NO-releasing Nonsteroidal Anti-inflammatory Drugs Research Articles

COX inhibitors and bone: A safer impact on osteoblasts by NO-releasing NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of pain and inflammation. Although it is well known that NSAIDs can suppress bone growth, remodelling and repair, they are largely used post-operatively and post-traumatically to achieve analgesia and reduce inflammation in bone tissue. AimsThe impact of two NO-releasing, non-selective NSAIDs, NCX-4016 and HCT-3012 (NO-derivatives of Aspirin and Naproxen, respectively) on osteoblasts were evaluated and compared to the non-selective, parent chemicals and to the COX-2-selective inhibitor Celecoxib. Main methodsUsing MG-63 osteoblast-like cells, we considered proliferation, the early and late stage of differentiation, and the activity of proteinases thought to be involved in osteoid degradation, a preliminary fundamental event of bone remodelling. Key findingsUnlike Aspirin, Naproxen and Celecoxib, the two NO-NSAIDs did not alter proliferation and differentiation of osteoblasts. They also reduced the activity of plasminogen activator, metalloproteinases, and cathepsin B. Similar inhibitory effects against these proteinases were recapitulated by the NO-donor sodium nitroprusside, thereby suggesting a NO-mediated mechanism. SignificanceDue to a differential effect on cell proliferation and differentiation, the two NO-NSAIDs exhibit a safer impact on osteoblast metabolism compared to Celecoxib and their parent compounds. This suggests an advantageous option for these drugs in individuals with a need of COX-inhibiting treatment, in general. In addition, their capability of modulating the proteinases involved in osteoid degradation may specifically suggest an additional safer use in comorbidity conditions of inflammation or pain with bone disorders characterized by high rate of remodelling, such as high-turnover osteoporosis in post-menopausal women.

Drug-Mediated Intracellular Donation of Nitric Oxide Potently Inhibits 5-Lipoxygenase: A Possible Key to Future Antileukotriene Therapy.

5-Lipoxygenase (5-LO) is the key enzyme of leukotriene (LT) biosynthesis and is critically involved in a number of inflammatory diseases such as arthritis, gout, bronchial asthma, atherosclerosis, and cancer. Because 5-LO contains critical nucleophilic amino acids, which are sensitive to electrophilic modifications, we determined the consequences of a drug-mediated intracellular release of nitric oxide (NO) on 5-LO product formation by human granulocytes and on 5-LO-dependent pulmonary inflammation in vivo. Clinically relevant concentrations of NO-releasing nonsteroidal anti-inflammatory drugs and other agents releasing NO intracellularly suppress 5-LO product synthesis in isolated human granulocytes via direct S-nitrosylation of 5-LO at the catalytically important cysteines 416 and 418. Furthermore, suppression of 5-LO product formation was observed in ionophore-stimulated human whole blood and in an animal model of pulmonary inflammation. Here, we report for the first time that drugs releasing NO intracellularly are efficient 5-LO inhibitors in vitro and in vivo at least equivalent to approved 5-LO inhibitors. Our findings provide a novel mechanistic strategy for the development of a new class of drugs suppressing LT biosynthesis by site-directed nitrosylation. The results may also help to better understand the well-recognized anti-inflammatory clinically relevant actions of NO-releasing drugs. Furthermore, our study describes in detail a novel molecular mode of action of NO. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16: 293-296, 2012) with the following serving as open reviewers: Angel Lanas, Hartmut Kühn, Joan Clària, Orina Belton. Antioxid. Redox Signal. 28, 1265-1285.

Nitric oxide in cancer metastasis

Cancer metastasis is the spread and growth of tumor cells from the original neoplasm to further organs. This review analyzes the role of nitric oxide (NO), a signaling molecule, in the regulation of cancer formation, progression, and metastasis. The action of NO on cancer relies on multiple factors including cell type, metastasis stage, and organs involved. Various chemotherapy drugs cause cells to release NO, which in turn induces cytotoxic death of breast, liver, and skin tumors. However, NO has also been clinically connected to a poor cancer prognosis because of its role in angiogenesis and intravasation. This supports the claim that NO can be characterized as both pro-metastatic and anti-metastatic, depending on specific factors. The inhibition of cell proliferation and anti-apoptosis pathways by NO donors has been proposed as a novel therapy to various cancers. Studies suggest that NO-releasing non-steroidal anti-inflammatory drugs act on cancer cells in several ways that may make them ideal for cancer therapy. This review summarizes the biological significance of NO in each step of cancer metastasis, its controversial effects for cancer progression, and its therapeutic potential.

