gastric acid secretion . Omeprazole was followed by other PPIs like lansoprazole, pantoprazole, rabeprazole, and so forth . Another report has indicated the formulation of lansoprazole, in the form of fast disintegrating tablet to reduce GI injury . Esomeprazole, the S-isomer of omeprazole, has been found to provide a sustained gastric acid control as compared to other PPIs . Considerable reduction of adverse GI symptoms has been observed in patients prescribed with esomeprazole along with NSAIDs or selective COX-2 inhibitors [69, 70]. The first NSAID/PPI single tablet formulation to be approved is ketoprofen/omeprazole modified release capsules .
Dual antiplatelet therapy with thienopyridine like clopidogrel and NSAID like aspirin is prescribed to decrease adverse cardiac events in patients suffering from acute coronary syndromes or placement of an intracoronary stent [72, 73], but they are associated with high risks of GI bleeding . PPIs are found to be effective in reducing the risk of GI bleeding in such patients . Clopidogrel is a prodrug that is transformed in vivo to an active metabolite by the cytochrome P450 enzyme system . However, some reports have suggested that PPIs interfere with clopidogrel to impair platelet function [23, 24, 75]. PPIs possibly inhibit hepatic cytochrome P450 2C19 (CYP2C19) isoenzyme preventing the conversion of clopidogrel into its active metabolite. It has been reported that concurrent use of clopidogrel plus a PPI was associated with a significant increase in risk of an adverse cardiovascular event in patients with acute chronic syndrome [76, 77]. In contrast to this, some other trials did not find any enhanced risk of adverse effects of the use of PPI in combination with clopidogrel [78, 79]. Thus, though routine use of a PPI is not recommended for patients in general, but it is coprescribed in patients with potential risk of GI bleeding [25, 80].
The main drawback of PPIs is that they are less effective against mucosal injury in more distal parts of the intestine like NSAID-induced colonopathy . Moreover, these agents are not prescribed to patients suffering from H. pylori infection because of occurrence of corpus gastritis .
5.2. Selective COX-2 Inhibitors
Selective COX-2 inhibitors, as the name suggests, are a group of drugs which selectively inhibit the COX-2 inhibitors, thus maintaining the anti-inflammatory properties of NSAIDs, yet retaining the gastroprotective action elicited by COX-1 pathway [83–85]. By far, celecoxib and rofecoxib stand out as the most effective COX-2 inhibitors and show efficacy over nonselective NSAIDs in regard to GI complications including mucosal lesions and other adverse GI symptoms [86, 87].
Several classes of COX-2-selective inhibitors have been identified, including the diarylheterocyclics (or tricyclics), acidic sulfonamides, and 2,6-ditert-butyl phenols, as well as the derivatives of the nonselective inhibitors zomepirac, indomethacin, piroxicam, and aspirin [88–90]. Celecoxib was first identified in 1997 and approved in 1998 [91, 92]. It has been found to preferentially inhibit COX-2 but exhibited the anti-inflammatory, antipyretic, and analgesic activities of NSAIDs [86, 93, 94]. Rofecoxib launched in 1999 was found to be effective in the treatment of osteoarthritis and pain [87, 95–97]. Similarly, nimesulide was highly selective against COX-2, so that at concentrations attained in vivo, while it had no substantial effect on COX-1, it suppressed COX-2 significantly .
Though COX-2 inhibitors decrease the GI toxicity to a considerable amount, there is an associated risk of cardiovascular complications due to myocardial infarction and thrombosis associated with their use [99–104]. COX-2 inhibitors have been demonstrated to inhibit the production of vascular prostacyclin, which has vasodilatory effects, and inhibits platelet aggregation unlike nonselective NSAIDs [105, 106]. Longer term gastrointestinal data from the celecoxib study (CLASS) and cardiovascular adverse event data from the rofecoxib study (VIGOR) have questioned the usage of these new drugs [86, 87, 107]. Some of these potent drugs have even been withdrawn .
6. Recent Advances in NSAID Treatments
6.1. Prodrugs of NSAIDs
NSAID prodrugs are potential agents for enhancing the antioxidant activity, water solubility and dissolution, release of nitric oxide and hydrogen sulfide, site-specific targeting and delivery, and inhibiting anticholinergic and acetylcholinesterase activity [109–113].
6.1.1. Nitric Oxide Releasing NSAIDs
It has been observed that nitric oxide (NO) imparts gastroprotection by increasing blood flow, mucus production, and bicarbonate secretion in the gastric mucosa [114–116]. NO formed by the action of nitric oxide synthase increases mucus and bicarbonate secretion as well as microcirculation and decreases neutrophil-endothelial adherence . This led to the development of new therapeutic drugs: nitric oxide releasing NSAIDs (NO-NSAIDs) . These drugs are developed by modifying NSAIDs esterified to a NO releasing moiety. Animal studies have demonstrated that NO-NSAIDs do not affect the gastroduodenal mucosa [119–121]. NO naproxen has been also been found to enhance anti-inflammatory and antinociceptive efficacy . NO aspirin has been found to impart an increased antithrombotic potency compared with conventional aspirin [123, 124].
6.1.2. Hydrogen Sulfide Releasing NSAID
Hydrogen sulfide (H2S) also exerts its gastroprotective effects and reverses preexisting ulcers. Derivatives of naproxen, diclofenac, and indomethacin which can release H2S have been reported [125–128]. Phosphatidylcholine-associated NSAIDs as well as NO- and H2S-releasing NSAIDs are under extensive preclinical testing for their influence on NSAID induced GI toxicity [129, 130].
Further studies are in progress to develop promising new NSAIDs imparting total GI (upper and lower GI tracts) protection and without cardiovascular toxicity. Recently a diclofenac prodrug, 1-(2,6-dichlorophenyl)indolin-2-one, has been demonstrated with anti-inflammatory properties that can decrease PGE2 levels, COX-2 expression, and ulceration . In yet another experiment, it was observed that ibuprofen R(−) isomer is a better agent in preventing GI toxicity than S(+) isomer because of short plasma-elimination half-life, its limited ability to inhibit PG synthesis. The R(−) isomer is then converted in the body to the S(+) isomer after absorption in the GI tract .
6.2. Simultaneous Inhibition of COX and 5-LOX
NSAID-induced inhibition of COX also results in increased production of leukotrienes, one of the potent mediators of inflammation [49–51]. Recent approach for addressing NSAID-induced GI injury is by development of inhibitors of COX/5-LOX simultaneously [133, 134]. Licofelone ([2,2-dimethyl-6-(4-chloropheny-7-phenyl-2,3-dihydro-1H-pyrrazoline-5-yl]acetic acid) has been identified as one of the most convincing compounds in this group . Licofelone imparts significant analgesic and anti-inflammatory effects without any GI side-effects as observed in animal models . It significantly improved indomethacin-induced gastric ulceration and prevented NSAID-induced increase in leukotriene levels in gastric mucosa . The preclinical evaluation has suggested that licofelone has a promising pharmacodynamic effect . Further clinical trials are in progress in osteoarthritis patients . Licofelone has also been found to be effective because of its antithrombotic and platelet aggregation inhibiting functions . Earlier to this, benoxaprofen identified as a dual COX/5-LOX inhibitor was withdrawn because it was found to induce severe hepatic and other toxicities .
6.3. Role of Lactoferrin in Reducing NSAID-Induced Gut Damage
Some preliminary reports have shown that bovine colostrum has the ability to prevent NSAID-induced gastric ulcers [142, 143]. Further studies have demonstrated the role of recombinant human lactoferrin in decreasing acute NSAID-induced GI bleeding and reduction of gastric ulcers [144, 145]. Recent reports also suggest that C-lobe of lactoferrin, which is resistant to enzymatic degradation , has excellent sequestering property for such class of drugs . Further reports have shown that C-lobe of lactoferrin can also bind to COX-2-specific drugs and produce observable effects against gastric inflammation and bleeding . Experiments on rodent model suggest that C-lobe of lactoferrin considerably diminishes the NSAID-induced GI bleeding and inflammation in case of conventional NSAIDs as well as COX-2-specific NSAIDs . In this regard, development of such new molecules that can sequester the unbound drug molecules is essential for addressing the NSAID-related GI damage.
The therapeutic effects of NSAIDs have made these drugs extremely popular against inflammatory disorders for the past several decades. However, these drugs suffer from serious drawbacks in cases of long-term administration, including severe GI complications. Several strategies have been adapted to control the critical side-effects. Though, these treatments are effective to some extent, but most of them are also associated with other risks.
Thus, there is no drug yet formulated that can avert the potential side-effects completely. There is an urgent need to develop novel therapeutic agents to make the use of NSAIDs safer. New measures of treatments such as dual COX/5-LOX inhibitors, prodrugs of NSAIDs, or agents that can effectively sequester the unbound NSAIDs without interfering their efficacy can prove to be superior strategies compared to the existing ones.
The authors acknowledge financial support from the Department of Biotechnology (DBT), New Delhi. T. P. Singh thanks the Department of Biotechnology (DBT), for the award of Distinguished Biotechnology Research Professorship awarded to him. M. Sinha thanks Department of Science and Technology (DST), Ministry of Science and Technology, New Delhi, L. Gautam thanks Council of Scientific and Industrial Research (CSIR), New Delhi, and P. K. Shukla thanks Indian Council of Medical Research (ICMR), New Delhi, for the award of fellowships.
- J. R. Vane, “The mode of action of aspirin and similar compounds,” Journal of Allergy and Clinical Immunology, vol. 58, no. 6, pp. 691–712, 1976.
- J. R. Vane, “The fight against rheumatism: from willow bark to COX-1 sparing drugs,” Journal of Physiology and Pharmacology, vol. 51, no. 4, pp. 573–586, 2000.
- G. Nuki, “Pain control and the use of non-steroidal analgesic anti-inflammatory drugs,” British Medical Bulletin, vol. 46, no. 1, pp. 262–278, 1990.
- W. E. Smalley, W. A. Ray, J. R. Daugherty, and M. R. Griffin, “Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons,” American Journal of Epidemiology, vol. 141, no. 6, pp. 539–545, 1995.
- J. DeRuiter, “Non-steroidal antiinflammatory drugs (NSAIDS),” Principles of Drug Action, vol. 2, pp. 1–25, 2002.
- W. E. Smalley and R. N. DuBois, “Colorectal cancer and nonsteroidal anti-inflammatory drugs,” Advances in Pharmacology, vol. 39, pp. 1–20, 1997.
- R. N. DuBois and W. E. Smalley, “Cyclooxygenase, NSAIDs, and colorectal cancer,” Journal of Gastroenterology, vol. 31, no. 6, pp. 898–906, 1996.
- J. R. Vane, “Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs,” Nature New Biology, vol. 43, pp. 232–235, 1971.
- S. H. Saverymuttu, A. Thomas, A. Grundy, and J. D. Maxwell, “Ileal stricturing after long-term indomethacin treatment,” Postgraduate Medical Journal, vol. 62, no. 732, pp. 967–968, 1986.