Nitric oxide donor exisulind is an effective inhibitor of murine photocarcinogenesis.

NO-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) have been shown to have anti-inflammatory, antiproliferative and apoptosis-inducing effects in tumor cells. Herein, we have investigated the effects of NO-exisulind on the growth of UVB-induced skin tumor development in a murine model. We found that the topical treatment with NO-exisulind significantly reduced UVB-induced tumors in SKH-1 hairless mice. The tumors/tumor bearing mouse, the number of tumors/mouse and tumor volume/mouse decreased significantly (P < 0.05) as compared with vehicle-treated and UVB-irradiated positive controls. Consistently, NO-exisulind-treated animals showed reduced expression of proliferation markers, such as PCNA and cyclin D1. These mice also manifested increased expression of proapoptotic Bax and decreased expression of antiapoptotic Bcl2 with an increase in the number of TUNEL-positive cells in tumors. We also investigated whether NO-exisulind-treated tumors are less invasive and progress less efficiently from benign to malignant carcinomas. For this, tumors were stained for various epithelial-mesenchymal transition (EMT) markers. NO-exisulind decreased the expression of mesenchymal markers, such as Fibronectin, N-cadherin, SNAI, Slug and Twist and enhanced the epithelial marker E-cadherin. Similarly, UVB-induced phosphorylation of Erk1/2 and p38 was decreased in NO-exisulind-treated animals. These data suggest that NO-exisulind reduces tumor growth and inhibits tumor progression by blocking proliferation, inducing apoptosis and reducing EMT.

Differential Modulation of Nitric Oxide Synthases in Aging: Therapeutic Opportunities

Vascular aging is the term that describes the structural and functional disturbances of the vasculature with advancing aging. The molecular mechanisms of aging-associated endothelial dysfunction are complex, but reduced nitric oxide (NO) bioavailability and altered vascular expression and activity of NO synthase (NOS) enzymes have been implicated as major players. Impaired vascular relaxation in aging has been attributed to reduced endothelial NOS (eNOS)-derived NO, while increased inducible NOS (iNOS) expression seems to account for nitrosative stress and disrupted vascular homeostasis. Although eNOS is considered the main source of NO in the vascular endothelium, neuronal NOS (nNOS) also contributes to endothelial cells-derived NO, a mechanism that is reduced in aging. Pharmacological modulation of NO generation and expression/activity of NOS isoforms may represent a therapeutic alternative to prevent the progression of cardiovascular diseases. Accordingly, this review will focus on drugs that modulate NO bioavailability, such as nitrite anions and NO-releasing non-steroidal anti-inflammatory drugs, hormones (dehydroepiandrosterone and estrogen), statins, resveratrol, and folic acid, since they may be useful to treat/to prevent aging-associated vascular dysfunction. The impact of these therapies on life quality in elderly and longevity will be discussed.

Nitric Oxide-Releasing Nonsteroidal Anti-Inflammatory Drugs: Gastrointestinal-Sparing Potential Drugs

The nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs in the world. Their use as anti-inflammatory, antipyretic, antithrombotic, and analgesic agents is, however, restricted by their adverse effects on gastrointestinal (GI) tract. To overcome this problem with NSAIDs, two new strategies in the development of these drugs are explained. The first approach is the development of selective inhibitors of the enzyme cyclooxygenase (COX)-2, the inducible isoform of the prostaglandin G/H synthetase enzyme. COX exists in two isoforms, viz., COX-1 and COX-2. Selective inhibitors of COX-2 will suppress prostaglandin synthesis at the sites of inflammation, but they will not interfere with the activity of COX-1, in tissues like the GI tract. The use of selective COX-2 inhibitors, however, lacks the cardioprotective effects mediated by COX-1. An alternate approach to reduce the GI toxicity of NSAIDs is the development of nitric oxide (NO)-releasing NSAIDs. It has been reported that NO does not affect the gastroduodenal mucosa and produces the same effects as endogenous prostaglandins. The present article focuses on the NO-releasing NSAIDs, which are from the conventional class of COX-2 inhibitors that have potential clinical applications, as well as some drug candidates still under development.

NSAIDs, coxibs, CINOD and H 2S-releasing NSAIDs: What lies beyond the horizon

Nonsteroidal anti-inflammatory drugs are widely prescribed for treatment of pain and inflammation, despite their association with gastrointestinal complications, including bleeding and perforation. Inhibition of cyclo-oxygenases, is the main mechanism of action of aspirin and nonsteroidal anti-inflammatory drugs. Non-selective nonsteroidal anti-inflammatory drugs inhibit cyclo-oxygenase-1 and cyclo-oxygenase-2. Inhibition of cyclo-oxygenase-1 derived prostanoids in the stomach represent the underlying mechanism involved in development of gastric and duodenal ulcers in patients taking nonsteroidal anti-inflammatory drugs. Selective cyclo-oxygenases-2 inhibitor (coxibs) spare cyclo-oxygenase-1 show enhanced safety profile in the gastrointestinal tract, but increase the risk of heart attack and stroke. Spurred by these findings, two coxibs, rofecoxib and valdecoxib, were withdrawn from the market. In addition to prostanoids, two gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H 2S) exert protective effects in gastric mucosa. The inhibitory effects of NO on nonsteroidal anti-inflammatory drugs-induced leukocyte adherence have been exploited in the development of NO-releasing nonsteroidal anti-inflammatory drugs, also indicated as cyclo-oxygenase-inhibiting NO-donating drugs. Despite its non-selective profile versus cyclo-oxygenase isoenzymes, naprocyclo-oxygenase-inhibiting NO-donating drugs, the prototype of this class of anti-inflammatory agents, reduces systemic blood pressure and might have enhanced cardiovascular safety than coxibs, while causing less gastrointestinal damage than its parent drug, the naproxen. H 2S-releasing nonsteroidal anti-inflammatory drugs derivatives have been recently developed, based on the observed ability of this gaseous mediator to cause vasodilation and to prevent leukocyte adherence. In pre-clinical settings, H 2S-releasing nonsteroidal anti-inflammatory drugs produce less gastric damage as compared to the parent drugs. Cyclo-oxygenases-inhibiting NO-donating drugs and H 2S-releasing nonsteroidal anti-inflammatory drugs represent examples of new anti-inflammatory drugs created through the exploitation of the beneficial effects of endogenous gaseous mediators in the gastrointestinal and cardiovascular systems.

Building a better aspirin: gaseous solutions to a century‐old problem

The gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) have been recognized since shortly after the introduction of aspirin to the marketplace over a century ago. However, the underlying pathogenesis of NSAID-induced gastropathy remains incompletely understood. Advances in understanding some of the factors that contribute to the mucosal injury have provided clues for the development of safer NSAIDs. The inhibitory effects of nitric oxide (NO) on NSAID-induced leukocyte adherence were exploited in the development of NO-releasing NSAIDs. As well as eliciting less gastrointestinal damage than conventional NSAIDs, these drugs do not elevate blood pressure and show anti-inflammatory effects, additional to those of the parent drugs. Modification of other drugs in a similar manner (i.e., NO-releasing derivatives) has similarly resulted in more effective drugs. More recently, hydrogen sulphide-releasing derivatives of NSAIDs and of other drugs, have been developed, based on the observed ability of H(2)S to reduce inflammation and pain in experimental models. H(2)S-releasing NSAIDs produce negligible gastric damage and exhibit enhanced anti-inflammatory potency as compared to the parent drugs. The NO-NSAIDs and H(2)S-releasing NSAIDs represent examples of new anti-inflammatory drugs with greatly reduced toxicity and improved therapeutic activity, both created through the concept of exploiting the beneficial effects of endogenous gaseous mediators.