- I. Bjarnason, J. Hayllar, A. J. MacPherson, and A. S. Russell, “Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans,” Gastroenterology, vol. 104, no. 6, pp. 1832–1847, 1993.
- C. J. Hawkey, “Nonsteroidal anti-inflammatory drug gastropathy,” Gastroenterology, vol. 119, no. 2, pp. 521–535, 2000.
- M. Koch, “Non-steroidal anti-inflammatory drug gastropathy: clinical results with misoprostol,” Italian Journal of Gastroenterology and Hepatology, vol. 31, no. 1, pp. S54–S62, 1999.
- C. Scarpignato and I. Pelosini, “Prevention and treatment of non-steroidal anti-inflammatory drug-induced gastro-duodenal damage: rationale for the use of antisecretory compounds,” Italian Journal of Gastroenterology and Hepatology, vol. 31, no. 1, pp. S63–S72, 1999.
- L. Laine, “The role of proton pump inhibitors in NSAID—associated gastropathy and upper gastrointestinal symptoms,” Reviews in Gastroenterological Disorders, vol. 3, no. 4, pp. S30–S39, 2003.
- R. Micklewright, S. Lane, W. Linley, C. McQuade, F. Thompson, and N. Maskrey, “Review article: NSAIDs, gastroprotection and cyclo-oxygenase-II-selective inhibitors,” Alimentary Pharmacology and Therapeutics, vol. 17, no. 3, pp. 321–332, 2003.
- P. Patrignani, S. Tacconelli, and M. L. Capone, “Risk management profile of etoricoxib: an example of personalized medicine,” Therapeutics and Clinical Risk Management, vol. 4, no. 5, pp. 983–997, 2008.
- C. Mattia and F. Coluzzi, “Oxycodone. Pharmacological profile and clinical data in chronic pain management,” Minerva Anestesiologica, vol. 71, no. 7-8, pp. 461–470, 2005.
- J. A. Baron, R. S. Sandler, R. S. Bresalier et al., “Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial,” The Lancet, vol. 372, no. 9651, pp. 1756–1764, 2008.
- L. A. García Rodríguez, S. Tacconelli, and P. Patrignani, “Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population,” Journal of the American College of Cardiology, vol. 52, no. 20, pp. 1628–1636, 2008.
- F. L. Lanza, F. K. Chan, and E. M. Quigley;, “Practice Parameters Committee of the American College of Gastroenterology, Guidelines for prevention of NSAID-related ulcer complications,” American Journal of Gastroenterology, vol. 104, no. 3, pp. 728–738, 2009.
- N. G. Vallurupalli and S. Z. Goldhaber, “Gastrointestinal complications of dual antiplatelet therapy,” Circulation, vol. 113, no. 12, pp. e655–e658, 2006.
- D. L. Bhatt, J. Scheiman, N. S. Abraham et al., “ACCF/ACG/AHA, 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use,” American Journal of Gastroenterology, vol. 103, no. 11, pp. 2890–2907, 2008.
- M. Gilard, B. Arnaud, G. Le Gal, J. F. Abgrall, and J. Boschat, “Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin,” Journal of Thrombosis and Haemostasis, vol. 4, no. 11, pp. 2508–2509, 2006.
- D. N. Juurlink, T. Gomes, D. T. Ko et al., “A population-based study of the drug interaction between proton pump inhibitors and clopidogrel,” Canadian Medical Association Journal, vol. 180, no. 7, pp. 713–718, 2009.
- N. S. Abraham, M. A. Hlatky, E. M. Antman et al., “ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use,” American Journal of Gastroenterology, vol. 105, no. 12, pp. 2533–2549, 2010.
- N. Muller, E. Payan, F. Lapicque, B. Bannwarth, and P. Netter, “Pharmacological aspects of chiral nonsteroidal anti-inflammatory drugs,” Fundamental and Clinical Pharmacology, vol. 4, no. 6, pp. 617–634, 1990.
- R. F. Grace, Y. Lin, S. R. Edwards, I. Power, and L. E. Mather, “Effects of diclofenac in the rat tail ischaemia-reperfusion injury model of acute hyperalgesia,” Pain, vol. 89, no. 2-3, pp. 117–125, 2001.
- D. W. Hahn, R. Carraher, and J. L. McGuire, “Effects of suprofen and other prostaglandin synthetase inhibitors in a new animal model for myometrial hyperactivity,” Prostaglandins, vol. 23, no. 1, pp. 1–16, 1982.
- C. E. Chapleau, R. P. White, and J. T. Robertson, “Cerebral vasodilation and prostacyclin. The effects of aspirin and meclofenamate in vitro,” Journal of Neurosurgery, vol. 53, no. 2, pp. 188–192, 1980.
- A. J. Lonigro, M. H. Hagemann, A. H. Stephenson, and C. L. Fry, “Inhibition of prostaglandin synthesis by indomethacin augments the renal vasodilator response to bradykinin in the anesthetized dog,” Circulation Research, vol. 43, no. 3, pp. 447–455, 1978.
- A. Morimoto, N. Murakami, and T. Watanabe, “Effect of prostaglandin E2 on thermoresponsive neurones in the preoptic and ventromedial hypothalamic regions of rats,” Journal of Physiology, vol. 405, pp. 713–725, 1988.
- A. Wit and S. C. Wang, “Temperature-sensitive neurons in preoptic-anterior hypothalamic region: actions of pyrogen and acetylsalicylate,” The American Journal of Physiology, vol. 215, no. 5, pp. 1160–1169, 1968.