232 In vitro and in vivo antitumor efficacy of NCX-4040, a nitric oxide-releasing non-steroidal anti-inflammatory drug, in combination with antineoplastic drugs on human colon cancer lines

The metabolic fate of nitric oxide (NO) released from nitroaspirin, benzoic acid, 2-(acetyloxy)-3-[(nitrooxy)methyl]phenyl ester (NCX 4016), the lead compound of a new class of NO-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) has been studied in eight healthy male Caucasian subjects following p.o. administration of 1600 mg (single dose), by monitoring at different times in plasma the bioactive storage forms of NO, S-nitrosothiols (RSNO) and its oxidation products (NOx). Plasma levels of NOx and RSNO and urinary levels of NOx were determined by an ozone-based chemiluminescent assay using a sensitive Nitric Oxide Analyzer (LOQ: 10 pmol NO injected). In parallel plasma samples were analyzed by a newly developed LC–MS/MS method for analysis of NCX 4015, the metabolite bearing the nitrate ester function. Using MS/MS with multiple reaction monitoring (MRM) in negative ion mode for NCX 4015 and the internal standard (NCX 4015-13C-D2) it was possible to detect with sufficient accuracy and precision the metabolite in plasma with a quantification limit of 78.1 ng ml−1. Concentration versus time profile of plasma NCX 4015 gave a Cmax value of 161.94±47.4 ng ml−1 and a tmax 4.5±1 h. The results indicate that both NOx and RSNO (these last for the first time determined in vivo in man following oral administration of a NO-donor drug) are effective plasma markers of NO release in vivo, the latter being an earlier indicator of NO distribution (tmax 2.0±0.6 h versus 5.4±1.2 h).

Nitric oxide release and distribution following oral and intraperitoneal administration of nitroaspirin (NCX 4016) in the rat

The metabolic fate of nitric oxide (NO) released from nitroaspirin, benzoic acid, 2-(acetyloxy)-3-[(nitrooxy)methyl]phenyl ester (NCX 4016), the lead compound of a new class of NO-releasing non steroidal anti-inflammatory drugs (NO-NSAIDs), has been studied in the rat following p.o. and i.p. administration of 100 mg/kg, by monitoring in plasma the bioactive storage forms of NO (S-nitrosothiols, RS-NO) and its oxidation products (nitrites/nitrates, NOx) by a chemiluminescent assay. In parallel, plasma was analyzed for unchanged drug and metabolites by reverse-phase HPLC. In orally treated rats, no unchanged drug is observed in the 0–24 h interval post-dosing, but only salicylic acid (SA), NOx and RS-NO. The time-course of SA formation parallels that of plasma NOx (plateau after 6 h). Nitrosothiols in plasma are detectable at 1 h, peak at 4 h post-administration, and decline thereafter. The results relative to i.p. administration show a more pronounced and rapid NO delivery (peak of both NOx and RS-NO at 1 h and plateau between 1 and 2 h), still coincident with the peak of SA, and the presence in plasma of NCX 4015 (a metabolite of NCX 4016 which still bears the nitrate function). In myocardial tissue from p.o. treated rats, no drug or metabolites were ever detected, and the NOx levels were always in the range of the controls. Conversely, following i.p. treatment, we observed a rapid compartmentalization within the heart of the unchanged drug, which rapidly disappears in favour of its breakdown products NCX 4015 and SA, with a concomitant rise in myocardial NOx levels up to 2 h. To check the stability of NCX 4016 in the acidic gastric milieu and to explain the different distribution of the drug following p.o. or i.p. administration, the gastric content of the orally-treated animals at different post-dosing times was analysed by HPLC. The unchanged drug was detected up to 8 h post-dosing (levels slowly decreased with time), and the only metabolite to be detected was the O-deacetylated derivative (NCX 4023), which was present in low concentrations up to 4 h post-dosing. This indicates that NCX 4016 does not undergo biotransformation in the upper part of gastrointestinal tract (no direct release of NO in this district) and that the stomach acts as a reservoir for the drug.

Chemiluminescence and LC–MS/MS analyses for the study of nitric oxide release and distribution following oral administration of nitroaspirin (NCX 4016) in healthy volunteers

The metabolic fate of nitric oxide (NO) released from nitroaspirin, benzoic acid, 2-(acetyloxy)-3-[(nitrooxy)methyl]phenyl ester (NCX 4016), the lead compound of a new class of NO-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) has been studied in eight healthy male Caucasian subjects following p.o. administration of 1600 mg (single dose), by monitoring at different times in plasma the bioactive storage forms of NO, S-nitrosothiols (RSNO) and its oxidation products (NO x ). Plasma levels of NO x and RSNO and urinary levels of NO x were determined by an ozone-based chemiluminescent assay using a sensitive Nitric Oxide Analyzer (LOQ: 10 pmol NO injected). In parallel plasma samples were analyzed by a newly developed LC–MS/MS method for analysis of NCX 4015, the metabolite bearing the nitrate ester function. Using MS/MS with multiple reaction monitoring (MRM) in negative ion mode for NCX 4015 and the internal standard (NCX 4015- 13C-D 2) it was possible to detect with sufficient accuracy and precision the metabolite in plasma with a quantification limit of 78.1 ng ml −1. Concentration versus time profile of plasma NCX 4015 gave a C max value of 161.94±47.4 ng ml −1 and a t max 4.5±1 h. The results indicate that both NO x and RSNO (these last for the first time determined in vivo in man following oral administration of a NO-donor drug) are effective plasma markers of NO release in vivo, the latter being an earlier indicator of NO distribution ( t max 2.0±0.6 h versus 5.4±1.2 h).

Nitric oxide-releasing aspirin protects gastric mucosa against ethanol damage in rats with functional ablation of sensory nerves.

The aim of the present study was to investigate, whether sensory nerves are involved in the gastroprotection induced by NO releasing non-steroidal anti-inflammatory drugs (NO-NSAID). Studies were performed in Wistar rats with intact or inactivated sensory nerves by pretreatment with large dose of capsaicin (125 mg/kg sc). Acute gastric lesions were induced by 100% ethanol (100% EtOH). 1 h before exposure to 100% EtOH, rats received vehicle, aspirin (ASA) or NO-releasing aspirin (NO-ASA) in the same dose (50 mg/kg). The animals were killed 1 h after exposure to 100% EtOH. Determinations were made of gastric mucosal injury, mucosal gastric blood flow, mucosal mRNA expression of glutathione peroxidase (GPx), zinc copper superoxide dismutase (SOD) and heat shock protein (HSP70) by RT-PCR and protein expression for HSP70 by Western blotting. Pretreatment with ASA aggravated the acute gastric injury induced by 100% EtOH, whereas pretreatment with NO-ASA led to a significant reduction in this injury. Administration of 100% EtOH was accompanied by a pronounced upregulation of HSP70, which was reduced by ASA, but enhanced by NO-ASA application. Sensory deactivation with capsaicin enhanced acute ethanol lesions and led to a significant attenuation in HSP70 expression. In contrast to ASA, NO-ASA attenuated gastric mucosal lesions and significantly upregulated HSP70 expression despite blockade of sensory nerves. NO-ASA, but not ASA, caused an upregulation of SOD and GPx mRNA in gastric mucosa with or without sensory denervation. NO-ASA protects gastric mucosa even after blockade of sensory nerves due to the upregulation of HSP70 expression and attenuation of the oxidative injury resulting from strong upregulation of genes for antioxidant enzymes.

Colon cancer prevention with NO-releasing NSAIDs

A seminal advance in the prevention of colon cancer has been the observation that nonsteroidal antiinflammatory drugs (NSAIDs) reduce the incidence of and mortality from colon cancer by about half. Among current efforts to overcome the side effects of NSAIDs, an important limitation for their application as chemopreventive agents, is the synthesis of nitric oxide-releasing NSAIDs. These novel compounds may display greater safety and greater efficacy compared to their parent traditional NSAIDs and thus hold significant promise as chemopreventive agents against human colon cancer. In this review we discuss salient features of their pharmacology, in vitro and animal data pertaining to colon cancer, their mechanisms of action, and assess their potential in the chemoprevention of colon cancer.