- F. H. Lovejoy Jr., “Aspirin and acetaminophen: a comparative view of their antipyretic and analgesic activity,” Pediatrics, vol. 62, no. 5, part 2, pp. 904–909, 1978.
- N. Zidar, K. Odar, D. Glavac, M. Jerse, T. Zupanc, and D. Stajer, “Cyclooxygenase in normal human tissues—is COX-1 really a constitutive isoform, and COX-2 an inducible isoform?” Cellular and Molecular Medicine B, vol. 13, no. 9, pp. 3753–3763, 2009.
- K. Gudis and C. Sakamoto, “The role of cyclooxygenase in gastric mucosal protection,” Digestive Diseases and Sciences, vol. 50, no. 1, pp. S16–S23, 2005.
- S. J. Konturek, P. C. Konturek, T. Pawlik, Z. Sliwowski, W. Ochmański, and E. G. Hahn, “Duodenal mucosal protection by bicarbonate secretion and its mechanisms,” Journal of Physiology and Pharmacology, vol. 55, pp. 5–17, 2004.
- K. Seibert, Y. Zhang, K. Leahy et al., “Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain,” Proceedings of National Academy of Sciences, vol. 91, no. 25, pp. 12013–12017, 1994.
- K. Seibert and J. L. Masferrer, “Role of inducible cyclooxygenase (COX-2) in inflammation,” Receptor, vol. 4, no. 1, pp. 17–23, 1994.
- J. A. Mitchell, P. Akarasereenont, C. Thiemermann, R. J. Flower, and J. R. Vane, “Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 24, pp. 11693–11697, 1993.
- L. Laine, “Nonsteroidal anti-inflammatory drug gastropathy,” Gastrointestinal Endoscopy Clinics of North America, vol. 6, no. 3, pp. 489–504, 1996.
- T. A. Miller, “Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms,” The American Journal of Physiology, vol. 245, no. 5, part 1, pp. G601–G623, 1983.
- S. Somasundaram, S. Rafi, J. Hayllar et al., “Mitochondrial damage: a possible mechanism of the 'topical' phase of NSAID induced injury to the rat intestine,” Gut, vol. 41, no. 3, pp. 344–353, 1997.
- W. Tomisato, C. K. Tanaka, T. Katsu et al., “Membrane permeabilization by non-steroidal anti-inflammatory drugs,” Biochemical and Biophysical Research Communications, vol. 323, no. 2, pp. 1032–1039, 2004.
- L. M. Lichtenberger, “Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal injury? Topical injury revisited,” Biochemical Pharmacology, vol. 61, no. 6, pp. 631–637, 2001.
- H. W. Davenport, “Salicylate damage to the gastric mucosal barrier,” The New England Journal of Medicine, vol. 276, no. 23, pp. 1307–1312, 1967.
- L. M. Lichtenberger, “The hydrophobic barrier properties of gastrointestinal mucus,” Annual Review of Physiology, vol. 57, pp. 565–583, 1995.
- W. Tomisato, S. Tsutsumi, K. Rokutan, T. Tsuchiya, and T. Mizushima, “NSAIDs induce both necrosis and apoptosis in guinea pig gastric mucosal cells in primary culture,” American Journal of Physiology, vol. 281, no. 4, pp. G1092–G1100, 2001.
- P. M. Vaananen, C. M. Keenan, M. B. Grisham, and J. L. Wallace, “Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy,” Inflammation, vol. 16, no. 3, pp. 227–240, 1992.
- N. Hudson, M. Balsitis, S. Everitt, and C. J. Hawkey, “Enhanced gastric mucosal leukotriene B4 synthesis in patients taking non-steroidal anti-inflammatory drugs,” Gut, vol. 34, no. 6, pp. 742–747, 1993.
- B. M. Peskar, “Role of leukotriene C4 in mucosal damage caused by necrotizing agents and indomethacin in the rat stomach,” Gastroenterology, vol. 100, no. 3, pp. 619–626, 1991.
- D. M. McCafferty, D. N. Granger, and J. L. Wallace, “Indomethacin-induced gastric injury and leukocyte adherence in arthritic versus healthy rats,” Gastroenterology, vol. 109, no. 4, pp. 1173–1180, 1995.
- F. J. Andrews, C. Malcontenti-Wilson, and P. E. O'Brien, “Effect of nonsteroidal anti-inflammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa,” American Journal of Physiology, vol. 266, no. 4, part 1, pp. G657–G664, 1994.
- L. Santucci, S. Fiorucci, M. Giansanti, P. M. Brunori, F. M. Di Matteo, and A. Morelli, “Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha,” Gut, vol. 35, no. 7, pp. 909–915, 1994.
- J. L. Wallace, “Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years,” Gastroenterology, vol. 112, no. 3, pp. 1000–1016, 1997.
- F. E. Silverstein, D. Y. Graham, J. R. Senior et al., “Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial,” Annals of Internal Medicine, vol. 123, no. 4, pp. 241–249, 1995.
- Y. Graham, R. H. White, L. W. Moreland et al., “Duodenal and gastric ulcer prevention with misoprostol in arthritis patients taking NSAIDs. Misoprostol Study Group,” Annals of Internal Medicine, vol. 119, no. 4, pp. 257–262, 1993.
- J. L. Goldstein, L. R. Larson, and B. D. Yamashita, “Prevention of nonsteroidal anti-inflammatory drug-induced gastropathy: clinical and economic implications of a single-tablet formulation of diclofenac/misoprostol,” American Journal of Managed Care, vol. 4, no. 5, pp. 687–697, 1998.
- D. Lapenna, S. De Gioia, A. Mezzetti et al., “H2-receptor antagonists are scavengers of oxygen radicals,” European Journal of Clinical Investigation, vol. 24, no. 7, pp. 476–481, 1994.
- K. Biswas, U. Bandyopadhyay, I. Chattopadhyay, A. Varadaraj, E. Ali, and R. K. Banerjee, “A novel antioxidant and antiapoptotic role of omeprazole to block gastric ulcer through scavenging of hydroxyl radical,” Journal of Biological Chemistry, vol. 278, no. 13, pp. 10993–11001, 2003.
- M. G. Robinson, J. W. Griffin, J. Bowers et al., “Effect of ranitidine gastroduodenal mucosal damage induced by nonsteroidal antiinfalmmatory drugs,” Digestive Diseases and Sciences, vol. 34, no. 3, pp. 424–428, 1989.
- R. S. B. Ehsanullah, M. C. Page, G. Tildesley, and J. R. Wood, “Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine,” British Medical Journal, vol. 297, no. 6655, pp. 1017–1021, 1988.
- M. M. Wolfe, D. R. Lichtenstein, and G. Singh, “Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs,” The New England Journal of Medicine, vol. 341, no. 7, pp. 1888–1899, 1999.
- N. J. Bell and R. H. Hunt, “Progress with proton pump inhibition,” Yale Journal of Biology and Medicine, vol. 65, no. 6, pp. 649–657, 1992.
- L. Laine, “Proton pump inhibitor co-therapy with nonsteroidal anti-inflammatory drugs—nice or necessary?” Reviews in Gastroenterological Disorders, vol. 4, supplement 4, pp. S33–S41, 2004.
- J. Hawkey, J. A. Karrasch, L. Szczepanski et al., “Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprozole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group,” The New England Journal of Medicine, vol. 338, no. 11, pp. 727–734, 1998.
- L. S. Welage and R. R. Berardi, “Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases,” Journal of the American Pharmaceutical Association, vol. 40, no. 1, pp. 52–62, 2000.
- F. Baldi and P. Malfertheiner, “Lansoprazole fast disintegrating tablet: a new formulation for an established proton pump inhibitor,” Digestion, vol. 67, no. 1-2, pp. 1–5, 2003.
- N. D. Yeomans, C. J. Hawkey, R. Jones et al., “Esomeprazole provides effective control of NSAID-associated upper GI symptoms in patients continuing to take NSAIDs,” Gastroenterology, vol. 124, supplement 1, no. 4, p. A107, 2003.
- C. H. Wilder-Smith, K. Röhss, C. Nilsson-Pieschl, O. Junghard, and L. Nyman, “Esomeprazole 40 mg provides improved intragastric acid control as compared with lansoprazole 30 mg and rabeprazole 20 mg in healthy volunteers,” Digestion, vol. 68, no. 4, pp. 184–188, 2003.
- P. J. Kahrilas, G. W. Falk, D. A. Johnson et al., “Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial,” Alimentary Pharmacology and Therapeutics, vol. 14, no. 10, pp. 1249–1258, 2000.
- A. ] Gigante and I. Tagarro, “Non-steroidal anti-inflammatory drugs and gastroprotection with proton pump inhibitors: a focus on ketoprofen/omeprazole,” Clinical Drug Investigation, vol. 32, no. 4, pp. 221–231, 2012.
- D. L. Bhatt and E. J. Topol, “Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial,” American Heart Journal, vol. 148, no. 2, pp. 263–268, 2004.
- D. L. Bhatt, K. A. Fox, W. Hacke et al., “Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events,” The New England Journal of Medicine, vol. 354, no. 16, pp. 1706–1717, 2006.
- J. M. Pereillo, M. Maftouh, A. Andrieu et al., “Structure and stereochemistry of the active metabolite of clopidogrel,” Drug Metabolism and Disposition, vol. 30, no. 11, pp. 1288–1295, 2002.
- S. M. Bhurke, B. C. Martin, C. Li, A. M. Franks, Z. Bursac, and Q. Said, “Effect of the clopidogrel-proton pump inhibitor drug interaction on adverse cardiovascular events in patients with acute coronary syndrome,” Pharmacotherapy, vol. 32, no. 9, pp. 809–818, 2012.
- M. Gilard, B. Arnaud, J. C. Cornily et al., “Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin. The Randomized, Double-Blind OCLA (Omeprazole CLopidogrel Aspirin) Study,” Journal of the American College of Cardiology, vol. 51, no. 3, pp. 256–260, 2008.
- P. M. Ho, T. M. Maddox, L. Wang et al., “Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome,” The Journal of the American Medical Association, vol. 301, no. 9, pp. 937–944, 2009.
- D. L. Bhatt, B. L. Cryer, C. F. Contant et al., “Clopidogrel with or without omeprazole in coronary artery disease,” The New England Journal of Medicine, vol. 363, no. 20, pp. 1909–1917, 2010.
- M. L. O'Donoghue, E. Braunwald, E. M. Antman et al., “Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials,” The Lancet, vol. 374, no. 9694, pp. 989–997, 2009.
- J. P. Depta and D. L. Bhatt, “Omeprazole and clopidogrel: should clinicians be worried?” Cleveland Clinic Journal of Medicine, vol. 77, no. 2, pp. 113–116, 2010.
- E. C. Klinkenberg-Knol, F. Nelis, J. Dent et al., “Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa,” Gastroenterology, vol. 118, no. 4, pp. 661–669, 2000.