Gastrointestinal sparing anti-inflammatory drugs--effects on ulcerogenic and healing responses.

The use of nonsteroidal antiinflammatory drugs (NSAIDs) is associated with a wide array of alterations in gastrointestinal integrity and function. Various approaches have been taken to developing NSAIDs with reduced gastrointestinal toxicity, and few have been successfully reduced the incidence of adverse reactions. These include cyclooxygenase-2 (COX-2) selective inhibitors and nitric oxide (NO)-releasing NSAIDs. Especially, much has been written about the potential of COX-2 inhibitors as anti-inflammatory and analgesic agents that lack the gastrointestinal side effects of traditional NSAIDs. COX-2 expression is most evident at sites of inflammation, while COX-1 accounts for the majority of prostaglandin synthesis in the normal gastrointestinal tract. However, there are distinct examples of circumstances in which COX-2-derived prostaglandins play a role in the maintenance of gastrointestinal mucosal integrity, particularly when the mucosa is injured, and the delineation of COX-1 and COX-2 might not be quite as clear as has been suggested. On the other hand, the rational behind the NO-releasing NSAIDs is that the NO released from the derivatives will exert beneficial effects on the gastrointestinal mucosa. This approach has been successfully demonstrated to lessen the incidence of gastrointestinal damage and to promote the healing of gastric ulcers. The present article overviews the roles of COX and NO in housekeeping functions of the gastrointestinal mucosa in various circumstances, and the effects of gastrointestinal sparing NSAIDs, mainly COX-2 selective inhibitors and NO-releasing derivatives of NSAIDs, on the ulcerogenic and healing responses in the gastrointestinal mucosa of experimental animals.

Prevention of gastric damage by no-releasing aspirin (NCX-4016) is mediated by inhibition of ICE/-like proteases in gastric mucosa and endothelial cells

Background. Tumor necrosis factor-ct (TNFtx), a proinflammatory cytokine, is released in vivo and in vitro after exposure to non-steroidal anti-inflammatory drugs (NSAIDs). TNFct receptor binding leads to activation of multiple interleukin-1 converting enzyme (ICE)-like proteases (caspases) and endothelial cell death. Endothelial cell dysfunction is an early step in the process of NSAID-gastropathy. Nilric oxide(NO)-releasing NSAIDs, are a new class of NSAID derivatives with markedly reduced gastrointestinal toxicity. NO-releasing agents (sodium nitroprusside [SNP] and L-Arginine) prevent TNF-induced ICE/caspase 1 activation in human endothelial ceils (HUVECs). Aims. To assess whether NO-NSAIDs modulate ICE-like proteases in vivo and in vitro and protect endothelial cells from TNFct-induced apoptosis. Methods. Macrophages, prepared from mouse spleen, were used to investigate TNFet release in vitro. Gastric damage was induced in rat by oral administration of 150 mg/kg aspirin or an equimolar dose (249 mg/kg) of NCX-4016 (NicOx, Milan, Italy). ICE-like activity was measured in cell Iysates and gastric homogenates using YVAD.AMC as substrate in a fluorimetric assay. HUVEC apoptosis was assessed by FACS-scan analysis. Results. In vitro studies demonstrated that aspirin, but not NCX-4016, released TNFct from mouse macrophages. Co-incubation with 1-100 laM SNP resulted in a concentrationdependent inhibition of aspirin-induced TNFct-release. In viw) aspirin administration caused a time-dependent increase in gastric mucosal damage and gastric mucosa ICE/caspase activity. Pretreating rats with 0.1 mM L-Arginine, SNP and Z.VAD.fmk, a pan-ICE/caspase inhibitor, prevented both gastric mucosal damage and ICE/caspase upregulation induced by aspirin. No gastric damage was detectable with any dose of NCX-4016 tested. Like aspirin NCX-4016 was largely metabolized to salicylate. In contrast to aspirin NCX-416 significantly increased plasma nitrite/nitrate concentrations and inhibited the aspirin-induced upregulation of ICE/caspase activity into the gastric mucosa. Although aspirin had no effect on HUVEC apoptosis induced by TNFcq NCX-4016 and SNP caused a concentrationdependent inhibition of apoptosis and prevented ICEqike pmteases activation as demonstrated by Westem blot analysis and fluorimetric assay. NCX-4016 inhibited IL-113 release from endotoxin-stimulated macrophages. Conclusions. 1) Activation of ICE/caspase pmteases is a key step in the process of NSAID-gastropathy; 2) NCX-4016 spares the gastric mucosa and protects endothelial cells from TNFetinduced apoptosis. The potential of NO-releasing NSAIDs to modulate ICE-like pmteases and IL-113 release might help to explain the anti-inflammatory activity of these compounds.