- A. Meining, G. Kiel, and M. Stolte, “Changes in Helicobacter pylori-induced gastritis in the antrum and corpus during and after 12 months of treatment with ranitidine and lansoprazole in patients with duodenal ulcer disease,” Alimentary Pharmacology and Therapeutics, vol. 12, no. 8, pp. 735–740, 1998.
- K. K. Wu, “Cyclooxygenase 2 induction: molecular mechanism and pathophysiologic roles,” Journal of Laboratory and Clinical Medicine, vol. 128, no. 3, pp. 242–245, 1996.
- J. L. Masferrer, P. C. Isakson, and K. Seibert, “Cyclooxygenase-2 inhibitors: a new class of anti-inflammatory agents that spare the gastrointestinal tract,” Gastroenterology Clinics of North America, vol. 25, no. 2, pp. 363–372, 1996.
- C. C. Chan and I. W. Rodger, “Selective cyclooxygenase-2 inhibitors as potential therapeutic agents for inflammatory diseases,” Advances in Experimental Medicine and Biology, vol. 407, pp. 157–161, 1997.
- C. Bombardier, L. Laine, A. Reicin et al., “Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis,” The New England Journal of Medicine, vol. 343, no. 21, pp. 1520–1528, 2000.
- F. E. Silverstein, G. Faich, J. L. Goldstein et al., “Gastrointestinal toxicity with Celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and reumatoid arthritis: the CLASS study: a randomized controlled trial,” The Journal of the American Medical Association, vol. 284, no. 10, pp. 1247–1255, 2000.
- C. K. Lau, W. C. Black, M. Belley et al., “From indomethacin to a selective COX-2 inhibitor: development of indolalkanoic acids as potent and selective cyclooxygenase-2 inhibitors,” Advances in Experimental Medicine and Biology, vol. 407, pp. 73–78, 1996.
- D. Riendeau, M. D. Percival, S. Boyce et al., “Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor,” British Journal of Pharmacology, vol. 121, no. 1, pp. 105–117, 1997.
- L. J. Marnett and A. S. Kalgutkar, “Design of selective inhibitors of cyclooxygenase-2 as nonulcerogenic anti-inflammatory agents,” Current Opinion in Chemical Biology, vol. 2, no. 4, pp. 482–490, 1998.
- T. D. Penning, J. J. Talley, S. R. Bertenshaw et al., “Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)- 3(trifluoromethyl)-1h-pyrazol-1-yl]benzenesulfonamide (sc-58635, celecoxib),” Journal of Medicinal Chemistry, vol. 40, no. 9, pp. 1347–1365, 1997.
- L. S. Simon, F. L. Lanza, P. E. Lipsky et al., “Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects,” Arthritis Rheumatism, vol. 41, no. 9, pp. 1591–1602, 1998.
- L. S. Simon, A. L. Weaver, D. Y. Graham et al., “Anti-inflammatory andupper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial,” The Journal of American Medical Association, vol. 282, no. 20, pp. 1921–1928, 1999.
- F. K. Chan, L. C. Hung, B. Y. Suen et al., “Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis,” The New England Journal of Medicine, vol. 347, pp. 2104–2110, 2002.
- L. Laine, S. Harper, T. Simon et al., “A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis,” Gastroenterology, vol. 117, no. 4, pp. 776–783, 1999.
- E. Woolf, I. Fu, and B. Matuszewski, “Determination of rofecoxib, a cyclooxygenase-2 specific inhibitor, in human plasma using high-performance liquid chromatography with post-column photochemical derivatization and fluorescence detection,” Journal of Chromatography B, vol. 730, no. 2, pp. 221–227, 1999.
- T. J. Schnitzer, K. Truitt, R. Fleischmann et al., “The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis,” Clinical Therapeutics, vol. 21, no. 10, pp. 1688–1702, 1999.
- L. Cullen, L. Kelly, S. O. Connor, and D. J. Fitzgerald, “Selective cyclooxygenase-2 inhibition by nimesulide in man,” Journal of Pharmacology and Experimental Therapeutics, vol. 287, no. 2, pp. 578–582, 1998.
- P. Patrignani, S. Tacconelli, and M. L. Capone, “Risk management profile of etoricoxib: an example of personalized medicine,” Therapeutics and Clinical Risk Management, vol. 4, no. 5, pp. 983–997, 2008.
- C. Mattia and F. Coluzzi, “COX-2 inhibitors: pharmacological data and adverse effects,” Minerva Anesthesiology, vol. 71, no. 7-8, pp. 461–470, 2005.
- L. A. G. Rodríguez, S. Tacconelli, and P. Patrignani, “Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population,” Journal of the American College of Cardiology, vol. 52, no. 20, pp. 1628–1636, 2008.
- P. L. McGeer, E. G. McGeer, and K. Yasojima, “Cardiovascular events and COX-2 inhibitors,” The Journal of American Medical Association, vol. 286, no. 22, p. 2810, 2001.
- J. K. Hennan, J. Huang, T. D. Barrett et al., “Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries,” Circulation, vol. 104, no. 7, pp. 820–825, 2001.
- D. Mukherjee, S. E. Nissen, and E. J. Topol, “Risk of cardiovascular events associated with selective COX-2 inhibitors,” The Journal of the American Medical Association, vol. 286, no. 8, pp. 954–959, 2001.
- J. Y. Jeremy, D. P. Mikhailidis, M. A. Barradas, R. M. Kirk, and P. Dandona, “The effect of nabumetone and its principal active metabolite on in vitro human gastric mucosal prostanoid synthesis and platelet function,” British Journal of Rheumatology, vol. 29, no. 2, pp. 116–119, 1990.