Gastrointestinal-sparing anti-inflammatory drugs: The development of nitric oxide-releasing NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed medications, but their use continues to be limited by significant toxicity, particularly in the gastrointestinal tract and kidney. Better understanding of the pathogenesis of these adverse effects has led to the development of a series of derivatives of standard NSAIDs that are not only less toxic but more efficacious. The coupling of a nitric oxide-releasing moiety to a range of NSAIDs greatly reduces their ability to induce gastrointestinal damage, and greatly increases their tolerability in situations in which there is preexisting gastrointestinal inflammation. There is also evidence that these compounds are much better tolerated by the kidney. On the other hand, the analgesic and anti-thrombotic properties of NO-releasing NSAIDs significantly exceed those of the parent drugs. These compounds appear to represent a significant advance in the treatment of inflammation and pain and for prophylaxis of thrombotic conditions. Drug Dev. Res. 42:144–149, 1997. © 1997 Wiley-Liss, Inc.

A nitric oxide-releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats

Background & Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) have well-characterized inhibitory effects on gastric ulcer healing. A new class of gastrointestinal-sparing, nitric oxide-releasing NSAID derivatives has been recently described. This study was performed to determine if one of these compounds (nitrofenac) would influence healing of a preexisting ulcer. Methods: Seven days after induction of gastric ulcer with serosal acetic acid, daily oral treatment with antiinflammatory doses of diclofenac, nitrofenac, or vehicle was started. After 7 days of treatment, the ulcer area was measured. The effects of misoprostol and two drugs that show in vitro selectivity for inhibiting cyclooxygenase 2 (nabumetone and L745,337) were also assessed. Results: Diclofenac, nabumetone, and L745,337 had no effect on ulcer healing when compared with vehicle. Only diclofenac significantly decreased hematocrit and weight gain. On the other hand, nitrofenac significantly accelerated healing. Glyceryl trinitrate also significantly and dose dependently accelerated healing. Nitrofenac suppressed cyclooxygenase 1 activity to a similar extent as diclofenac. Conclusions: These results show that an NO-releasing NSAID derivative and an NO donor could accelerate ulcer healing, whereas a standard NSAID, misoprostol, and two inhibitors of cyclooxygenase 2 had no effect. In addition to sparing the gastrointestinal tract, NO-releasing NSAIDs, despite suppressing cyclooxygenase activity, are capable of accelerating tissue repair.

Nitric oxide-releasing non-steroidal anti-inflammatory drugs: a novel approach for reducing gastrointestinal toxicity.

The use of non-steroidal anti-inflammatory drugs (NSAID) for treatment of inflammatory conditions is significantly limited by the untoward effects of these compounds on the gastrointestinal tract. While the pathogenesis of 'NSAID-gastropathy' is not completely understood, there is good evidence that the process is directly linked to suppression of prostaglandin synthesis and possibly to neutrophil adherence to the vascular endothelium. Pretreatment of rats with a nitric oxide (NO) donor (sodium nitroprusside) was found to significantly reduce the extent of gastric injury induced by flurbiprofen. We therefore tested the effects of a novel derivative of flurbiprofen. This compound contains a moiety similar to the NO-releasing moieties found in many organic nitrates. This compound suppressed gastric prostaglandin synthesis as effectively as flurbiprofen, but caused significantly less haemorrhagic damage. The compound was also found not to induce small intestinal injury. Since the compound was found to exert anti-inflammatory effects comparable with flurbiprofen, NO-releasing NSAID may represent a novel class of drugs with markedly reduced gastrointestinal toxicity.