- M. A. Konstam and M. R. Weir, “Current perspective on the cardiovascular effects of coxibs,” Cleveland Clinic Journal of Medicine, vol. 69, supplement 1, pp. SI47–SI52, 2002.
- A. Nguyen and A. Chaiton, “Cyclooxygenase (COX-2) selective inhibitors: any better than NSAIDs?” Canadian Family Physician, vol. 47, pp. 1398–1400, 2001.
- B. Sibbald, “Rofecoxib (Vioxx) voluntarily withdrawn from market,” Canadian Medical Association Journal, vol. 171, no. 9, pp. 1027–1028, 2004.
- J. E. Saavedra, T. R. Billiar, D. L. Williams, Y. M. Kim, S. C. Watkins, and L. K. Keefer, “Targeting nitric oxide (NO) delivery in vivo. Design of a liver- selective NO donor prodrug that blocks tumor necrosis factor-α-induced apoptosis and toxicity in the liver,” Journal of Medicinal Chemistry, vol. 40, no. 13, pp. 1947–1954, 1997.
- K. R. A. Abdellatif, M. A. Chowdhury, Y. Dong et al., “Dinitroglyceryl and diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of aspirin, indomethacin and ibuprofen: synthesis, biological evaluation and nitric oxide release studies,” Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 11, pp. 3014–3018, 2009.
- W. Fan, Y. Wu, X. K. Li et al., “Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen,” European Journal of Medicinal Chemistry, vol. 46, no. 9, pp. 3651–3661, 2011.
- S. C. Young, K. M. Fabio, M. T. Huang et al., “Investigation of anticholinergic and non-steroidal anti-inflammatory prodrugs which reduce chemically induced skin inflammation,” Journal of Applied Toxicology, vol. 32, no. 2, pp. 135–141, 2012.
- A. M. Qandil, “Prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs), more than meets the eye: a critical review,” International Journal of Molecular Sciences, vol. 13, no. 12, pp. 17244–17274, 2012.
- S. J. Konturek, T. Brzozowski, J. Majka, A. Szlachcic, and J. Pytko-Polonczyk, “Implications of nitric oxide in the action of cytoprotective drugs on gastric mucosa,” Journal of Clinical Gastroenterology, vol. 17, supplement 1, pp. S140–S145, 1993.
- S. J. Konturek, T. Brzozowski, J. Majka, A. Szlachcic, and K. Czarnobilski, “Nitric oxide in gastroprotection by sucralfate, mild irritant, and nocloprost: role of mucosal blood flow,” Digestive Diseases and Sciences, vol. 39, no. 3, pp. 593–600, 1994.
- A. Szlachcic, G. Krzysiek-Maczka, R. Pajdo et al., “The impact of asymmetric dimethylarginine (ADAMA), the endogenous nitric oxide (NO) synthase inhibitor, to the pathogenesis of gastric mucosal damage,” Current Pharmaceutical Design, vol. 19, no. 1, pp. 90–97, 2013.
- J. L. Wallace and M. J. S. Miller, “Nitric oxide in mucosal defense: a little goes a long way,” Gastroenterology, vol. 119, no. 2, pp. 512–520, 2000.
- E. Koç and S. G. Küçükgüzel, “Medicinal chemistry and anti-inflammatory activity of nitric oxide-releasing NSAI drugs,” Mini-Reviews in Medicinal Chemistry, vol. 9, no. 5, pp. 611–619, 2009.
- S. Fiorucci, E. Antonelli, L. Santucci et al., “Gastrointestinal safety of nitric oxide-derived aspirin is related to inhibition of ICE-like cysteine proteases in rats,” Gastroenterology, vol. 116, no. 5, pp. 1089–1106, 1999.
- N. M. Davies, A. G. Roøseth, C. B. Appleyard et al., “NO-naproxen vs. naproxen: ulcerogenic, analgesic and anti-inflammatory effects,” Alimentary Pharmacology and Therapeutics, vol. 11, no. 1, pp. 69–79, 1997.
- K. Takeuchi, H. Mizoguchi, H. Araki, Y. Komoike, and K. Suzuki, “Lack of gastric toxicity of nitric oxide-releasing indomethacin, NCX-530, in experimental animals,” Digestive Diseases and Sciences, vol. 46, no. 8, pp. 1805–1818, 2001.
- C. Cicala, A. Ianaro, S. Fiorucci et al., “NO-naproxen modulates inflammation, nociception and downregulates T cell response in rat Freund's adjuvant arthritis,” British Journal of Pharmacology, vol. 130, no. 6, pp. 1399–1405, 2000.
- J. E. Keeble and P. K. Moore, “Pharmacology and potential therapeutic applications of nitric oxide-releasing non-steroidal anti-inflammatory and related nitric oxide-donating drugs,” British Journal of Pharmacology, vol. 137, no. 3, pp. 295–310, 2002.
- J. L. Wallace, W. McKnight, P. Del Soldato, A. R. Baydoun, and G. Cirino, “Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative,” Journal of Clinical Investigation, vol. 96, no. 6, pp. 2711–2718, 1995.
- S. Fiorucci, E. Antonelli, A. Mencarelli et al., “The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis,” Hepatology, vol. 42, no. 3, pp. 539–548, 2005.
- J. L. Wallace, “Hydrogen sulfide-releasing anti-inflammatory drugs,” Trends in Pharmacological Sciences, vol. 28, no. 10, pp. 501–505, 2007.
- Y. J. Lim, J. S. Lee, Y. S. Ku, and K. B. Hahm, “Rescue strategies against non-steroidal anti-inflammatory drug-induced gastroduodenal damage,” Journal of Gastroenterology and Hepatology, vol. 24, no. 7, pp. 1169–1178, 2009.
- L. Liu, J. Cui, C. J. Song et al., “H(2)S-releasing aspirin protects against aspirin-induced gastric injury via reducing oxidative stress,” PLoS One, vol. 7, no. 9, Article ID e46301, 2012.
- L. M. Lichtenberger, M. Barron, and U. Marathi, “Association of phosphatidylcholine and nsaids as a novel strategy to reduce gastrointestinal toxicity,” Drugs of Today, vol. 45, no. 12, pp. 877–890, 2009.
- L. M. Lichtenberger, Y. Zhou, V. Jayaraman et al., “Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine,” Biochimica et Biophysica Acta, vol. 1821, no. 7, pp. 994–1002, 2012.
- J. L. Santos, V. Moreira, M. L. Campos et al., “Pharmacological evaluation and preliminary pharmacokinetics studies of a new diclofenac prodrug without gastric ulceration effect,” International Journal of Molecular Sciences, vol. 13, no. 11, pp. 15305–15320, 2012.
- K. D. Rainsford, “Ibuprofen: from invention to an OTC therapeutic mainstay,” International Journal of Clinical Practice, vol. 178, pp. 9–20, 2013.
- J. Martel-Pelletier, D. Lajeunesse, P. Reboul, and J. P. Pelletier, “Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs,” Annals of the Rheumatic Diseases, vol. 62, no. 6, pp. 501–509, 2003.
- M. M. Skelly and C. J. Hawkey, “Dual COX inhibition and upper gastrointestinal damage,” Current Pharmaceutical Design, vol. 9, no. 27, pp. 2191–2195, 2003.
- J. L. Wallace, L. Carter, W. McKnight, S. Tries, and S. Laufer, “ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury,” European Journal of Pharmacology, vol. 271, no. 2-3, pp. 525–531, 1994.
- S. K. Kulkarni and V. P. Singh, “Licofelone—a novel analgesic and anti-inflammatory agent,” Current Topics in Medicinal Chemistry, vol. 7, no. 3, pp. 251–263, 2007.
- H. Ulbrich, O. Soehnlein, X. Xie et al., “Licofelone, a novel 5-LOX/COX-inhibitor, attenuates leukocyte rolling and adhesion on endothelium under flow,” Biochemical Pharmacology, vol. 70, no. 1, pp. 30–36, 2005.
- F. Celotti and T. Durand, “The metabolic effects of inhibitors of 5-lipoxygenase and of cyclooxygenase 1 and 2 are an advancement in the efficacy and safety of anti-inflammatory therapy,” Prostaglandins and Other Lipid Mediators, vol. 71, no. 3-4, pp. 147–162, 2003.
- A. F. Cicero and L. Laghi, “Activity and potential role of licofelone in the management of osteoarthritis,” Clinical Interventions in Aging, vol. 2, no. 1, pp. 73–79, 2007.
- S. Tries, W. Neupert, and S. Laufer, “The mechanism of action of the new antiinflammatory compound ML3000: inhibition of 5-LOX and COX-1/2,” Inflammation Research, vol. 51, no. 3, pp. 135–143, 2002.
- D. F. V. Lewis, C. Ioannides, and D. V. Parke, “A retrospective study of the molecular toxicology of benoxaprofen,” Toxicology, vol. 65, no. 1-2, pp. 33–47, 1990.
- R. J. Playford, D. N. Floyd, C. E. Macdonald et al., “Bovine colostrum is a health food supplement which prevents NSAID induced gut damage,” Gut, vol. 44, no. 5, pp. 653–658, 1999.
- R. J. Playford, C. E. Macdonald, D. P. Calnan et al., “Co-administration of the health food supplement, bovine colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability,” Clinical Science, vol. 100, no. 6, pp. 627–633, 2001.
- F. J. Troost, W. H. M. Saris, and R. J. M. Brummer, “Recombinant human lactoferrin ingestion attenuates indomethacin-induced enteropathy in vivo in healthy volunteers,” European Journal of Clinical Nutrition, vol. 57, no. 12, pp. 1579–1585, 2003.
- E. J. Dial, A. J. Dohrman, J. J. Romero, and L. M. Lichtenberger, “Recombinant human lactoferrin prevents NSAID-induced intestinal bleeding in rodents,” Journal of Pharmacy and Pharmacology, vol. 57, no. 1, pp. 93–99, 2005.
- S. Sharma, T. P. Singh, and K. L. Bhatia, “Preparation and characterization of the N and C monoferric lobes of buffalo lactoferrin produced by proteolysis using proteinase K,” Journal of Dairy Research, vol. 66, no. 1, pp. 81–90, 1999.
- R. Mir, N. Singh, G. Vikram et al., “The structural basis for the prevention of nonsteroidal antiinflammatory drug-induced gastrointestinal tract damage by the C-lobe of bovine colostrum lactoferrin,” Biophysical Journal, vol. 97, no. 12, pp. 3178–3186, 2009.
- R. Mir, N. Singh, G. Vikram et al., “Structural and binding studies of C-terminal half (C-lobe) of lactoferrin protein with COX-2-specific non-steroidal anti-inflammatory drugs (NSAIDs),” Archives of Biochemistry and Biophysics, vol. 500, no. 2, pp. 196–202, 2010.
Copyright © 2013 Mau Sinha et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.